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CLODOVEO FERRI

COLLABORATORE DI RICERCA
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

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Pubblicazioni

2023 - COVID-19 vaccination rate and safety profile in a multicentre Italian population affected by mixed cryoglobulinaemic vasculitis [Articolo su rivista]
Vacchi, Caterina; Testoni, Sofia; Visentini, Marcella; Zani, Roberta; Lauletta, Gianfranco; Gragnani, Laura; Filippini, Davide; Mazzaro, Cesare; Fraticelli, Paolo; Quartuccio, Luca; Padoan, Roberto; Castelnovo, Laura; Zignego, Anna Linda; Ferri, Clodoveo; Scarpato, Salvatore; Casato, Milvia; Hoxha, Ariela; Salvarani, Carlo; Monti, Giuseppe; Galli, Massimo; Sebastiani, Marco
abstract

Mixed cryoglobulinaemic vasculitis (MCV) is an immune-complex-mediated systemic vasculitis characterised by heterogeneous clinical manifestations mainly involving lymphatic system, skin, kidney and peripheral nervous system. Although MCV patients have been included in priority programs for vaccination against SARS-CoV-2 in Italy, limited information is available for these patients. Aims of this multicentre Italian study were to investigate SARS-CoV-2 vaccination rate in MCV patients and its safety profile.

2023 - Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC) [Articolo su rivista]
Quartuccio, Luca; Bortoluzzi, Alessandra; Scirè, Carlo Alberto; Marangoni, Antonio; Del Frate, Giulia; Treppo, Elena; Castelnovo, Laura; Saccardo, Francesco; Zani, Roberta; Candela, Marco; Fraticelli, Paolo; Mazzaro, Cesare; Renoldi, Piero; Scaini, Patrizia; Filippini, Davide Antonio; Visentini, Marcella; Scarpato, Salvatore; Giuggioli, Dilia; Mascia, Maria Teresa; Sebastiani, Marco; Zignego, Anna Linda; Lauletta, Gianfranco; Fiorilli, Massimo; Casato, Milvia; Ferri, Clodoveo; Pietrogrande, Maurizio; Pioltelli, Pietro Enrico; De Vita, Salvatore; Monti, Giuseppe; Galli, Massimo
abstract

Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is a systemic small-vessel vasculitis characterized by the proliferation of B-cell clones producing pathogenic immune complexes, called cryoglobulins. It is often secondary to hepatitis C virus (HCV), autoimmune diseases, and hematological malignancies. CV usually has a mild benign clinical course, but severe organ damage and life-threatening manifestations can occur. Recently, evidence in favor of rituximab (RTX), an anti-CD 20 monoclonal antibody, is emerging in CV: nevertheless, questions upon the safety of this therapeutic approach, especially in HCV patients, are still being issued and universally accepted recommendations that can help physicians in MCS treatment are lacking. A Consensus Committee provided a prioritized list of research questions to perform a systematic literature review (SLR). A search was made in Medline, Embase, and Cochrane library, updated to August 2021. Of 1227 article abstracts evaluated, 27 studies were included in the SLR, of which one SLR, 4 RCTs, and 22 observational studies. Seventeen recommendations for the management of mixed cryoglobulinemia with rituximab from the Italian Study Group of Cryoglobulinemia (GISC) were developed to give a valuable tool to the physician approaching RTX treatment in CV.

2022 - COVID-19 VACCINATION RATE AND SAFETY PROFILE IN PATIENTS AFFECTED BY MIXED CRYOGLOBULINEMIC VASCULITIS [Abstract in Rivista]
Vacchi, C; Testoni, S; Visentini, M; Zani, R; Lauletta, G; Gragnani, L; Filippini, Da; Mazzaro, C; Fraticelli, P; Quartuccio, L; Padoan, R; Castelnovo, L; Zignego, Al; Ferri, C; Hoxha, A; Salvarani, C; Monti, G; Galli, M; Sebastiani, M
abstract

2021 - Covid-19 And Rheumatic Autoimmune Systemic Diseases: Role of Pre-Existing Lung Involvement and Ongoing Treatments [Articolo su rivista]
Ferri, Clodoveo; Giuggioli, Dilia; Raimondo, Vincenzo; L'Andolina, Massimo; Dagna, Lorenzo; Tavoni, Antonio; Caso, Francesco; Ursini, Francesco; Piero, Ruscitti; Caminiti, Maurizio; Foti, Rosario; Riccieri, Valeria; Guiducci, Serena; Pellegrini, Roberta; Zanatta, Elisabetta; Varcasia, Giuseppe; Olivo, Domenico; Gigliotti, Pietro; Cuomo, Giovanna; Murdaca, Giuseppe; Cecchetti, Riccardo; De Angelis, Rossella; Romeo, Nicoletta; Ingegnoli, Francesca; Cozzi, Franco; Codullo, Veronica; Cavazzana, Ilaria; Colaci, Michele; Abignano, Giuseppina; De Santis, Maria; Lubrano, Ennio; Fusaro, Enrico; Rossa, Alessandra Della; Spinella, Amelia; Lumetti, Federica; De Luca, Giacomo; Bellando-Randone, Silvia; Visalli, Elisa; Dal Bosco, Ylenia; Amato, Giorgio; Giannini, Daiana; Bilia, Silvia; Masini, Francesco; Pellegrino, Greta; Pigatto, Erika; Generali, Elena; Mariano, Giuseppa Pagano; Pettiti, Giorgio; Zanframundo, Giovanni; Brittelli, Raffaele; Aiello, Vincenzo; Caminiti, Rodolfo; Scorpiniti, Daniela; Ferrari, Tommaso; Campochiaro, Corrado; Brusi, Veronica; Fredi, Micaela; Moschetti, Liala; Cacciapaglia, Fabio; Gragnani, Laura; Monti, Monica; Lorini, Serena; Paparo, Sabrina Rosaria; Ragusa, Francesca; Mazzi, Valeria; Elia, Giusy; Ferrari, Silvia Martina; Di Cola, Ilenia; Vadacca, Marta; Lorusso, Sebastiano; Barsotti, Simone; Aprile, Maria Letizia; Marco, Tasso; Miccoli, Mario; Bosello, Silvia; Matucci-Cerinic, Marco; D'Angelo, Salvatore; Doria, Andrea; Franceschini, Franco; Meliconi, Riccardo; Iannone, Florenzo; Giacomelli, Roberto; Zignego, Anna Linda; Varcasia, Poupak; Antonelli, Alessandro
abstract

The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations.

2021 - COVID-19 and systemic sclerosis: clinicopathological implications from Italian nationwide survey study [Articolo su rivista]
Ferri, C.; Giuggioli, D.; Raimondo, V.; Dagna, L.; Riccieri, V.; Zanatta, E.; Guiducci, S.; Tavoni, A.; Foti, R.; Cuomo, G.; De Angelis, R.; Cozzi, F.; Murdaca, G.; Cavazzana, I.; Romeo, N.; Codullo, V.; Ingegnoli, F.; Pellegrini, R.; Varcasia, G.; Rossa, A. D.; De Santis, M.; Abignano, G.; Colaci, M.; Caminiti, M.; L'Andolina, M.; Lubrano, E.; Spinella, A.; Lumetti, F.; De Luca, G.; Bellando-Randone, S.; Visalli, E.; Bilia, S.; Giannini, D.; Masini, F.; Pellegrino, G.; Pigatto, E.; Generali, E.; Dall'Ara, F.; Mariano, G. P.; Barsotti, S.; Pettiti, G.; Zanframundo, G.; Brittelli, R.; Aiello, V.; Scorpiniti, D.; Ferrari, T.; Caminiti, R.; Campochiaro, C.; D'Angelo, S.; Iannone, F.; Matucci-Cerinic, M.; Doria, A.; Miccoli, M.; Fallahi, P.; Antonelli, A.; Della Rossa, A.; Pagano Mariano, G.; Cecchetti, R.; Gigliotti, P.; Olivo, D.; Ursini, F.; Brusi, V.; Meliconi, R.; Scarpa, R.; Fusaro, E.; Zignego, A. L.; Paparo, S. R.; Ragusa, F.; Elia, G.; Ferrari, S. M.
abstract

2021 - Impaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients’ subgroups [Articolo su rivista]
Ferri, C.; Ursini, F.; Gragnani, L.; Raimondo, V.; Giuggioli, D.; Foti, R.; Caminiti, M.; Olivo, D.; Cuomo, G.; Visentini, M.; Cacciapaglia, F.; Pellegrini, R.; Pigatto, E.; Urraro, T.; Naclerio, C.; Tavoni, A.; Puccetti, L.; Varcasia, G.; Cavazzana, I.; L'Andolina, M.; Ruscitti, P.; Vadacca, M.; Gigliotti, P.; La Gualana, F.; Cozzi, F.; Spinella, A.; Visalli, E.; Dal Bosco, Y.; Amato, G.; Masini, F.; Pagano Mariano, G.; Brittelli, R.; Aiello, V.; Caminiti, R.; Scorpiniti, D.; Rechichi, G.; Ferrari, T.; Monti, M.; Elia, G.; Franceschini, F.; Meliconi, R.; Casato, M.; Iannone, F.; Giacomelli, R.; Fallahi, P.; Santini, S. A.; Zignego, A. L.; Antonelli, A.
abstract

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53–1203) vs 825 (451–1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

2021 - Insights into the knowledge of complex diseases: Environmental infectious/ toxic agents as potential etiopathogenetic factors of systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; Arcangeletti, Maria-Cristina; Caselli, Elisabetta; Zakrzewska, Krystyna; Maccari, Clara; Calderaro, Adriana; D’Accolti, Maria; Soffritti, Irene; Arvia, Rosaria; Sighinolfi, Gianluca; Artoni, Erica; Giuggioli, Dilia
abstract

Systemic sclerosis (SSc) is a connective tissue disease secondary to three cardinal pathological features: immune- system alterations, diffuse microangiopathy, and fibrosis involving the skin and internal organs. The etiology of SSc remains quite obscure; it may encompass multiple host genetic and environmental -infectious/chemical- factors. The present review focused on the potential role of environmental agents in the etiopathogenesis of SSc based on epidemiological, clinical, and laboratory investigations previously published in the world literature. Among infectious agents, some viruses that may persist and reactivate in infected individuals, namely human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6), and parvovirus B19 (B19V), and retroviruses have been proposed as potential causative agents of SSc. These viruses share a number of biological activities and consequent pathological alterations, such as endothelial dysfunction and/or fibroblast activation. Moreover, the acute worsening of pre-existing interstitial lung involvement observed in SSc patients with symptomatic SARS-CoV-2 infection might suggest a potential role of this virus in the overall disease outcome. A variety of chemical/occupational agents might be regarded as putative etiological factors of SSc. In this setting, the SSc complicating silica dust exposure represents one of the most promising models of study. Considering the complexity of SSc pathogenesis, none of suggested causative factors may explain the appearance of the whole SSc; it is likely that the disease is the result of a multifactorial and multistep pathogenetic process. A variable combination of potential etiological factors may modulate the appearance of different clinical pheno- types detectable in individual scleroderma patients. The in-deep investigations on the SSc etiopathogenesis may provide useful insights in the broad field of human diseases characterized by diffuse microangiopathy or altered fibrogenesis.

2021 - Letters to the Editors [Articolo su rivista]
Ciaffi, J.; Giuggioli, D.; Mari, A.; D Onghia, M.; Spinella, A.; Brusi, V.; Mancarella, L.; Lisi, L.; Faranda Cordella, J.; Freeman, D.; Landini, M. P.; Ferri, C.; Meliconi, R.; Ursini, F.
abstract

2021 - POS1246 COVID-19 IN ITALIAN PATIENTS WITH RHEUMATIC AUTOIMMUNE SYSTEMIC DISEASES: RESULTS OF A NATIONWIDE SURVEY STUDY [Poster]
Ferri, C; Giuggioli, D; Raimondo, V; Dagna, L; Riccieri, V; Zanatta, E; Guiducci, S; Tavoni, A; Foti, R; Cuomo, G; De Angelis, R; Cozzi, F; Murdaca, G; Cavazzana, I; Romeo, N; Codullo, V; Ingegnoli, F; Pellegrini, R; Varcasia, G; Della Rossa, A; De Santis, M; Abignano, G; Colaci, M; Caminiti, M; L’Andolina, M; Lubrano, E; Spinella, A; Lumetti, F; De Luca, G; Bellando Randone, S; Visalli, E; Bilia, S; Masini, F; Pellegrino, G; Pigatto, E; Generali, E; Franceschini, F; Pagano Mariano, G; Barsotti, S; Pettiti, G; Zanframundo, G; Brittelli, R; Aiello, V; Scorpiniti, D; Ferrari, T; Caminiti, R; Campochiaro, C; Gigliotti, P; Cecchetti, R; Olivo, D; Ursini, F; Brusi, V; Meliconi, R; Caso, F; Scarpa, R; D’Angelo, S; Iannone, F; Matucci-Cerinic, M; Doria, A; Miccoli, M; Paparo, Sr; Ragusa, F; Elia, G; Ferrari, Sm; Fallahi, P; Antonelli, A
abstract

Background: SARS-CoV-2 infection poses a serious challenge for patients with rheumatic autoimmune systemic diseases (ASD), characterized by marked immune-system dysregulation and frequent visceral organ involvement. Objectives: To evaluate the impact of Covid-19 pandemic in a large series of Italian patients with ASD. Methods: Our multicenter telephone survey (8-week period, March-April 2020) included a large series of 2,994 patients (584 M, 2,410 F, mean age 58.9±13.4SD years) with ASD followed at 34 tertiary referral centers of 14 regions of northern, central, and southern Italian macro areas, characterized by different prevalence of SARS-CoV-2 infection. According to currently used criteria, Covid-19 was classified as definite Covid-19 (signs or symptoms of Covid-19 confirmed by positive oral/nasopharyngeal swabs at PCR testing) or highly suspected Covid-19 (signs or symptoms highly …

2020 - Systemic sclerosis progression INvestiGation (SPRING) Italian registry: Demographic and clinico-serological features of the scleroderma spectrum [Articolo su rivista]
Ferri, C.; Giuggioli, D.; Guiducci, S.; Lumetti, F.; Bajocchi, G.; Magnani, L.; Codullo, V.; Ariani, A.; Girelli, F.; Riccieri, V.; Pellegrino, G.; Bosello, S.; Foti, R.; Visalli, E.; Amato, G.; Benenati, A.; Cuomo, G.; Iannone, F.; Cacciapaglia, F.; de Angelis, R.; Ingegnoli, F.; Talotta, R.; Campochiaro, C.; Dagna, L.; de Luca, G.; Bellando-Randone, S.; Spinella, A.; Murdaca, G.; Romeo, N.; de Santis, M.; Generali, E.; Barsotti, S.; della Rossa, A.; Cavazzana, I.; Dall'Ara, F.; Lazzaroni, M. G.; Cozzi, F.; Doria, A.; Pigatto, E.; Zanatta, E.; Ciano, G.; Beretta, L.; Abignano, G.; D'Angelo, S.; Mennillo, G. A.; Bagnato, G.; Calabrese, F.; Caminiti, M.; Pagano Mariano, G.; Battaglia, E.; Lubrano, E.; Zanframundo, G.; Iuliano, A.; Furini, F.; Zanetti, A.; Carrara, G.; Rumi, F.; Scire, C. A.; Matucci-Cerinic, M.
abstract

Objective. Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation). Methods. The SPRING is a multicentre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud’s phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc. Results. Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic ‘late’ pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features. Conclusion. Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.

2019 - AB0212 LONG-TERM TREATMENT WITH RITUXIMAB IN SYSTEMIC SCLEROSISMANAGEMENT: AN OVERVIEW OF THE CLINICAL EXPERIENCE FROM A REAL-LIFE SETTING [Abstract in Rivista]
Lumetti, Federica; Spinella, Amelia; Colaci, Michele; Cocchiara, Emanuele; Magnani, Luca; Baiocchi, Gianluigi; Ferri, Clodoveo; Salvarani, Carlo; Giuggioli, Dilia
abstract

2019 - Established coronary artery disease in systemic sclerosis compared to type 2 diabetic female patients: a cross-sectional study [Articolo su rivista]
Colaci, Michele; Giuggioli, Dilia; Spinella, Amelia; Vacchi, Caterina; Lumetti, Federica; Mattioli, Anna Vittoria; Coppi, Francesca; Aiello, Vincenzo; Perticone, Maria; Malatino, Lorenzo; Ferri, Clodoveo
abstract

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by endothelial dysfunction, which is also associated with other disorders, such as atherosclerosis. The direct role of SSc in facilitating cardiovascular events should be clarified. We compared the prevalence of established coronary artery disease (CAD) between SSc and type 2 diabetes, a well-known phenotype associated with high cardiovascular risk. Methods: In this cross-sectional study, we evaluated a cohort of 290 unselected female SSc patients, in comparison with 265 aged-matched female type 2 diabetics. “Established CAD” was defined as previous myocardial infarction, unstable angina or ischemia documented by ECG and troponin elevation, necessity/previous treatment with coronary angioplasty or stenting. Age subgroups < 45 (Q1), 45–54 (Q2), 55–64 (Q3), 65–74 (Q4), and ≥ 75 (Q5) years were considered for SSc and diabetes. Results: CAD prevalence resulted lower in SSc patients than in diabetics (10% (95%CI 6.9–14.1) versus 19.2% (95%CI 14.9–24.4); p = 0.0023). In Q2 patients, CAD never occurred in SSc (95%CI 0–8.4), but in 9.4% of diabetics (95%CI 3.7–20.7, p = 0.0567); in Q3 subjects, CAD was reported in 5.6% (95%CI 1.8–13.8) of SSc, but in 20% (95%CI 12.4–30.5) of diabetics (p = 0.0127). Instead, for Q4 and particularly Q5 patients, CAD prevalence was comparable in SSc and diabetes. Conclusions: The prevalence of established CAD in SSc was lower compared with diabetics. However, in older SSc patients the prevalence of CAD was similar to that observed in diabetics.

2019 - Iloprost use and medical management of systemic sclerosis-related vasculopathy in Italian tertiary referral centers: results from the PROSIT study [Articolo su rivista]
Negrini, S.; Magnani, O.; Matucci-Cerinic, M.; Carignola, R.; Data, V.; Montabone, E.; Santaniello, A.; Adorni, G.; Murdaca, G.; Puppo, F.; Indiveri, F.; Della Rossa, A.; D'Ascanio, A.; Barsotti, S.; Giuggioli, D.; Ferri, C.; Lumetti, F.; Bosello, S. L.; Canestrari, G.; Bellando Randone, S.; Bruni, C.; Guiducci, S.; Battaglia, E.; De Andres, M. I.; Russo, A. A.; Beretta, L.
abstract

Vasculopathy is a crucial feature of systemic sclerosis (SSc), and Raynaud’s phenomenon (RP) and digital ulcers (DU) have a deep impact on the quality of patients’ life. The management of vascular disease can be challenging for the clinician because of the suboptimal tolerability of the treatments and lack of consensus on the best therapeutic approach. Intravenous iloprost, a synthetic analogue of prostacyclin, is broadly used for the treatment of RP and ischemic ulcers secondary to SSc. However, no standardized protocol on iloprost use is currently available and, consequently, the management of this treatment is largely based on the experience of each single center. The PROSIT project is an observational, multicenter study aiming to investigate the current treatments for SSc vasculopathy, the use of prostanoids, with special regard to iloprost, and the perception of the treatment from a patient’s perspective. The study was conducted on a cohort of 346 patients from eight Italian centers and included a structured survey addressed to physicians, data collected from patient’s medical records and two patient-administered questionnaires assessing the level of satisfaction, tolerability and perception of the efficacy of Iloprost. PROSIT data confirmed that in the contest of SSc iloprost represents the first-line choice for the management of severe RP and DU. Moreover, it is a well-tolerated treatment as reported by patients’ experience. Although a standard protocol for the treatment of SSc-related vasculopathy is lacking, PROSIT study identified different therapeutic approaches largely supported by tertiary Italian centers. Further studies are needed in order to optimize the best treatment for SSc vascular diseases, in particular to improve the best iloprost schedule management.

2019 - Immunomodulation of CXCL10 secretion by hepatitis C virus: Could CXCL10 be a prognostic marker of chronic hepatitis C? [Articolo su rivista]
Ferrari, S. M.; Fallahi, P.; Ruffilli, I.; Elia, G.; Ragusa, F.; Paparo, S. R.; Patrizio, A.; Mazzi, V.; Colaci, M.; Giuggioli, D.; Ferri, C.; Antonelli, A.
abstract

Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and “chronic hepatitis C virus (HCV) infection” (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.

2019 - THU0289 PERSISTENCE OF CIRCULATING CRYOGLOBULINS AND RELATED SYMPTOMS AFTER HEPATITIS C VIRUS ERADICATION IN PATIENTS WITH MIXED CRYOGLOBULIN SYNDROME [Abstract in Rivista]
Bassoli, Cinzia Roberta; Oreni, Letizia; Sollima, Salvatore; Saccardo, Francesco; Sebastiani, Marco; Vacchi, Caterina; Mazzaro, Cesare; Zani, Roberta; Ferri, Clodoveo; Zignego, Anna Linda; Monti, Giuseppe; Brancaccio, Giuseppina; Gentile, Ivan; Masarone, Mario; Gabiati, Claudia; Pontali, Emanuele; Castelnovo, Laura; Messina, Vincenzo; Galli, Massimo
abstract

2018 - AB0724 Cardio-pulmonary disease management in patients with systemic sclerosis: cardio-rheumatology clinic and patient care standardisation proposal [Abstract in Rivista]
Spinella, A; Lumetti, F; Mattioli, Av; Coppi, F; Rosario, R; Cocchiara, Emanuele; Colaci, M; Ferri, C; Salvarani, C; Giuggioli, D
abstract

2018 - Apheresis treatment of cryoglobulinemic vasculitis: A multicentre cohort study of 159 patients [Articolo su rivista]
Marson, P.; Monti, G.; Montani, F.; Riva, A.; Mascia, M. T.; Castelnovo, L.; Filippini, D.; Capuzzo, E.; Moretto, M.; D'Alessandri, G.; Marenchino, D.; Zani, R.; Fraticelli, P.; Ferri, C.; Quartuccio, L.; De Silvestro, G.; Oreni, L.; Accorsi, P.; Galli, M.
abstract

Objective: To assess the effectivenessof apheresis therapy (AT) in treating the clinical manifestations of patients with complicated cryoglobulinemic vasculitis (CV). Methods: A retrospective cohort study of 159 CV patients attending 22 Italian Centers who underwent at least one AT session between 2005 and 2015. The response to AT was evaluated on the basis of a defined grading system. Results: Peripheral neuropathy was the most frequent clinical condition leading to AT. Therapeutic plasma exchange was used in 70.4% of cases. The outcome of AT was rated very good in 19 cases, good in 64, partial/transient in 40, and absent/not assessable in 36. Life-threatening CV-related emergencies and renal impairment independently correlated with failure to respond to AT. The independent variables associated with an increased risk of death were age at the time of the first AT session, multi-organ life-threatening CV, the presence of renal impairment and failure to respond to AT. The time-dependent probability of surviving until CV-related death in the second year was 84%, with an AHR in patients with absent/not assessable response to AT of 11.25. Conclusion: In this study AT is confirmed to be a safe procedure in patients with CV. Early AT should be considered in patients with severe CV, especially in cases with impending renal involvement, in order to prevent irreversible kidney damage. Although its efficacy in patients with multi-organ failure is limited, AT is the only treatment that can rapidly remove circulating cryoglobulins, and should be considered an emergency treatment.

2018 - Cardiac involvement in systemic sclerosis: identification of high-risk patient profiles in different patterns of clinical presentation [Articolo su rivista]
Coppi, Francesca; Giuggioli, Dilia; Spinella, Amelia; Colaci, Michele; Lumetti, Federica; Farinetti, Alberto; Migaldi, Mario; Rossi, Rosario; Ferri, Clodoveo; Boriani, Giuseppe; Mattioli, Anna Vittoria
abstract

Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by widespread microvascular damage, dysregulation of fibroblasts with collagen overproduction and excessive fibrosis of the skin and internal organs, as well as complex immune system abnormalitie….

2018 - Cardio-pulmonary disease management in patients with systemic sclerosis: cardio-rheumatology clinic and patient care standardisation proposal [Abstract in Atti di Convegno]
Spinella, A; Lumetti, F; Mattioli, Av; Coppi, F; Rosario, R; Cocchiara, Emanuele; Colaci, M; Ferri, C; Salvarani, C; Giuggioli, D
abstract

Background Systemic sclerosis (SSc) is a chronic connective tissue disease characterised by endothelial dysfunction, dysregulation of fibroblasts with excessive fibrosis of the skin and internal organs and autoimmune abnormalities. Cardio-pulmonary manifestations are common in SSc and their detection in the early stage of the disease as well as their careful follow-up are mandatory in order to counteract their impact on the overall disease outcome. Despite the need of establishing a proper methodology, literature provides few reports about this issue. Objectives To evaluate the activity of our Cardio-Rheumatology Clinic in order to optimise diagnostic management of cardio-pulmonary disease in SSc patients. Methods We retrospectively analysed data from 350 consecutive SSc patients referred to our University-based Rheumatology Centre and SSc Unit (F/M 308/42; lc/dcSSc 45/305; mean age 50.8±14.7 years; mean disease duration 10.9±7.0 years). All patients underwent general and cardio-pulmonary assessment, in particular they were evaluated in the Cardio-Rheumatology Clinic. The following parameters were considered: physical examination; past and current drugs; blood tests, in particular Erythrocyte sedimentation rate-ESR, C-reactive protein-CRP, CPK enzymes, troponin, NT-pro-BNP, d-dimer, serum autoantibodies, 25-OH-vitamin D; capillaroscopy; pulmonary function tests; high resolution scan of the lungs (HRCT); standard electrocardiogram (ECG) and 24 hour Holter ECG monitoring; Doppler echocardiography; cardiac stress test; coronary angiography and right heart catheterization (RHC); cardiac MRI and CT; vascular ultrasound (intima-media-thickness, carotid-femoral and brachial-ankle pulse-wave-velocity). The clinicians decided to perform these examinations according to clinical picture and current methodologies.Results In the last 12 months we assessed 300 patients with 1st-level screening (cardio-rheumatologic evaluation, standard ECG, Doppler echocardiography, pulmonary function tests, thoracic imaging). Among 2nd-level, 30 procedures of 24 hour Holter ECG and 15 RHC tests were performed. Cardiac MRI, coronary CT angiography and vascular ultrasound were assessed, when requested, as 3rd-level examinations (30 procedures). After 1 year we observed a mean time of 10±5 days between request and clinical cardio-rheumatologic evaluation, 20±12 days to perform 1st-level screening, 25±15 days to execute the 2nd-level examinations. Figure-1 shows Cardio-Rheumatology algorithm for the management of SSc cardio-pulmonary disease. Conclusions The activity of our Cardio-Rheumatology Clinic optimises the cardio-pulmonary SSc assessment, determining an early detection of these harmful complications with reduced waiting times which are critical issues. Screening algorithms are useful to stratify the risk and to establish the most appropriate diagnostic-therapeutic protocols, improving outcome of scleroderma patients. The development of a cardio-pulmonary risk score and the standardisation of a patient care approach, according to international quality indeces, could represent further tools to optimise SSc management.

2018 - Efficacy of Belimumab for active lupus nephritis in a young Hispanic woman intolerant to standard treatment: a case report [Articolo su rivista]
Fontana, Francesco; Alfano, Gaetano; Leonelli, Marco; Cerami, Caterina; Ligabue, Giulia; Spinella, Amelia; Citriniti, Giorgia; Manzini, Carlo Umberto; Ferri, Clodoveo; Cappelli, Gianni
abstract

BackgroundLupus nephritis (LN) is a frequent severe complication of Systemic Lupus Erythematosus (SLE), especially in patients of non-Caucasian ethnicity. Induction treatment for LN consists in the combination of steroids plus a second agent (cyclophosphamide or mycophenolate mofetil) or, as a second-line, calcineurin inhibitors or Rituximab. Induction treatment for LN can be complicated by a series of side effects, the most severe being serious infections. Belimumab is a fully humanized monoclonal antibody that targets soluble B lymphocyte stimulator (BLyS), approved for treatment of serologically active SLE in addition to standard of care.Case presentationA young Hispanic woman was diagnosed with SLE at the age of 15. After several immunosuppressive treatments for arthritic symptoms (high-dose steroids, mycophenolate mofetil, Rituximab, cyclophosphamide) leading to serious complications and scarce clinical improvement, she developed severe LN. Induction treatment with a combination of intravenous high-dose methylprednisolone and cyclophosphamide was started but, after few days, the patient developed cryptococcal meningitis. After institution of appropriate antifungal therapy, treatment with Tacrolimus was attempted but poorly tolerated by the patient and withdrawn. Eventually, Belimumab was initiated off-label as a last resource to treat LN. Belimumab was well tolerated by the patient and resulted in a rapid and marked improvement in clinical symptoms and reduction in proteinuria, serum complement levels and anti-dsDNA titer; of note, the patient developed no infectious complications.ConclusionsWe report the case of a severe LN in a young Hispanic woman who did not respond to conventional and second-line induction therapies, due both to intolerance and to the development of serious infectious complications. Eventually, Belimumab was successfully added to steroids and was well tolerated by the patient, resulting in a marked improvement in clinical and biochemical parameters. We suggest that Belimumab should be considered as a potentially efficacious treatment in patients with LN who cannot tolerate conventional therapies.

2018 - FRI0442 Long-term treatment with rituximab in interstitial lung disease related to systemic sclerosis: our clinical experience [Abstract in Rivista]
Lumetti, F; Spinella, A; Ariani, A; Cocchiara, E; Colaci, M; Silva, M; Sverzellati, N; Ferri, C; Salvarani, C; Giuggioli, D
abstract

2018 - From Localized Scleroderma to Systemic Sclerosis: Coexistence or Possible Evolution [Articolo su rivista]
Giuggioli, D.; Colaci, M.; Cocchiara, E.; Spinella, A.; Lumetti, F.; Ferri, C.
abstract

Background. Systemic sclerosis (SSc) and localized scleroderma (LoS) are two different diseases that may share some features. We evaluated the relationship between SSc and LoS in our case series of SSc patients. Methods. We analysed the clinical records of 330 SSc patients, in order to find the eventual occurrence of both the two diseases. Results. Eight (2.4%) female patients presented both the two diagnoses in their clinical histories. Six developed LoS prior to SSc; in 4/6 cases, the presence of autoantibodies was observed before SSc diagnosis. Overall, the median time interval between LoS and SSc diagnosis was 18 (range 0-156) months. Conclusions. LoS and SSc are two distinct clinical entities that may coexist. Moreover, as anecdotally reported in pediatric populations, we suggested the possible development of SSc in adult patients with LoS, particularly in presence of Raynaud's phenomenon or antinuclear antibodies before the SSc onset.

2018 - High serum levels of silica nanoparticles in systemic sclerosis patients with occupational exposure: Possible pathogenetic role in disease phenotypes [Articolo su rivista]
Ferri, C.; Artoni, E.; Sighinolfi, G. L.; Luppi, F.; Zelent, G.; Colaci, M.; Giuggioli, D.
abstract

Background: Systemic sclerosis (SSc) is an autoimmune systemic disease characterized by diffuse fibrosis of skin and visceral organs due to different genetic, infectious, and/or environmental/occupational causative factors, including the inhalation of silica dust. Objectives: To investigate serum trace elements including silicon (s-Si) levels in SSc patients living in a restricted geographical area with high density of worksites with silica exposure hazard. Methods: This case-control study included 80 SSc patients (M:F 10:70; aged 58.4 ± 11.9SD years, mean disease duration 10.1 ± 7.8SD) and 50 age-/sex-matched healthy control subjects consecutively investigated at our University-based Rheumatology Unit. Patients and controls were evaluated for environmental/occupational exposure categories (structured questionnaire), morphological characterization of serum micro-/nanoparticles (Environmental Scanning Electron Microscopy and Energy Dispersive X-ray Spectroscopy microanalysis), and quantitative assessment of trace elements (inductively coupled plasma atomic emission spectroscopy). Results: Among various categories, only occupational exposure to silica dust was recorded in a significant proportion of SSc patients compared to controls (55% vs. 11%; p <.0001). Qualitative analysis showed serum silica micro- and nanoparticles in all exposed patients. Quantitative evaluation evidenced significantly higher s-Si levels in SSc patients versus controls (p <.0001); in addition, higher s-Si levels were detected in patients with occupational exposure (p <.0001), diffuse cutaneous SSc (p =.0047), myositis (p =.0304), and/or lung fibrosis (p =.0004) compared to those without; notably, the severity of lung fibrosis scoring positively correlated with s-Si levels (p <.0001). Conclusions: The study first demonstrated high s-Si levels in exposed SSc patients; this element might represent a pathogenetic co-factor of more severe clinical phenotypes, mainly diffuse scleroderma with lung fibrosis.

2018 - Long-term treatment with rituximab in interstitial lung disease related to systemic sclerosis: our clinical experience [Abstract in Atti di Convegno]
Lumetti, F; Spinella, A; Ariani, A; Cocchiara, E; Colaci, M; Silva, M; Sverzellati, N; Ferri, C; Salvarani, C; Giuggioli, D
abstract

Background Systemic sclerosis (SSc) is an immune-mediated disorder characterised by abnormal fibrosis and diffuse microangiopathy with skin and internal organ involvement. Interstitial lung disease (ILD) represents one of the most challenging complication of SSc, difficult to manage and correlate with a poor prognosis. Chest Computed Tomography (CT) is the gold standard for detection and evaluation of SSc-ILD by means of semi-quantitative scoring of extent of lung involvement. Some preliminary data suggest that rituximab (RTX) may be usefully employed in the treatment of SSc patients. Objectives To investigate the role and effect of RTX on ILD in our SSc patients’ series. Methods We retrospectively evaluated a series of 18 SSc patients (M/F 6/12, mean age 54.6±17.6 SD years, mean disease duration 11.4±6.5 SD years, L/D cutaneous subsets 6/12) who received one or more cycles of RTX (4 weekly infusions of 375 mg/m2) every 6 months for a total of 1–6 cycles. Lung involvement was studied by means of pulmonary function tests (PFTs) (18/18) and inspiratory chest CT (10/18) before and after treatment. In particular, we considered PFTs performed 6 months before RTX, at time 0, one year after the first RTX cycle, and at the end of follow-up (13.7±7.3 years). ILD extent score was assessed by the semi-quantitative method proposed by Goh et al (2008).1 Results Forced vital capacity (FVC%) significantly reduced during the year before RTX treatment [from 95.2±17.4 to 84.8±16.4; p=0.0017], as well as the diffusing capacity for carbon monoxide (DLCO%) [from 58.1±14.3 to 47.6±12.9; p=0.0002]. Conversely, FVC% and DLCO% stabilised one year after the first RTX cycle (80.8±23 and 47.8±15.7, respectively), and at the end of the follow-up (84.3±24.6 and 54.8.8±12.3, respectively; p=0.0001). In our cohort, only 7/10 patients had ILD detectable on CT before treatment. At the end of the follow-up we observed that ILD extented in 6/7 cases one patient remained stable, the three subjects without ILD did not developed pulmonary fibrosis. Conclusions According to PFTs results, our study showed that RTX could stabilise the progression of lung function tests in SSc patients. However, the semi-quantitative visual score identified radiological pulmonary worsening in many patient with stabilised PFTs. Therefore, the correlations between functional and radiological outcomes are so weak that many Authors suggested they should be considered together in SSc-ILD assessment.

2018 - Management of cardiopulmonary disease in patients with systemic sclerosis: cardiorheumatology clinic and patient care standardization proposal [Articolo su rivista]
Spinella, Amelia; Coppi, Francesca; Mattioli, Anna Vittoria; Lumetti, Federica; Rossi, Rosario; Cocchiara, Emanuele; Colaci, Michele; Boriani, Giuseppe; Ferri, Clodoveo; Salvarani, Carlo; Giuggioli, Dilia
abstract

Management of cardiopulmonary disease in patients with systemic sclerosis: cardiorheumatology clinic and patient care standardization proposal

2018 - Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature [Articolo su rivista]
Giuggioli, D.; Manfredi, A.; Lumetti, F.; Colaci, M.; Ferri, C.
abstract

Background: Skin ulcers (SU) are one of the most frequent manifestations of systemic sclerosis (SSc). SSc-SU are very painful, often persistent and recurrent; they may lead to marked impairment of patient's activities and quality of life. Despite their severe impact on the whole SSc patient's management, the proposed definition, classification criteria, and therapeutic strategies of SSc-SU are still controversial. Objective: The present study aimed to elaborate a comprehensive proposal of definition, classification, and therapeutic strategy of SSc-SU on the basis of our long-term single center experience along with a careful revision of the world literature on the same topic. Methods: A series of 282 SSc patients (254 females and 28 males; 84% with limited and 16% diffuse cutaneous SSc; mean age of 51.5 ± 13.9SD at SSc onset; mean follow-up 5.8 ± 4.6SD years) enrolled during the last decade at our Rheumatology Unit were retrospectively evaluated with specific attention to SSc-SU. The SSc-SU were classified in 5 subtypes according to prominent pathogenetic mechanism(s) and localization, namely 1. digital ulcers (DU) of the hands or feet, 2. SU on bony prominence, 3. SU on calcinosis, 4. SU of lower limbs, and 5. DU presenting with gangrene. This latter is a very harmful evolution of both DU of the hands and feet needing a differential diagnosis with critical limb ischemia. Results: During the follow up period, one or more episodes of SSc-SU were recorded in over half patients (156/282, 55%); skin lesions were often recurrent and difficult-to-heal because of local complications, mainly infections (67.3%), in some cases associated to osteomyelitis (19.2%), gangrene (16%), and/or amputation (11.5%). SSc-SU were significantly associated with lower patients' mean age at the disease onset (p = 0.024), male gender (p = 0.03), diffuse cutaneous subset (p = 0.015), calcinosis (p = 0.002), telangiectasia (p = 0.008), melanodermia (p < 0.001), abnormal PAPs (p = 0.036), and/or altered inflammation reactant (CRP, p = 0.001). Therapeutic strategy of SSc-SU included both systemic and local pharmacological treatments with particular attention to complicating infections and chronic/procedural pain, as well as a number of non-pharmacological measures. Integrated local treatments were often decisive for the SSc-SU healing; they were mainly based on the wound bed preparation principles that are summarized in the acronym TIME (necrotic Tissue, Infection/Inflammation, Moisture balance, and Epithelization). The updated review of the literature focusing on this challenging issue was analyzed in comparison with our experience. Conclusions: The recent advancement of knowledge and management strategies of SSc-SU achieved during the last years lead to the clear-cut improvement of patients' quality of life and reduced long-term disability.

2018 - Tocilizumab for the treatment of patients with rheumatoid arthritis and interstitial lung diseases: a case series [Articolo su rivista]
Manfredi, A.; Sebastiani, M.; Cassone, G.; Colaci, M.; Sandri, G.; Ferri, C.
abstract

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2017 - Associations between Systemic Sclerosis and Thyroid Diseases [Articolo su rivista]
Fallahi, Poupak; Ruffilli, Ilaria; Giuggioli, Dilia; Colaci, Michele; Ferrari, Silvia Martina; Antonelli, Alessandro; Ferri, Clodoveo
abstract

We have reviewed scientific literature about the association of systemic sclerosis (SSc) and thyroid disorders. A high incidence, and prevalence, of new cases of autoimmune thyroiditis (AT) and/or hypothyroidism have been shown in sclerodermic patients (overall in the female gender). An association among a Th1 immune-predominance, low vitamin D levels, and AT have been also shown in SSc patients. Cases of Graves' disease (GD) have been described in SSc patients, too, according with the higher prevalence of thyroid autoimmunity. It has been also shown a higher prevalence of papillary thyroid cancer (PTC), in association with AT, in SSc patients. However, in order to confirm results about GD and thyroid cancer, studies in larger number of patients with SSc are needed. During the follow-up of SSc patients it would be appropriate to monitor carefully their thyroid status. The abovementioned data strongly suggest a periodic thyroid function follow-up in female SSc patients [showing a borderline high (although in the normal range) thyroid-stimulating hormone level, antithyroid peroxidase antibody positivity, and a small thyroid with a hypoechoic pattern], and, when necessary, appropriate treatments. In conclusion, most of the studies show an association among SSc, AT, and hypothyroidism, such as an increased prevalence of TC overall in SSc patients with AT. Only few cases of GD have been also described in SSc.

2017 - Cardiac Involvement in Systemic Vasculitis [Capitolo/Saggio]
Sebastiani, Marco; Manfredi, Andreina Teresa; Ferri, Clodoveo
abstract

Systemic vasculitides are a heterogeneous group of diseases characterized by inflammation of vessels, which can result in their obstruction and/or aneurysm formation. The evidence of the inflammation of blood vessel walls in at least one occasion during the course is a shared defining feature of all categories of vasculitis. Their classification varies according to etiology, pathogenesis, type of vessel affected, type of inflammation, and favored organ distribution. Almost all primary vasculitides can target the heart; even if cardiac manifestations are rarely predominant, they can be life threatening and, therefore, require specific diagnostic and therapeutic strategies. Although cardiac involvement occurs in less than 10% of all patients affected by systemic vasculitides, certain entities, such as eosinophilic granulomatosis with polyangiitis (EGPA) and Takayasu’s arteritis (TAK) can cause heart complications in up to 60% of patients. After briefly reviewing the definitions, classification, and pathogenic mechanisms of vasculitides, we describe the cardiac manifestations that can occur in each vasculitis and their corresponding therapies.

2017 - Chemokines in the pathogenesis and as therapeutical markers and targets of HCV chronic infection, and HCV extrahepatic manifestations [Articolo su rivista]
Fallahi, Poupak; Ferrari, Silvia Martina; Giuggioli, Dilia; Sebastiani, Marco; Colaci, Michele; Ferri, Clodoveo; Antonelli, Alessandro
abstract

Cytokines and chemokines, hepatitis C virus (HCV) infection-induced, participate in viral control and liver damage. The complex cytokine network, operating during initial infection allows a coordinated and effective development of innate and adaptive immune responses. "HCV interferes with cytokines at various levels and escapes immune response by inducing a T helper (Th)2/T cytotoxic 2 cytokine profile". A predominance of the Th1 immune response (and related cytokines) has been evidenced in chronic hepatitis C infection and in extrahepatic manifestations. Interferon (IFN)- and IFN--inducible chemokine (C-X-C motif) ligand (CXCL)9, -10 and -11 recruit inflammatory infiltrates into the liver parenchyma due to the incapability to control the infection process, resulting in extensive liver damage and liver cirrhosis. "The most important systemic HCV-related extrahepatic diseases - mixed cryoglobulinemia, lymphoproliferative disorders, diabetes and autoimmune thyroid disorders - are associated with a complex dysregulation of the cytokine/chemokine network and involve pro-inflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN- may result in viral clearance during persistent infection and reverts this process" reducing circulating CXCL10 levels. "Several studies have reported interleukin (IL)-28B polymorphisms, and circulating CXCL10, may be prognostic markers for HCV treatment efficacy in HCV infection". Other studies have also shown that HCV clearance by directly acting antiviral agents therapy decreases circulating CXCL10 levels. "Theoretically agents that selectively neutralize CXCL10 could increase patient responsiveness to traditional IFN-based HCV therapy", simultaneously reducing inflammatory immune cell activation.

2017 - COST ANALYSIS RELATED TO SUBCUTANEOUS IMMUNOGLOBULINS IN PATIENTS WITH INFLAMMATORY MYOPATHIES AND IMMUNE-MEDIATED CHRONIC NEUROPATHIES. RESULTS OF AN OPEN LABEL STUDY [Abstract in Rivista]
Vacchi, Caterina; Sebastiani, Marco; Manfredi, Andreina Teresa; Cassone, Giulia; Campomori, Federica; Ferri, Clodoveo
abstract

Background: Intravenous Immunoglobulins (IVIg) represent a relevant treatment option in various immune-mediated disorders such as idiopathic inflammatory muscle diseases (IIMD), immune-mediated chronic neuropathies (IMCN), hematologic autoimmune diseases, Still disease, Felty syndrome, systemic lupus erythematosus, vasculitis, some organ-specific autoimmune disease, and atopic diseases. The IVIg treatment is expensive and need of hospital-based assistance for administration; the recent avaibility of home-therapy with subcutaneous immunoglobulins (SCIg) may significantly reduce costs and improve the patient's quality of life. Objectives: The primary objective was to perform an analysis of costs of SCIg administration in patients affected by IIMD or IMCN compared to that of previous IVIg treatments. Methods: We prospectively evaluated 6 consecutive patients (3 males and 3 females, mean age 65,3 years, range 63 - 77), 2 affected by IIMD in the context of polymiositis and 4 by IMCN, 3 in the context of vasculitis and 1 in the context of undifferentiated connective tissue disease. All patients were previously treated with IVIg at the dosage of 2g/Kg monthly, (mean monthly dosage 143 g, range 98 – 160, average patient weight 71,5 kg, range 49 - 80), with good clinical and humoral response. After a mean therapy duration of 49.8 months (range 12 – 125) all patients were shifted to SCIg at the dosage of 10 g twice a week (80 g monthly). Each patient was followed-up by humoral and clinical evaluation, including Medical Research Council (MRC) score to quantify muscle strength and INCAT Sensory Score to evaluate sensory symptoms. The costs of the two therapeutic strategies were also compared, excluding indirect costs (absences from work and productivity losses, transport and parking, health care sector costs). Results: In 5/6 patients, we observed the maintenance of clinical and humoral status after a mean follow-up of 21 months (range 4 - 51), in particular we observed a stability in MRC score in patients presenting loss of strenght and INCAT score in patients presenting sensory symptoms. Furthermore, the treatment with SCIg was well-accepted and preferred to IVIg by all patients. In one patient SCIg were discontinued after 2 weeks, because of the appearance of a haemorrhagic lesions nearby the injection site (in the same patient IVIg have been stopped because of a hypertensive crisis during the infusion). Direct cost associated to IVIg amount to 252€ for 5 g of immunoglobulins (7,056€ monthly, considering a protocol of 2 g/kg/monthly and a patient-weight of 70kg), while direct costs associated to SCIg (20g weekly) amount to 6,400€/monthly, with a saving of 656€/monthly and 7,872€/yearly. In our case-series the annual saving was 9,686.40€/patient (from 86,486.40€ to 76,800€, for IVIg and SCIg, respectively). Conclusions: Our experience suggests that the shift to SCIg from IVIg in patients affected by IIMD and IMCN is feasible, cost-effective, safe and well-accepted by patients. Further studies are needed to evaluate the effectiveness of SCIg in first-line therapy of these diseases.

2017 - Diagnosis and treatment of rheumatoid arthritis in the Emilia Romagna region: a prospective population-based study [Articolo su rivista]
Addimanda, Olga; Marino, Massimiliano; Farina, Ilaria; Trevisani, Marica; Arrigoni, Eugenio; Lumetti, Federica; Crescentini, Filippo; Sambo, Paola; Bezzi, Alessandra; Bruschi, Marco; Santilli, Daniele; Reta, Massimo; Bosi, Simona; Delsante, Giovanni; Girelli, Francesco; Montaguti, Luca; Meliconi, Riccardo; Sebastiani, Marco; Ferri, Clodoveo; Malavolta, Nazzarena; Govoni, Marcello; Trombetti, Susanna; De Palma, Rossana; Salvarani, Carlo
abstract

OBJECTIVES: To perform a population-based study in rheumatoid arthritis (RA) patients, in order to evaluate the efficacy and safety of pharmacologic treatments. METHODS: 1087 patients with RA were enrolled; inclusion criteria were: newly diagnosed RA, already diagnosed RA with high disease activity (HDA) (DAS28≥4.2) starting biologic DMARDs (bDMARDs), already diagnosed RA with HDA continuing with conventional DMARDs (cDMARDs). The following data were collected: demographics, clinical and laboratory features, imaging and prescribed drugs. All parameters except immunology and imaging (performed yearly) were repeated at each follow-up evaluations (after 3, 6 and 12 months, and thereafter every 12 months). In order to evaluate clinical response, the EULAR response criteria were used as the gold standard. RESULTS: 414 (38.1%) newly diagnosed patients with RA, 477 (43.9%) RA patients who started bDMARDs and 196 (18.0%) RA patients who continued with cDMARDs were enrolled from April 2012 to March 2015 at 12 Rheumatology Centres in the Emilia Romagna Region. Statistical analyses showed a relative risk ratio (RRR) for moderate response of 1.65 in RA patients who started bDMARDs (p=0.16) and 2.49 for newly diagnosed RA (p=0.01). Sex, age and Health Assessment Questionnaire were not statistically significant. A RRR of 2.00 has been confirmed for RA patients who started bDMARDs (p<0.0005) for a good response as well as 2.20 for newly diagnosed RA (p<0.0005). An increase in adverse events among bDMARDs was found, but when looking at infections or neoplasia, no differences were highlighted between RA which started bDMARDs and RA who continued with cDMARDs. CONCLUSIONS: Our results are in line with already published papers from British and Swedish Registries: a greater likelihood to have a good response is demonstrated for not longstanding RA starting cDMARDs or RA with HDA when a bDMARD is started. Also a good safety profile is demonstrated.

2017 - Erratum to: Prevalence and characterization of non-sicca onset primary Sjögren syndrome with interstitial lung involvement (Clinical Rheumatology, (2017), 36, 6, (1261-1268), 10.1007/s10067-017-3601-1) [Articolo su rivista]
Manfredi, A.; Sebastiani, M.; Cerri, S.; Cassone, G.; Bellini, P.; Della Casa, G.; Luppi, F.; Ferri, C.
abstract

This article originally published with all author names incorrectly listed. All author names have now been transposed and appear correctly above. The original article was corrected.

2017 - Fatigue in patients with systemic sclerosis and hypothyroidism. A review of the literature and report of our experience [Articolo su rivista]
Antonelli, A; Fallahi, P; Di Bari, F; Giuggioli, D; Ferrari, Sm; Ferri, C
abstract

Persistent fatigue (defined as ongoing exhaustion, disproportionate to exertion and not adequately alleviated by rest) reduces health-related quality of life of systemic sclerosis (SSc) patients. Fatigue in SSc is associated with reduced capacity to carry out daily activities, work disability and impaired physical function.Clinical studies demonstrated a high prevalence of autoimmune thyroiditis and hypothyroidism in patients with SSc. Since hypothyroidism and the associated fatigue symptoms could be cured by L-thyroxine (L-T4) substitutive therapy, the evolution of fatigue symptoms in SSc hypothyroid patients treated with substitutive therapy has been recently evaluated, showing an amelioration of the fatigue symptoms.We have treated 10 clinical hypothyroid and 23 subclinical hypothyroid female SSc patients (all with diffuse scleroderma) with L-T4 substitutive therapy. Mean baseline General Fatigue Index scores in hypothyroid SSc (15.7 +/- 5.1) were significantly higher (greater fatigue; p&lt;0.01) than in the same patients after reaching euthyroidism at 4 months (9.6 +/- 3.1). The results suggest that female SSc patients could be screened for thyroid function, overall in presence of fatigue symptoms, and that an appropriate L-T4 substitutive therapy could be useful to mitigate these symptoms.Further studies are needed in larger samples of hypothyroid patients with SSc to confirm these data. Further longitudinal studies could be also aimed to evaluate if L-T4 therapy could be useful in alleviating complications of SSc (such as skin thickness, pulmonary hypertension, etc.).

2017 - Haematological Malignancies in Systemic Sclerosis Patients: Case Reports and Review of the World Literature [Articolo su rivista]
Colaci, Michele; Giuggioli, Dilia; Vacchi, Caterina; Ferri, Clodoveo
abstract

Background.The association of systemic sclerosis (SSc) and haematological cancers was reported in a large number of case reports and cohort studies, describing SSc patients with highly heterogeneous clinical pictures. Objective. We reviewed the literature to better describe SSc patients with haematological malignancies. Methods. SSc cases complicated by haematological malignancies described in the world literature were collected; other 2 cases referred to our centre were reported. Results. One hundred-thirty SSc subjects were collected from 1954 up to date. The mean age of patients at cancer diagnosis was 56.1 ± 16.7 years; 72% of patients were females. In 60% of cases, the diagnosis of haematological malignancy was described within 5 years of SSc diagnosis. In 7.8% of cases, coexistence of Sj¨ogren’s syndrome or other autoimmune disorders was cited. Sixty-six cases with lymphoma (in the majority of cases B-cell neoplasms), 28 with leukaemia (chronic lymphocytic form in 9), 14 with multiple myeloma plus one solitary IgM plasmocytoma, and 16 with myeloproliferative disorders were found. No specific SSc subsets seem to be related to haematological malignancies. Conclusions. We remarked the importance of clinical work-up in SSc, in order to early diagnose and treat eventual occult haematological malignancies, especially during the first years of the disease.

2017 - HCV-related rheumatic manifestations and therapeutic strategies [Articolo su rivista]
Sebastiani, Marco; Giuggioli, Dilia; Colaci, Michele; Fallahi, Poupak; Gragnani, Laura; Antonelli, Alessandro; Zignego, Anna Linda; Ferri, Clodoveo
abstract

A number of hepatic and extra-hepatic autoimmune disorders may complicate a percentage of patients with hepatitis C virus (HCV) infection that is both hepatotropic and lymphotropic agent; the resulting clinical phenotypes can be grouped into the so-called HCV syndrome. This latter includes various rheumatic disorders that are frequently characterized by clinical or serological overlap; thus, a correct patients' classification is necessary prior to decide the therapy. The management of these conditions is particularly difficult, given the coexistence of viral infection and immunological alterations. In this scenario, cryoglobulinemic vasculitis represents the prototype of HCV-related rheumatic disorders that can be treated at different levels by means of etiological (antivirals) and/or pathogenetic and/or symptomatic treatments (rituximab, cyclophosphamide, steroids, plasmapheresis, etc). In clinical practice, the therapeutic strategy should take into account the specific symptoms combination and the severity/activity of the disease, according to each patient's conditions. This review focuses on the clinico-diagnostic assessments and therapeutical approaches of some rheumatic disorders complicating HCV infection, mainly arthritis, sicca syndrome, and osteosclerosis; while, cryoglobulinemic vasculitis is comprehensively examined in another article of the present issue.

2017 - HCV-unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian Group for the Study of Cryoglobulinaemias (GISC) [Articolo su rivista]
Galli, Massimo; Oreni, Letizia; Saccardo, Francesco; Castelnovo, Laura; Filippini, Davide; Marson, Piero; Mascia, Maria Teresa; Mazzaro, Cesare; Origgi, Laura; Ossi, Elena; Pietrogrande, Maurizio; Pioltelli, Piero; Quartuccio, Luca; Scarpato, Salvatore; Sollima, Salvatore; Riva, Agostino; Fraticelli, Paolo; Zani, Roberta; Giuggioli, Dilia; Sebastiani, Marco; Sarzi Puttini, Piercarlo; Gabrielli, Armando; Zignego, Anna Linda; Scaini, Patrizia; Ferri, Clodoveo; De Vita, Salvatore; Monti, Giuseppe
abstract

Objective. To investigate the clinical and laboratory patterns of HCV-unrelated cryoglobulinaemic vasculitis (CV), and the factors influencing its outcome. Methods. Prospective study of all anti-HCV and HCV-RNA negative patients with CV who have been observed since January 2004 in 17 centres participating in the Italian Group for the Study of Cryoglobulinaemias (GISC). Results. 175 enrolled were followed up for 677 person-years. The associated conditions were primary Sjogren's syndrome (21.1%), SLE (10.9%), other autoimmune disorders (10.9%), lymphoproliferative diseases (6.8%), solid tumours (2.3%) and HBsAg positivity (8.6%), whereas 69 patients (39.4%) had essential CV. There were significant differences in age (p&lt;0.001), gender (p=0.002), the presence of purpura (p=0.005), arthralgia (p=0.009), liver abnormalities (p&lt;0.001), sicca syndrome (p&lt;0.001), lymphadenopathy (p=0.003), splenomegaly (p=0.002), and rheumatoid factor titres (p&lt;0.001) among these groups. Type II mixed cryoglobulins were present in 96 cases (54.9%) and were independently associated with purpura and fatigue (odds ratio [OR14.3; 95% confidence interval [CI] 1.8-10.2; p=0.001; and OR2.8; 95%CI 1.3-6.3; p=0.012). Thirty-one patients died during follow-up, a mortality rate of 46/1000 person-years. Older age (for each additional year, adjusted hazard ratio [aHRJ 1.13; 95%CI 1.06-1.20; p&lt;0.001), male gender (aHR 3.45; 95%Cl 1.27-9.40; p=0.015), type II MCG (aHR 3.31; 95%CI 0.09-1.38; p=0.047) and HBsAg positivity (aHR 7.84; 95%Cl 1.20-36.04; p=0.008) were independently associated with greater mortality. Conclusion. HCV-unrelated CV is a multifaceted and often disabling disorder. The associated conditions influence its clinical severity, giving rise to significantly different clinical and laboratory profiles and outcomes.

2017 - International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement [Articolo su rivista]
Zignego, Anna Linda; Ramos Casals, Manuel; Ferri, Clodoveo; Saadoun, David; Arcaini, Luca; Roccatello, Dario; Antonelli, Alessandro; Desbois, Anne Claire; Comarmond, Cloe; Gragnani, Laura; Casato, Milvia; Lamprecht, Peter; Mangia, Alessandra; Tzioufas, Athanasios G; Younossi, Zobair M; Cacoub, Patrice
abstract

Hepatitis C virus (HCV) is both hepatotrophic and lymphotropic virus that causes liver as well extrahepatic manifestations including cryoglobulinemic vasculitis, the most frequent and studied condition, lymphoma, and neurologic, cardiovascular, endocrine-metabolic or renal diseases. HCV-extrahepatic manifestations (HCV-EHMs) may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Different clinical manifestations may coexist in the same patient. Due to the variety of HCV clinical manifestations, a multidisciplinary approach along with appropriate therapeutic strategies are required. In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches. The present recommendations, based on qualified expert experience and specific literature, will focus on etiological (antiviral) therapies and/or traditional pathogenetic treatments that still maintain their therapeutic utility.

2017 - Interstitial lung disease is associated to infections of lower respiratory tract in immunocompromised rheumatoid arthritis patients [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Cassone, Giulia; Sandri, Gilda; Cerri, Stefania; Ferri, Clodoveo
abstract

Immunosuppressive treatment increase the risk of lower respiratory tract infections particularly in RA-ILD patients, suggesting a more careful surveillance in this subgroup of patients

2017 - Long-term treatment of scleroderma-related digital ulcers with iloprost: a cohort study [Articolo su rivista]
Colaci, Michele; Lumetti, Federica; Giuggioli, Dilia; Guiducci, Serena; Bellando randone, Silvia; Fiori, Ginevra; Matucci cerinic, Marco; Ferri, Clodoveo
abstract

Raynaud's phenomenon and chronic/recurrent digital ulcers (DU) are main features of systemic sclerosis (SSc). Their treatment includes both systemic (i.e., iloprost) and local therapies. We report the therapeutic effects of iloprost in a cohort of SSc patients during a long-lasting follow-up period. METHODS: Fifty consecutive SSc patients (M/F 7/43, age at SSc diagnosis 43.5±12.7SD years) received iloprost infusions for 10±4.2SD years. Iloprost schedule consisted in monthly infusion at 0.8-1 ng/kg body weight/min (average cumulative dose 25 μg), according to patients' tolerance. For recalcitrant cases, continuous infusion of iloprost (3 days, average 0.2 mg) was administered. RESULTS: 31/50 (62%) patients showed DU at the beginning of iloprost therapy: among them, 22 (71%) resolved during the follow-up, while the other 9 presented recurrent or chronic DU, despite the treatment. With regards the 19/50 patients without DU at baseline, only one developed skin lesions at the end of 10-year follow-up, when severe pulmonary hypertension developed, which lead to exitus. Considering the 31 patients with DU at baseline, a diffuse skin subset was present in 3/22 patients with healed DU, and in 5/9 who did not (13.6% vs. 55.5%; p=0.027). CONCLUSIONS: Iloprost is a long-term effective treatment to achieve healing and prevention in SSc-related DU. Besides the possible problems concerning patients' tolerability or clinical management, iloprost therapy may be considered of great help in the therapeutic strategy of SSc-related ischaemic manifestations.

2017 - Micro and nanoparticles as possible pathogenetic co-factors in mixed cryoglobulinemia [Articolo su rivista]
Artoni, Erica; Sighinolfi, G. L; Gatti, A. M; Sebastiani, Marco; Colaci, Michele; Giuggioli, Dilia; Ferri, Clodoveo
abstract

Mixed cryoglobulinemia (MC) is a rare multisystem disease whose aetiopathogenesis is not completely understood. Hepatitis C virus (HCV) infection may have a causative role, and genetic and/or environmental factors may also contribute. AIMS: To investigate the presence and possible role of environmental agents in MC. METHODS: We recruited 30 HCV-infected MC patients with different clinical manifestations and a control group of 30 healthy, sex-/age-matched volunteers. We collected serum samples from each patient and incubated at 4°C for 7 days to obtain cryoprecipitate samples. We used environmental scanning electron microscopy (ESEM) and energy dispersive X-ray spectroscopy microanalysis to verify the presence of microparticles (MPs) and nanoparticles (NPs) in serum and cryoprecipitate samples. We evaluated environmental exposure using a medical and occupational history questionnaire for each subject. RESULTS: MC patients had a significantly higher risk of occupational exposure (OR 5.6; 95% CI 1.84-17.50) than controls. ESEM evaluation revealed a significantly higher concentration, expressed as number of positive spots (NS), of serum inorganic particles in MC patients compared with controls (mean NS 18, SD = 16 versus NS 5.4, SD = 5.1; P &lt; 0.05). Cryoprecipitate samples of MC patients showed high concentrations of inorganic particles (mean NS 49, SD = 19). We found a strong correlation between NS and cryocrit (i.e. percentage of cryoprecipitate/total serum after centrifugation at 4°C) levels (P &lt; 0.001). CONCLUSIONS: In addition to HCV infection, MPs and NPs might play an important role in the aetiopathogenesis of MC.

2017 - NEW PERSPECTIVES IN DIAGNOSIS OF INTERSTITIAL LUNG DISEASE RELATED TO RHEUMATOID ARTHRITIS. VALIDATION STUDY OF AN ELECTRONIC STETHOSCOPE AND AD HOC SOFTWARE FOR DETECTION OF PULMONARY CRACKLES [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Cassone, Giulia; Fedele, A. L.; Venerito, V.; Trevisani, M.; Furini, F.; Addimanda, O.; Gremese, E.; Iannone, F.; DELLA CASA, Giovanni; Cerri, Stefania; Sandri, Gilda; Pancaldi, Fabrizio; Luppi, Fabrizio; Ferri, Clodoveo
abstract

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial joint swelling and tenderness, secondary to the immune-system dysfunction, often complicated by extra-articular manifestations. Among them, lung involvement is very frequent and interstitial lung disease (ILD) represents one of the deleterious complications of RA with impact on both therapeutic approach and overall prognosis. Nevertheless, diagnosis of ILD often remains missing or delayed. Objectives: To preliminarily evaluate the predictive value of pulmonary sound recorded by an electronic stethoscope (ES) and elaborated by an ad hoc software in identification of RA-ILD diagnosed by mean of high resolution computed tomography (HRCT) in a multicenter study. Methods: RA patients who underwent HRCT in the last 12 months were enrolled. They were all auscultated with the ES (Littmann 3200TM 3M, USA), bilaterally, at dorsal level, in at least 3 pulmonary fields (medium and basal). All tracks recorded were analyzed by a suitably developed software capable of recognizing pathological crackles in lung sounds. Results were compared with radiologic findings detected in a blind manner by an expert radiologist. Results: One hundred and six RA patients were enrolled (M/F: 1/2.5, mean age 68.7±10.3); among them 45 (42.5%) showed ILD at HRCT. Three patients were excluded because of a low quality of the sound recorded. The algorithm showed a sensitivity and specificity of 72.1% and 84.4%, respectively and a positive/negative predictive value of 69.1% and 86.3%, respectively. Conclusions: Despite preliminary, these data suggest an important role of ES in clinical practice for an early diagnosis of ILD in RA patients and a significant reduction of inappropriate prescription of HRCT. Since very different types of ILD can occur in course of RA, with different radiologic features and localization, proper development of the measurement setup (ES and ad hoc software for the detection of PC) could further increase its predictive value, in particular to avoid incorrect records and misdiagnosis. The routinely employment of ES and proper software, combined to clinical findings (cough, dyspnea) and respiratory lung function, could increase our ability to early identify ILD in RA patients.

2017 - Prevalence and characterization of non-sicca onset primary Sjögren syndrome with interstitial lung involvement [Articolo su rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Cerri, Stefania; Cassone, Giulia; Bellini, Pierantonio; DELLA CASA, Giovanni; Luppi, Fabrizio; Ferri, Clodoveo
abstract

Primary Sjögren syndrome (pSS)-related interstitial lung disease (ILD) involved about 10–20% of patients. In 20% of cases, ILD can be diagnosed before pSS; anyway, few studies have investigated the frequency of ILD as the first clinically relevant manifestation of pSS, generally referred to retrospective studies. Aim of our prospective study was to describe prevalence, clinical, serological, and instrumental features of non-sicca onset pSS patients with interstitial lung involvement. During a period of 48 months, all consecutive patients diagnosed as pSS were enrolled. For all patients, the reason for the first visit was recorded. When present, ILD was categorized as definite, possible, or inconsistent with usual interstitial pneumonia (UIP) pattern, according to the current criteria. ILD was the main presenting symptom in 13/77 new diagnoses of pSS patients; in particular, 6/13 patients were initially diagnosed as idiopathic ILD, and only later developed clinical manifestations suggestive for pSS; ILD-pSS patients were older than others and showed a higher EULAR primary Sjögren’s syndrome disease activity index. A radiologic definite or possible UIP pattern was detected in 12/13 pSS. For the first time, we prospectively observed a prevalence of 16.8% of non-sicca onset pSS patients with ILD. Interestingly, UIP pattern was the most frequently detected, while typical autoantibodies were often absent. These features stressed the importance of differential diagnosis in the first stage of the disease, considering the possible poorer prognosis in this subgroup of patients. Multidisciplinary approach is crucial for a correct and early diagnosis, at both onset and follow-up.

2017 - Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: The glucocorticoid induced OsTeoporosis TOol (GIOTTO) study [Articolo su rivista]
Rossini, M; Viapiana, O.; Vitiello, M.; Malavolta, N.; La Montagna, G.; Maddali Bongi, S.; Di Munno, O.; Nuti, R.; Manzini, C. U.; Ferri, Clodoveo; Bogliolo, L.; Mathieu, A.; Cantatore, F.; Del Puente, A.; Muratore, M.; Grassi, W.; Frediani, B.; Saviola, G.; Delvino, P.; Mirone, L.; Ferraccioli, G.; Tripi, G.; Piazza, I.; Gatti, D.
abstract

Osteoporosis and fractures are common and invalidating consequences of chronic glucorticoid (GC) treatment. Reliable information regarding the epidemiology of GC induced osteoporosis (GIOP) comes exclusively from the placebo group of randomized clinical trials while observational studies are generally lacking data on the real prevalence of vertebral fractures, GC dosage and primary diagnosis. The objective of this study was to evaluate the prevalence and incidence of osteoporotic fractures and to identify their major determinants (primary disease, GC dosage, bone mineral density, risk factors, specific treatment for GIOP) in a large cohort of consecutive patients aged &gt;21 years, on chronic treatment with GC (≥5 mg prednisone - PN - equivalent) and attending rheumatology centers located all over Italy. Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) is a national multicenter cross-sectional and longitudinal observational study. 553 patients suffering from Rheumatoid Arthritis (RA), Polymyalgia Rheumatica (PMR) and Connective Tissue Diseases (CTDs) and in chronic treatment with GCs were enrolled. Osteoporotic BMD values (T score &lt;-2.5) were observed in 28%, 38% and 35% of patients with CTDs, PMR or RA at the lumbar spine, and in 18%, 29% and 26% at the femoral neck, respectively. Before GC treatment, prevalent clinical fractures were reported by 12%, 37% and 17% of patients with CTDs, PMR, or RA, respectively. New clinical fragility fractures during GC treatment were reported by 12%, 10% and 23% of CTDs, PMR and RA patients, respectively. Vertebral fractures were the prevailing type of fragility fracture. More than 30% of patients had recurrence of fracture. An average of 80% of patients were in supplementation with calcium and/or vitamin D during treatment with GCs. Respectively, 64%, 80%, and 72% of the CTDs, PMR and RA patients were on pharmacological treatment for GIOP, almost exclusively with bisphosphonates. The GIOTTO study might provide relevant contributions to clinical practice, in particular by highlighting and quantifying in real life the prevalence of GIOP and relative fractures, the frequency of the main risk factors, and the currently sub-optimal prevention. Moreover, these results emphasize the importance of the underlying rheumatic disease on the risk of GIOP associated fractures.

2017 - Reactive Granulomatous Dermatitis during Anti-TNF Therapy: A Case Report and Review of the Literature [Articolo su rivista]
Cassone, G; Citriniti, G; Sebastiani, M; Manfredi, A; Cesinaro, Am; Ferri, C
abstract

2017 - Renal Manifestations of Hepatitis C Virus [Articolo su rivista]
Ferri, Clodoveo; Giuggioli, Dilia; Colaci, Michele
abstract

Hepatitis C virus (HCV) is a hepatotropic and lymphotropic virus responsible for hepatic and extrahepatic autoimmune and neoplastic disorders, including renal involvement, which is the consequence of immune-mediated organ damage due to glomerular deposition of immune-complex and/or anti-HCV IgG antibodies and complement. It can appear at any time during the natural history of HCV infection, more often as membranoproliferative glomerulonephritis, alone or in association with other HCV-related disorders. The presence of renal involvement should be investigated in HCV-infected individuals at the first referral and during clinical follow-up.

2017 - Serum 25-OH vitamin D levels in systemic sclerosis: analysis of 140 patients and review of the literature [Articolo su rivista]
Giuggioli, Dilia; Colaci, Michele; Cassone, Giulia; Fallahi, P.; Lumetti, Federica; Spinella, Amelia; Campomori, Federica; Manfredi, Andreina Teresa; Manzini, CARLO UMBERTO; Antonelli, Andrea; Ferri, Clodoveo
abstract

Hypovitaminosis D is increasingly reported in autoimmune diseases. We investigated the 25-OH-vitamin D (25-OH-vitD) levels in systemic sclerosis (SSc) patients, in correlation with disease’s features. We measured the 25-OH-vitD serum levels in 140 consecutive patients (F/M 126/15; mean age 61&nbsp;±&nbsp;15.1&nbsp;years), 91 without (group A) and 49 with (group B) 25-OH-cholecalciferol supplementation. Patients of group A invariably showed low 25-OH-vitD levels (9.8&nbsp;±&nbsp;4.1&nbsp;ng/ml vs. 26&nbsp;±&nbsp;8.1&nbsp;ng/ml of group B); in particular, 88/91 (97%) patients showed vitamin D deficiency (&lt;20&nbsp;ng/ml), with very low vitamin D levels (&lt;10&nbsp;ng/ml) in 40 (44%) subjects. Only 15/49 (30.6%) patients of group B reached normal levels of 25-OH-vitD (≥30&nbsp;ng/ml), whereas vitamin D deficiency persisted in 12/49 (24.5%) individuals. Parathormone levels inversely correlated with 25-OH-vitD (r&nbsp;=&nbsp;−0.3, p&nbsp;&lt;&nbsp;0.0001). Of interest, hypovitaminosis D was statistically associated with autoimmune thyroiditis (p&nbsp;=&nbsp;0.008), while calcinosis was more frequently observed in patients of group A (p&nbsp;=&nbsp;0.057). Moreover, we found significantly higher percentage of serum anticentromere antibodies in group B patients with 25-OH-vitD level ≥30&nbsp;ng/ml (8/15 vs. 6/34; p&nbsp;=&nbsp;0.017). In literature, hypovitaminosis D is very frequent in SSc patients. An association with disease duration, calcinosis, or severity of pulmonary involvement was occasionally recognized. Hypovitaminosis D is very frequent in SSc and severe in a relevant percentage of patients; furthermore, less than one third of supplemented subjects reached normal levels of 25-OH-vitD. The evaluation of 25-OH-vitD levels should be included in the routine clinical work-up of SSc. The above findings expand previous observations and may stimulate further investigations.

2017 - Thyroid Involvement in Hepatitis C Virus-Infected Patients with/without Mixed Cryoglobulinemia [Articolo su rivista]
Ferri, Clodoveo; Colaci, Michele; Fallahi, Poupak; Ferrari, Silvia Martina; Antonelli, Alessandro; Giuggioli, Dilia
abstract

Thyroid involvement is a common condition that can be recorded during the natural course of different systemic rheumatic diseases, including the mixed cryoglobulinemia (MC) syndrome or cryoglobulinemic vasculitis. MC is triggered by hepatitis C virus (HCV) chronic infection in the majority of cases; it represents the prototype of autoimmune-lymphoproliferative disorders complicating a significant proportion of patients with chronic HCV infection. HCV is both hepato- and lymphotropic virus responsible for a great number of autoimmune/lymphoproliferative and/or neoplastic disorders. The complex of HCV-related hepatic and extrahepatic manifestations, including MC and thyroid involvement, may be termed "HCV syndrome." Here, we describe the prevalence and clinico-serological characteristics of thyroid involvement, mainly autoimmune thyroiditis and papillary thyroid cancer, in patients with HCV syndrome with or without cryoglobulinemic vasculitis.

2017 - Treatment of HCV-related mixed cryoglobulinemia [Articolo su rivista]
Giuggioli, Dilia; Sebastiani, Marco; Colaci, Michele; Fallahi, Poupak; Gragnani, Laura; Zignego, Anna Linda; Antonelli, Alessandro; Ferri, Clodoveo
abstract

Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis, involving skin, joints, peripheral nerves, and several internal organs. Hepatitis C virus (HCV) is recognized as the etiologic agent for the majority of MCs patients, as well as of number of autoimmune, lymphoproliferative, and neoplastic disorders. In this context, HCV-related MCs represents an important model autoimmune/neoplastic disease triggered by a virus in humans. With regard the therapeutic strategies of MCs, we can treat these patients at different steps by means of etiological (antivirals), pathogenetic, symptomatic drugs (mainly immunosuppressors, corticosteroids, plasmapheresis). In the majority of individuals, MCs shows a mild, slow-progressive clinical course needing only symptomatic treatments, generally low doses of corticosteroids. Considering the etiopathogenesis of MCs, the eradication of HCV should be considered the gold standard in the treatment of MCs. The use of combined peg-interferon-α/ribavirin and/or novel antiviral drugs may lead to HCV eradication in a significant percentage of cases with possible remission of MCs. On the other hand, the presence of rapidly progressive, diffuse vasculitis with multiple organ involvement may be successfully treated with aggressive immunosuppressive and anti-inflammatory therapies, mainly based on cyclophosphamide or rituximab, high dose corticosteroids, and plasma aphaeresis. Moreover, sequential/combined antiviral or immunosuppressive treatments could represent an useful therapeutic strategy particularly in MCs patients with major clinical manifestations. The treatment of MCs should be decided for every patient according to the severity of clinical picture. Thus, a careful follow-up of the disease is necessary, with particular attention to the possibility of cancers onset, such as B-cell lymphoma. The present review focuses on the different therapeutic strategies in patients with MCs, including the treatment of cryoglobulinemic skin ulcers, which represents one of the most discouraging complications of the disease.

2016 - Adult-onset Still’s disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients [Articolo su rivista]
Sfriso, Paolo; Priori, Roberta; Valesini, Guido; Rossi, Silvia; Montecucco, Carlo Maurizio; D’Ascanio, Anna; Carli, Linda; Bombardieri, Stefano; Laselva, Gaetana; Iannone, Florenzo; Lapadula, Giovanni; Alivernini, Stefano; Ferraccioli, Gianfranco; Colaci, Michele; Ferri, Clodoveo; Iacono, Daniela; Valentini, Gabriele; Costa, Luisa; Scarpa, Raffaele; Lomonaco, Andrea; Bagnari, Valentina; Govoni, Marcello; Piazza, Ilaria; Adami, Silvano; Ciccia, Francesco; Triolo, Giovanni; Alessandri, Elisa; Cutolo, Maurizio; Cantarini, Luca; Galeazzi, Mauro; Ruscitti, Piero; Giacomelli, Roberto; Caso, Francesco; Galozzi, Paola; Punzi, Leonardo
abstract

Adult-onset Still’s disease (AOSD) is a systemic inflammatory condition of unknown aetiology characterized by typical episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. Given the lack of data in Italian series, we promote a multicentric data collection to characterize the clinical phenotype of Italian patients with AOSD. Data from 245 subjects diagnosed with AOSD were collected by 15 centres between March and May 2013. The diagnosis was made following Yamaguchi’s criteria. Data regarding clinical manifestations, laboratory features, disease course and treatments were reported and compared with those presented in other published series of different ethnicity. The most frequent features were the following: arthritis (93 %), pyrexia (92.6 %), leukocytosis (89 %), negative ANA (90.4 %) and neutrophilia (82 %). As compared to other North American, North European, Middle Eastern and Far Eastern cohorts, Italian data show differences in clinical and laboratory findings. Regarding the treatments, in 21.9 % of cases, corticosteroids and traditional DMARDs have not been able to control the disease while biologics have been shown to be effective in 48 to 58 patients. This retrospective work summarizes the largest Italian multicentre series of AOSD patients and presents clinical and laboratory features that appear to be influenced by the ethnicity of the affected subjects.

2016 - Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials. [Articolo su rivista]
Khanna, D; Denton, Cp; Merkel, Pa; Krieg, T; Le Brun, Fo; Marr, A; Papadakis, K; Pope, J; Matucci Cerinic, M; Furst, De; Zochling, J; Stevens, W; Proudman, S; Feenstra, J; Youssef, P; Soroka, N; Tyabut, T; Mikhailova, Ei; Rashkov, R; Batalov, A; Yablanski, K; Keystone, E; Pope, J; Jones, N; Dunne, J; Masetto, A; Calabresse, Rj; Cabezas, Pc; Silva, Mo; Sariego, Ia; Escalente, Wj; Anić, B; Kaliterna, Dm; Morović Vergles, J; Novak, S; Prus, V; Artuković, M; Soukup, T; Bečvař, R; Fojtík, Z; Mouthon, L; Kollert, F; Krieg, Tm; Riemekasten, G; Lahner, N; Fierlbeck, G; Ahmadi Simab, K; Diehm, C; Szücs, G; Kumánovics, G; Nagy, G; Pal, S; Veeravalli, Sc; Danda, D; Ferri, Clodoveo; Cerinic, Mm; Cozzi, F; Ferraccioli, G; Wiland, P; Rudnicak, L; Zwolak, R; Roszkiewicz, J; Oleynikov, V; Nikulenkova, N; Lesnyak, O; Kaydashev, I; Kurytar, O; Piura, O; Chopyak, V; Chatterjee, S; Furst, De; Hsu, V; Hummers, L; Martin, R; Domsic, R; Schiopu, E; Khanna, D; Shanahan, J; Murphy, Ft; Kaine, J; Davis, W; Grau, R; Eimon, A; Catoggio, Lj; Laborde, Ha; Caeiro, F; Savio, Vg; Amitrano, Cb; Vanthuyne, M; Zeng, X; Zhang, X; Zhu, P; Velásquez Franco, Cj; Choueka, Ps; Sanchez, Pj; Hermann, W; Sticherling, M; Steinbrink, K; Hein, R; Aschoff, R; Sfikakis, P; Settas, L; Fraser, A; Veale, D; Balbir Gurman, A; Lidar, M; Litinsky, I; Levy, Y; Carrillo Vazquez, Sm; Rodriguez Reyna, T; Medrano Ramirez, G; Morales Torres, J; Pacheco Tena, Cf; Sanchez Ortiz, A; Vonk, Mc; Stebbings, S; Solanki, K; Steele, R; Ng, Kp; Zubrzycka Sienkiewicz, A; Brzosko, M; Szepietowski, Jc; Hrycaj, P; da Silva, If; dos Santos Lda, C; Coelho, Pj; Rios, G; Chernykh, T; Grunina, E; Stanislav, M; Ally, M; Kalla, A; Birlik, Am; Kovalenko, V; Petrov, A; Shevchuk, S; Stanislavchuk, M; Anderson, M; Denton, Cp; Herrick, A; Belch, J; Chung, L; Csuka, Me; Frech, T; Goldberg, A; Kahaleh, B; Mayes, Md; Rothfield, N; Simms, Rw; Spiera, R; Steen, V; Varga, J; Sikes, D; Derk, Ct; Merkel, Pa; Kohen, M. D.
abstract

IMPORTANCE: Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. OBJECTIVE: To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. DESIGN, SETTING, AND PARTICIPANTS: Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients. INTERVENTIONS: Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or &gt;3). MAIN OUTCOMES AND MEASURES: The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups. RESULTS: In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3 mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10 mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. CONCLUSIONS AND RELEVANCE: Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.

2016 - Effect of treatment with iloprost with or without bosentan on nailfold videocapillaroscopic alterations in patients with systemic sclerosis [Articolo su rivista]
Cestelli, V; Manfredi, Andreina Teresa; Sebastiani, Marco; Praino, E; Cannarile, F; Giuggioli, D; Ferri, Clodoveo
abstract

Introduction: Vascular involvement plays a decisive role in systemic sclerosis (SSc) pathogenesis; it is responsible for some important clinical manifestations of the disease such as Raynaud’s phenomenon and digital ulcers (DU). Bosentan, a dual receptor endothelin antagonist, and iloprost, often in combination therapy, seems to be able to interfere with the scleroderma microangiopathy. Objectives: Aim of the study was to evaluate the effect of bosentan and iloprost on scleroderma microangiopathy, analyzed by means of capillaroscopic skin ulcer risk index (CSURI), in SSc patients treated for the prevention of DU. Methods: Nailfold videocapillaroscopy (NVC) was performed in 95 SSc patients, treated with iloprost alone (group 1) or combination therapy with iloprost and bosentan (group 2), at baseline and after one year. In all patients CSURI was calculated according to the formula “diameter × number of megacapillaries/(total number of capillaries)2”: in addition, total number of capillaries, giant capillaries, micro-hemorrhages, disorganization of the vascular array, and ramified capillaries were evaluated by means of a semiquantitative score. Results: After 12 months, we observed a reduction of the number of giant capillaries in both groups, while an increase of ramified capillaries was recorded only in group 2. CSURI improved slightly in group 2 without statistical significance; on the contrary, in group 1 a significant worsening was recorded (p ≤ 0.001). Conclusions: Our study confirms the effectiveness of bosentan, in combination with iloprost, in SSc microangiopathy observed to NVC. Moreover, the observed findings further support the role of CSURI in the evaluation and monitoring of SSc microangiopathy.

2016 - Hepatitis C virus infection and chronic kidney disease: Time for reappraisal [Articolo su rivista]
Cacoub, P; Desbois, Ac; Isnard Bagnis, C; Rocatello, D; Ferri, Clodoveo
abstract

Hepatitis C virus (HCV) infection is associated with tremendous morbidity and mortality due to liver complications. HCV infection is also associated with many extrahepatic manifestations including cardiovascular diseases, glucose metabolism impairment, cryoglobulinemia vasculitis, B cell non-Hodgkin lymphoma and chronic kidney disease (CKD). Many studies have shown a strong association between HCV and CKD, by reporting (i) an increased prevalence of HCV infection in patients on haemodialysis, (ii) an increased incidence of CKD and proteinuria in HCV-infected patients, and (iii) the development of membranoproliferative glomerulonephritis secondary to HCV-induced cryoglobulinemia vasculitis. HCV seropositivity is found to be associated with an increased relative risk for all-cause and cardiovascular mortality in the dialysis population. HCV seropositivity is linked to lower patient and graft survival after kidney transplantation. Such poor HCV-associated prognosis should have encouraged clinicians to treat HCV in CKD patients. However, due to frequent side effects and the poor efficacy of interferon-based treatments, very few HCV dialysis patients have received HCV medications until now. The emergence of new direct acting, interferon-free antiviral treatment, leading to HCV cure in most cases with a satisfactory safety profile, will shortly modify the management of HCV infection in CKD patients. In patients with a glomerular filtration rate (GFR) &gt;30 ml/min, the choice of DM is not restricted. In those with a GFR &lt;30 and &gt;15 ml/min, only paritaprevir/ritonavir/ombitasvir/dasabuvir or a grazoprevir plus elbasvir regimen are approved. In patients with end stage renal disease (GFR &lt;15 ml/min or dialysis), current data only allows for the use of a grazoprevir plus elbasvir combination. No doubt these data will be modified in the future with the advent of new studies including larger cohorts of HCV patients with renal impairment. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

2016 - Impegno cardiaco nella sclerosi sistemica [Articolo su rivista]
Colaci, Michele; Giuggioli, Dilia; Spinella, Amelia; Rossi, Rosario; Ferri, Clodoveo
abstract

L'impegno cardiaco in corso di sclerosi sistemia consta di uno spettro variabile di manifestazioni cliniche conseguenti ad alterazioni di natura microangiopatica, elettrica e/o emodinamica. In danno ischemico e/o flogistico autoimmune del miocardio producono, in ultima analisi, il quadro istopatologico caratteristico della 'necrosi a bande' con deposizione di tessuto fibroso, responsabile della riduzione di elasticità e della capacità contrattile muscolare. ....

2016 - Incidence of thyroid disorders in mixed cryoglobulinemia: Results from a longitudinal follow-up [Articolo su rivista]
Fallahi, Poupak; Ferrari, Silvia Martina; Ruffilli, Ilaria; Elia, Giusy; Giuggioli, Dilia; Colaci, Michele; Ferri, Clodoveo; Antonelli, Alessandro
abstract

No study has evaluated the incidence of new cases of thyroid autoimmunity (AT) and dysfunction (TD) in hepatitis C-associated mixed cryoglobulinemia (MC) patients.We aimed to evaluate the incidence of new cases of AT and TD in a wide group of MC patients vs. age- and gender-matched controls from the same geographic area.After exclusion of MC patients with TD at the initial evaluation, the appearance of new cases of TD was evaluated in 112 MC patients and 112 matched controls, with similar iodine intake (median follow-up 67 months in MC vs. 78 in controls).A high incidence (P < 0.05) of new cases of hypothyroidism, TD, anti-thyroperoxidase antibody (AbTPO) positivity, appearance of a hypoechoic thyroid pattern, and thyroid autoimmunity in MC patients vs. controls was shown. A logistic regression analysis showed that in MC, the appearance of hypothyroidism was related to female gender, a borderline high initial thyroid-stimulating hormone (TSH), AbTPO positivity, a hypoechoic, and small thyroid.In conclusion, we show a high incidence of new cases of AT and TD in MC patients. MC patients at high risk (female gender, a borderline high initial TSH, AbTPO positivity, a hypoechoic, and small thyroid) should have periodically thyroid function follow-up.

2016 - Increased risk of papillary thyroid cancer in systemic sclerosis associated with autoimmune thyroiditis [Articolo su rivista]
Antonelli, Alessandro; Ferri, Clodoveo; Ferrari, Silvia Martina; Di Domenicantonio, Andrea; Giuggioli, Dilia; Galleri, David; Miccoli, Paolo; Fallahi, Poupak
abstract

Patients with SSc have an increased risk of malignancy compared with the general population. Before now, no study has evaluated the risk of thyroid cancer (TC) in SSc patients. The aim of the study was to evaluate the prevalence of TC in SSc patients.

2016 - International diagnostic guidelines for patients with HCV-related extrahepatic manifestations. A multidisciplinary expert statement [Articolo su rivista]
Ferri, Clodoveo; Ramos Casals, Manuel; Zignego, Anna Linda; Arcaini, Luca; Roccatello, Dario; Antonelli, Alessandro; Saadoun, David; Desbois, Anne Claire; Sebastiani, Marco; Casato, Milvia; Lamprecht, Peter; Mangia, Alessandra; Tzioufas, Athanasios G; Younossi, Zobair M; Cacoub, Patrice
abstract

Hepatitis C virus (HCV) infection is responsible for both hepatic and extra-hepatic disorders (HCV-EHDs); these latter are correlated on one hand clearly with HCV lymphotropism causing immune-system dysregulation as well as with viral oncogenic potential, and on the other hand probably with chronic inflammatory status causing cardio-metabolic complications as well as neurocognitive disturbances. The spectrum of HCV-EHDs ranges from mild or moderate manifestations, such as arthralgia, sicca syndrome, peripheral neuropathy, to severe, life-threatening complications, mainly vasculitis and neoplastic conditions. Given the clinical heterogeneity of HCV-EHDs, HCV-infected individuals are inevitably referred to different specialists according to the presenting/prevalent symptom(s); therefore, the availability of comprehensive diagnostic guidelines is necessary for a patient's whole assessment that is decisive for early diagnosis and correct therapeutic approach of various hepatic and HCV-EHDs, regardless of the specific competencies of different physicians or referral centers. In this respect, a multidisciplinary network of experts, the International Study Group of Extrahepatic Manifestations Related to Hepatitis C Virus Infection (ISG-EHCV), was organized with the intention to formulate diagnostic guidelines for the work-up of possible HCV-EHDs. There was a broad consensus among ISG-EHCV members on the proposed guidelines, which essentially are based on two main levels of patient's assessment. At the referral stage, it is proposed that all patients with HCV infection should be invariably examined by means of first-line diagnostic procedures including virological and hepatic parameter evaluation, as well as the detection of clinical findings that may suggest one or more HCV-EHDs. This preliminary assessment should reveal specific HCV-EHDs, which will be deeper analyzed by means of second-line, targeted investigations. The proposed multidisciplinary expert statement represents the first attempt to draw comprehensive diagnostic guidelines for HCV-infected individuals encompassing the entire spectrum of HCV-related disorders, namely typical hepatic manifestations along with less common, often unpredictable HCV-EHDs. The HCV-EHDs may compromise to a substantial degree the overall disease outcome in a significant number of HCV-infected individuals that renders their timely identification and treatment an imperative. In conclusion, the application of standardized but thorough diagnostic guidelines of HCV-EHDs is advisable at the referral stage as well as during the follow-up period of HCV infected patients. It is envisioned that the proposed strategy will result in improvement of clinical outcomes in such patients.

2016 - INTERSTITIAL LUNG DISEASE IS ASSOCIATED TO INFECTIONS OF LOWER RESPIRATORY TRACT IN IMMUNOCOMPROMISED RHEUMATOID ARTHRITIS PATIENTS [Abstract in Rivista]
Cassone, Giulia; Sebastiani, Marco; Manfredi, Andreina Teresa; Campomori, Federica; Spinella, Amelia; Sandri, Gilda; Luppi, Fabrizio; Cerri, Stefania; Ferri, Clodoveo
abstract

Objectives. To investigate the possible association between demographic, serological and clinical features of rheumatoid arthritis (RA) and the lower respiratory tract (LRT) infections. We further analyzed the possible relationships between demographic, serological and clinical features and LRT infections in a sub-group of patients with RA-associated interstitial lung disease (ILD). Materials and Methods. Demographic, serological, clinical and therapeutic features of 563 RA patients were retrospectively analyzed (female/male ratio 3.43, mean age 64.8±13.6SD years, mean disease duration 11.5±9.4SD years). Results. During a mean follow-up of 138.9±131.3SD months, we observed 47 patients with at least one episode of LRT infection.The presence of RA-associated ILD, therapy with steroids, and b-DMARDs were significantly associated to LRT infections (p=0.016, p=0.000, and p=0.01 for ILD, steroids and b-DMARDs, respectively). All variables remained independently associated to infections of LRT also at logistic regression analysis; while no differences were observed with regard to the kind of the b-DMARDs, namely anti-tumor necrosis factors alpha inhibitors, rituximab, abatacept, tocilizumab. Moreover, the presence of ILD was associated to more severe LRT infectious complications, requiring hospitalization in 55.6% of patients, compared to 27.8% of patients without ILD (p=0.042). Since patients with ILD showed a risk to develop an infection of LRT 4.5 times higher of patients without ILD, we further analyzed this peculiar sub-group of patients. Among 33/563 (5.9%) patients with ILD (female/male ratio 2/1, mean age 71.8±10.6 years, mean disease duration 16.1±13.0 years), only b-DMARDs were associated to infections of LRT (p=0.002). Of interest, a combination therapy with b-DMARDs, methotrexate, and corticosteroids was significantly more frequently recorded in RA-ILD patients compared to those without LRT infections (81.8% vs 13.6% of patients; p=0.001). Conclusions. ILD is an important extra-articular complication of RA, involving about 5-10% of patients, and its current therapeutic approach is still under debate, because the lack of evidences that immunosuppressants are effective both on joint and lung involvement. Idiopathic pulmonary fibrosis (IPF) is usually compared to RA-ILD for their similarity in radiological and histological features. In IPF patients, the PANTHER-IPF study showed an excess mortality due to pulmonary infection in azathioprine and prednisone treatment arm, and corticosteroids increase the risk of serious infection fourfold. Our data confirm, with the limit of a low number of patients analyzed, that immunosuppressive treatment increase the risk of LRT infections particularly in RA-ILD patients, suggesting a more careful surveillance in this sub-group of patients. In conclusion, in patients with RA-ILD, it is necessary to balance the control of joint inflammation with the risk of drug-related LRT infections; this latter could be significantly reduced by tailoring both drug combination and doses (corticosteroids, traditional, and b-DMARDs) on individual patients.

2016 - Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: Our interdisciplinary rheumatology-pneumology experience, and review of the literature [Articolo su rivista]
Ferri, Clodoveo; Manfredi, Andreina; Sebastiani, Marco; Colaci, Michele; Giuggioli, Dilia; Vacchi, Caterina; Della Casa, Giovanni; Cerri, Stefania; Torricelli, Pietro; Luppi, Fabrizio
abstract

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lungs, varying from idiopathic interstitial pneumonias to secondary variants, including the ILDs associated to connective tissue diseases (CTDs). In addition, a number of patients are recognized as unclassifiable ILD (U-ILD), because of the inability to reach a definite diagnosis; some of them show autoimmune manifestations not fulfilling the classification criteria of a given CTD. The term interstitial pneumonia with autoimmune features (IPAF) has been recently proposed for this particular ILD subset. Methods: Here, we report our experience resulting from the integrated - pneumology/rheumatology - approach to patients with suspected ILDs or CTDs referred to our university-based Center for the Rare Pulmonary Diseases and Rheumatology Unit, from January 2009 to June 2015, with particular attention to the above-mentioned U-ILD, IPAF, and undifferentiated connective tissue disease (UCTD). The comparative analysis of these clinical variants was carried out; moreover, the observed findings were compared with the results of the updated review of the literature. Results: After the first clinical assessment, the U-ILD were identified in 50 patients; afterwards, on the basis of clinico-serological and radiological findings U-ILD group was subdivided into 2 subgroups, namely U-ILD without any clinical extra-thoracic manifestations and/or immunological alterations (15 pts) and IPAF according to the above-mentioned classification criteria (35 pts). Patients with either IPAF or U-ILD were compared with a series of 52 stable UCTD (disease duration ≥. 3. years), followed at our Rheumatology Unit. Some important differences were evidenced among the 3 series of U-ILD, IPAF, and UCTD: firstly, female gender was more frequent in patients with UCTD (86%) or IPAF (69%) compared with U-ILD (60%) or idiopathic pulmonary fibrosis (24%; p = 0.001). In addition, UCTD patients were younger and showed longer disease duration. More interestingly, both UCTD and IPAF series show a comparable prevalence of various clinical manifestations, with the exception of the interstitial lung involvement detectable in a very small percentage of UCTD patients.Concordantly, the review of the literature evidenced two main subsets of U-ILD, one is characterized by isolated unclassifiable interstitial pneumonia and another one composed by subjects with clinically prevalent lung involvement in the setting of not definite CTD, the recently proposed IPAF. Conclusion: We hypothesize that IPAF and UCTD might represent two clinical variants of the same systemic autoimmune disorders. The marked difference regarding the prevalence of ILD, which is the clinical hallmark of IPAF but very rare in UCTD, may at least in part reflect a selection bias of patients generally referred to different specialist centers, i.e. pneumology or rheumatology, according to the presence/absence of clinically dominant ILD, respectively. Well-integrated, interdisciplinary teams are recommended for the assessment and management of these patients in the clinical practice. Finally, the cooperation between multidisciplinary groups with different experiences may be advisable for a validation study of the proposed nomenclature and classification criteria of these indefinable ILD/CTD variants.

2016 - Nailfold Videocapillaroscopic and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study. [Articolo su rivista]
Cutolo, M; Herrick, Al; Distler, O; Becker, M; Beltran, E; Carpentier, P; Ferri, Clodoveo; Inanç, M; Vlachoyiannopoulos, P; Chadha Boreham, H; Cottreel, E; Pfister, T; Rosenberg, D; Torres, Jv; Smith, V.
abstract

OBJECTIVE: To identify nailfold videocapillaroscopic and other clinical risk factors for new digital ulcers (DUs) in a 6-month period in patients with systemic sclerosis (SSc), the videoCAPillaroscopy (CAP) study. METHODS: Overall 623 patients with SSc from 59 centers (14 countries) were stratified into two groups: "DU History" and "No-DU History". At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and an assessment of demographics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression analyses. RESULTS: Of the "DU History" group (n = 468), 79.5% were female, the mean age was 54.0 ± 13.7 years, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by multivariable logistic regression (MLR) in the "DU History" group included: mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs (0, 1, 2, ≥3), and presence of critical digital ischemia. The receiver operating characteristic area under the curve (ROC-AUC) (95% confidence interval [CI]) of the final MLR model was 0.738 (0.681-0.795). Internal validation through bootstrap generated a ROC-AUC (95% CI) of 0.633 (0.510-0.756). CONCLUSION: This international, prospective study including detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc identified the mean number of capillaries/mm in the middle finger of the dominant hand, number of DUs and presence of critical digital ischemia at enrollment as risk factors for the development of new DUs. This article is protected by copyright. All rights reserved.

2016 - Nailfold Videocapillaroscopy Alterations in Dermatomyositis and Systemic Sclerosis: Toward Identification of a Specific Pattern [Articolo su rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Campomori, Federica; Pipitone, Nicolò; Giuggioli, Dilia; Colaci, Michele; Praino, Emanuela; Ferri, Clodoveo
abstract

The term scleroderma pattern typically defines capillary abnormalities of scleroderma spectrum disorders, mainly systemic sclerosis (SSc) and dermatomyositis (DM). Our study aimed to investigate differences in nailfold videocapillaroscopy (NVC) between DM and SSc, with a cross-sectional and longitudinal evaluation. METHODS: NVC features of 29 consecutive patients with DM were compared with 90 patients with SSc categorized into the 3 subsets of scleroderma pattern: early, active, and late. Twenty patients with DM and all with SSc were also longitudinally reevaluated after 30 months of followup. RESULTS: At baseline, all SSc groups showed giant capillaries, with significant differences with DM only for early and active pattern. Ramified capillaries were significantly more frequent and severe in DM than in early and active patterns, while DM showed an opposite trend compared with late pattern. Capillary loss was lower in early pattern and higher in active and late, compared with DM. Finally, giant-ramified capillaries were almost exclusive of DM. During followup, NVC showed a different evolution in DM and SSc. In DM we recorded a reduction of giant capillaries, while ramified capillaries increased both in DM and in early and active SSc pattern. The number of capillaries recovered in DM; conversely, capillary loss slightly worsened in all SSc patterns. Giant-ramified capillaries significantly decreased in patients with DM, remaining rare in patients with SSc. CONCLUSION: Our study strengthens the specificity of DM and SSc microangiopathy and points out the need for large prospective studies to confirm our results and possibly to revise current terminology by distinguishing between "scleroderma" and "dermatomyositis" patterns.

2016 - Novel Therapies for Thyroid Autoimmune Diseases [Articolo su rivista]
Fallahi, Poupak; Ferrari, Silvia Martina; Elia, Giusy; Nasini, Francesco; Colaci, Michele; Giuggioli, Dilia; Vita, Roberto; Benvenga, Salvatore; Ferri, Clodoveo; Antonelli, Alessandro
abstract

ABSTRACT: C-X-C chemokine receptor (CXCR)3 and its interferon(IFN)γ-dependent chemokines (CXCL10, CXCL9, CXCL11) are implicated in the immune-pathogenesis of autoimmune thyroiditis (AT), Graves disease (GD) and Graves Ophthalmopathy (GO). In tissue, recruited Th1 lymphocytes produce IFNγ, enhancing the tissue secretion of IFNγ-inducible chemokines, initiating and perpetuating the autoimmune process. Patients with AT (with hypothyroidism), and with GO and GD, particularly in the active phase, have high IFNγ-inducible chemokines. Peroxisome proliferator-activated receptor (PPAR)γ or -α agonists and methimazole exert an immune-modulation on CXCR3 chemokines in AT, GD and GO. Other studies are ongoing to evaluate new molecules acting as antagonists of CXCR3, or blocking CXCL10, in Hashimoto thyroiditis (HT), GD and GO. Recently, novel molecules targeting the various agents involved in the pathogenesis of GO, such as rituximab, have been proposed as an alternative to corticosteroids. However, randomized and controlled studies are needed to generalize these interesting results.

2016 - Radiologic classification of usual interstitial pneumonia in rheumatoid arthritis-related interstitial lung disease: correlations with clinical, serological and demographic features of disease [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Cerri, Stefania; Della Casa, Giovanni; Luppi, Fabrizio; Ferri, Clodoveo
abstract

Interstitial lung disease (ILD) is a relevant extra-articular manifestation of rheumatoid arthritis (RA) and usual interstitial pneumonia (UIP) is considered the most frequent histo-pathological pattern of RA-ILD; high-resolution computed tomography (HRCT) is crucial for the evaluation of ILD patterns without recourse to lung biopsy. In 2011, the ATS/ERS/JRS/ALAT statement for diagnosis and management of idiopathic pulmonary fibrosis (IPF) provided consensus guidelines to identify a definite, possible or inconsistent with UIP pattern on HRCT, based on radiological features; previous studies suggest that the above classification should also be appropriate for RA-ILD. We retrospectively identified 97 unselected RA patients, classified according to 2010 ACR/EULAR classification criteria, referred to our Rheumatology Unit from October 2004 to March 2013, with at least one chest HRCT, regardless of its indication. Demographic, clinical, serological data, and drugs administered before HRCT were collected for all patients (table 1). RA-ILD diagnosis was conventionally identified with HRCT. A thoracic radiologist experienced in interstitial lung disease scored all HRCT images, classifying them as definite, possible or inconsistent with UIP. Among 97 RA patients, 32 showed RA-ILD (15 with definite or possible UIP pattern and 17 with an inconsistent with UIP pattern), while the 65 patients without ILD were used as control group. With the exception of dyspnea, no differences were observed comparing patients with or without ILD. According to radiological classification, we also compared patients with a definite or possible UIP pattern (UIP group), patients with a pattern inconsistent with UIP (non UIP group), and controls. No differences were observed comparing anti-CCP, rheumatoid factor, and ANA positivity, while ENA were more frequent in the UIP group, compared to the controls (p=0.039). Anti-Jo1 and anti-SSA were the prevalent specificities of ENA, without differences between the groups (only 1 patient fullfilled also criteria for Sjogren’s syndrome). All patients with UIP pattern had more than 63 years at the time of HRCT, and they were more frequently males and smokers (table 1). The occurrence of UIP pattern increased according to the number of significantly associated features (namely, male gender, smoking habit, presence of ENA, and age higher than 63 years). In fact, patients with UIP pattern showed the co-presence of 3 or 4 factors in 61% of cases, compared with no cases in non UIP group and 13.6% in control group (p<.001 and p=.001, respectively). Since IPF showed similar associations (particularly with male gender, elderly and smoke), it would be interesting a future speculation on potential pathogenic and therapeutic overlap between the two diseases. On the other side, the presence of anti-ENA in UIP pattern could only theoretically suggest partial overlap with connective tissue disease in RA-ILD, with possible prognostic and therapeutic implications. Published data have not clarified the association with anti-CCP and rheumatoid factor. The link between RA-ILD and drugs is still uncertain. The poor quality of published data and the lack of randomized controlled trials contribute to confounding information in clinical practice. HRCT could improve diagnosis and classification of ILD in RA patients, reserving lung biopsy only for selected cases. Moreover, at present, definition and classification of RA-ILD are still under debate, and the use of classifications based on radiological findings could improve the identification of more homogeneous groups of patients with different lung involvement. Interestingly, our study highlights the peculiarities of UIP pattern, showing different clinical associations from the ones of the whole ILD group. Since ILD can significantly affect the survival, a careful follow-up for ILD is mandatory in all RA patients and a mult

2016 - Systemic sclerosis chronic ulcers: Preliminary results of treatment with allogenic skin grafting in a cohort of italian patients [Articolo su rivista]
Barsotti, S.; Mattaliano, V.; D'ascanio, A.; Mosti, G.; Rossa, A. D.; Mattaliano, C.; Giuggioli, D.; Giraldi, E.; Ferri, C.; Mosca, M.
abstract

2015 - ALTERAZIONI CAPILLAROSCOPICHE IN CORSO DI DERMATOMIOSITE E SCLEROSI SISTEMICA; VERSO L’INDIVIDUAZIONE DI PATTERN SPECIFICI [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Campomori, Federica; Pipitone, N; Praino, E; Cannarile, F; Giuggioli, Dilia; Colaci, Michele; Ferri, Clodoveo
abstract

Introduzione. Sclerosi sistemica (SSc) e dermatomiosite (DM) sono le malattie reumatiche in cui più frequentemente si riscontra uno scleroderma pattern alla capillaroscopia. Lo scleroder- ma pattern è descritto come un insieme di alterazioni capillaroscopiche variamente associate fra loro, tipico delle connettiviti dello scleroderma spectrum. Ectasie, microemorragie, riduzio- ne della densità capillare, aree avascolari, disorganizzazione dell’architettura microvascolare ne rappresentano gli elementi caratteristici. Nonostante alcuni Autori suggeriscano peculiarità fra le alterazioni capillaroscopiche osservate in corso delle diverse malattie, queste non sono tuttora chiaramente definite. Scopo dello studio. Evidenziare eventuali differenze nelle caratteristiche dello scleroderma pattern associato alla DM rispetto a quello descritto nella SSc. Metodi. Lo studio analizza i reperti capillaroscopici di pazienti consecutivi affetti da DM che presentassero uno scleroderma pattern e confrontate con un gruppo di pazienti affetti da SSc comparabili per sesso ed età. Le capillaroscopie venivano eseguite mediante VideoCap 3 (DS Medica, Milano), con ottica 200x. Megacapillari, microemorragie e ramificazioni venivano valutati mediante score semiquantitativo (0= no alterazioni, 1= meno del 33%; 2= 33-66%; 3= più del 66% di alterazioni capillaroscopiche per millimetro lineare); la densità capillare veniva misurata come 0 (> o =7 capillari/mm), 1 (4-6 capillari/mm), or 2 (> o =3 capillari/mm); megacapillari, microemorragie, ramificazioni capillari e disorganizzazione architetturale venivano valutati anche come resenza/assenza. Risultati. Venivano arruolati 20 DM (M/F 4/16; età media 54,4 anni; durata media di malattia 2,3 mesi) e 38 SSc (M/F 5/33; età media 54,3 anni; durata media malattia 11,3 mesi). I pazienti con DM presentavano più frequentemente capillari arborescenti (p=0,002) rispetto ai pazienti sclerodermici; inoltre, le microemorragie erano più frequenti pur senza raggiungere la significatività statistica (p=0,051). Arborescenze capillari e microemorragie erano inoltre più diffuse e marcate nei pazienti con DM se valutate con score semiquantitativo (p=0,002 e p=0,023, rispettivamente, vedi tabella I). L’osservazione longitudinale di 11 pazienti con DM, di cui era disponibile una seconda valutazione capillaroscopica (f/u medio di 31,6 mesi), evidenziava significativo incremento delle arborescenze (score medio da 1,17 a 1,81; p=0,024) e riduzione dei megacapillari (score medio da 1,9 a 0,9; p=0,018). In 4/11 pazienti con DM si osservava la regressione dello scleroderma pattern. Conclusioni. I risultati di questo studio mostrano che le arborescenze e le microemorragie si riscontrano più frequentemente e con maggiore severità nelle DM rispetto alla SSc. L’osservazione longitudinale ha confermato aumento delle arborescenze, riduzione della severità dei megacapillari e la regressione dello scleroderma pattern in alcuni pazienti con DM. Questi dati suggeriscono alcune peculiarità della microangiopatia tipica della DM che, se confermate su più ampie casistiche, ne consentirebbero la differenziazione dal pattern tipicamente associato alla SSc.

2015 - Application of Agents Against Interferon-Gamma-Dependent Chemokines in Immunotherapy [Articolo su rivista]
Fallahi, Poupak; Ferrari, Silvia Martina; Giuggioli, Dilia; Ferri, Clodoveo; Antonelli, Alessandro
abstract

The CXC chemokine receptor (CXCR) 3 and its chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune disesases. Under the influence of interferon (IFN) γ, the IFNγ-inducible chemokines are secreted by lymphocytes, and by target cells (fibroblasts, epithelial cells, etc). In target tissues, Th1 lymphocytes are recruited; hence IFNγ is enhanced, which stimulates IFNγ-inducible chemokines (CXCL9, CXCL10, CXCL11) secretion reiterating the autoimmune process. Many studies have evaluated if blockade of ...

2015 - BCG and Autoimmunity [Capitolo/Saggio]
Bernini, Luigi; Manzini, Carlo Umberto; Ferri, Clodoveo
abstract

The bacillus Calmette-Guérin (BCG) is a live, attenuated vaccine from Mycobacterium bovis obtained by Albert Calmette and Camille Guerin through 230 in vitro passages between 1908 and 1921. This chapter presents clinical applications of BCG such as tuberculosis, leprosy, asthma and other hypersensitivity diseases, Type 1 diabetes, multiple sclerosis, and cancer. BCG can be described as a “double-acting tool” because its own immunogenicity produces a preventive effect in a variety of diseases and may trigger a number of autoimmune phenomena. An acute inflammatory polyarthritis with skin maculopapular rash was reported in a healthy woman following intradermal BCG. Side effects such as granulomatous pneumonia and hepatitis are reported without sufficient data to support the possible link with intravesical BCG and the autoimmune mechanism. Even the kidney may be the target of hypersensitivity reaction to intravesical BCG, which can induce an interstitial nephritis with non-necrotizing, sterile granulomas responsive to steroid therapy.

2015 - Cryoglobulinemic Vasculitis and Primary sjögren's Syndrome are Independent Risk Factors for Lymphoma in a Large Worldwide Population of Patients with Positive Serum Cryoglobulins [Abstract in Rivista]
Quartuccio, L; Corazza, L; Ramos Casals, M; Retamozo, S; Ragab, Gm; Ferraccioli, G; Gremese, E; Tzioufas, A; Voulgarelis, M; Vassilopoulos, D; Koutsianas, C; Scarpato, S; Salvarani, Carlo; Guillevin, L; Terrier, B; Cacoub, P; Saccardo, F; Gabrielli, A; Fraticelli, P; Tomsic, M; Tavoni, A; Nishimoto, N; Filippini, D; Scaini, P; Zignego, Al; Ferri, Clodoveo; Sansonno, D; Monti, G; Pietrogrande, M; Galli, M; Bombardieri, S; Vita, S. De
abstract

Background Serum cryoglobulins (SC) may be found in many diseases (1), and the presence of serum cryoglobulins is a known risk factor for lymphoma evolution in some non malignant diseases. Objectives The aim of this study was to distiguish the role of cryoglobulinemic vasculitis (CV), classified according to the recent validated criteria (1,2), and primary Sjögren's syndrome (pSS) as risk factors of lymphoma in patients positive serum cryoglobulins. Importantly, SC, CV and pSS may occur together. Methods 950 charts from consecutive patients with positive SC were evaluated. Patients carrying both pSS and HCV infection, as well as incomplete charts, were excluded. Results 657 patients with SC were selected, 374 with CV and 283 without CV, according to the published criteria (2,3). PSS, classified according to the American-European Group Criteria was present in 96 patients (44 with CV, 52 without). Lymphoma was reported in 61/657 (9.8%) patients with SC. Among them, CV was present in 44/61 (72,1%; 14 also with pSS), and pSS in 17/61 (27,9%; and 14/17 had CV). Patients with SC with CV showed an higher prevalence of lymphoma than patients with SC without CV (44/374, 11.5% vs.17/283, 6.3%; p=0.025, OR=1.93 [95%IC: 1.08-3.39]. Patients with pSS, SC and CV also showed a higher prevalence of lymphoma than patients with pSS, SC but without CV (14/44, 31.8% vs. 3/52, 7.4%; p=0.001, OR=7.62 [95%CI 2.02-28.74]. CV and pSS were confirmed as independent risk factor for lymphoma by multivariate analysis (OR 2,18 95%CI 1,18-3,83, p=0,012; OR 2,65 95%CI 1,04-6,76, p=0,042, respectively). Infection by the hepatitis C virus (HCV) was detected in 467/561 (83,2%) patients with SC without pSS, and did not statistically predispose to lymphoma when associated with CV in this subset (p=1,0). Conclusions Cryoglobulinemic vasculitis and pSS are independent risk factors for lymphoma in patients with evidence of SC. Patients with both the conditions (CV and pSS) have the highest risk. In the follow-up of SC positive patients, a very high attention should be deserved to pSS, in particular when CV is present.

2015 - Cryoglobulinemic vasculitis and skin ulcers. Our therapeutic strategy and review of the literature [Articolo su rivista]
Giuggioli, Dilia; Manfredi, Andreina Teresa; Lumetti, Federica; Sebastiani, Marco; Ferri, Clodoveo
abstract

Objective: Cryoglobulinemic vasculitis (CV) involving small- and medium-sized vessels is very frequently associated with hepatitis C virus and may be responsible for multiple organ involvement and skin ulcers (SU). Skin ulcers are often non-healing cutaneous lesions, possibly complicated by local infection and gangrene; they may severely affect the patients[U+05F3] quality of life and the overall prognosis. Therefore, the treatment of cryoglobulinemic SU is particularly challenging in the clinical practice.The present work evaluated the prevalence and correlations of cryoglobulinemic SU with other clinico-epidemiological features of CV; moreover, our long-term experience with the management strategies of these cutaneous lesions was compared with the world literature on this topic. Methods: The study included 126 CV patients (24 male and 102 female, aged 69 ± 11.2 SD years, disease duration 7 ± 6.9 SD years), followed at our Rheumatology Unit during the past decade. All patients were carefully evaluated regarding the entire cryoglobulinemic syndrome with particular concern for clinical characteristics and treatment of SU. Results: Among 126 CV patients, 36 individuals (29%) experienced at least one episode of SU, more commonly localized at the lower limbs. Patients with complicating SU showed significantly higher percentage of purpuric manifestations (p < 0.01) and liver (p < 0.001), peripheral nerve (p < 0.02), and/or thyroid involvement (p = 0.019).Therapeutic approach to SU included both systemic (immunosuppressors, corticosteroids, and/or plasma exchange) and local treatments. Local treatments consisted of sharp or surgical debridement as well as interactive dressing according to the condition of wound bed, perilesional skin, and the possible presence of infection, detected in 29 of 36 (81%) individuals in our Rheumatology unit. All patients underwent analgesic treatment for SU-related background pain as well as procedural pain, which was critical for an effective local SU management.The large majority of patients with SU healed at a variable time interval according to the severity of the single lesion; only five patients with very severe, non-healing SU needed amputation.The updated review of the literature revealed the presence of SU in around a quarter of CV patients. Among systemic treatments, the anti-CD20 monoclonal antibody rituximab represents one of the most effective and frequently employed therapies; however, the available data focusing on local therapeutic approach are generally limited to anecdotal observations. Conclusions: Overall, the treatment of cryoglobulinemic SU should be tailored to the single patient[U+05F3]s conditions using combined systemic and local treatments; lesional sharp debridement and interactive dressing as well as procedural pain management were decisive, particularly for more severe, non-healing cutaneous lesions.

2015 - CXCL10 in psoriasis [Articolo su rivista]
Ferrari, Silvia Martina; Ruffilli, Ilaria; Colaci, Michele; Antonelli, Alessandro; Ferri, Clodoveo; Fallahi, Poupak
abstract

Chemokine (C-X-C motif) ligand (CXCL)10 is involved in the pathogenesis of psoriasis. It has been demonstrated that chemokine (C-X-C motif) receptors (CXCR)3 and CXCL10 were detected in keratinocytes and the dermal infiltrate obtained from active psoriatic plaques and that successful treatment of active plaques decreased the expression of CXCL10. Elevated CXCL10 serum levels have been shown in patients with psoriasis, with a type 1 T helper cells immune predominance at the beginning of the disease, while a decline of this chemokine has been evidenced later, in long lasting psoriasis. Circulating CXCL10 is significantly higher in patients with psoriasis in the presence of autoimmune thyroiditis. It has been hypothesized that CXCL10 could be a good marker to monitor the activity or progression of psoriasis. Efforts have been made to modulate or inhibit the CXCR3/CXCL10 axis in psoriasis to modify the course of the disease.

2015 - Elevated Troponin Serum Levels in Adult Onset Still's Disease [Articolo su rivista]
Manzini, Carlo Umberto; Brugioni, Lucio; Colaci, Michele; Tognetti, Maurizio; Spinella, Amelia; Sebastiani, Marco; Giuggioli, Dilia; Ferri, Clodoveo
abstract

Adult onset Still's disease (AOSD) is a rare inflammatory systemic disease that occasionally may affect myocardium. Diagnosis is based on typical AOSD symptoms after the exclusion of well-known infectious, neoplastic, or autoimmune/autoinflammatory disorders. In the case of abrupt, recent onset AOSD, it could be particularly difficult to make the differential diagnosis and in particular to early detect the possible heart involvement. This latter event is suggested by the clinical history of the four patients described here, incidentally observed at our emergency room. All cases were referred because of acute illness (high fever, malaise, polyarthralgias, skin rash, and sore throat), successively classified as AOSD, and they presented abnormally high levels of serum troponin without overt symptoms of cardiac involvement. The timely treatment with steroids (3 cases) or ibuprofen (1 case) leads to the remission of clinicoserological manifestations within few weeks. These observations suggest that early myocardial injury might be underestimated or entirely overlooked in patients with AOSD; routine cardiac assessment including troponin evaluation should be mandatory in all patients with suspected AOSD.

2015 - Evoluzione dello CSURI (Capillaroscopic Skin Ulcer Risk Index) in pazienti affetti da sclerosi sistemica in terapia con antiendotelina-1 e prostanoidi [Abstract in Rivista]
Cestelli, V; Sebastiani, Marco; Manfredi, Andreina Teresa; Praino, E; Cannarile, F; Giuggioli, Dilia; Colaci, Michele; Sandri, Gilda; Iannone, F; Gerli, R; Ferri, Clodoveo
abstract

Il ruolo della capillaroscopia nei pazienti affetti da sclerosi sistemica (SSc) è progressivamente cresciuto nel corso degli ultimi anni. I farmaci vasoattivi utilizzati nel trattamento e nella prevenzione delle ulcere digitali, in particolare iloprost e bosentan, sembrano in grado di migliorare la microangiopatia sclerodermica, anche se i dati a favore di tale ipotesi sono piuttosto limitati. Lo CSURI (Capillaroscopic Skin Ulcer Risk Index), dimostratosi efficace nell’individuare i pazienti a rischio di sviluppare ulcere digitali, potrebbe rappresentare un ottimo indicatore dell’effetto di questi farmaci sul microcircolo. Scopo dello studio. Valutare l’evoluzione della microangiopatia in pazienti affetti da SSc con storia di ulcere digitali in terapia con iloprost (ILO) o con bosentan e iloprost (BOS+ILO). Materiali e Metodi. 95 pazienti sclerodermici consecutivi secondo i criteri ACR/EULAR 2013 (M/F 3,3/1; età media 52,7±14,3 anni) venivano sottoposti a videocapillaroscopia periungueale al basale e dopo 12 mesi. Tutti i pazienti erano in trattamento infusionale mensile con ILO, mentre 33 assumevano terapia di combinazione con BOS+ILO. Di ogni paziente venivano valutati i principali parametri capillaroscopici (megacapillari, microemorragie, neoangiogenesi, disorganizzazione del letto capillare) e calcolato lo CSURI, registrando: numero minimo di capillari, numero massimo di megacapillari e diametro massimo capillare. Risultati. I dati capillaroscopici ottenuti al basale ed al termine del follow-up sono riportati in tabella I. All’inizio del follow-up il 30% dei pazienti del gruppo ILO e il 54,5% dei pazienti in terapia di associazione BOS+ILO presentava uno CSURI positivo. Tutti i pazienti in terapia con BOS avevano presentato almeno un’ulcera digitale nella propria storia clinica, evento presentatosi nel 73,4% dei pazienti in monoterapia con ILO. Al termine del follow-up la percentuale dei pazienti del gruppo BOS+ILO con CSURI positivo si riduceva al 45,5% (p non significativo), mentre aumentava al 45,2% nei pazienti in terapia con ILO (p<0,001). In entrambi i gruppi si osservava inoltre una significativa riduzione dei megacapillari, mentre nel gruppo BOS+ILO si associava un significativo incremento delle neoangiogenesi (p=0,020). Conclusioni. Le ulcere digitali rappresentano una delle principali complicanze in corso di SSc ed un numero crescente di pazienti viene trattato con farmaci vasoattivi, fra cui iloprost e bosentan sono i più utilizzati, da soli o in associazione. Entrambi hanno dimostrato di essere in grado di influenzare la microangiopatia sclerodermica riducendo il numero dei megacapillari, anche se l’associazione con il bosentan sembrerebbe determinare anche uno stimolo rigenerativo, come evidenziato dall’incremento delle neoangiogenesi. Le variazioni dello CSURI confermano l’effetto di iloprost+bosentan sulla microangiopatia e la maggiore stabilizzazione del quadro capillaroscopico rispetto alla monoterapia con iloprost. Questi dati confermano inoltre la sensibilità della capillaroscopia e suggeriscono per lo CSURI un ruolo nel monitoraggio della microangiopatia sclerodermica in corso di terapie vasoattive.

2015 - Gynaecological Screening for Cervical and Vulvar Malignancies in a Cohort of Systemic Sclerosis Patients: Our Experience and Review of the Literature [Articolo su rivista]
Colaci, Michele; Giuggioli, Dilia; Cassone, Giulia; Vacchi, Caterina; Campomori, Federica; Boselli, F; Sebastiani, Marco; Manfredi, Andreina Teresa; Ferri, Clodoveo
abstract

Background. Increased incidence of cancer was frequently reported in scleroderma (SSc), but no association with gynaecological malignancies was described in literature. Objectives. To investigate gynaecological neoplasms in SSc patients. Methods. In this cross-sectional analysis, we evaluated 80 SSc patients, living in the same geographical area. We considered all patients undergoing gynaecological evaluation, including pap test as screening for cervical cancer, between January 2008 and December 2014. Results. 55 (68.7%) patients were negative and 20 (25%) presented inflammatory alterations, while cancer or precancerous lesions were found in 5 (6.2%) cases (2 showed cervical cancer (one of them in situ), 1 vulvar melanoma, 1 vulvar intraepithelial neoplasia, and 1 endocervical polyp with immature squamous metaplasia). The frequency of cervical cancer in our series seems higher in comparison to the incidence registered in the same geographical area. The presence of atypical cytological findings correlated with anti-Scl70 autoantibodies (p = 0.022); moreover, the patients with these alterations tended to be older (median 65, range 46-67), if compared to the whole series (p = 0.052). Conclusions. A relatively high frequency of gynaecological malignancies was found in our SSc series. In general, gynaecological evaluation for SSc women needs to be included in the routine patients' surveillance.

2015 - Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin's lymphoma, and cancer [Articolo su rivista]
Ferri, Clodoveo; Sebastiani, Marco; Giuggioli, Dilia; Colaci, Michele; Fallahi, Poupak; Piluso, Alessia; Antonelli, Alessandro; Zignego, Anna Linda
abstract

The clinical course of chronic hepatitis C virus (HCV) infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several immune-mediated disorders; a poly-oligoclonal B-lymphocyte expansion, commonly observed in a high proportion of patients with HCV infection, are responsible for the production of different autoantibodies and immune-complexes, such as mixed cryoglobulins. These serological alterations may characterize a variety of autoimmune or neoplastic diseases. Cryoglobulinemic vasculitis due to small-vessel deposition of circulating mixed cryoglobulins is the prototype of HCV-driven immune-mediated and lymphoproliferative disorders; interestingly, in some cases the disease may evolve to frank malignant lymphoma. In addition, HCV shows an oncogenic potential as suggested by several clinico-epidemiological and laboratory studies; in addition to hepatocellular carcinoma that represents the most frequent HCV-related malignancy, a causative role of HCV has been largely demonstrated in a significant percentage of patients with isolated B-cells non-Hodgkin's lymphomas. The same virus may be also involved in the pathogenesis of papillary thyroid cancer, a rare neoplastic condition that may complicate HCV-related thyroid involvement. Patients with HCV infection are frequently asymptomatic or may develop only hepatic alteration, while a limited but clinically relevant number can develop one or more autoimmune and/or neoplastic disorders. Given the large variability of their prevalence among patients' populations from different countries, it is possible to hypothesize a potential role of other co-factors, i.e., genetic and/or environmental, in the pathogenesis of HCV-related extra-hepatic diseases.

2015 - INTERSTIZIOPATIA POLMONARE NON CLASSIFICABILE O SECONDARIA A CONNETTIVITE INDIFFERENZIATA. IMPORTANZA E DIFFICOLTÀ DI UNA DIAGNOSI DIFFERENZIALE. [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Cerri, Stefania; DELLA CASA, Giovanni; Vacchi, Caterina; Giuggioli, Dilia; Colaci, Michele; Luppi, Fabrizio; Ferri, Clodoveo
abstract

Introduzione. Le interstiziopatie polmonari rappresentano un ampio gruppo di malattie che causano fibrosi o infiammazione del parenchima polmonare. Le principali forme sono quelle secondarie ad esposizione ambientale, fibrosi polmonari idiopatiche, polmoniti interstiziali non specifiche (NSIP), forme secondarie a sarcoidosi e quelle secondarie alle connettiviti. Quando per qualche motivo (limiti diagnostici, fattori confondenti, quadri atipici, ecc.) non è possibile classificare un’interstiziopatia nei sottotipi soprariportati, questa viene definita come non classificabile (U-ILD). Le connettiviti indifferenziate (UCTD) sono malattie sistemiche caratterizzate da caratteristiche cliniche e sierologiche tipiche di altre connettiviti definite ma che non ne soddisfano i criteri classificativi esistenti. Il coinvolgimento polmonare è raramente descritto in pazienti affetti da UCTD e non è solitamente considerato a fini diagnostici e classificativi come possibile manifestazione d’esordio. Recentemente alcuni autori hanno suggerito che alcune interstiziopatie non classificabili potrebbero essere meglio inquadrate come secondarie a connettiviti. Nella pratica clinica, soprattutto quando il quadro respiratorio sembra essere il sintomo d’esordio della patologia, la diagnosi differenziale può essere estremamente complessa, eppure di sostanziale importanza alla luce delle implicazioni terapeutiche. Scopo dello studio. Individuare le caratteristiche cliniche e sierologiche che distinguono le U-ILD dalle interstiziopatie secondarie ad UCTD (UCTD-ILD) per migliorare la diagnosi differenziale e individuare pazienti candidati a terapia immunosoppressiva. Metodi. Fra settembre 2011 a novembre 2014, 50 pazienti valutati presso il nostro centro venivano classificati come affetti da UCTD o U-ILD, dopo discussione interdisciplinare, secondo i criteri presenti in letteratura. Il quadro radiologico rilevato alla TC ad alta risoluzione veniva classificato come usual interstitial pneumonia (UIP) definito, possibile o non compatibile, secondo i criteri classificativi della fibrosi polmonare idiopatica. Risultati. Le principali caratteristiche dei pazienti sono riportate nella tabella. Il fenomeno di Raynaud, la xeroftalmia e la positività dell’ANA test risultavano più frequenti nei pazienti con UCTD (rispettivamente p=0.27, p=0-07, p=0.2). Un pattern radiologico non compatibile con UIP veniva rilevato in circa il 70% dei pazienti con UCTD. Un modello predittivo basato su fenomeno di Raynaud, xeroftalmia, positività dell’ANA test mostrava un valore predittivo dell’85,7% (le UCTD venivano classificate nel 90,5% e le U-ILD nel 78,6%). Conclusioni. Il coinvolgimento polmonare è una possibile manifestazione d’esordio delle UCTD. La diagnosi differenziale con le U-ILD può essere problematica ma è assolutamente necessaria per le conseguenti implicazioni nell’approccio terapeutico. A questo scopo, un’attenta valutazione di alcune caratteristiche cliniche e sierologiche può essere di aiuto. Un lavoro in team multidisciplinare che includa reumatologo, pneumologo, radiologo, anatomo-patologo rappresenta l’approccio migliore al paziente con interstiziopatia polmonare da definire.

2015 - Nailfold capillaroscopic changes in dermatomyositis and polymyositis [Articolo su rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Cassone, Giulia; Pipitone, N; Giuggioli, Dilia; Colaci, Michele; Salvarani, Carlo; Ferri, Clodoveo
abstract

Inflammatory myopathies (IM) are a group of muscle diseases occurring both in children and adults. Nailfold videocapillaroscopy (NVC) alterations are described in IM, but available data are discordant, including differences between polymyositis (PM) and dermatomyositis (DM). The aim of this study was to describe the capillaroscopic differences between PM and DM patients and possible correlation with clinical and serological features. We analyzed 52 unselected patients with IM in a cross-sectional study in a 6-month period. NVC findings of 29 DM and 23 PM patients were compared with those of 52 patients with primary Raynaud's phenomenon. Tortuosities, capillary loss, enlarged and giant capillaries, microhemorrhages, and ramified capillaries were scored by a semiquantitative rating; disorganization of the vascular array, avascular areas, and scleroderma pattern were scored as presence/absence. Sex, mean age, and mean disease duration were similar in both groups. Disorganization of the vascular array, enlarged and giant capillaries, capillary loss, and scleroderma-like pattern were observed almost only in IM patients. Significant differences were observed between PM and DM with higher frequency and mean score of NVC changes in DM. In DM patients with disease duration ≤6 months (14/29 patients), capillary density was significantly reduced (P = 0.039) and giant capillaries more frequent (P = 0.027), compared with patients with longer disease duration, while a scleroderma pattern tended to be more frequent in patients with a disease duration of less than 6 months. On the contrary, no differences were observed for ramified capillaries with regard to disease duration. Capillaroscopic alterations are identified only in DM patients as expression of diffuse microangiopathy; surprisingly, more severe changes were associated with shorter disease duration, while persistence of ramified capillaries with long-standing disease.

2015 - PAP-TEST FEATURES IN A COHORT OF SYSTEMIC SCLEROSIS PATIENTS [Abstract in Rivista]
Colaci, Michele; Giuggioli, D.; Sebastiani, Marco; Manfredi, Andreina Teresa; Cassone, Giulia; Vacchi, Caterina; Boselli, F.; Ferri, Clodoveo
abstract

Background: Increased incidence of malignancies was frequently reported in systemic sclerosis (SSc), as well as for other autoimmune diseases. Besides the previously observed association with lung cancer1 and the increased risk for breast cancer2, no association with cancer of the cervix has been described in literature. However, cervical uterus malignancy is one of the most frequent cancer in women so that public health programs of screening have been established in several countries worldwide. In Italy, the pap cytology test is recommended every 3 years for all women between 25 and 64 years old. Objectives: To investigate pap-test features in SSc patients. Methods: We retrospectively evaluated a cohort of 80 consecutive female SSc patients (mean age 51.2±12SD years, disease duration 7.9±5.8SD years, limited/diffuse skin subsets 72/8), who underwent to pap cytology tests as screening for cancer of the cervix, during the period between January 1st, 2008 and December 31th, 2014. All patients came from the same geographical area (province of Modena, Northern Italy). Clinical, serological, and instrumental data of SSc patients were collected and related to cytological findings. Results: At gynaecological and pap test evaluations, 55 (68.7%) patients were negative, while 20 (25%) presented inflammatory alterations (i.e. chronic cervicitis); while atypical cells related to cancer or pre-cancerous lesions were found in 5 (6.2%) cases. Namely, 2 women showed cervix cancer (one of them in situ), 1 a vulvar melanoma, 1 a vulvar intraepithelial neoplasia, and 1 an endocervical polyp with immature squamous metaplasia at histology. The frequency of cervix cancer in our series seems to be clearly higher in comparison to the incidence registered in the same geographical area and in the same years (standardized rate 8, 95%IC 5.2-10.7 cases out of 100,000 subjects). At statistical analysis, the atypical cytological findings correlated with serum anti-Scl70 autoantibodies (4/5 vs. 19/75; p=0.022); moreover, the patients with these alterations tended to be older (median 65, range 46-67), if compared to the whole series (p=0.052). No statistical correlations with skin or visceral involvements, smoking history, treatment with immunosuppressors were found. Conclusions: In our SSc patients' series, we found a relatively high frequency of cancerous lesions of the cervix by means of pap test. A significant correlation with anti-Scl70 autoantibodies was also found. These preliminary findings need to be verified in larger controlled epidemiological studies.

2015 - Prediction risk chart for scleroderma digital ulcers: A composite predictive model based on capillaroscopic, demographic and clinico-serological parameters [Articolo su rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Carraro, Valeria; Iudici, Michele; Bocci, Mario; Vukatana, Gentiana; Gerli, Roberto; De Angelis, Rossella; Del Medico, Patrizia; Praino, Emanuela; Lo Monaco, Andrea; D'Amico, Roberto; DEL GIOVANE, Cinzia; Mazzuca, Salvatore; Colaci, Michele; Giuggioli, Dilia; Ferri, Clodoveo
abstract

BACKGROUND: Digital ulcers (DU) affect 50% of systemic sclerosis (SSc) patients, representing a challenging clinical problem. Despite a high negative predictive value, capillaroscopic scores proposed to select patients at risk for DU show an inadequate positive predictive value, especially in patients without previous DU. AIM OF THIS STUDY: To increase the predictive value for DU development of capillaroscopy, through a predictive risk chart taking into account capillaroscopic, demographic, and clinico-serological parameters. PATIENTS AND METHODS: Two hundred and nineteen unselected SSc patients from 8 Italian Rheumatology Centers were consecutively enrolled during a 6-month period. Demographic, clinical, serological and instrumental data and capillaroscopy skin ulcers risk index (CSURI) were collected. RESULTS: A multivariate logistic regression analysis showed a significant positive association between DU appearance and male gender, DU history, altered CSURI, and ESR. A prediction risk chart of the development of DU within 6 months were built on the basis of the above parameters. According to the risk level, four risk classes were identified: low (≤19.3%); medium (>19.3%, ≤58.6%); high (>58.6%, ≤89.2%), and very high risk (>89.2%). CONCLUSIONS: The systematic evaluation of the above parameters can be helpful to identify patients at risk to develop DU optimizing preventive vasoactive therapy.

2015 - Predictive Value of DLCO Reduction in Scleroderma Patients Without Cardio-Pulmonary Involvement at Baseline [Abstract in Rivista]
Colaci, Michele; Giuggioli, Dilia; Sebastiani, Marco; Manfredi, Andreina Teresa; Lumetti, Federica; Luppi, Fabrizio; Cerri, Stefania; Ferri, Clodoveo
abstract

Background Impaired diffusing capacity of the lung for carbon monoxide (DLCO) was frequently observed in systemic sclerosis (SSc) patients, generally related to the presence of interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). However, in clinical practice abnormally low DLCO values may be found also in the absence of these SSc complications. Objectives To investigate the prospective clinical relevance of isolated DLCO reduction at baseline in SSc patients. Methods Ninety-seven SSc female patients (age at the diagnosis: 51.3±14.5 years; disease duration: 10.4±6.6 years; limited/diffuse skin subsets: 92/5), without any clinical, radiological (high resolution computed tomography), and echocardiographic manifestations of ILD or PAH at baseline, nor other lung or heart diseases able to affect DLCO, were recruited at our Rheumatology Centre. Patients with DLCO <55%1 (15 patients; group A) were compared with those with normal DLCO (82 patients; group B), at baseline and at the end of follow-up. Results At baseline, patients of group A showed significantly higher percentage of anticentromere autoantibodies compared to group B (13/15, 86.6% vs. 48/82, 58.5%; p=0.044). More interestingly, at the end of long-lasting clinical follow-up (11.6±6.7 years), pre-capillary PAH (right heart catheterization) solely developed in some patients of group A (3/15, 20% vs. 0/82; p=0.003). Conclusions In SSc patients, the presence at baseline of isolated, marked DLCO reduction (<55% of predicted) and serum anticentromere autoantibodies might characterize a peculiar SSc subset that may precede the development of PAH. Therefore, careful clinical follow-up of patients with isolated moderate-severe DLCO reduction should be mandatory.

2015 - Predictive value of isolated DLCO reduction in systemic sclerosis patients without cardio-pulmonary involvement at baseline [Articolo su rivista]
Colaci, Michele; Giuggioli, Dilia; Sebastiani, Marco; Manfredi, Andreina Teresa; Lumetti, Federica; Luppi, Fabrizio; Cerri, Stefania; Ferri, Clodoveo
abstract

Impaired diffusing capacity of the lung for carbon monoxide (DLCO) was frequently observed in systemic sclerosis (SSc) patients, generally related to the presence of interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). However, in clinical practice abnormally low DLCO values may be found also in the absence of these SSc complications. The objective was to investigate the prospective clinical relevance of isolated DLCO reduction at baseline in SSc patients. Ninety-seven SSc female patients (age at the diagnosis: 51.3±14.5 years; disease duration: 10.4±6.6 years; limited/diffuse skin subsets: 92/5), without any clinical, radiological (high resolution computed tomography), and echocardiographic manifestations of ILD or PAH at baseline, nor other lung or heart diseases able to affect DLCO, were recruited at our Rheumatology Centre. Patients with DLCO <55% (15 patients; group A) were compared with those with normal DLCO (82 patients; group B), at baseline and at the end of follow-up. At baseline, patients of group A showed significantly higher percentage of anticentromere autoantibodies compared to group B (13/15, 86.6% vs 48/82, 58.5%; p=0.044). More interestingly, at the end of long-lasting clinical follow-up (11.6±6.7 years), pre-capillary PAH (right heart catheterization) solely developed in some patients of group A (3/15, 20% vs 0/82; p=0.003). In SSc patients, the presence at baseline of isolated, marked DLCO reduction (<55% of predicted) and serum anticentromere autoantibodies might characterize a peculiar SSc subset that may precede the development of PAH. Therefore, careful clinical follow-up of patients with isolated moderate-severe DLCO reduction should be mandatory.

2015 - Prevalence and evolution of scleroderma pattern at nailfold videocapillaroscopy in systemic sclerosis patients: Clinical and prognostic implications [Articolo su rivista]
Ghizzoni, Cecilia; Sebastiani, Marco; Manfredi, Andreina Teresa; Campomori, Federica; Colaci, Michele; Giuggioli, Dilia; Ferri, Clodoveo
abstract

Background: Microvascular involvement plays a decisive role in systemic sclerosis (SSc) pathogenesis occurring early in the course of the disease. Microangiopathy is responsible of important clinical manifestations, such as Raynaud's phenomenon, digital ulceration, and pulmonary arterial hypertension. Typical microvascular alterations, called scleroderma pattern, are detectable at nailfold capillaroscopy in a significant percentage of SSc patients: however its prevalence is highly variable in published studies. Aim: The aims of this study are to evaluate the prevalence and the evolution of scleroderma pattern in SSc patients and analyze their demographic, clinical and prognostic characteristics according to capillaroscopic features. Methods: Two hundred and seventy-five SSc patients, underwent at least two nailfold videocapillaroscopy during follow-up, were retrospectively enrolled. Results: A scleroderma pattern was observed in 80% of patients at baseline and 87.1% during follow-up, and it was significantly associated to digital ulcers, interstitial lung disease, reduction of diffusion lung of carbon monoxide <75%, teleangectasias and melanodermia, while sicca syndrome and arthralgias were associated to normal/nonspecific pattern. Digital ulcers, teleangectasias, sicca syndrome, and arthralgias remained independently associated with scleroderma pattern on multivariate analysis. In conclusion, the main clinical manifestation correlated with scleroderma pattern is the occurrence of digital ulcers, and their appearance is strictly correlated with the variation of capillaroscopic feature during the time. Further studies should confirm the association between SSc pattern and lung fibrosis.

2015 - Procedural pain management in the treatment of scleroderma digital ulcers [Articolo su rivista]
Giuggioli, Dilia; Manfredi, Andreina Teresa; Vacchi, Caterina; Sebastiani, Marco; Spinella, Amelia; Ferri, Clodoveo
abstract

Objective: Digital ulcers (DU) may develop in half of systemic sclerosis (SSc) patients; they are often resistant to treatments. Deep wound debridement is crucial for DU healing, but very difficult to carry out without adequate procedural pain management. Here, we report the results of our experience on procedural pain management in scleroderma DU. Methods: The study included 51 DU observed in 32 consecutive SSc patients; procedural pain was treated following a definite schedule: local lidocaine and prilocaine (25 mg of either agent per gram of cream, EMLA 5%) were initially used in all cases, followed by local and oral morphine, according to the severity of pain scored on a 10 cm visual analogue scale (VAS). Results: At baseline, higher pain VAS was recorded in more severe (p=0.0001) and/or infected DU (p=0.0001). Good compliance to DU debridement was observed in patients with mild pain (VAS ≤4) treated with only EMLA, and in 5 cases with moderate-severe pain (VAS &gt;4) at baseline. While, the majority of DU with moderate-severe pain (34/39) needed a combined therapy with EMLA and local morphine (8/34) or with EMLA, local and oral morphine (26/34). On the whole, pain management during DU debridement required only EMLA application in 33% of cases, EMLA plus local morphine in 16%, while combined EMLA, local and oral morphine were necessary in 51%, generally with more severe and/or infected lesions. Conclusion: The present study showed valuable control of procedural pain during DU debridement with sequential, combined analgesic treatment.

2015 - Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV-related cryoglobulinemic vasculitis: Long-term follow up data of a randomized controlled multicentre study [Articolo su rivista]
Quartuccio, Luca; Zuliani, Francesca; Corazza, Laura; Scaini, Patrizia; Zani, Roberta; Lenzi, Marco; Tavoni, Antonio; Sebastiani, Marco; Baldovino, Simone; Urraro, Teresa; Saccardo, Francesco; Sbreglia, Costanza; Mazzaro, Cesare; Pioltelli, Piero; Fraticelli, Paolo; Filippini, Davide; Gabrielli, Armando; Perrella, Oreste; Scarpato, Salvatore; Roccatello, Dario; Zignego, Anna Linda; Ferri, Clodoveo; Bombardieri, Stefano; Pietrogrande, Maurizio; Monti, Giuseppe; Galli, Massimo; De Vita, Salvatore
abstract

Objective: To evaluate the efficacy and safety in the long term of a retreatment regimen with Rituximab (RTX) alone administered at clinical relapse in cryoglobulinemic vasculitis (CV). Methods: Thirty patients with severe HCV-related CV, previously enrolled in the multicentre Italian trial on RTX in the treatment of CV, were retrospectively evaluated after the end of the trial. All of them were managed with RTX alone at clinical relapse, if any. Disease activity at the last available follow up was defined as complete remission (absence of active disease), partial remission (response &gt; 50% of at least one manifestation among glomerulonephritis, peripheral neuropathy or skin ulcers) or active disease. Results: The mean follow up after the first RTX cycle was 72.6 (20.4) months. After the end of the trial, 21/30 (70%) patients showed an active follow up [81.7 (10.9) months)], 3/30 (10%) lost follow up and 6/30 (20%) died. 12/21 (57.1%) patients were in complete disease remission, 5/21 (23.8%) showed a partial response and 4/21 (19%) had an active disease. 17/30 (56.7%) patients needed retreatment for relapse with a mean time to retreatment of 22.3 (12.1) months. Treatment survival of this regimen was 7.6 (0.3) years. Recurrent non-severe infections occurred in 3/30, with chronic hypogammaglobulinemia in 2/3 patients. Conclusions: A long-term regimen of retreatment with RTX alone given at clinical relapse seems to be effective and safe in CV, with a low rate of infections and severe hypogammaglobulinemia.

2015 - Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature [Articolo su rivista]
Giuggioli, Dilia; Lumetti, Federica; Colaci, Michele; Fallahi, Poupak; Antonelli, Alessandro; Ferri, Clodoveo
abstract

The treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities.

2015 - Role of CXCL10 in cryoglobulinemia [Articolo su rivista]
Mazzi, Valeria; Ferrari, Silvia Martina; Giuggioli, Dilia; Antonelli, Alessandro; Ferri, Clodoveo; Fallahi, Poupak
abstract

Interferon (IFN)-γ-induced protein 10 (IP-10/CXCL10) and its receptor, C-X-C motif receptor 3, appear to contribute to the pathogenesis of hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC) (HCV+MC). The secretion of CXCL10 by cluster of differentiation (CD) CD4+, CD8+, and natural killer-T cells is dependent on IFN-γ, which is itself mediated by the interleukin-12 cytokine family. Under the influence of IFN-γ, CXCL10 is secreted by several cell types including lymphocytes, hepatocytes, endothelial cells, fibroblasts, etc. In tissues, recruited T helper 1 lymphocytes may be responsible for enhanced IFN-γ and tumour necrosis factor-α production, which in turn stimulates CXCL10 secretion from the cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process. High levels of CXCL10 in circulation have been found in HCV+MC, especially in patients with clinically active vasculitis. Furthermore, HCV+MC patients with autoimmune thyroiditis (AT) have higher levels than those without AT. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis, and to evaluate whether CXCL10 is a novel therapeutic target in HCV-related MC.

2015 - SAT0470 Pap-Test Features in a Cohort of Systemic Sclerosis Patients [Abstract in Rivista]
Colaci, Michele; Giuggioli, D; Sebastiani, Marco; Manfredi, A; Cassone, Giulia; Vacchi, Caterina; Boselli, F; Ferri, Clodoveo
abstract

2015 - SAT0633-HPR Articular Involvement of the Scleroderma Hand: An Assessment Protocol for Planning Occupational Therapy Strategies [Abstract in Rivista]
Mercanti, Catia; Zingarello, L. A.; Franchi, Franca; Sartini, Silvana; Giuggioli, D.; Ferri, Clodoveo; Mascia, Maria Teresa
abstract

Background: Systemic sclerosis (SSc) is a rare inflammatory connective tissue disease acquired, chronic, progressive of unknown etiology characterized by irregular autoimmune response, changes in the small circle due to vascular disease, fibrosis of the skin and internal organs. Hand impairment is a major cause of morbidity and disability in about 90% of SSc patients Although physiotherapy and rehabilitation programs to prevent and reduce the disability resulting from osteo-articular and skin involvement are recommended, only a few studies have been published on this feature. Objectives: Our study aims an analysis of scleroderma hand through the application of instrumental tests and rating scales to suggest a specific evaluation protocol in order to highlight the main anomalies for planning occupational therapy strategies and to have specific outcome measure. Methods: The study was conducted on 45 patients with SSc. In the protocol were included total active motion-TAM (Strickland), strength of the grip (Jamar dynamometer and pinchmeter) and the evaluation of 16 different types of prehension of objects encountered during activities of daily life. Results: The Strickland measurement showed a symmetrical involvement of the hands for almost all patients (93%); furthermore observed that only 30% of patients have an excellent level in TAM (percentage of scoring higher 85%). A statistically significant reduced total active movement of the dominant hand was documented in diffuse SSc. Furthermore, the fingers more limited and therefore with lower TAM are the 2nd and 5th finger in both hands. At the second finger there is a statistically significant weaker strength of dominant hand related to disease duration in patients with dSSc (P value equals 0.0021). The grip strength (Jamar Dynamometer and Jamar pinchmeter) is extremely reduced in 75% of patients and focuses mainly on the dominant hand. If <15 kg (below normal range), the difference between the strength of dominant and non dominant hand is considered to be very statistically significant and the dominant is weaker (P value <0.017); in subjects without involvement of the hands with strength normal, dominant hand is stronger but there are not statistical difference (p=0.55) The evaluation of 16 different types of prehension tested by a set of objects of different shapes has documented the impairment mainly of palmar grip (44%), tip to tip (37%) and vice (30%), followed by thenar grip, spherical grip and three jaw in a few cases. Conclusions: The documentation for greater involvement of the dominant hand with a reduction of the ROM in particular of 2 and 5 finger associated to decreased grip strength focus on confirm the importance of the hand use in daily life as the cause of greater disease damage. It is essential to plan quickly in patients with early systemic sclerosis an educational program to make the best use of work strategies equally distributed between dominant and non dominant hand and replacement activities for digit handheld, end-to- terminal and vice grip.

2015 - Semeiotica dell'articolazione temporo-mandibolare [Capitolo/Saggio]
Sebastiani, Marco; Colaci, Michele; Ferri, Clodoveo
abstract

Ha senso, nel 3° millennio ormai inoltrato, proporre un manuale di semeiotica clinica reumatologica? Negli ultimi due decenni la medicina si è avvalsa sempre più della tecnologia e i vantaggi che le sue applicazioni offrono a pazienti, clinici e ricercatori sono tutti ben evidenti. La Reumatologia non è rimasta impermeabile a questo nuovo corso, vedendo crescere in modo esponenziale il ruolo assunto dalla diagnostica per immagini. Chi ha vissuto la Reumatologia ai suoi albori si è adoperato per conferire alla disciplina autonomia accademica e nosografica dotandola, tra le altre cose, di un solido impianto clinico-semeiologico a supportare la convinzione che la Reumatologia sia una disciplina eminentemente clinica. Di questo lascito siamo debitori nei confronti di chi ci ha preceduto. Le nuove metodiche di imaging come l'ecografia e la risonanza magnetica (per citare le più diffuse) hanno aperto nuovi orizzonti su scenari prima sconosciuti o solo parzialmente esplorati e costretto le nuove generazioni di clinici ad una seria e critica revisione del loro patrimonio culturale in ambito clinico-semeiologico. In questo nuovo scenario alcune nozioni e pratiche semeiologiche storicamente sedimentate nel corso degli anni sono, oggi, da ritenersi troppo imprecise, se non addirittura superflue o desuete.

2015 - Severe alopecia complicating systemic sclerosis [Articolo su rivista]
Giuggioli, Dilia; Colaci, Michele; Cassone, Giulia; Ferri, Clodoveo
abstract

Aims: To describe a case of systemic sclerosis (SSc) associated with severe alopecia areata (AA) responsive to topical and systemic treatments, including vasoactive and immunosuppressive drugs (mycophenolate mofetil). Presentation of the Case: A 56 year old woman, affected by SSc as from 5 years back, developed a rapid hair loss that progressively involved a large area of the scalp. AA was diagnosed, after the exclusion of an overlapping systemic lupus erythematosus or fungal infection. Treatment with topical steroids and minoxidil, plus mycophenolate mofetil that was introduced for interstitial lung disease, led to progressive improvement of alopecia up to a complete resolution within 4 months. Discussion: This is an interesting observation of SSc complicated by severe AA, which is often observed in patients affected by various autoimmune disorders. A possible common pathogenesis of AA and SSc is also discussed.

2015 - Treatment with Rituximab in Systemic Sclerosis Patients: Our Experience in a Pilot Clinical Trial [Abstract in Rivista]
Giuggioli, Dilia; Lumetti, Federica; Colaci, Michele; Cassone, Giulia; Cestelli, V; Ferri, Clodoveo
abstract

Background Systemic sclerosis (SSc) is an immune-mediated disorder characterized by abnormal fibrosis and diffuse microangiopathy with skin and internal organ involvement due to both T- and B-lymphocyte activation. The present study aimed to assess the efficacy of long-term treatment with rituximab (RTX), a chimeric monoclonal antibody that targets B-cell CD20. The rationale for the use of RTX in SSc is based on experimental data suggesting a key role for B cells in regulating the fibrotic process. Objectives The present study aimed to assess the efficacy of long-term treatment with rituximab (RTX) in systemic sclerosis patients. Methods Eleven SSc patients (M/F 3/8, mean age 43.2±10.5SD years, mean disease duration 3.6±6.2SD years) underwent to RTX cycle (weekly infusion of RTX 375 mg/m2 of body surface plus 100 mg methylprednisolone for 4 weeks); in 10/11 RTX was repeated every 6 months for a total of 2-6 cycles. Patients' clinical-serological evaluation, including HAQ assessment and visual analogical scale (VAS), was performed every six months. Results At the end of the follow-up period (3.7±2.8 SD years) an improvement of the skin sclerosis involvement was constantly observed; in particular, patients with diffuse SSc cutaneous variant showed a significant decrease of modified Rodnan skin score (from 25±4.1 to 17.2±4.1; p<0.004). Similarly, the articular involvement, melanodermia, and calcinosis ameliorated if compared to baseline; these positive clinical variations were mirrored by a subjective recovery of patients' well being in all cases (HAQ, VAS). No significant variations were observed with regards to other SSc clinical manifestations; in particular, lung involvement remained stable or showed a moderate progression at the last patients' evaluation. Finally, in no cases significant side effects were observed. Conclusions Our results indicate that treatment of SSc patients with RTX may be particularly effective for severe skin sclerosis, as suggested by other preliminary trials. The scarce efficacy of RTX on some disease manifestations may suggest the use of combined treatment, namely RTX with other antifibrotic/vasoactive drugs.

2015 - UNCLASSIFIABLE INTERSTITIAL LUNG DISEASE OR UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE? A CHALLENGING DIFFERENTIAL DIAGNOSIS [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Cerri, Stefania; DELLA CASA, Giovanni; Giuggioli, D.; Vacchi, Caterina; Colaci, Michele; Spinella, Amelia; Luppi, Fabrizio; Ferri, Clodoveo
abstract

Background: Interstitial lung disease (ILD) includes a group of disorders of the pulmonary parenchyma including ILD secondary to environmental exposure, to sarcoidosis and connective tissue diseases, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonitis. Unclassifiable-ILD (U-ILD) is defined when ILD cannot be included in one of these subtypes, because of inadequate findings or impossibility to complete diagnostic iter. Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune diseases characterized by clinical and serological features typical of other CTD, but not fulfilling any of the existing classification criteria. It has been recently suggested that UCTD should be responsible for ILD, although the available classification criteria do not consider lung manifestations. Differential diagnosis between U-ILD or ILD secondary to UCTD (UCTD-ILD) can be difficult, but fundamental for therapeutic implications. Objectives: To evaluate the clinical and serological features of patients with ILD secondary to UCTD compared to unclassifiable ILD, to improve differential diagnosis and identify patients candidate to immuno-suppressive therapy. Secondary outcome was to construct a clinical algorithm, using a priori variables, helpful to predict ILD-UCTD in clinical practice. Methods: From September 2011 to November 2014, 50 patients referred to our Center were diagnosed for UCTD (26/50) or U-ILD (24/50), after a multidisciplinary discussion according to standard available criteria. Results: Main features and comparison between UCTD-ILD and U-ILD are reported in the table. An inconsistent with usual interstitial pneumonia (UIP) pattern at high resolution computerized tomography (HRCT) was more frequently detected in UCTD-ILD compared to U-ILD. A predictive model based on Raynaud's phenomenon, ocular dryness, and antinuclear antibodies showed a predictive value of 85.7% (UCTD-ILD were correctly classified in 90.5% and U-ILD in 78.6%). Clinical and demographic features of patients with interstitial lung disease UCTD U-ILD p Number of patients 26 24 Sex 19F/7M 14F/10M ns Age at diagnosis 61.7±12.7 67.1±9.1 ns Raynaud's phenomenon 68.0% 29.4% 0.027 Oral dryness 60.0% 35.3% ns Ocular dryness 60.0% 13.3% 0.007 Schirmer test 41.6% 4.2% 0.006 Arthritis 19.2% 0 0.05 Skin manifestations 30.4% 0 0.029 Thrombocytopenia 16.7% 18.2% ns Anemia 33.3% 18.2% ns Antinuclear antibodies 87% 52.4% 0.02 ENA 38.1% 10% ns Rheumatoid factor 13.6% 9.1% ns UIP pattern to HRCT 41.2% 58.8% ns Inconsitent with UIP pattern to HRCT 66.7% 33.3% ns Conclusions: Lung involvement is a possible presenting symptom of UCTD; therefore, differential diagnosis with U-ILD is crucial due to the relevant therapeutic implications; a multidisciplinary approach, including rheumatologist, pulmonologist, radiologist, and pathologist, is mandatory. Some clinical-serological features potentially helpful in differential diagnosis should be carefully evaluated

2015 - Validation study of predictive value of capillaroscopic skin ulcer risk index (CSURI) in scleroderma patients treated with bosentan [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Cestelli, Valentina; Praino, Emanuela; Cannarile, Francesca; Giuggioli, Dilia; Colaci, Michele; Ferri, Clodoveo
abstract

In this validation study, the predictive value of capillaroscopic skin ulcer risk index (CSURI) in scleroderma patients treated with bosentan has been investigated. Seventy-six consecutive SSc patients treated with bosentan 125 mg bid were enrolled in a multicentre study. The area under the curve was 0.69 (95%CI 0.57-0.79, p=0.0019) and, at the validated cut-off value of 2.96, sensitivity was 86.1%, specificity 60.0%, positive and negative likehood ratio 2.15 and 0.23, while negative and positive predictive values were 82.1% and 64.6%, respectively. CSURI showed a lower negative predictive value in the bosentan group when compared with the control group, while the positive predictive value was similar.

2015 - Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection [Articolo su rivista]
Zignego, Anna Linda; Gragnani, Laura; Piluso, Alessia; Sebastiani, Marco; Giuggioli, Dilia; Fallahi, Poupak; Antonelli, Alessandro; Ferri, Clodoveo
abstract

HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.

2014 - A Multicenter, Prospective Cohort Study Using Nailfold Videocapillaroscopy and Other Clinical Characteristics to Determine the Risk of Developing New Digital Ulcers in Patients with Systemic Sclerosis [Abstract in Rivista]
Vanessa, Smith; Maurizio, Cutolo; Ariane, Herrick; Oliver, Distler; Mike, Becker; Emma, Beltran; Patrick, Carpentier; Ferri, Clodoveo; Murat, Inanc; Panayiotis, Vlachoyiannopoulos; Harbajan Chadha, Boreham; Emmanuelle, Cottreel; Thomas, Pfister; Daniel, Rosenberg; Juan, Torres
abstract

The study investigated the role of videocapillaroscopy to determine the risk of digital ulcers in scleroderma patients

2014 - [A review on thyroid autoimmune disorders and HCV chronic infection] [Articolo su rivista]
Di Domenicantonio, A; Politti, U; Marchi, S; De Bortoli, N; Giuggioli, D; Antonelli, A; Ferri, Clodoveo
abstract

Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographical signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender, vs healthy controls, or hepatitis B virus infected patients. In patients with "HCV-associated mixed cryoglobulinemia" (MC+HCV), a higher prevalence of autoimmune thyroid disorders was shown not only compared to controls, but also compared to HCV patients without cryoglobulinemia. Patients with MC+HCV or with HCV chronic infection, show an higher prevalence of papillary thyroid cancer than in controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC+HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine than patients without thyroiditis. Probably, HCV thyroid infection acts by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes, that secrete interferon-gamma and tumor necrosis factor-alpha. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, that may lead into the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function and nodules are recommanded in HCV patients.

2014 - ADULT ONSET STILL'S DISEASE: A MULTICENTER RETROSPECTIVE COHORT STUDY OF 233 ITALIAN PATIENTS [Abstract in Rivista]
P., Sfriso; R., Priori; S., Colafrancesco; G., Valesini; S., Rossi; C., Montecucco; A., D'Ascanio; L., Carli; S., Bombardieri; G., La Selva; F., Iannone; G., Lapadula; S., Alivernini; G., Ferraccioli; F., Caso; Colaci, Michele; Ferri, Clodoveo; D., Iacono; G., La Montagna; L., Costa; R., Scarpa; A. Lo Monacov V., Bagnari; M., Govoni; I. Piazzav S., Adami; C. Schinoccav F., Ciccia; G., Triolo; E., Alessandri; M., Cutolo; L., Cantarini; M., Galeazzi; L., Punzi
abstract

Description of a cohort of Italian patients affected by adult onset Still's disease

2014 - ALLOGENIC SKIN GRAFTING FOR SYSTEMIC SCLEROSIS ULCERS: PRELIMINARY DATA OF AN ITALIAN COHORT [Abstract in Rivista]
Ferri, Clodoveo
abstract

not available

2014 - Autoimmune and neoplastic thyroid diseases associated with hepatitis C chronic infection [Articolo su rivista]
Fallahi, Poupak; Ferrari, Silvia Martina; Politti, Ugo; Giuggioli, Dilia; Ferri, Clodoveo; Antonelli, Alessandro
abstract

Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographic signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender versus healthy controls, or hepatitis B virus infected patients. In patients with "HCV-associated mixed cryoglobulinemia" (MC + HCV), a higher prevalence of thyroid autoimmune disorders was shown not only compared to controls, but also versus HCV patients without cryoglobulinemia. Patients with MC + HCV or HCV chronic infection show a higher prevalence of papillary thyroid cancer than controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC + HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine, but normal levels of Th2 (C-C motif) ligand 2 chemokine, than patients without thyroiditis. HCV thyroid infection could act by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes that secrete interferon-γ and tumor necrosis factor-α. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, which may lead to the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function, particularly where nodules occur, is recommended in HCV patients.

2014 - Breast cancer in systemic sclerosis: Results of a cross-linkage of an Italian Rheumatologic Center and a population-based Cancer Registry and review of the literature. [Articolo su rivista]
Colaci, Michele; Giuggioli, D; Vacchi, Caterina; Lumetti, Federica; Iachetta, Francesco; Marcheselli, L; Federico, Massimo; Ferri, Clodoveo
abstract

OBJECTIVE: Increased frequency of few types of cancer in systemic sclerosis (SSc) has been reported in the literature; in particular, breast carcinoma has been proposed as one of the most frequent malignancy in SSc patients, even though data are not univocal. The aim of the present study was to retrospectively evaluate the prevalence of breast cancer in our SSc series, compared with sex-/age-matched general population of the same geographical area, and the possible correlations with SSc features, including X-ray exposure for clinical investigations. A review of the world literature about this topic was also done. METHODS: Clinical records of 318 consecutive SSc patients, 31 M and 287 F, age 51.5±14.5 SD years, disease duration 10±6.5 SD years, referred to our Rheumatology Unit between January 2002 and December 2012 were evaluated. RESULTS: Twelve (3.8%) cases of breast cancer were recorded, including 11/287 females (3.8%) and 1/31 (3.2%) male patients. Considering the subgroup of 202 SSc patients resident in the Province of Modena compared with data of the local Tumor Registry, the incidence of breast cancer observed in our SSc series is significantly higher than expected (SIR 2.1; 95% interval of confidence: 1.13-3.90; p<0.01). On the whole, the comparison between SSc patients with cancer and those without did not show any significant differences with regard to SSc clinical features, including the X-ray exposure. Of note is the relatively shorter disease duration at the time of breast cancer detection (median 2.5years, range 1-21; disease duration of mean 10±6.5 SD years in the entire cohort). The review of the literature revealed that the observed incidence of breast cancer in our case series is comparable to the few studies reporting the highest percentages of this malignancy. CONCLUSIONS: A significant increase of breast cancer incidence compared to sex-age-matched general population from the same geographic area was observed. Moreover, a close temporal relationship between SSc and breast cancer onset was found, independently from clinical, serological, and instrumental features of SSc. The possible pathogenetic link between this systemic autoimmune disease and complicating breast cancer, as well as the results of previous studies, are discussed.

2014 - Chapter 52 - Cryoglobulins and Cryoglobulins Secondary to Hepatitis C Virus Infection [Capitolo/Saggio]
Ferri, Clodoveo; Sebastiani, Marco; Giuggioli, Dilia; Poupack, Fallahi; Alessandro, Antonelli
abstract

The term cryoglobulinemia refers to the presence in the serum of one (monoclonal cryoimmunoglobulinemia) or more immunoglobulins (mixed cryoglobulinemia, MC), which precipitate at temperatures below 37 °C and redissolve on rewarming; this is an in vitro phenomenon that can be associated to a large number of benign or malignant disorders. In addition, type II mixed cryoglobulins are often composed by oligoclonal IgM or a mixture of polyclonal and monoclonal IgM. This type II–III MC could represent an intermediate, evolutive state from type III to type II MC; it may be in keeping with the most recent molecular studies showing the presence of oligoclonal B-lymphocyte proliferation in liver and bone marrow biopsies from patients with MC. Commonly, serum cryoglobulins represent an isolated laboratory finding without any clinical consequence; type I cryoglobulinemia is frequently associated with well-known hematologic disorders, as well as mixed cryoglobulins (type II and III) are detectable in a great number of infectious or systemic disorders. On the contrary, the so-called ‘essential’ MC represents a distinct disorder, classified among systemic vasculitides; this vasculitis is secondary to vascular deposition of circulating IC, mainly cryoglobulins and complement. It is included in the subgroup of systemic vasculitides involving small and medium arteries, capillaries, and veins; they are characterized by leukocytoclastic vasculitis of the skin. The terms MC syndrome and ‘cryoglobulinemic vasculitis’ are often used as synonyms. MC syndrome is considered to be a rare disorder; numerous cohort studies of series of patients from different countries suggest its geographically heterogeneous distribution; the disease is more common in southern Europe than in northern Europe or Northern America. Considering the clinical polymorphism of MC (skin vasculitis, hepatitis, nephritis, peripheral neuropathy, etc.), the patients with MC are often referred to different specialties according to the prevalent clinical feature(s); consequently, a correct diagnosis might be delayed or overlooked entirely and the actual prevalence of the disease might be underestimated.

2014 - Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. [Articolo su rivista]
Antonelli, A; Ferrari, Silvia Martina; Giuggioli, D; Ferrannini, E; Ferri, Clodoveo; Fallahi, P.
abstract

(C-X-C motif) ligand (CXCL)10 (CXCL10) belongs to the ELR(-) CXC subfamily chemokine. CXCL10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3), a seven trans-membrane receptor coupled to G proteins. CXCL10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, autoimmune thyroiditis, Graves' disease and ophthalmopathy), or systemic (such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, mixed cryoglobulinemia, Sjögren syndrome, or systemic sclerosis). The secretion of CXCL10 by cluster of differentiation (CD)4+, CD8+, natural killer (NK) and NK-T cells is dependent on interferon (IFN)-γ, which is itself mediated by the interleukin-12 cytokine family. Under the influence of IFN-γ, CXCL10 is secreted by several cell types including endothelial cells, fibroblasts, keratinocytes, thyrocytes, preadipocytes, etc. Determination of high level of CXCL10 in peripheral fluids is therefore a marker of host immune response, especially T helper (Th)1 orientated T-cells. In tissues, recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor-α production, which in turn stimulates CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of autoimmune diseases and to evaluate whether CXCL10 is a novel therapeutic target in various autoimmune diseases.

2014 - Correlation of articular involvement, skin disfigurement, and unemployment with depressive symptoms in patients with systemic sclerosis: a hospital sample [Articolo su rivista]
Tedeschini, Enrico; Pingani, Luca; Simoni, Elena; Ferrari, D; Giubbarelli, C; Giuggioli, D; Lumetti, F; Rigatelli, Marco; Ferri, Clodoveo; Ferrari, Silvia
abstract

Background: Systemic sclerosis (SSc) is a connective tissue disease associated with increased functional impairment, body image distress due to skin lesions, and psychosocial comorbidity, particularly depression. Prevalence of depressive symptoms in SSc patients ranges from 36% to 65% and it contributes to the worsening of any aspect of the disease. The aim of this study was to investigate the prevalence and clinical and non-clinical correlates of depressive symptoms in a sample of outpatients with SSc. Methods: Seventy-eight consecutive SSc outpatients were recruited from February 2005 to July 2007. Sociodemographic and SSc-related clinical data were collected, including a modified Rodnan Skin Score, the Valentini Disease Activity Index and psycho-metric assessment of disability and pain. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Two questions on perception of support from relatives and impact of disfigurements were also directly addressed to subjects. Results: The BDI mean score was 10.5 ( 8.3), with 36 subjects (46.2%) scoring above clinical significance. Unemployment, increased disability, pain, disease activity and articular involvement were significantly associated with more depressive symptoms. Older age, unemployment and more depressive symptoms were also related with complaints of disfigurements due to skin involvement. Conclusions: Depression is an influential prognostic factor in SSc. The present study contributes to the knowledge of the relationship between depression and clinical features routinely collected in rheumatology settings in order to develop a standardized assessment of psychosocial distress in routine rheumatologic procedures.

2014 - [Cryoglobulinemia and the α-chemokine IP-10] [Articolo su rivista]
Corrado, A; Mazzi, V; Ferrari, Silvia Martina; Politti, U; Giuggioli, D; Antonelli, A; Fallahi, P; Ferri, Clodoveo
abstract

IFN-γ-induced protein 10 (IP-10) and its receptor, CXCR3 chemokine (C-X-C motif) receptor 3 (CXCR3), appear to contribute to the pathogenesis of HCV related mixed cryoglobulinemia (HCV+MC). The secretion of IP-10 by CD4+, CD8+ and natural killer (NK)-T cells is dependent on interferon (IFN)-γ, which is itself mediated by the interleukin (IL)-12 cytokine family. Under the influence of IFN-γ, IP-10 is secreted by several cell types including lymphocytes, hepatocytes, endothelial cells, fibroblasts, etc. In tissues, recruited T helper (Th) 1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor (TNF)-α production, which in turn stimulates IP-10 secretion from the cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process. High levels circulation of IP-10 have been found in HCV+MC, especially in patients with clinically active vasculitis. Furthermore, HCV+MC patients with autoimmune thyroiditis (AT), have higher levels than those without AT. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis, and to evaluate whether IP-10 is a novel therapeutic target in HCV+MC.

2014 - [CXCR3 and CXCL10 in autoimmune thyroiditis] [Articolo su rivista]
Ruffilli, I; Ferrari, Silvia Martina; Colaci, Michele; Ferri, Clodoveo; Politti, U; Antonelli, A; Fallahi, P.
abstract

The chemokine (C-X-C motif) ligand 10 (CXCL10, also called IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. CXCL10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). CXCL10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves' disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of CXCL10 by CD4+, CD8+, and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, CXCL10 is secreted by thyrocytes. Determination of high level of CXCL10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating CXCL10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, CXCL10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, that is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons it has been postulated that CXCL10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether CXCL10 is a novel therapeutic target in AT.

2014 - DIGITAL NECROSIS IN SYSTEMIC SCLEROSIS NOT ONLY A MICROVASCULAR DISEASE: A CASE REPORT [Abstract in Rivista]
Spinella, Amelia; Giuggioli, Dilia; Manfredi, Andreina Teresa; Lumetti, Federica; Campomori, Federica; Ferri, Clodoveo
abstract

not available

2014 - Efficacy and safety of rituximab with and without methotrexate in the treatment of rheumatoid arthritis patients: results from the GISEA register [Articolo su rivista]
Sebastiani, Marco; Anelli, Maria Grazia; Atzeni, Fabiola; Bazzani, Chiara; Farina, Ilaria; Fedele, Anna Laura; Favalli, Ennio Giulio; Fineschi, Irene; Cino, Nicolò; Dal Forno, Ilaria; Gasparini, Stefania; Cassarà, Emanuele; Giardina, Rita; Bruschi, Eleonora; Addimanda, Olga; Cassone, Giulia; Lopriore, Simona; Sarzi Puttini, Piercarlo; Filippini, Matteo; Pignatti, Federica; Gremese, Elisa; Biggioggero, Martina; Manganelli, Stefania; Amato, Giorgio; Caimmi, Cristian; Salaffi, Fausto; Iannone, Florenzo; Ferri, Clodoveo; Sandri, Gilda; Lapadula, Giovanni; Gorla, Roberto; Govoni, Marcello; Ferraccioli, Gianfranco; Marchesoni, Antonio; Galeazzi, Mauro; Foti, Rosario; Carletto, Antonio; Cantini, Fabrizio; Triolo, Giovanni; Epis, Oscar Massimiliano; Salvarani, Carlo
abstract

Introduction Rituximab (RTX) is a monoclonal anti-CD20 antibody approved for the treatment of rheumatoid arthritis (RA) in association with methotrexate (MTX). Objectives To evaluate the efficacy and safety of RTX–MTX combination therapy compared with RTX alone in the treatment of RA. Methods We analyzed data from a prospective cohort study, the Italian biologic register GISEA, to investigate the efficacy and safety of rituximab. Moreover, the adverse events (AE) and the causes of discontinuation therapy were analyzed. Results We identified 338 RA patients, 162 treated with RTX and 176 with RTX–MTX. After 52 and 104 weeks of therapy the disease activity score in 28 joints and the Health Assessment Questionnaire Score were available in 168 patients (78 with RTX–MTX and 60 with RTX alone), showing significant reduction without differences among the two groups. AE were reported in 142 patients (42%), for a total of 368 recorded side effects. The majority (90.5%) of AE were mild to moderate in severity. Comparable percentages of severe AE were reported in the 2 groups (9.9% for RTX alone and 9.3% for RTX + MTX). A poor disease control was observed in 14.2% and 13.5% of patients treated with RTX + MTX and RTX, respectively; while 12 patients (4.5% in RTX + MTX, and 2.5% in RTX group) suspended therapy for AE. Conclusions RTX showed a good efficacy and safety profile in the real-life management of RA patients regardless of the association with MTX.

2014 - HAND DISABILITY IN PATIENTS WITH SYSTEMIC SCLEROSIS: THE ROLE OF AN INDIVIDUALIZED REHABILITATION PROGRAM [Abstract in Rivista]
Ferri, Clodoveo
abstract

not available

2014 - Hepatitis C virus infection and type 1 and type 2 diabetes mellitus [Articolo su rivista]
Antonelli, Alessandro; Ferrari, Silvia Martina; Giuggioli, Dilia; Di Domenicantonio, Andrea; Ruffilli, Ilaria; Corrado, Alda; Fabiani, Silvia; Marchi, Santino; Ferri, Clodoveo; Ferrannini, Ele; Fallahi, Poupak
abstract

Hepatitis C virus (HCV) infection and diabetes mellitus are two major public health problems that cause devastating health and financial burdens worldwide. Diabetes can be classified into two major types: type 1 diabetes mellitus (T1DM) and T2DM. T2DM is a common endocrine disorder that encompasses multifactorial mechanisms, and T1DM is an immunologically mediated disease. Many epidemiological studies have shown an association between T2DM and chronic hepatitis C (CHC) infection. The processes through which CHC is associated with T2DM seem to involve direct viral effects, insulin resistance, proinflammatory cytokines, chemokines, and other immune-mediated mechanisms. Few data have been reported on the association of CHC and T1DM and reports on the potential association between T1DM and acute HCV infection are even rarer. A small number of studies indicate that interferon-α therapy can stimulate pancreatic autoimmunity and in certain cases lead to the development of T1DM. Diabetes and CHC have important interactions. Diabetic CHC patients have an increased risk of developing cirrhosis and hepatocellular carcinoma compared with non-diabetic CHC subjects. However, clinical trials on HCV-positive patients have reported improvements in glucose metabolism after antiviral treatment. Further studies are needed to improve prevention policies and to foster adequate and cost-effective programmes for the surveillance and treatment of diabetic CHC patients.

2014 - HRCT Patterns Of Usual Interstitial Pneumonia In Rheumatoid Lung [Abstract in Rivista]
Tonelli, Roberto; Sverzellati, Nicola; DELLA CASA, Giovanni; Spagnolo, Paolo; Cerri, Stefania; Manfredi, Andreina Teresa; Sebastiani, Marco; Cocconcelli, Elisabetta; DEL GIOVANE, Cinzia; Balduzzi, Sara; Richeldi, Luca; Torricelli, Pietro; Ferri, Clodoveo; Luppi, Fabrizio
abstract

RATIONALE. Interstitial lung disease (ILD) is a well-recognized complication of rheumatoid arthritis (RA) and can present with different patterns on high-resolution computed tomography (HRCT) of the chest. It has been recently shown that a definite HRCT usual interstitial pneumonia (UIP) pattern is highly specific and moderately sensitive for a histopathologic UIP pattern. The aims of the present study were: i) to evaluate the prevalence of the UIP pattern on HRCT in patients with RA-ILD, as compared with patients with idiopathic pulmonary fibrosis (IPF) and ii) to assess the level of agreement between two experienced chest radiologists in detecting the UIP pattern in the two groups of patients. METHODS. 30 patients with RA and at least one chest HRCT showing interstitial changes were retrospectively identified from a single-center cohort of RA patients. Fifty-two patients with IPF based on current diagnostic criteria served as diseased controls. For patients who had more than one HRCT the more recent HRCT was selected. Two experienced thoracic radiologists (radiologist A and B) blinded to patient diagnosis scored all HRCT images independently. Radiologic patterns were categorized as definite UIP, possible UIP or inconsistent with UIP according to the most current international guidelines. The prevalence of the different patterns was assessed for both groups and compared by using the chi square test. The concordance between radiologists was determined using the Cohen kappa score. RESULTS. Radiologist A detected 4 definite UIP (13%), 10 possible UIP (33%) and 16 inconsistent with UIP patterns (53%) among patients with RA-ILD and 16 definite UIP (30%), 24 possible UIP (46%) and 12 inconsistent with UIP patterns (23%) among patients with IPF (chi square 0.016). Radiologist B identified 6 definite UIP (20%), 9 possible UIP (30%) and 15 inconsistent with UIP patterns (50%) in the RA-ILD group and 23 definite UIP (44%), 16 possible UIP (30%) and 13 inconsistent with UIP patterns (25%) in the IPF group (chi square 0.036). Diagnostic agreement in UIP pattern detection was 71.2% (κ= 0.57) for the IPF group and 76.7% (κ =0.62) for the RA-ILD group. CONCLUSIONS. A definite UIP pattern can be identified in chest HRCT of a sizeable fraction of patients with RA-ILD. Moreover, the possible UIP pattern appears to be almost equally distributed in patients with RA-ILD and IPF. Of note, the level of agreement between two experienced chest radiologists in detecting the UIP pattern is higher in patients with RA-ILD than in IPF.

2014 - IP-10 in autoimmune thyroiditis [Articolo su rivista]
Ruffilli, I; Ferrari, Silvia Martina; Colaci, Michele; Ferri, Clodoveo; Fallahi, P; Antonelli, A.
abstract

The interferon-γ-inducible protein 10 (IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. IP-10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). IP-10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves' disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of IP-10 by (CD)4+, CD8+, and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, IP-10 is secreted by thyrocytes. Determination of high level of IP-10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating IP-10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, IP-10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, which is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons, it has been postulated that IP-10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in AT.

2014 - Large Vessel Vasculitis Occurring in Rheumatoid Arthritis Patient under Anti-TNF Therapy [Articolo su rivista]
Cestelli, Valentina; Spinella, Amelia; Campomori, Federica; Esposito, Carmela; Ciaffi, Sara; Sandri, Gilda; Ferri, Clodoveo
abstract

Vasculitis is a heterogeneous group of disorders characterized by the presence of necrotic inflammatory phenomena and destruction of blood vessels. Vasculitis is classified as primary (idiopathic) or secondary to infections, connective tissue diseases and drugs but can also be considered as a paraneoplastic phenomenon. Evidence shows that the increasing use of biological agents results in a growing number of reports of autoimmune diseases induced by these therapies. An inflammatory articular chronic disease such as rheumatoid arthritis may be complicated by extra-articular manifestations, such as cutaneous or systemic vasculitis. Herewith, we describe the case of a great vessels arteritis in a patient affected by rheumatoid arthritis in therapy with an anti-TNF agent (etanercept).

2014 - LONG-TERM CLINICAL EFFECTIVENESS OF ADALIMUMAB, ETANERCEPT, AND INFLIXIMAB IN RHEUMATOID ARTHRITIS (RA): AN OBSERVATIONAL STUDY FROM ITALIAN REGISTER, GISEA [Abstract in Rivista]
Ferri, Clodoveo
abstract

not available

2014 - Lung involvement in systemic sclerosis: role of high resolution computed tomography and its relationship with other pulmonary and clinico-serological features. [Articolo su rivista]
Colaci, Michele; Sebastiani, Marco; Manfredi, Andreina Teresa; Giuggioli, D; Cassone, Giulia; Manzini, Cu; Ghizzoni, C; Cerri, Stefania; Ferri, Clodoveo
abstract

The study investigated the characteristic of interstitial lung disease in a large series of systemic sclerosis (SSc) patients by means of HRCT and the correlations between functional lung parameters, serological features and the extent of lung involvement evaluated by high-resolution computed tomography (HRCT). One hundred and seven SSc patients, consecutively investigated by means of HRCT, standard chest X-ray, and pulmonary function tests, were retrospectively evaluated. Chest radiogram and HRCT scores were strongly associated (Pearson 's r=0.82, p < .0001); moreover, the first significantly correlated with spirometric parameters, even if weakly. Anti-Scl70 and anti-centromere antibodies were associated with higher (p=0.01) and lower HRCT score (p=0.0002), respectively. The extension of interstitial lung involvement in SSc evaluated with HRCT is directly proportional to functional lung parameters. HRCT, spirometry and DLco should be considered essential in the core-set of non-invasive diagnostic tools for the first-line assessment of scleroderma lung involvement.

2014 - Measuring microangiopathy abnormalities in systemic sclerosis patients: the role of capillaroscopy-based scoring models [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Cassone, Giulia; Giuggioli, Dilia; Ghizzoni, Cecilia; Ferri, Clodoveo
abstract

Capillaroscopy is a noninvasive imaging technique for the in vivo study of microcirculation. The role of a qualitative evaluation of capillaroscopy in the assessment of Raynaud's phenomenon secondary to scleroderma spectrum disorder, particularly systemic sclerosis (SSc), is well defined. The usefulness of capillaroscopy in the follow-up of SSc patients and the possible prognostic role for the appearance of typical SSc vascular and visceral involvement, namely, digital ulcers, pulmonary arterial hypertension, and mortality, is suggested by many authors but still under debate. In this regard, and for a reliable and repeatable longitudinal evaluation of SSc microangiopathy, a quantitative analysis should be required. In this review, we describe the current classifications proposed to define the SSc microvascular involvement and the scoring methods suggested for a semiquantitative and quantitative analysis of microangiopathy and its correlation with clinical manifestations of disease.

2014 - Modulatory effects of peroxisome proliferator-activated receptor-γ on CXCR3 chemokines [Articolo su rivista]
Ferrari, Silvia Martina; Antonelli, Alessandro; Di Domenicantonio, Andrea; Manfredi, Andreina Teresa; Ferri, Clodoveo; Fallahi, Poupak
abstract

An increasing body of evidence shows the importance of the chemokine (C-X-C motif) receptor (CXCR)3 and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10 and CXCL11 in the T helper 1 immune response, and in inflammatory diseases such as bowel inflammatory disorders, allograft rejection, thyroid autoimmune disorders, vascular and renal inflammation, and others. Peroxisome proliferator-activated receptor (PPAR)-γ agonists show a strong inhibitory effect on the expression and production of CXCR3 chemokines in vitro, in various kinds of cells, such as denditric cells, monocytes, macrophages, endothelial and vascular smooth muscle cells, intestinal cells, thyrocytes, fibroblasts, preadypocytes and mesangial cells, and in vivo in animal models. As rosiglitazone has recently been linked to a higher risk of heart failure, stroke, and all-cause mortality in old patients, it has been interrupted from the European market. On the contrary, the safety profile of pioglitazone seems favorable. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of the above mentioned inflammatory disorders, and many interesting patents have been recently applied.

2014 - NAILFOLD CAPILLAROSCOPIC ALTERATIONS IN DERMATOMYOSITIS AND POLYMYOSITIS [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Cassone, Giulia; Pipitone, N; Giuggioli, Dilia; Colaci, Michele; Salvarani, Carlo; Ferri, Clodoveo
abstract

NAILFOLD CAPILLAROSCOPIC ALTERATIONS IN DERMATOMYOSITIS AND POLYMYOSITIS

2014 - NAILFOLD VIDEOCAPILLAROSCOPY AND OTHER PREDICTIVE FACTORS ASSOCIATED WITH NEW DIGITAL ULCERS IN SYSTEMIC SCLEROSIS: RESULTS FROM THE CAP STUDY [Abstract in Rivista]
Ferri, Clodoveo
abstract

not available

2014 - Neurologic Complications Associated with Sjögren's Disease: Case Reports and Modern Pathogenic Dilemma [Articolo su rivista]
Colaci, Michele; Cassone, Giulia; Manfredi, Andreina Teresa; Sebastiani, Marco; Giuggioli, Dilia; Ferri, Clodoveo
abstract

Objectives. Sjögren's syndrome (SS) may be complicated by some neurological manifestations, generally sensory polyneuropathy. Furthermore, involvement of cranial nerves was described as rare complications of SS. Methods. We reported 2 cases: the first one was a 40-year-old woman who developed neuritis of the left optic nerve as presenting symptom few years before the diagnosis of SS; the second was a 54-year-old woman who presented a paralysis of the right phrenic nerve 7 years after the SS onset. An exhaustive review of the literature on patients with cranial or phrenic nerve involvements was also carried out. Results. To the best of our knowledge, our second case represents the first observation of SS-associated phrenic nerve mononeuritis, while optic neuritis represents the most frequent cranial nerve involvement detectable in this connective tissue disease. Trigeminal neuropathy is also frequently reported, whereas neuritis involving the other cranial nerves is quite rare. Conclusions. Cranial nerve injury is a harmful complication of SS, even if less commonly recorded compared to peripheral neuropathy. Neurological manifestations may precede the clinical onset of SS; therefore, in patients with apparently isolated cranial nerve involvement, a correct diagnosis of the underlying SS is often delayed or overlooked entirely; in these instances, standard clinicoserological assessment is recommendable.

2014 - Radiological thymus alterations in systemic sclerosis: our experience and a review of the literature. [Articolo su rivista]
Colaci, Michele; Giuggioli, D; Manfredi, Andreina Teresa; Vacchi, Caterina; DELLA CASA, Giovanni; Ferri, Clodoveo
abstract

Objective. Thymus alterations have been related to several autoimmune disorders. In particular, previous studies identified a significant frequency of gland abnormalities by chest high-resolution CT (HRCT) in SSc patients. In this study we aimed to investigate the prevalence of radiological thymic alterations and their correlation with clinical and serological features in a large SSc series.Methods. We retrospectively evaluated thymic shape on CT scans of 200 consecutive, unselected SSc patients aged over 30 years The presence of radiological abnormalities, i.e. enlarged gland >13 mm or nodular lesions >7 mm, was correlated with SSc clinico-serological features. Moreover, the patients were also classified using a second thickness cut-off of 7 mm in order to identify incomplete thymic involution.Results. Twenty-four of 200 (12%) SSc patients presented an abnormal thymus at HRCT, including hyperplasic (19/24) and nodular (5/24) glands. Otherwise, using the cut-off of 7 mm for gland thickness and excluding subjects with nodular thymus, 50/195 (25.6%) patients presented an incomplete thymic involution. Thymic radiological alterations are significantly correlated with younger age and diffuse cutaneous SSc. Moreover, an abnormally enlarged thymus tended to be more common in patients with shorter disease duration.Conclusion. The present report on a large series of SSc patients further reinforces previous data present in the literature that includes other cohort studies and a number of anecdotal observations. Even though the actual role of thymus radiological abnormalities remains unclear, possible involvement of the gland in the early phase of immune-mediated SSc pathogenesis might be supposed.

2014 - RHEUMATOID ARTHRITIS RELATED INTERSTITIAL LUNG DISEASE. RADIOLOGICAL PATTERNS AND CORRELATIONS WITH CLINICAL, SEROLOGICAL AND DEMOGRAPHIC FEATURES OF DISEASE [Abstract in Rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Tonelli, Roberto; Spagnolo, Paolo; Campomori, Federica; Vacchi, Caterina; Cocconcelli, Elisabetta; Cerri, Stefania; Colaci, Michele; Luppi, Fabrizio; DELLA CASA, Giovanni; Sverzellati, N; Torricelli, Pietro; Richeldi, Luca; Ferri, Clodoveo
abstract

RHEUMATOID ARTHRITIS RELATED INTERSTITIAL LUNG DISEASE. RADIOLOGICAL PATTERNS AND CORRELATIONS WITH CLINICAL, SEROLOGICAL AND DEMOGRAPHIC FEATURES OF DISEASE

2014 - SEVERE VITAMIN D DEFICIENCY IN SYSTEMIC SCLEROSIS [Abstract in Rivista]
Lumetti, Federica; Giuggioli, Dilia; Spinella, Amelia; Campomori, Federica; Manfredi, Andreina Teresa; Ferri, Clodoveo
abstract

not available

2014 - Systemic sclerosis evolution of disease pathomorphosis and survival. Our experience on Italian patients' population and review of the literature [Articolo su rivista]
Ferri, Clodoveo; Sebastiani, Marco; Lo Monaco, Andrea; Iudici, Michele; Giuggioli, Dilia; Furini, Federica; Manfredi, Andreina Teresa; Cuomo, Giovanna; Spinella, Amelia; Colaci, Michele; Govoni, Marcello; Valentini, Gabriele
abstract

The clinical spectrum and prognosis of systemic sclerosis (SSc) seem to vary among patients' populations recruited during different time periods. In order to verify this possible evolution we investigated the clinico-serological and survival rate in a large Italian SSc series (821 patients; 746 females, 75 males; mean age 53.7±13.9SD years) recruited between 2000 and 2011. The observed findings were compared with previous studies of the world literature.Compared to older Italian SSc series, the present patients' population showed a significantly increased prevalence of limited cutaneous SSc (from 72 to 87.5%; p ≤.0001) and serum anti-centromere antibodies (from 39 to 47,4%; p ≤.001), with a significant reduction of lung (from 81 to 63.7%; p ≤.0001), heart (from 35 to 20.5%; p ≤.0001), and renal involvement (from 10 to 3.8%; p ≤.0001), and skin ulcers (from 54 to 16.5%; p ≤.0001). Cumulative 10th-year survival showed a clear-cut increase (80.7%) compared to our previous series (69.2%). These findings were mirrored by the results of survival studies published during the last five decades, grouped according to the time periods of patients'' recruitment at the referral centers. A clear progression of 10th-year survival rates was detectable, from the 54% median survival of the oldest studies (1935-1974) to 74% and 83.5% of the more recent SSc series, 1976-1999 and after 1999, respectively. In conclusion, the favorable evolution of SSc pathomorphosis and prognosis during the last decades might be related to more diffuse physician/patient awareness of this harmful disease and availability of diagnostic tools, the consequent wider recruitment of patients in the early stages of the disease, as well as to the improved therapeutic strategies.

2014 - Targeting chemokine (C-X-C motif) receptor 3 in thyroid autoimmunity [Articolo su rivista]
Fallahi, Poupak; Ferrari, Silvia Martina; Corrado, Alda; Giuggioli, Dilia; Ferri, Clodoveo; Antonelli, Alessandro
abstract

The C-X-C chemokine receptor (CXCR)3 and its chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune thyroiditis (AT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). Under the influence of interferon(IFN)γ, the IFNγ-induced protein 10 (IP-10/CXCL10) is secreted by thyrocytes, orbital fibroblasts and preadipocytes. In tissue, Th1 lymphocytes are recruited; hence IFNγ is enhanced, which stimulates CXCL10 secretion reiterating the autoimmune process. The presence of elevated levels of CXCL10 in peripheral liquids is considered a marker of Th1 orientated immune response. High levels of circulating CXCL10 (sCXCL10) have been shown in patients with AT, overall with hypothyroidism. In GD and GO patients high sCXCL10 have been shown particularly in the active disease. A modulatory role of peroxisome proliferator-activated receptor (PPAR)γ or - α agonists on CXCR3 chemokines in AT, GD and GO and the immuno-modulatory effect of methimazole on CXCR3 chemokines in GD have been shown. Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied.

2014 - [The alpha chemokine "Interferon gamma-induced protein 10" (IP-10) in Graves' disease] [Articolo su rivista]
Mancusi, C; Di Domenicantonio, A; Politti, U; Giuggioli, D; Antonelli, A; Ferri, Clodoveo; Fallahi, P.
abstract

The alpha chemokine Interferon gamma-induced protein 10 (IP-10) and its receptor, CXC receptor 3, appear to contribute to the pathogenesis of Graves' disease (GD) and Graves' ophthalmopathy (GO). Under the influence of Interferon-γ, IP-10 is secreted by thyrocytes (in GD), fibroblasts and preadipocytes (in GO). Determination of high level of IP-10 in peripheral liquids is therefore a marker of a Th1 orientated immune response. Circulating IP-10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. Methimazole reduces IP-10 secretion by isolated thyrocytes, decreases serum IP-10 levels, and promotes a transition from Th1 to Th2 dominance in patients in GD active phase. In GD patients the decrease of IP-10 after thyroidectomy and radioiodine strongly suggests that this chemokine is mainly produced by the thyroid itself. In GO patients the increased concentrations of IP-10, at least in part, reflect the activity of orbital inflammation. A significant reductions in IP-10 serum concentrations during corticosteroids and or radiotherapy treatments, as compared both to control group and to basal values in GO patients, suggest that this chemokine could serve as a guideline in therapeutic decision-making in patients with GO. Further studies are needed to evaluate whether IP-10 is a novel therapeutic target in GD and GO.

2014 - [The alpha chemokine "Interferon gamma-induced protein 10" (IP-10) in Graves' disease and Graves'ophthalmopathy] [Articolo su rivista]
Di Domenicantonio, A; Politti, U; Giuggioli, D; Antonelli, A; Ferri, Clodoveo; Fallahi, P.
abstract

Interferon(IFN)γ-induced protein 10 (IP-10) and its receptor, CXC receptor 3, appear to contribute to the pathogenesis of Graves' disease (GD) and Graves' ophthalmopathy (GO). Under the influence of IFN-γ, IP-10 is secreted by thyrocytes (in GD), fibroblasts and preadipocytes (in GO). Determination of high level of IP-10 in peripheral liquids is therefore a marker of a Th1 orientated immune response. Circulating IP-10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. Methimazole reduces IP-10 secretion by isolated thyrocytes, decreases serum IP-10 levels, and promotes a transition from Th1 to Th2 dominance in patients with GD active phase. In GD patients the decrease of IP-10 after thyroidectomy and radioiodine strongly suggests that this chemokine is mainly produced by the thyroid itself. In GO patients the increased concentrations of IP-10, at least in part, reflect the activity of orbital inflammation. A significant reductions in IP-10 serum concentrations during corticosteroids and or radiotherapy treatments, as compared both to control group and to basal values in GO patients, suggest that this chemokine could serve as a guideline in therapeutic decision-making in patients with GO. Further studies are needed to evaluate whether IP-10 is a novel therapeutic target in GD and GO.

2014 - Therapeutic options after treatment failure in rheumatoid arthritis or spondyloarthritides [Articolo su rivista]
Govoni, Marcello; Bortoluzzi, Alessandra; Lo Monaco, Andrea; Adami, Silvano; Addimanda, Olga; Caimmi, Cristian; De Vita, Salvatore; Ferri, Clodoveo; Manfredi, Andreina Teresa; Orsolini, Giovanni; Possemato, Niccolò; Quartuccio, Luca; Salvarani, Carlo; Zabotti, Alen; Rossini, Maurizio
abstract

The prognosis for patients with rheumatoid arthritis or spondyloarthritides has improved dramatically due to earlier diagnosis, recognition of the need to treat early with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), alone or in combinations, the establishment of treatment targets, and the development of biological DMARDs (bDMARDs). Many patients are now able to achieve clinical remission or low disease activity with therapy, and reduce or eliminate systemic corticosteroid use. Guidelines recommend methotrexate as a first-line agent for the initial treatment of rheumatoid arthritis; however, a majority of patients will require a change of csDMARD or step up to combination therapy with the addition of another csDMARD or a bDMARD. However, treatment failure is common and switching to a different therapy may be required. The large number of available treatment options, combined with a lack of comparative data, makes the choice of a new therapy complex and often not evidence based. We summarize and discuss evidence to inform treatment decisions in patients who require a change in therapy, including baseline factors that may predict response to therapy.

2014 - Thyroid involvement in hepatitis C - associated mixed cryoglobulinemia [Articolo su rivista]
Fallahi, Poupak; Ferrari, Silvia Martina; Giuggioli, Dilia; Manfredi, Andreina Teresa; Mancusi, Caterina; Fabiani, Silvia; Centanni, Marco; Marchi, Santino; Ferri, Clodoveo; Antonelli, Alessandro
abstract

The prevalence and clinical features of thyroid involvement in patients with hepatitis C virus-associated mixed cryoglobulinemia (MC+HCV) have been reviewed.

2014 - Type 1 diabetes and (C-X-C motif) ligand (CXCL) 10 chemokine [Articolo su rivista]
Corrado, A; Ferrari, Silvia Martina; Ferri, Clodoveo; Ferrannini, E; Antonelli, A; Fallahi, P.
abstract

The upregulation of (C-X-C motif) receptor 3 (CXCR3) and its ligand (C-X-C motif) ligand (CXCL)10 (CXCL10) has been documented in many autoimmune disorders. Many studies have suggested that the CXCL10/CXCR3 axis plays a critical role in the autoimmune process and in β-cell destruction in Type 1 Diabetes (T1D). Serum CXCL10 level "Th1 chemokine" is high in T1D patients, and this suggests that CXCL10 may be a candidate for a predictive marker of T1D. Furthermore, serum CXCL10 levels measurement may be useful to assess the pathophysiology of the disease course in T1D. Blocking of the CXCL10 chemokine expression in newly onset of diabetes seems to be a possible approach for the therapy of T1D. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of T1D.

2014 - Validation of the classification criteria for cryoglobulinaemic vasculitis [Articolo su rivista]
Quartuccio, Luca; Isola, Miriam; Corazza, Laura; Ramos Casals, Manuel; Retamozo, Soledad; Ragab, Gaafar Mohamed; Zoheir, Mostafa Naguib; El Menyawi, Manal Abdel Moneim; Salem, Mohamed Nabil; Sansonno, Domenico; Ferraccioli, Gianfranco; Gremese, Elisa; Tzioufas, Athanasios; Voulgarelis, Michael; Vassilopoulos, Dimitris; Scarpato, Salvatore; Pipitone, Nicolò; Salvarani, Carlo; Guillevin, Loic; Terrier, Benjamin; Cacoub, Patrice; Filippini, Davide; Saccardo, Francesco; Gabrielli, Armando; Fraticelli, Paolo; Sebastiani, Marco; Tomsic, Matija; Tavoni, Antonio; Mazzaro, Cesare; Pioltelli, Pietro; Nishimoto, Norihiro; Scaini, Patrizia; Zignego, Anna Linda; Ferri, Clodoveo; Monti, Giuseppe; Pietrogrande, Maurizio; Bombardieri, Stefano; Galli, Massimo; De Vita, Salvatore
abstract

Objective. The aim of this study was to validate the classification criteria for cryoglobulinaemic vasculitis (CV). Methods. Twenty-three centres were involved. New patients with CV (group A) and controls, i.e. subjects with serum cryoglobulins but lacking CV based on the gold standard of clinical judgment (group B) and subjects without cryoglobulins but with clinical features that can be observed in the course of CV (group C), were studied. Positivity of serum cryoglobulins was necessary for CV classification. Sensitivity and specificity of the criteria were calculated by comparing group A vs group B. The group A vs group C comparison was done to demonstrate the possible diagnostic utility of the criteria. Results. The study included 268 patients in group A, 182 controls in group B and 193 controls in group C (small vessel vasculitis, 51.8%). The questionnaire (at least 2/3 positive answers) showed 89.0% sensitivity and 93.4% specificity; the clinical item (at least 3/4 clinical involvement) showed 75.7% sensitivity and 89.0% specificity and the laboratory item (at least 2/3 laboratory data) showed 80.2% sensitivity and 62.4% specificity. The sensitivity and specificity of the classification criteria (at least 2/3 positive items) were 89.9% and 93.5%, respectively. The comparison of group A with group C demonstrated the clinical utility of the criteria in differentiating CV from CV mimickers. Conclusion. Classification criteria for CV were validated in a second, large, international study confirming good sensitivity and specificity in a complex systemic disease.

2014 - Viral infections and systemic sclerosis. [Articolo su rivista]
Ferri, Clodoveo; Giuggioli, D; Colaci, Michele
abstract

non presente in quanto trattasi di Lettera all'editore

2013 - Capillaroscopic Skin Ulcers Risk Index (CSURI) calculated with different videocapillaroscopy devices: how its predictive values change [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Lo Monaco, A.; Praino, E.; Riccieri, V.; Grattagliano, V.; Bortoluzzi, A.; Stefanantoni, K.; D'Amico, Roberto; Giuggioli, D.; Ferri, Clodoveo
abstract

INTRODUCTION: Digital ulcers (DU) occur in about 50% of systemic sclerosis (SSc) patients. Scleroderma DU are responsible for chronic pain and disability with the need of systemic and local treatments. Recently, capillaroscopic skin ulcer risk index (CSURI) has been validated as useful tool in predicting the appearance of new scleroderma ulcers and/or persistence of non-healing lesions, within 3 months from capillaroscopy evaluation. OBJECTIVES: Since the image length of 1.57 mm might represent a critical factor for CSURI calculation, the present study aimed to evaluate the reliability of CSURI using three different videocapillaroscopy devices with distinct image widths. METHODS: One hundred and seventy-six unselected SSc patients were consecutively enrolled for the study during a six-month period, using three different capillaroscopy devices (image widths of 1.33, 1.57, and 1.70 mm). RESULTS: After a three month-follow-up new DU or persisting non-healing ulcers were observed in 46/176 patients (26.1%). The receiver operating characteristic curve analysis for CSURI showed an area under curve respectively of 0.705 for the image width of 1.33 mm, 0.786 for the image of 1.70 mm, and 0.888 for the image width of 1.57 mm. CONCLUSIONS: The good sensitivity, specificity and positive predictive value of CSURI was confirmed in the whole patients` series, as well as in the three subgroups on different image widths obtained with various available devices. In addition, the negative predictive value of the capillaroscopic index remained very high regardless of the picture length adopted.

2013 - Carotidynia Possibly due to Localized Vasculitis in a Patient with Latent Mycobacterium tuberculosis Infection. [Articolo su rivista]
Cassone, Giulia; Colaci, Michele; Giuggioli, D; Manfredi, Andreina Teresa; Sebastiani, Marco; Ferri, Clodoveo
abstract

Carotidynia is a syndrome characterized by tenderness of the carotid artery near the bifurcation due to numerous, heterogeneous causes. Here we reported the case of a 31-year-old Moroccan woman with right-sided neck pain and tenderness with irradiation to ipsilateral ear, eye, and occipital region. Clinical symptoms and imaging findings were suggestive of primary variant of carotidynia syndrome. In particular, color-Doppler ultrasonography revealed a concentric wall thickening of the distal common carotid artery, while thoracic magnetic resonance showed localized perivascular enhancement of the soft tissue in the right medial-distal common carotid artery in T1-weighted images, without intraluminal diameter variation. Moreover, careful clinicoserological and imaging investigations (cranial, cervical, and thoracic angiocomputed tomography and magnetic resonance) excluded well-known disorders potentially responsible for carotidynia syndrome. The patient was scarcely responsive to nonsteroidal anti-inflammatory drugs, but clinical symptoms resolved after three months. Of interest, the patient showed latent Mycobacterium tuberculosis infection (positive tuberculosis interferon-gamma release assay; QuantiFERON-TB Gold); this finding suggested a possible triggering role of mycobacterial antigens in the immune-mediated mechanism responsible for localized carotid injury.

2013 - COMPLEMENT DEPLETION IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TOCILIZUMAB: A MARKER OF CLINICAL EFFICACY? [Abstract in Rivista]
Sandri, Gilda; Lumetti, Federica; Ferri, Clodoveo; Mascia, Maria Teresa
abstract

Objectives: Tocilizumab (TCZ) is a humanized monoclonal antibody against the α-chain of the IL6 receptor. In clinical trials TCZ had been shown to lower complement levels in Rheumatoid Arthritis (RA) patients independently of disease activity. We therefore evaluated complement factors in our series of patients treated with anti IL6 to show whether there was any correlation. Methods: 16 patients with active RA (14 F/2 M; mean age 56.3±11.2SD) were treated with TCZ (13 after anti-TNF failure and 3 naives). The patients were monitored for therapy response (DAS 28), HAQ, including clinical and laboratory parameters. All patients received DMARDs treatment and prednisolone ≤ 7.5 mg/day. Results: Prior to the treatment, therapy complement levels were normal: C3 124.65±14.52 and C4 23.88±7.23 (normal values: C3 90-180 mg/dl, C4 10-40 mg/dl). Revaluation of these parameters revealed a decrease already after the first 3-month treatment. The complement depletion increased at the 6th month and persisted during the ongoing therapy. After the 12th month mean values were C3 89.35±10.21 and C4 11.64±6.39. In four patients the treatment was stopped for the clinical remission with normalization of C3/C4 factors in the follow-up. Concerning the RA disease activity, 14/16 patients showed a good EULAR response (initial DAS28: 5.79±0.86, ESR 41.94±18.81, CRP 3.62±3.14, HAQ 1.39±0.71; after 3 months DAS 28 2.23±0.52, ESR 6.13±3.10, CRP 0.27±0.24, HAQ 0.79±0.73). After 24 weeks, for 2/16 patients (1F/1M) the therapy was stopped for inefficacy; in both patients the levels of complement factors did not decrease during TCZ treatment. In all patients no signs for the development of autoimmunity or infection could be observed. Conclusions: In the Tocilizumab OPTION study, mean levels of complement proteins C3 and C4 decreased but the data were not shown. It can be hypothesized that complement factors are consumed during the elimination process of immune complexes (IL6-anti-IL6Ab); moreover, in a case report of six RA patients the authors commented that this phenomenon requires further observation with respect to the clinical relevance. In an open label, dose-escalating, Phase I study Tocilizumab in Systemic Lupus Erythematosus complement C3 and C4 showed clear dose-related decreases. The Authors of such trial provided the first evidence that the TCZ-associated hypocomplementemia represents decreased production rather than increased activation. Also Olokizumab, a novel IL6 inhibitor in trials showed in RA patients the same dose-related reductions in complement C3 and C4. Reduction in complement levels is therefore believed to be consecutive to the inhibition by TCZ of IL6 stimulation of hepatocyte acute phase protein synthesis and of significant C3 upregulation. In our patients there is a good correlation between C3 and C4 decrease and clinical response, while we have not observed any decrease in patients unresponsive to TCZ. The levels of C3 and C4 are more related to the efficacy than PCR or ESR values, which in 1 patient decreased in absence of clear clinical improvement. The number of patients is too small to reach a conclusion but we hypothesize that the dosage of the C3 and C4 can be a rapid and sensitive marker of the response to anti-IL6 treatment. Therefore, a close follow-up of these parameters at 2-3 months from the start of the therapy can guide the therapeutic strategy.

2013 - Cryoglobulins and Cryoglobulins Secondary to Hepatitis C Virus Infection [Capitolo/Saggio]
Ferri, C.; Sebastiani, M.; Giuggioli, D.; Fallahi, P.; Antonelli, A.
abstract

The term cryoglobulinemia refers to the presence in the serum of one (monoclonal cryoimmunoglobulinemia) or more immunoglobulins (mixed cryoglobulinemia, MC), which precipitate at temperatures below 37 °C and redissolve on rewarming; this is an in vitro phenomenon. © 2014 Elsevier B.V. All rights reserved.

2013 - DANCE CLASS DEDICATED TO SCLERODERMA PATIENTS: JOINT EVALUATION, FUNCTIONAL AND QUALITY OF LIFE BEFORE AND AFTER TREATMENT – CLINICAL TRIAL [Abstract in Rivista]
Schiavi, Margherita; Giuggioli, Dilia; Spinella, Amelia; Ferri, Clodoveo; Mascia, Maria Teresa
abstract

Background: Systemic sclerosis (SSc) is a complex and multi systemic disorder of connective tissue, characterized by progressive thickening and fibrosis of the skin and internal organs, as well as by widespread microvascular damage. A number of studies have described in these patients a high prevalence of depressive symptoms, pain, and body image dissatisfaction. Physical and occupational therapy showed to be useful in preserving mobility in patients with scleroderma but no specific study was found that investigated exactly what kind of activity could improve disability, encourage participation and improve mood. Objectives: Dance (as a work of stretching, coordination, strength, aerobic, rhythmic, and recreational activity) could lead not just to accept and reconnect the patients with their bodies, enhance self-expression, address feelings of isolation and depression, but also to improve joint width, functionality, and autonomy. The study aims to compare the effects of dance/movement therapy and standard care with standard care alone in patients with systemic sclerosis. Methods: 15 female patients diagnosed with SSc were divided into an experimental group -A-(5 patients enrolled spontaneously, considering that not all are willing to participate) and in a control group-C- (10 patients). The group A followed a dance routine devotedly for 4 months (1 hour twice a week). at T0 and after 4 months were evaluated: Subjective Functionality upper limb (QUICK DASH), Autonomy of daily living (SHAQ Scleroderma- Health Assessment Questionnaire), mood ( CES-D), Fatigue (FS Scale) Objective- Six Minutes Walking Test (6MWT), ROM of the shoulder and hip. In both groups, the changes in the outcome measures between the baseline and 16-week assessments were assessed with a paired t-test. Results: There has been a statistically significant improvement in the group A in the objective evaluation: joint ROM of flexion of the hip and shoulder, meters walked in 6MWT(p< 0.03), test Borg dyspnea before the 6MWT is reduced from 0.6 to 0 and after the 6MWT is reduced from 2 to 0.8, while in the control group both remain unchanged (from 0.8 to 1 and 2.1 to 2.2). The self-assessment questionnaires show in the dancer group an improvement in the perception of fatigue (p <0.02) and of mood (p <0.01). No improvement was recorded in HAQ (0.58 to 0.65) and in the functionality of the upper limb (Quick Dash) due to worsening in work items (from 21.9 to 46.2) and a marked improvement in the free time items (from 40.6 to 21.5) probably attributable to awareness of disease. The results of the objective and subjective tests at time 0 and after 4 months were unchanged in the control group. Conclusions: The results should be interpreted with caution given the small sample. However, it can be said that the experimental dance program has brought a gain in aerobic performance, perception of fatigue, mood as well as hip and shoulder joints flexibility. The patients indicated that they liked the course and continued to dance even at the end of the trial outside of the dance school

2013 - Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the Monitor Net database. [Articolo su rivista]
Scirè, Ca; Caporali, R; Sarzi Puttini, P; Frediani, B; Di Franco, M; Tincani, A; Sinigaglia, L; Sfriso, P; Tirri, R; Bellis, E; Delsante, G; Porru, G; Salaffi, F; Giuggioli, D; Rossini, M; Todoerti, M; Bazzichi, L; Govoni, M; Gerli, R; Raschetti, R; Minisola, G; Montecucco, C; Todesco, S; Todesco, S; Raschetti, R; Naldi, L; Galeazzi, M; Sarzi Puttini, P; Fantini, F; Mathieu, A; Valesini, G; Ferri, Clodoveo; Bambara, Lm; Grassi, W; Trotta, F; Gerli, R; Adami, S; Lapadula, G; Pellerito, R; De Vita, S; Minisola, G; Foti, R; Paolazzi, G; Bagnato, G; Cutolo, M; Rocchetta, Pa; Ferraccioli, G; Canesi, Ba; Matucci Cerinic, M; Vittorio, M; Canzoni, M.
abstract

OBJECTIVES: To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. METHODS: All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). RESULTS: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. CONCLUSIONS: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF.

2013 - Erratum: Unusual association between Budd-Chiari syndrome secondary to antiphospholipid syndrome and relapsing polychondritis: A case report and review of the literature (Clinical Rheumatology (2013) 32 (905-907) DOI: 10.1007/s10067-013-2229-z) [Articolo su rivista]
Sebastiani, M.; Manzini, C. U.; Campomori, F.; Spinella, A.; Vacchi, C.; Giuggioli, D.; Schepis, F.; Ferri, C.
abstract

2013 - Functional impairment of systemic scleroderma patients with digital ulcerations: results from the DUO Registry [Articolo su rivista]
Raffier, B; Hirschi, M; Trautinger, F; Schmidt, P; Stetter, M; Hundstorfer, M; Reinhart, V; Monshi, B; Pirkhammer, D; Richter, L; Hamberger, N; Metz, S; Feldmann, R; Semmelweis, K; Lackner, K; Tomi, N; Kolle, H; Hafner, F; Brodmann, M; Kuen Spiegel, M; Minmair, G; Heil, Pm; Broil, H; Holzer, G; Illmer, X; Rintelen, B; Sautner, J; Takacs, M; Thun, M; Zemanova, I; Soukup, T; Smrzova, A; Bohmova, J; Prochazkova, L; Nemec, P; Fojtik, Z; Suchy, D; Becvar, R; Olsen, Ab; Sondergaard, Kh; Luosu jarvi, R; Vidqvist, Kl; Madaule, S; Beneton, N; Maillard, H; Charlanne, H; Granelbrocard, F; Hachulla, E; Hatron, Py; Jourdain, N; Lambert, M; Launay, D; Morell, S; Woijtasik, G; Skowron, F; Zenone, T; Dadban, A; Lok, C; Ferrandiz, D; Magybertrand, N; Moiton, Mp; Taieb, A; Balquiere, S; Belin, E; Droitcourt, C; Julien, S; Prey, S; Boulon, C; Constans, J; Doutre, Ms; Kostrzwewa, E; Richez, C; Greco, M; Misery, L; Sassolas, B; Collet, E; Berthier, S; Leguy Seguin, V; Imbert, B; Carpentier, P; Blaise, S; Couraud, A; Doeffel Hantz, V; Spars, A; Bezanahary, H; Boussely, N; Dumonteil, S; Fauchais, Al; Goudran, G; Loustaud Ratti, V; Manea, P; Vidal, E; Coppere, B; Desmursclavel, H; Girard Madoux, Mh; Hot, A; Ninet, J; Granel, B; Cohen, Jd; Keynote, A; Khau van Kien, A; Le Quellec, A; Riviere, S; Rullier, P; Bessis, D; Farcas, C; Bravetti, V; Moline, T; Wahl, D; Zuily, S; Granel Brocard, F; Agard, C; Durant, C; Fuzibet, Jg; Queyrel, V; Berezne, A; Guillevin, L; Mouthon, L; Cabane, J; Tiev, K; Toledano, C; Lazareth, I; Michon Pasturel, U; Priollet, P; Reguiai, Z; Cazaletslacoste, C; Jego, P; Letremy, A; Perlat, A; Duval Modeste, Ab; Chatelus, E; Chiffot, H; Sibillia, J; Sordet, C; Adoue, D; Couret, B; Moulis, G; Pugnet, G; Sailler, L; Diot, E; Gaches, F; Farge, D; Keshtmand, H; Frances, C; von Elling, A; Bora, D; Ebel, J; Ahmadi Simab, K; Klein, E; Hahn, K; Schulze, K; Rasche, C; Riemekasten, G; Lee, Hh; Deuschle, K; Mattat, K; Becker, M; Worm, M; Mensing, C; Klings, D; Mensing, H; Messall, J; Zuper, R; Eilbacher, P; Saar, P; Kaufmann, P; Hallermann, C; Schmidt, K; Wahn, H; Schildt, K; Schuart, T; Kaczmarczyk, A; Kellner, C; von Oelhafen, J; Baron von Bildering, P; Kunze, S; Kleiner, Hj; Alsheimer, B; Schuetz, N; Miirker Hermann, E; Gottl, Kh; Weiss, E; Reischel, N; Kern, S; Goettl, Kh; Goetheuniversitiitsklinikum, Jw; Himsel, A; Henkemeier, U; Schwarting, A; Hazenbiller, A; Nichelmann, V; Rumbaur, C; Boesenberg, I; Schmeiser, T; Mueller Ladner, U; Unholzer, A; Starz, H; Welzel, J; Plaumann, K; Stoeckl, F; Sperling, S; Podda, M; Wagner, N; Rapprich, H; Niedermeier, A; Messer, G; Sardy, M; Bekou, V; Dill MUller, D; Wlodarz, M; Belloni, B; Huettig, B; Ziai, M; Hein, R; Kneitz, C; Federow, I; Schneider, K; Semmler, M; Hapke, S; Metzler, C; Stein, T; Enderlein, M; Kayser, M; Werthmann, M; Guenther, Cu; Neul, S; Hellmich, B; Loeffler, C; Pflugfelder, J; Karaenke, P; Mueglich, C; Tony, Hp; Marina, P; Popp, M; Mittag, M; Mittag, M; Baumann, C; Baumann, C; Scheib, Eg; Scheib, Eg; Brand, H; Wilhelm, Hu; Wilhelm, Hu; Bohm, J; Dyballa, J; Boehm, J; Taggeselle, J; Taggeselle, J; Luthke, K; Wuerzburg, I; Luthke, K; Niefanger, K; Niefanger, K; Mayer, L; Drabek, J; Harmuth, W; Harmuth, W; Dietl, S; Moritz, D; Dietl, S; Gause, A; Gause, A; Gaubitz, M; Hallecker, A; Gaubitz, M; Krupp, E; Rumpel, H; Moosig, F; Frey, P; Kahl, S; Linke, M; Merk, B; Bloching, Hh; Ochs, W; Kurthen, R; Kurthen, R; Eiden, E; Guertler, I; Aries, Pm; Kirchberg, S; Jahnke, K; Mettler, S; Toeller, S; Zwenger, S; Langer, He; Deininger, F; Hartmann, F; Neeck, G; Neek, G; Wernitzsch, H; Meier, L; Herr, U; Meier, U; Aaig, W; Schwarting, A; Bruckner, L; Sheikh, N; Wollenhaupt, J; Krog, B; Wollersdorfer, E; Hall, R; Diehm, C; Tiggers, C; Peters, J; Kirschke, J; Schroeder, Jo; Zeuner, R; Uhlig, S; Barth, S; Huegel, R; Glaeser, R; Schaefer, C; Monshausen, M; Mengden, T; Funkert, A; Blank, N; Lupaschko, S; Voss, B; Megahed, M; Sadeghlar, F; Seidel, M; Wasmuth, Jc; Kreuter, A; Vosswinkel, J; Pfoehler, C; Ge
abstract

OBJECTIVES: Digital ulcers (DUs) are frequent manifestations of systemic scleroderma (SSc). This study assessed functional limitations due to DUs among patients enrolled in the Digital Ulcer Outcome (DUO) Registry, an international, multicentre, observational registry of SSc patients with DU disease. METHODS: Patients completed at enrolment a DU-specific functional assessment questionnaire with a 1-month recall period, measuring impairment in work and daily activities, and hours of help needed from others. Physician-reported clinical parameters were used to describe the population. For patients who completed at least part of the questionnaire, descriptive analyses were performed for overall results, and stratified by number of DUs at enrolment. RESULTS: This study included 2327 patients who completed at least part of the questionnaire. For patients with 0, 1-2, and ≥3 DUs at enrolment, mean overall work impairment during the prior month among employed/self-employed patients was 28%, 42%, and 48%, respectively. Across all included patients, ability to perform daily activities was impaired on average by 35%, 54%, and 63%, respectively. Patients required a mean of 2.0, 8.7, and 8.8 hours of paid help and 17.0, 35.9, and 63.7 hours of unpaid help, respectively, due to DUs in the prior month. Patients with DUs had more complications and medication use than patients with no DUs. CONCLUSIONS: With increasing number of DUs, SSc patients reported more impairment in work and daily activities and required more support from others.

2013 - HCV-related autoimmune disorders in HCV chronic infection. [Articolo su rivista]
Ferrari, Silvia Martina; Fallahi, P; Mancusi, C; Colaci, Michele; Manfredi, Andreina Teresa; Ferri, Clodoveo; Antonelli, A.
abstract

Patients with hepatitis C virus (HCV) chronic infection may develop a great number of extrahepatic manifestations. Among these latter, mixed cryoglobulinemia (MC) represents the prototype of HCV-associated autoimmune-lymphoproliferative disorders. Other rheumatological manifestations of HCV chronic infection are Siögren syndrome, arthritis and CREST syndrome. Thyroid autoimmmune disorders are among the most frequent manifestations of HCV chronic infections and are clinically relevant because of the association with thyroid dysfunctions and hypothyroidism. Autoimmune cytopenia is also reported in association with HCV infection. This paper reviews the association of HCV chronic infection with the above mentioned pathologies, and their immunopathogenesis.

2013 - Hepatitis C virus and type 1 diabetes [Articolo su rivista]
Fallahi, P; Di Domenicantonio, A; Mazzi, V; Santini, F; Fabiani, S; Sebastiani, Marco; Zignego, Al; Ferri, Clodoveo; Antonelli, A.
abstract

Hepatitis C virus infection and diabetes mellitus are two worldwide, major public health problems with increasing complication and mortality rates. Type 1 diabetes mellitus (T1D) is characterized by an autoimmune process leading to pancreatic beta cell destruction; only when the major part of pancreatic beta cells have been destroyed the diabetes become clinically manifest. At the basis of the development of the T1D there is an interplay among environmental factors, pancreatic beta cells, the innate and adaptive immune system, the genetic background and the comorbidities of the patient. Viral infections, including hepatitis C virus infection, may be one of the factors that can almost accelerate progression to diabetes, through different mechanism

2013 - Hepatitis C virus infection and type 2 diabetes. [Articolo su rivista]
Fallahi, P; Ferrari, Silvia Martina; Colaci, Michele; Ruffilli, I; Vita, R; Azzi, A; Ferri, Clodoveo; Antonelli, A; Ferrannini, E.
abstract

Hepatitis C virus (HCV) infection and Type 2 diabetes mellitus (T2DM) are two worldwide, major public health problems with increasing complication and mortality rates. Many epidemiological studies have demonstrated the significant association between T2DM and chronic HCV infection. In this paper we have reviewed the increasing evidence linking HCV infection and DM in more than one field (epidemiology, pathogenesis, clinical aspects, prevention and treatment). We have considered T2DM, acute and chronic HCV infection, and cirrhotic patients. Moreover, we have considered some particular populations, solid organ transplant recipients or HCV/human immunodeficiency virus (HIV) coinfected patients. In the final part we have analyzed the potential effect of the association between HCV infection and the development of DM in term of outcome and possibilities for prevention and treatment.

2013 - High circulating chemokines (C-X-C motif) ligand 9, and (C-X-C motif) ligand 11, in hepatitis C-associated cryoglobulinemia. [Articolo su rivista]
Antonelli, A; Fallahi, P; Ferrari, Silvia Martina; Frascerra, S; Mancusi, C; Colaci, Michele; Manfredi, Andreina Teresa; Sansonno, D; Zignego, Al; Ferri, Clodoveo
abstract

(C-X-C motif) ligand 9 and (C-X-C motif) ligand 11 (CXCL9 and CXCL11), are potent chemoattractants for activated T cells, and play an important role in T helper 1 (Th)1 cell recruitment in chronic hepatitis C. No study has evaluated CXCL9, together with CXCL11, circulating levels in patients with mixed cryoglobulinemia and hepatitis C (MC+HCV-p). The aim of the present study therefore was to measure serum CXCL9, and CXCL11 levels, in MC+HCV-p, and to relate the findings to the clinical phenotype. Serum CXCL9 and CXCL11 were measured in 71 MC+HCV-p and in matched controls. MC+HCV-p showed significantly higher mean CXCL9 and CXCL11 levels than controls (P less than 0.001, for both), in particular, in 32 patients with active vasculitis (P less than 0.001). By defining high CXCL9 or CXCL11 level as a value of at least 2 SD above the mean value of the control group ( greater than 100 pg/mL): 89 percent MC+HCV-p and 5 percent controls had high CXCL9 (P less than 0.0001, chi-square); 90 percent MC+HCV-p and 6 percent controls had high CXCL11 (P less than 0.0001, chi-square). In a multiple linear regression model of CXCL9 vs age, ALT, CXCL11, only CXCL11 was significantly (r = 0.452, P less than 0.0001) and independently related to CXCL9. Our study demonstrates in MC+HCV-p vs controls: (i) high serum CXCL9, and CXCL11, significantly associated with the presence of active vasculitis; (ii) a strong relationship between circulating CXCL9 and CXCL11. Future studies on a larger cohort of patients are needed to evaluate the relevance of serum CXCL9 and CXCL11 determination as clinico-prognostic marker of MC+HCV.

2013 - Incidence of thyroid disorders in systemic sclerosis: results from a longitudinal follow-up. [Articolo su rivista]
Antonelli, A; Fallahi, P; Ferrari, Silvia Martina; Mancusi, C; Giuggioli, D; Colaci, Michele; Ferri, Clodoveo
abstract

CONTEXT: Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, and several studies reported its association with thyroid autoimmune disorders. No study has evaluated longitudinally the incidence of new cases of thyroid autoimmunity and dysfunction in patients with SSc. OBJECTIVE: The purpose of this study was to evaluate the incidence of new cases of clinical and subclinical thyroid dysfunction in a wide group of women with SSc vs an age- and sex-matched control group from the same geographic area. DESIGN AND PATIENTS OR OTHER PARTICIPANTS: After exclusion of sclerodermic patients with thyroid dysfunction (n = 55) at the initial evaluation, the appearance of new cases of thyroid disorders was evaluated in 179 patients and 179 matched control subjects, with similar iodine intake (median follow-up 73 months in patients with SSc vs 94 months in control subjects). RESULTS: A high incidence (P < .05) of new cases of hypothyroidism, thyroid dysfunction, anti-thyroperoxidase antibody positivity, and appearance of a hypoechoic thyroid pattern in sclerodermic patients (15.5, 21, 11, and 14.6 of 1000 patients per year; respectively) vs that in control subjects was shown. A logistic regression analysis showed that in patients with SSc, the appearance of hypothyroidism was related to a borderline high initial TSH level, anti-thyroperoxidase antibody positivity, and a hypoechoic and small thyroid. CONCLUSIONS: Our study shows a high incidence of new cases of hypothyroidism and thyroid dysfunction in female sclerodermic patients. Female sclerodermic patients, who are at high risk (a borderline high [even if in the normal range] TSH value, anti-thyroperoxidase antibody positivity, and a hypoechoic and small thyroid) should have periodic thyroid function follow-up.

2013 - Increased CXCL9 serum levels in hepatitis C-related mixed cryoglobulinemia, with autoimmune thyroiditis, associated with high levels of CXCL10. [Articolo su rivista]
Antonelli, A; Fallahi, P; Ferrari, Silvia Martina; Colaci, Michele; Giuggioli, D; Saraceno, G; Benvenga, S; Ferri, Clodoveo
abstract

Until now, no study has evaluated CXCL9 in hepatitis C virus (HCV) infection-related mixed cryoglobulinemia (MC) patients in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCL10 have been measured in 60 patients with MC (MCo), in 35 patients with MC and AT (MC-AT), in sex and age-matched controls: 60 healthy (Control 1); 35 patients with AT without cryoglobulinemia (Control 2). CXCL9 and CXCL10 were higher in MC-AT patients than Control 2 (P<0.0001) and MCo (P=0.01), in MCo than Control 1 (P<0.0001), and in Control 2 than Control 1 (P<0.001). By defining a high CXCL9 level as a value>2 SD above the mean value of the Control 1 (>122 pg/mL), 5% of Control 1, 34% of Control 2, 91% of MCo, and 97% of MC+AT had high CXCL9 (P<0.0001, chi-square). By simple regression analysis CXCL9 and CXCL10 were related to each other in MCo (r=0.426, P=0.001) and in MC-AT (r=0.375, P=0.001). We first demonstrate high serum levels of CXCL9 in cryoglobulinemic patients, especially with AT. Further, a strong association between serum CXCL9 and CXCL10 has been observed in patients with MC in presence/absence of AT.

2013 - Interferon-α, -β and -γ induce CXCL11 secretion in human thyrocytes: modulation by peroxisome proliferator-activated receptor γ agonists. [Articolo su rivista]
Antonelli, A; Ferrari, Silvia Martina; Mancusi, C; Mazzi, V; Pupilli, C; Centanni, M; Ferri, Clodoveo; Ferrannini, E; Fallahi, P.
abstract

It has been previously shown IFN-α, -β, -γ and TNF-α (synergically with IFNs) dose-dependently induce the release of CXCL9 and CXCL10 chemokines by thyroid follicular cells, suggesting that this process may be related, at least in part, to the appearance of thyroid dysfunction during IFNs therapy. No study has evaluated the effect of IFN-α and -β on CXCL11 chemokine production in thyrocytes. The aims of this study were: (a) to test the effect of IFN-α, -β and -γ on the secretion of the Th1 chemokine CXCL11, in primary cultures of human thyroid follicular cells; (b) to assess the effect of PPAR-γ activation on CXCL11 secretion. In primary cultures of human thyroid follicular cells, CXCL11 was undetectable in the supernatant. IFN-γ, -α and -β dose dependently induced CXCL11 release. TNF-α alone had no effect. The combination of each of the IFNs with TNF-α had a significant synergistic effect on CXCL11 secretion. Treatment of primary cultures of human thyroid follicular cells with rosiglitazone dose dependently inhibited the IFNs stimulated CXCL11 release. Compared with IFN-α and -β, IFN-γ was the most potent stimulus of CXCL11 secretion. In conclusion, we first show that IFN-α, -β and -γ and TNF-α (synergically with IFNs) dose-dependently induce the release of CXCL11 by primary cultures of human thyroid follicular cells, suggesting that this process may be related to the appearance of thyroid dysfunction during IFNs therapy. Furthermore, PPAR-γ activation partially inhibits this process.

2013 - Lung cancer in scleroderma: results from an Italian rheumatologic center and review of the literature. [Articolo su rivista]
Colaci, Michele; Giuggioli, D; Sebastiani, Marco; Manfredi, Andreina Teresa; Vacchi, Caterina; Spagnolo, Paolo; Cerri, Stefania; Luppi, Fabrizio; Richeldi, Luca; Ferri, Clodoveo
abstract

The association between systemic sclerosis (SSc) and cancer was widely described, particularly with breast and lung carcinoma; while, data regarding possible associations between cancer and SSc features are still scarce. We retrospectively evaluated the prevalence of lung cancer in our SSc patient cohort (318 SSc patients, 31 M and 287 F, age 51.5±14.5SD years, disease duration 10.3±6.5SD years) and clinico-serological factors potentially associated to the development of this malignancy. A review of the world literature about this topic was also done. We found that lung cancer complicated 16/318 (5%) SSc patients; namely 11/287 females (4%) and 5/31 males (16.1%). Median age of SSc patients with lung cancer was 54 (range 38-72) years for female patients, and 63 (range 40-73) for males; 13/16 patients died because of the neoplasia. Considering the incidence of lung carcinoma in sex/age-matched general population of the same geographical area, the percentages of lung cancer in our SSc series are about 2.5 and &gt;5 times higher for male and female patients, respectively. The presence of lung cancer significantly correlated with male sex (p=0.011), presence of anti-Scl70 antibodies (p=0.0007), cyclophosphamide therapy (p=0.0001), forced vital capacity (FVC) &lt;75% (p=0.0001), and lung fibrosis (p=0.0127); moreover patients with cancer have a significantly lower age at the diagnosis of SSc (p=0.009) and longer disease duration (p=0.0175). The logistic regression analysis confirmed a significant association with the anti-Scl70 antibodies (OR 6.4, 95%IC 1.7-24.1; p=0.006) and the reduction of FVC (OR 6.7, 95%IC 2.2-20.7; p=0.001) only. Overall, the prevalence of lung cancer in the subset of SSc patients with anti-Scl70 antibodies was 12/105 (11.4%), 9/40 (22.5%) in patients with FVC% reduction, and 7/22 (31.8%) in patients with both. In literature, the median prevalence of lung cancer in SSc series was 2.4% (range 0-4.2%); even if sporadic, associations with lung involvement or antiScl70 autoantibodies were raised, according to our findings. Our study confirmed the higher frequency of lung cancer among SSc patients compared to general population, particularly within patients' subset with serum anti-Scl70 antibodies and lung involvement.

2013 - Micro and Nanoparticles As Possible Causative-Prognostic Co-Factors Of Mixed Cryoglobulinemia Syndrome [Abstract in Rivista]
Artoni, Erica; Gian Luca Sighinolfi, ; Daniele, Campioli; Sebastiani, Marco; Giuggioli, Dilia; Ferri, Clodoveo
abstract

Background/Purpose: We previously demonstrated that patients affected by membranoproliferative glomerulonephritis and mixed cryoglobulinemia syndrome (MCs) show the presence of circulating micro and nanoparticles (MPs and NPs) as possible causative/prognostic co-factors. This pilot study aimed to evaluate the possible role of occupational/environmental agents in the etiopathogenesis of MCs by investigating the patients’ exposure to both MPs and NPs. Methods: We investigated 20 consecutive HCV-positive MCs patients without renal involvement compared to 10 healthy, sex-/age-matched volunteers. All subjects completed a questionnaire concerning demographic data, dietary and smoking habits, prosthesis implants, air pollution, occupational and medical history. Environmental Scanning Electron Microscopy (ESEM) has been employed to detect inorganic MPs and NPs and to evaluate their presence in subjects with and without MCs. Energy Dispersive X-ray Spectroscopy (EDS) microanalysis was used to chemically characterize the elemental composition of the particles. Blood serum samples were spotted on metal free cover slips in a sterile environment. The complex of particles (MPs and NPs) was quantified using the number of spots (NS) containing inorganic particles in a fixed mapping area for each sample. Levels of NS were assessed statistically with Mann-Whitney U test. Results: Patients displayed higher serum levels of MPs/NPs particles (NS 36.6718.18, p0.0003), compared to controls (NS 5.626.25), independently of smoking habits. A direct correlation between the presence of particles and patients occupational exposure, environmental pollution and prosthesis implants was found. EDS microanalysis revealed that the particles have complex compositions, which includes several elements like Si, Fe, Al, Ti, Zn, Cu, Mn, and Ni. Conclusion: The ESEM analyses were a valuable tool to detect particulate matter in the serum samples. The complex of MPs/NPs particles was greater in MCs patients than in healthy subjects. These preliminary data suggest that, in addition to HCV infection, particulate complex might represent an environmental co-factor in the etiopathogenesis of MCs.

2013 - Mixed cryoglobulinemia and thyroid autoimmune disorders [Articolo su rivista]
Fallahi, P; Ferrari, Silvia Martina; Giuggioli, D; Corrado, A; Fabiani, S; Marchi, S; Ferri, Clodoveo; Antonelli, A.
abstract

In patients with hepatitis C virus-associated mixed cryoglobulinemia (MC+HCV) the following thyroid disorders are significantly more frequent than in HCV not infected controls: 1) high levels of serum anti-thyroperoxidase autoantibody (AbTPO), 2) high levels of serum AbTPO and/or anti-thyroglobulin (AbTg) autoantibody; 3) humoral and ultrasonographical signs of thyroid autoimmunity (35%); 4) prevalence of subclinical hypothyroidism (11%). Also, the prevalence of papillary thyroid cancer has been found higher in MC+HCV patients than in controls, in particular in patients with autoimmune thyroiditis. These results suggest a careful monitoring of thyroid function in these patients.

2013 - Osteomyelitis complicating scleroderma digital ulcers. [Articolo su rivista]
Giuggioli, D; Manfredi, Andreina Teresa; Colaci, Michele; Lumetti, Federica; Ferri, Clodoveo
abstract

Skin ulcers are very frequent in scleroderma (SSc), often complicated by local infection; the latter may be responsible for osteomyelitis (OM) of underlying bone. We retrospectively investigate the prevalence of OM in our SSc patients. The study included 248 SSc patients (M/F 21/227, mean age 61 ± 13.5 SD years) followed at our Rheumatology Unit for a mean time period of 60.8 ± 20.9 SD months. Patients with infected skin ulcers were carefully evaluated for complicating OM, which was diagnosed on the basis of typical clinical symptoms, laboratory, and radiological alterations. Skin ulcers were observed in 119/248 (48 %) SSc patients, more frequently digital ulcers (110/119, 92 %). These patients presented a significantly lower mean age (59 ± 14.5 SD vs. 64 ± 12.2 SD years; p = 0.005) and a lower percentage of anticentromere antibodies (40/119, 33.6 %, vs. 66/129, 51.2 %; p = 0.007) compared with those without ulcers. The prevalence of OM in the entire SSc patients' series was 7.7 % (19/248); it was invariably found in the setting of patients with infected digital ulcers, showing a surprisingly high percentage of underlying bone involvement (19/45, 42 %). The OM was localized at the hands in 14 patients and feet in 5; moreover, the most frequently isolated pathogens from infected digital ulcers were Staphylococcus aureus and Escherichia coli. Finally, patients with OM presented a significantly lower mean age (p < 0.016) and higher percentage of anti-Scl70 autoantibodies (p < 0.0128) compared to those without. We firstly demonstrated, in a large cohort of SSc patients, high prevalence of OM, invariably associated to infected digital ulcers, which represent the main predisposing condition for the development of such a harmful complication.

2013 - Parallel increase of circulating CXCL11 and CXCL10 in mixed cryoglobulinemia, while the proinflammatory cytokine IL-6 is associated with high serum Th2 chemokine CCL2 [Articolo su rivista]
Alessandro, Antonelli; Poupak, Fallahi; Ferrari, Silvia Martina; Alda, Corrado; Sebastiani, Marco; Giuggioli, Dilia; Mario, Miccoli; Anna Linda Zignego, ; Domenico, Sansonno; Santino, Marchi; Ferri, Clodoveo
abstract

The aim was to investigate circulating levels of interelukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, chemokine (C–X–C motif) ligand (CXCL)10, CXCL11 and chemokine (C–C motif) ligand (CCL)2 in “mixed cryoglobulinemia and hepatitis C” (MC + HCV). Serum levels of CXCL11, IL-1β, TNF-α, IL-6, and CCL2 were evaluated in 52 MC + HCV vs 52 sex- and age-matched controls to correlate them to the clinical features of mixed cryoglobulinemia. CXCL11 was significantly higher in MC + HCV than in controls (264 ± 279 vs 70 ± 16 pg/mL, respectively; P = 0.0002; univariate analysis of variance (ANOVA)), in particular in 23 MC + HCV with active vasculitis vs those without (293 ± 221 vs 168 ± 57 pg/mL, respectively; P < 0.001; ANOVA). Significantly high IL-1β, IL-6, TNF-α, CXCL10, and CCL2 in MC + HCV vs healthy controls were confirmed. In a multiple linear regression model (CXCL11 or CCL2, vs age, alanine aminotransferase, IL-1β, IL-6, TNF-α, and CXCL10), CXCL11 was significantly associated with high CXCL10 (P < 0.001), while CCL2 with high IL-6 (P < 0.001). This study demonstrates in MC + HCV high serum levels of (a) T-helper 1 chemokines, CXCL11 and CXCL10 (related to each other) and (b) proinflammatory cytokines IL-6 and CCL2 (related to each other).

2013 - Peroxisome proliferator-activated receptor γ agonists reduce cell proliferation and viability and increase apoptosis in systemic sclerosis fibroblasts [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Colaci, Michele; Ruffilli, I; Sebastiani, Marco; Fallahi, P.
abstract

Background  No study has evaluated the effect of the peroxisome proliferator-activated receptor γ (PPARγ) agonists on cell viability, proliferation and apoptosis in cultured systemic sclerosis (SSc) fibroblasts. Objectives  The effects of two pure PPARγ agonists (rosiglitazone and pioglitazone) in cultured SSc fibroblasts were evaluated and compared with effects in normal fibroblasts. Methods  The study included evaluation of cell viability and proliferation (based on the cleavage of tetrazolium salts and measurement of absorbance of the cell proliferation reagent WST-1), and determination of cell apoptosis (by means of the Hoechst dye uptake). Results  Rosiglitazone or pioglitazone (20 μmol L(-1) ) significantly reduced cell proliferation (cell count of 75% and 83% compared with baseline, respectively, after 2 h) and cell viability (absorbance reductions of 25% and 22% compared with baseline, respectively, after 2 h), and increased apoptosis (apoptotic cell percentages 9·9% and 8·6%, respectively, after 48 h of incubation) in SSc fibroblasts, whereas they did not present a significant influence on control fibroblasts. Conclusions  The effects of rosiglitazone or pioglitazone shown on SSc fibroblasts raise the hypothesis of a therapeutic role for PPARγ agonists in patients affected by SSc

2013 - Pulmonary hypertension in systemic sclerosis: prevalence, incidence and predictive factors in a large multicentric Italian cohort. [Articolo su rivista]
Iudici, M; Codullo, V; Giuggioli, D; Riccieri, V; Cuomo, G; Breda, S; Manfredi, Andreina Teresa; Iannace, N; D'Alto, M; Ghio, S; Rossi, R; Vizza, Cd; Caporali, R; Valesini, G; Ferri, Clodoveo; Valentini, G.
abstract

OBJECTIVES: This paper aims to investigate the prevalence, the incidence of pulmonary hypertension (PH) and its subtypes in Italian patients with systemic sclerosis (SSc) and to characterise features associated with and predictive of development of PH. METHODS: Eight-hundred and sixty-seven consecutive SSc patients recruited at 4 Italian centres were enrolled. At admission, all patients underwent a careful history, physical examination, EKG, lung high resolution computed tomography (HRCT), pulmonary function tests, B-mode echocardiography and right heart catheterisation (RHC), if indicated. Patients were then visited every 6-12 months. A RHC was performed in those patients in whom PH was suspected for the presence of pre-specified criteria. RESULTS: Among the 212 patients in whom it was suspected, PH was confirmed by RHC in 69 patients. On 31st December 2010, the point prevalence of P-arterial-H(PAH) and PH associated with interstitial lung disease (PH-ILD) was 3.7% and 1.4%, respectively; that of postcapillary PH was 1.3%. The estimated incidence rates of PH and PAH were respectively 1.85/100 patient-years and 1.02/100 patient-years. Multivariate analysis indicated that diffusing lung capacity for CO (DLCO) ≤55% (HR 4.45, 95%CI 2.24-8.83; p&lt;0.001) and sPAP &gt;40 mmHg (HR 18.03, 95%CI 9.01-36.06; p&lt;0.001) were associated with an increased risk to develop PAH. SystolicPAP &gt;40 mmHg resulted the only predictor of PH-ILD (HR 5.17, 95%CI 1.37-19.5; p=0.018) and post-capillary PH (HR 7.91, 95%CI 1.88-33.1; p=0.005) development. CONCLUSIONS: Our study confirms a lower prevalence of PH in Italy compared to Anglo-Saxon cohorts. We also identified patients at high risk, who should be carefully monitored.

2013 - Reactive arthritis induced by intravesical BCG therapy for bladder cancer: our clinical experience and systematic review of the literature [Articolo su rivista]
Bernini, Luigi; Cu, Manzini; D., Giuggioli; Sebastiani, Marco; Ferri, Clodoveo
abstract

Objective Intravesical instillation of BCG (ivBCG) is an effective and safe immunotherapy of bladder carcinoma but it may have, as side effect, a reactive arthritis (ReA). The authors describe 5 cases observed during their own clinical experience along with the updated review of the literature on this topic. Methods Seventy-three papers were present in the world literature, each reporting almost 1 case for a total of 112 patients. However, the review focused on 61 papers, selected on the basis of reporting suitable for a correct clinical evaluation; thus, a total of 89 patients, including the cases observed in our clinic, were carefully analyzed. Results Among the 89 patients identified 73 were males and 16 females. Europe is the geographical area with the higher number of reports, namely 80.6% of the papers including 74.2% of the patients. The Mediterranean area accounts for 62.9% of the papers and 59.6% of the cases. The symptoms of ReA appeared after a mean number of instillations of 5.8. Polyarthritis was present in 55.1%, oligoarthritis in 37.0% and monoarthritis in 7.9%. Polyarthritis was symmetric in 51.0% and asymmetric in 49.0% of the cases; oligoarthritis was symmetric in 33.3% and asymmetric in 66.7% of the cases. Overall, an asymmetric distribution of arthritis was present in 59.6%. Knee and ankle were the joints most frequently involved. The antigen HLA B27 was positive in 42.6%. The synovial fluid analysis was defined as flogistic–aseptic in 71.9% of the patients. Arthritis was recovered within 6 months in 93.2% of the cases and in 70.5% of the patients within the first two months. NSAIDs and corticosteroids, alone or in conjunction with other drugs, are used in 65.1% and in 40.4% of the cases, respectively. The clinical features of ivBCG ReA are compared with ReA from other triggering agents, from which it differs for some clinical aspects and overlaps for others. Conclusions Compared with a previous report, this review allows to modify some figures of this topic as a reduced prevalence of polyarthritis (from 70% to 55.1%) and of spinal and sacroiliac involvement; polyarthritis remains the more frequent clinical pattern of ivBCG ReA that, however, is characterized by rather asymmetrical distribution and involvement of the large joints of lower limbs. A definite linkage to HLA B27 is present, although without prognostic value. Moreover, arthritis is aseptic, has a latency time from antigen exposure, and is associated with extra-articular features as commonly observed in ReA from other triggering agents. Arthritis is usually benign and rarely develops into a chronic form. NSAIDs and/or corticosteroids are largely effective. Noteworthy, the overall clinical picture of arthritis triggered by ivBCG emerging from this updated review is comparable to that of ReA from other bacterial agents

2013 - Regional differences of vitamin D deficiency in rheumatoid arthritis patients in Italy [Articolo su rivista]
Rossini, M; D'Avola, G; Muratore, M; Malavolta, N; Silveri, F; Bianchi, G; Frediani, B; Minisola, G; Sorgi, Ml; Varenna, M; Foti, Rosario; Tartarelli, G; Orsolini, G; Adami, S; Study Group on, Osteoporosis; Metabolic Skeletal Diseases of the Italian Society of Rheumatology CollaboratorsAdami, Study Group on Osteoporosis; CollaboratorsAdami S, Metabolic Skeletal Diseases of the Italian Society of R. h. e. u. m. a. t. o. l. o. g. y.; Bagnato, G; Bianchi, G; Cacace, E; Caminiti, M; Cantatore, F; D'Avola, G; Del Puente, A; Di Munno, O; Ferri, Clodoveo; Foti, Rosario; Frediani, B; Iagnocco, Am; La Montagna, G; Maddali Bongi, S; Malavolta, N; Minisola, G; Muratore, M; Silveri, F; Sinigaglia, L; Sorgi, Ml; Tartarelli, G.
abstract

Vitamin D deficiency is very common in patients with rheumatoid arthritis (RA). Aim of this study was to evaluate the prevalence of vitamin D deficiency among the different Italian regions and whether these variations are associated with different severity of the disease. The study includes 581 consecutive RA patients (464 women), not taking vitamin D supplements, from 22 Italian rheumatology centres uniformly distributed across Italy. Together with parameters of disease activity (disease activity score 28), functional impairment (activities of daily living and health assessment questionnaire disability index) and mean sun exposure time, all patients had serum 25-hydroxyvitamin D (25OHD) measured in a centralized laboratory. Vitamin D deficiency (25OHD level &lt;20 ng/mL) was very frequent among RA patients; its prevalence was 60%, 52% and 38% in southern, central and northern Italy, respectively. Mean disease activity and disability scores were worse in southern regions of Italy. These scores were inversely related to 25OHD levels and this correlation remained statistically significant after adjusting for both body mass index (BMI) and sun exposure time. However, disease severity remained significantly higher in southern regions versus central-northern Italy after adjustment also for serum 25OHD levels, age and BMI. In RA Italian patients there are significant regional differences in the prevalence of vitamin D deficiency explained by different BMI, and sun exposure time, and inversely associated with disease activity and disability scores.

2013 - RESULTS OF THE CLASSIFICATION CRITERIA FOR CRYOGLOBULINEMIC VASCULITIS VALIDATION STUDY [Abstract in Rivista]
Ferri, Clodoveo; Salvarani, Carlo
abstract

not available

2013 - Systematic review of 2008-2012 literature and update of recommendations for the use of methotrexate in rheumatic diseases, with a focus on rheumatoid arthritis. [Articolo su rivista]
Todoerti, M; Maglione, W; Bernero, E; Bortoluzzi, A; Colaci, Michele; Galuppi, E; Paolino, S; Talarico, R; Cutolo, M; Ferri, Clodoveo; Trotta, F; Bombardieri, S; Montecucco, Cm; Sinigaglia, L.
abstract

The objective of this review is to update the recommendations of the 2010 Italian Consensus on the use of methotrexate (MTX) in rheumatoid arthritis (RA) and other rheumatic diseases. The literature published between 2008 and 2012 was systematically reviewed and updated recommendations on MTX use in rheumatic diseases, particularly RA, were formulated. These recommendations were approved by a panel of expert Italian Rheumatologists. A total of 10,238 references were identified, among which 70 studies were selected for critical evaluation. Sufficient evidence had accumulated to warrant changes to several of the recommendations in the new version. A new recommendation for patients with RA who are in MTX-induced clinical remission was also proposed and approved by the panel. Updated recommendations for the use of MTX in patients with RA or other rheumatologic disease are proposed.

2013 - Systemic sclerosis and cryoglobulinemia: our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of the literature. [Articolo su rivista]
Giuggioli, D; Manfredi, Andreina Teresa; Colaci, Michele; Manzini, Cu; Antonelli, A; Ferri, Clodoveo
abstract

OBJECTIVE: Systemic sclerosis (SSc) is an immune-mediated disorder characterized by multiple organ fibrotic alterations and diffuse microangiopathy. The SSc can be associated with other connective tissue diseases and less frequently with systemic vasculitides, including cryoglobulinemic vasculitis (CV). The aim of the present study was to investigate the prevalence of CV in a large series of SSc patients. METHODS: The presence of serum cryoglobulins was detected in 246 SSc patients (24 M and 222 F, age 61±13.5 SD years, disease duration 9.3±6.7 SD years); the observed clinico-serological findings, in particular the presence of SSc-CV overlapping syndrome, were carefully analyzed and compared with previous data reported in the literature. RESULTS: The presence of circulating cryoglobulins was found in 7/246 (2.8%) of SSc patients; namely, 2 subjects only trace amounts of cryoglobulins, while 5 (2%) showed mixed cryoglobulinemia (type II, IgG-IgMk), low C4, rheumatoid factor seropositivity, and hepatitis C virus infection. Among SSc patients with serum mixed cryoglobulins, 4 (1.6%) developed a clinically overt CV, while the other one was totally asymptomatic with regard to typical vasculitic manifestations. Patients with SSc-CV overlapping syndrome had limited cutaneous SSc with serum anticentromere antibodies, pulmonary hypertension, clinico-serological features of HCV-related CV, and non-healing skin ulcers of the lower limbs. In all cases, the diagnosis of SSc preceded the clinical onset of CV, from 3 to 17years. The treatment with rituximab was useful on skin ulcers of lower limb in 2/3 patients; however, the overall clinical outcome of the four SSc-CV patients was unusually severe: one with very severe skin ulcers complicated by gangrene required bilateral through-the knee amputation, the other three subjects died because of severe heart failure, and in two cases because of untreatable pulmonary hypertension. In the literature, the prevalence of mixed cryoglobulinemia in scleroderma patients is quite rare (range 0.3-2%); while, the association of SSc with clinically overt CV is only anecdotally described, always in the absence of HCV infection. CONCLUSION: The SSc-CV overlapping syndrome described here is characterized by markedly severe vascular manifestations responsible for very poor prognosis; these peculiar clinical manifestations suggest a synergic activity of typical scleroderma microangiopathy and cryoglobulinemic vasculitis.

2013 - Unusual association between Budd–Chiari syndrome secondary to antiphospholipid syndrome and relapsing polychondritis: a case report and review of the literature [Articolo su rivista]
Sebastiani, Marco; C. U., Manzini; Campomori, Federica; Spinella, Amelia; C., Vacchi; D., Giuggioli; Schepis, Filippo; Ferri, Clodoveo
abstract

Relapsing polychondritis is a rare immune-mediated condition, characterized by episodic inflammation of the cartilaginous tissue, in particular the ears, nose, and eyes, and involvement of joints and respiratory tract. Nearly one third of patients showed other associated diseases, such as systemic vasculitides, connective tissue diseases, or myelodysplastic syndromes. Antiphospholipid antibodies can be found in relapsing polychondritis in patients with no clinical thrombotic disease. However, when antiphospholipid syndrome is present, its clinical manifestations can be severe and life threatening. We describe the case of a patient with relapsing polychondritis associated to Budd–Chiari syndrome due to antiphospholipid syndrome. The present clinical observations together with the updated review of the literature suggest a search for antiphospholipid antibodies in all patients with relapsing polychondritis.

2013 - Validation Study Of The International Classification Criteria For The Cryoglobulinemic Vasculitis [Abstract in Rivista]
Luca, Quartuccio; Miriam, Isola; Laura, Corazza; Soledad, Retamozo; Manal Abdel Moneim El, Menyawi; Elisa, Gremese; Sebastiani, Marco; Nicolo, Pipitone; Teresa, Urraro; Vincenza, Conteduca; Christos, Koutsianas; Benjamin, Terrier; Mostafa Naguib, Zoheir; Alessandra, Ghinoi; Davide, Filippini; Francesco, Saccardo; Mohamed Nabil, Salem; Salvatore, Scarpato; Paolo, Fraticelli; Antonio, Tavoni; Eleonora, Catarsi; Cesare, Mazzaro; Pietro, Pioltelli; Mervat, Matar; Patrizia, Scaini; Matija, Tomsic; Norihiro, Nishimoto; Dimitrios, Vassilopoulos; Michael, Voulgarelis; Gaafar M., Ragab; Salvarani, Carlo; Armando, Gabrielli; Patrice, Cacoub; Loic, Guillevin; Domenico, Sansonno; Anna Linda, Zignego; Gianfranco, Ferraccioli; Athanasios G., Tzioufas; Manuel Ramos, Casals; Ferri, Clodoveo; Maurizio, Pietrogrande; Giuseppe, Monti; Massimo, Galli; Stefano, Bombardieri; Salvatore De, Vita
abstract

Background/Purpose: preliminary Classification Criteria for cryoglobulinemic vasculitis (CV) have been developed in 2011 by an European cooperative study, with an adequate methodology in a large number of real cases and controls (1). The aim of this study is to validate these classification criteria for CV. Methods: Centres from Europe, United States, Japan and Egypt, were involved. A dedicated chart included: l) a validated questionnaire for CV (1); 2) the pattern of organ involvement (4 items: constitutional, articular, vascular and neurologic involvement); 3) laboratory tests (3 items: rheumatoid factor, complement C4 and serum monoclonal component), according to the preliminary criteria (1). New patients with CV (Group A) and controls (Group B), i.e., subjects with cryoglobulins but lacking CV based on the golden standard clinical judgment, were studied. A sample size of at least 140 patients for each group was estimated in order to obtain a sensitivity and a specificity of at least 90.5%, based on the previous results (1). Sensitivity and specificity were calculated by comparing Group A versus Group B. Finally, not for classification purposes, but to disclose whether the Criteria may be also clinically helpful in patients lacking serum cryoglobulins, but where CV is suspected (1), Group A was also compared with Group C, including patients with diseases mimicking CV, but without serum cryoglobulins. Results: Six hundred forty-three patients were enrolled in 22 Centres (from Italy, Spain, France, Greece, Slovenia, Japan and Egypt). MajorA comprised 268 patients with CV, Group B 182 controls with serum cryoglobulins without CV, and Group C 193 controls without serum cryoglobulins. Notably, 20 patients showed type I cryoglobulinemia, 13 in Group A, and 7 in Group B. Group C included 108/193 (55.9%) systemic vasculitides, 100/108 (92.6%) were small vessel vasculitides. The classification criteria [positivity of at least 2/3 items among questionnaire (2/3 positive questions), clinical item (3/4 clinical manifestations), laboratory (2/3 tests)] showed 89.9% (95% CI 86.1–93.6) of sensitivity and 93.5% (95% CI 89.7–97.2) of specificity, replicating previous results (1). Sensitivity of 91.7% and specificity of 100% were observed in the subgroup of type I cryoglobulinemia. By the comparison of Group A vs. Group C, the Criteria showed a specificity 92.6% (88.8–96.5) and a sensitivity of 77.8% (72.6–83.0) when the laboratory item was positive (questionnairelaboratory item; or clinical laboratory item). Conclusion: the International Classification Criteria for the CV have been validated in a new real cohort. High specificity and sensitivity were confirmed. Notably, in patients where CV is suspected on clinical grounds, but where cryoglobulins are negative by initial testing, or not yet available (patients who cannot be classified as CV, as positive serum cryoglobulinemia is a conditio sine qua non for classification) (1), the Criteria appear relevant to strengthen the suspicion for CV, and to optimize the follow-up.

2013 - Vasculiti ANCA associate [Capitolo/Saggio]
Ferri, Clodoveo; Colaci, Michele; Giuggioli, Dilia
abstract

INTRODUZIONE. Le vasculiti associate agli anticorpi contro proteine dei granuli citoplasmatici dei neutrofili (ANCA) fanno parte delle cosiddette vasculiti sistemiche, un gruppo di condizioni morbose caratterizzate dalla presenza di flogosi e necrosi della parete vascolare e da una marcata eterogeneità dal punto di vista eziopatogenetico, clinico e prognostico. In generale, nelle vasculiti, il processo infiammatorio può essere a carico di arterie di vario calibro e può coinvolgere anche le vene ed i piccoli vasi (arteriole, capillari e venule). La vasculite è la risultante di un processo immuno-mediato a cui partecipano sia cellule dell’immunità innata (macrofagi, neutrofili, eosinofili) sia i linfociti B e T; inoltre, un ruolo importante è rivestito anche da fattori circolanti quali autoanticorpi, immunocomplessi, complemento e numerosi mediatori della flogosi. Vi è un certo overlap fra i differenti quadri istopatologici collegabili alle varie sindromi vasculitiche, anche se in alcuni di essi si può osservare una prevalenza di specifici infiltrati cellulari: linfociti, monociti, granulociti neutrofili ed eosinofili, e/o cellule giganti di derivazione macrofagica. Altri aspetti riscontrabili con una certa frequenza a livello della parete vascolare sono la necrosi fibrinoide o il fenomeno della cosidetta leucocitoclasia (dissoluzione di leucociti con frammentazione nucleare), così come la formazione di tipiche lesioni granulomatose. La flogosi della parete vascolare facilmente induce fenomeni trombotici ed ischemici a livello delle diramazioni vascolari nei vari organi coinvolti; quando invece viene danneggiata la parete di un vaso di medio-grosso calibro, vi può essere un cedimento strutturale che provoca lesioni aneurismatiche e manifestazioni emorragiche, oppure si generano le caratteristiche stenosi cinconferenziali.

2012 - A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis [Articolo su rivista]
De Vita, S; Quartuccio, L; Isola, M; Mazzaro, C; Scaini, P; Lenzi, M; Campanini, M; Naclerio, C; Tavoni, A; Pietrogrande, M; Ferri, Clodoveo; Mascia, Maria Teresa; Masolini, P; Zabotti, A; Maset, M; Roccatello, D; Zignego, Al; Pioltelli, P; Gabrielli, A; Filippini, D; Perrella, O; Migliaresi, S; Galli, M; Bombardieri, S; Monti, G.
abstract

OBJECTIVE: To conduct a long-term, prospective, randomized controlled trial evaluating rituximab (RTX) therapy for severe mixed cryoglobulinemia or cryoglobulinemic vasculitis (CV).METHODS: Fifty-nine patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had hepatitis C virus (HCV) infection, treatment of the HCV infection with antiviral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 gm each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months.RESULTS: Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3% versus 3.5% [P < 0.0001]), as well as at 3 months (92.9% versus 13.8% [P < 0.0001]), 6 months (71.4% versus 3.5% [P < 0.0001]), and 24 months (60.7% versus 3.5% [P < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean ± SD of 11.9 ± 5.4 at baseline to 7.1 ± 5.7 at month 2; P < 0.001) up to month 24 (4.4 ± 4.6; P < 0.0001). RTX appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well tolerated.CONCLUSION: RTX monotherapy represents a very good option for severe CV and can be maintained over the long term in most patients.

2012 - Aortic pulse wave velocity measurement in systemic sclerosis patients. [Articolo su rivista]
Colaci, Michele; Giuggioli, Dilia; Manfredi, Andreina Teresa; Sebastiani, Marco; Coppi, Francesca; Rossi, Rosario; Richeldi, Luca; Ferri, Clodoveo
abstract

Background. Systemic sclerosis (SSc) is characterized by endothelial dysfunction and widespread microangiopathy. However, a macrovascular damage could be also associated. Aortic pulse wave velocity (aPWV) is known to be a reliable indicator of arterial stiffness and a useful prognostic predictor of cardiovascular events. Moreover, aPWV may be easily measured by non-invasive, user-friendly tool. Aim of our study was to evaluate aPWV alterations in a series of SSc patients. Methods. The aPWV was evaluated in 35 consecutive female SSc patients and 26 sex- and age-matched healthy controls. aPWV alterations were correlated with cardiopulmonary involvement. Results. A significant increase of aPWV was observed in SSc patients compared to controls (9.4±3.2 m/s vs 7.3±1 m/s; P=0.002). In particular, 14/35 (40%) SSc patients and only 1/26 (4%) controls (P=0.0009) showed increased aPWV (&gt;9 m/s cut-off value). Moreover, echocardiography evaluation showed an increased prevalence of right atrial and ventricular dilatation (atrial volume: 23.6±6.2 mL vs 20.3±4.3 mL, P=0.026; ventricular diameter 19.5±4.9 mm vs 15.9±1.6 mm; P=0.001) associated to higher values of pulmonary arterial systolic pressure (PAPs) in SSc patients (31.5±10.4 mmHg vs 21.6±2.9 mmHg; P&lt;0.0001; 40% of SSc patients showed an abnormal PAPs). Clinically, SSc patients presented a reduction of six-minute walking test (413±96 m vs 491±49 m; P=0.001), not correlated with pulmonary function tests. Increased aPWV values were evidenced only in SSc patients &gt;50 years old. Furthermore, altered aPWV was more frequently associated with limited cutaneous pattern, longer disease duration (≥5 years), and/or presence of anticentromere antibody (ACA). Conclusions. A significantly higher prevalence of abnormally increased aPWV was evidenced in SSc patients compared to healthy controls. The possibility of more pronounced and diffuse vascular damage in a particular SSc subset (ACA-positive subjects with limited cutaneous scleroderma and longer disease duration) might be raised.

2012 - Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study [Articolo su rivista]
Taraborelli, Mara; Ramoni, Véronique; Brucato, Antonio; Airò, Paolo; Bajocchi, Gianluigi; Bellisai, Francesca; Biasi, Domenico; Blagojevic, Jelena; Canti, Valentina; Caporali, Roberto; Caramaschi, Paola; Chiarolanza, Ilaria; Codullo, Veronica; Cozzi, Franco; Cuomo, Giovanna; Cutolo, Maurizio; De Santis, Maria; De Vita, Salvatore; Di Poi, Emma; Doria, Andrea; Faggioli, Paola; Favaro, Maria; Ferraccioli, Gianfranco; Ferri, Clodoveo; Foti, Rosario; Gerosa, Alessandro; Gerosa, Maria; Giacuzzo, Sarah; Giani, Leopoldo; Giuggioli, Dilia; Imazio, Massimo; Iudici, Michele; Iuliano, Annamaria; Leonardi, Roberto; Limonta, Massimiliano; Lojacono, Andrea; Lubatti, Chiara; Matucci Cerinic, Marco; Mazzone, Antonino; Meroni, Marianna; Meroni, Pier Luigi; Mosca, Marta; Motta, Mario; Muscarà, Marina; Nava, Simona; Padovan, Melissa; Pagani, Giorgio; Paolazzi, Giuseppe; Peccatori, Susanna; Ravagnani, Viviana; Riccieri, Valeria; Rosato, Edoardo; Rovere Querini, Patrizia; Salsano, Felice; Santaniello, Alessandro; Scorza, Raffaella; Tani, Chiara; Valentini, Gabriele; Valesini, Guido; Vanoli, Massimo; Vigone, Barbara; Zeni, Silvana; Tincani, Angela
abstract

OBJECTIVE.: To assess fetal and maternal outcomes in women with systemic sclerosis (SSc). METHODS.: Prospectively collected data were retrospectively analyzed. In 25 Italian centers 99 SSc women were observed during 109 pregnancies (in 2000-2011) and compared to the general obstetrical population (GOP, 3939 deliveries). Maternal mean age at conception was 31.8 years (SD 5.3) and median disease duration was 60 months (range 2-193). RESULTS.: In SSc patients preterm deliveries (25% vs. 12%) and severe preterm deliveries (&lt;34 weeks) (10% vs. 5%), intrauterine growth restriction (6% vs. 1%) and very-low-birth-weight babies (5% vs. 1%) were significantly more frequent than in the GOP. Multivariable analysis found that corticosteroid use was associated with preterm deliveries (OR 3.63, 95% CI 1.12-11.78), while the use of folic acid was protective (OR 0.30, 95% CI 0.10-0.91), as were antitopoisomerase antibodies (OR 0.26, 95% CI 0.08-0.85). The disease remained stable in most SSc patients, but there were four cases of progression within one year from delivery, all in antitopoisomerase-positive women, three of them with less than three years' disease duration. CONCLUSIONS.: SSc patients can have successful pregnancies, but they have a higher than normal risk of preterm delivery, intrauterine growth restriction and very-low-birth-weight babies. Progression of the disease during or after pregnancy is rare but possible. High-risk multidisciplinary management should be standard for these patients and pregnancy should be avoided in cases with severe organ damage and postponed in women with SSc of recent onset, particularly if antitopoisomerase positive.

2012 - Chemokine (CXC motif) ligand 9 serum levels in mixed cryoglobulinemia are associated with circulating levels of IFN-γ and TNF-α [Articolo su rivista]
Antonelli, A; Fallahi, P; Ferrari, Silvia Martina; Corrado, A; Sebastiani, Marco; Manfredi, Andreina Teresa; Frascerra, S; Miccoli, M; Zignego, Al; Ferrannini, E; Ferri, Clodoveo
abstract

OBJECTIVES: No study evaluated circulating chemokine (CXC motif) ligand (CXCL)9 in 'patients with mixed cryoglobulinaemia and hepatitis C virus chronic infection' (MC+HCV). We aimed to measure CXCL9, IFN-γ and TNF-α in a series of MC+HCV to correlate these parameters to different clinical phenotypes. METHODS: Serum CXCL9, IFN-γ and TNF-α were assayed in 54 MC+HCV, in 54 patients with HCV chronic infection (HCV+) and in 54 sex- and age-matched controls. RESULTS: MC+HCV showed significantly higher mean CXCL9 than HCV+ patients (p=0.01; ANOVA) or controls (p=0.0001; ANOVA), in particular in 21 cryoglobulinaemic patients with active vasculitis compared to those without (p<0.001; ANOVA). Serum IFN-γ (in patients with detectable IFN-γ) and TNF-α were significantly higher in MC+HCV than in controls (p<0.05, Mann-Whitney U test; p<0.0001, Mann-Whitney U-test; respectively). CXCL9, evaluated by classes of IFN-γ (IFN-γ<2; 2<IFN-γ<5; IFN-γ>5 pg/mL), or TNF-α (TNF-α<2; 2<TNF-α<10; TNF-α>10 pg/mL), showed a progressive, but not significant, increase of circulating values. When the combination of high circulating levels of IFN-γ and TNF-α (IFN-γ>2 and TNF-α>10 pg/mL vs. IFN-γ<2 and/or TNF-α<10 pg/mL) was evaluated, significantly higher CXCL9 levels were observed (p<0.01; ANOVA). CONCLUSIONS: We demonstrated markedly high serum levels of CXCL9 in MC+HCV (vs. HCV+ patients or healthy controls), significantly associated with the presence of active vasculitis. A strong relation among high levels of circulating IFN-γ, TNF-α and serum CXCL9 has been shown in MC+HCV. Larger patients' series will be needed to evaluate the relevance of serum CXCL9 determination as clinico-prognostic marker of MC+HCV

2012 - Cryoglobulinaemia and hepatitis C virus [Capitolo/Saggio]
Ferri, Clodoveo; Sebastiani, Marco; Saadoun, D; Cacoub, P.
abstract

description of mixed cryoglobulinemia, pathophisiology, clinica features, prognosis, therapy guidelines.

2012 - Current treatment of hepatitis C-associated rheumatic diseases. [Articolo su rivista]
Ferri, Clodoveo; Sebastiani, Marco; Antonelli, A; Colaci, Michele; Manfredi, Andreina Teresa; Giuggioli, D.
abstract

ABSTRACT: The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient's conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögren's syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient's evaluation, including hepatic, virological, and immunological findings.

2012 - Cytokines and HCV-Related Disorders. [Articolo su rivista]
Fallahi, P; Ferri, Clodoveo; Ferrari, Silvia Martina; Corrado, A; Sansonno, D; Antonelli, A.
abstract

Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-gamma-inducible CXC chemokine ligand (CXCL)-9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases-mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes-are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-alpha may result in viral clearance during persistent infection and reverts this process.

2012 - D-penicillamine in the treatment of eosinophilic fasciitis: case reports and review of the literature. [Articolo su rivista]
Manzini, C. U.; Sebastiani, Marco; Giuggioli, D.; Manfredi, Andreina Teresa; Colaci, Michele; Cesinaro, A. M.; Ferri, Clodoveo
abstract

Eosinophilic fasciitis (EF) is a rare disease characterized by symmetrical thickness and hardening of the skin, especially localized to forearms and thorax, with eosinophilia. Corticosteroids represent the first-line therapy, even if some patients are scarcely responsive and/or may develop important side effects due to long-term treatment. Here, we describe three cases of EF, two of them refractory to previous steroid therapy, successfully treated with D-penicillamine. The present clinical observations together with the updated review of the literature suggest usefulness of D-penicillamine in EF patients, as well as its potential steroid-sparing value.

2012 - Endocrine Manifestations of HCV-Positive Cryoglobulinemia [Capitolo/Saggio]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Colaci, Michele; Corrado, A; Di Domenicantonio, A; Fallahi, P.
abstract

illustrations of endocrine disorders in patients with HCV-related mixed cryoglobulinemia

2012 - Factors Influencing Choice of Rituximab Versus an Alternative Tumor Necrosis Factor Inhibitor Following Tumor Necrosis Factor Inhibitor Failure in Patients with Rheumatoid Arthritis: Sub-Analysis of a Global, Observational Comparative Effectiveness Study [Abstract in Rivista]
Axel, Finckh; Jacques Eric, Gottenberg; Chiedzo, Mpofu; William, G. Bensen; Andrea, Rubbert Roth; Fedra, Irazoque; Victor, Martı’nez Taboada; Carol, Chung; Lykke, Hinsch Gylvin; Ferri, Clodoveo; Paul, Emery
abstract

Rituximab is more effective to treat rheumatoid arthritis compared to a second anti-TNFalpha blockers.

2012 - HEPATITIS C IS ASSOCIATED WITH HIGH LEVELS OF CIRCULATING N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE AND INTERLEUKIN-6 [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Di Domenicantonio, A; Mancusi, C; Marchi, S; De Bortoli, N; Metelli, Mr; Bruschi, F; Fallahi, P.
abstract

To our knowledge, no study has evaluated N-terminal pro-brain natriuretic peptide (NTproBNP) together with interleukin-6 (IL-6) and interferon (IFN)-gamma serum levels in a large series of patients with hepatitis C virus (HCV) as possible markers of cardiac dysfunction. NTproBNP and IL-6 serum levels were valued in 55 HCV-patients, and in 55 sex- and age-matched controls. HCV-patients showed significantly higher mean NTproBNP and IL-6 levels than controls (P= 0.001); no significant difference was observed for IFN-gamma. By defining high NTproBNP level as a value higher than 300 pg/mL (that is used to rule out heart failure in patients under 75 years of age), 12% (6/49) of HCV-patients and 0 of controls had NTproBNP (chi(2); P = 0.012). In conclusion, this study demonstrates high levels of circulating NTproBNP and IL-6 in HCV-patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunction. Further prospective studies quantifying symptoms and correlating these with echocardiographic parameters are needed to confirm this association.

2012 - High Levels of Circulating Chemokine (C-X-C motif) Ligand 11 Are Associated with Euthyroid or Subclinically Hypothyroid Autoimmune Thyroiditis and with Chemokine (C-X-C Motif) Ligand 10 [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Frascerra, S; Ruffilli, I; Caponi, L; Ulisse, S; Miccoli, M; Miccoli, P; Fallahi, P.
abstract

No data are available for chemokine (C-X-C motif) ligand 11 (CXCL11), together with CXCL10, circulating levels in autoimmune thyroiditis (AT). We measured serum CXCL11 and CXCL10 in 158 patients with newly diagnosed AT (26% with subclinical hypothyroidism), 56 euthyroid controls, and 20 patients with nontoxic multinodular goiter, all similar in gender distribution and age. CXCL11 was significantly higher in patients with AT (113±56 pg/mL) than in controls (67±16 pg/mL) or patients with multinodular goiter (75±18 pg/mL; P<0.0001). Among patients with AT, CXCL11 was significantly higher in those with a hypoechoic ultrasonographic pattern and hypothyroidism. In a multiple linear regression (MLR) model including age, thyroid volume, hypoechogenicity, hypervascularity, thyroid-stimulating hormone (TSH), and anti-thyroid peroxidase, age (P=0.009) and TSH (P<0.008) were significantly related to serum CXCL11. In an MLR model of CXCL11 (ln[pg/mL]) versus age, TSH, CXCL10 (ln[pg/mL]), TSH (P=0.028), and CXCL10 (P=0.003) were significantly and independently related to CXCL11. We first show that circulating CXCL11, together with CXCL10, is increased in patients with thyroiditis and hypothyroidism, and is related to CXCL10 levels. These results underline the importance of a Th1 immune attack in the initiation of AT.

2012 - KIENBOCK DISEASE IN A PATIENT WITH SSc: A CASE REPORT [Abstract in Rivista]
Lumetti, Federica; Manfredi, Andreina Teresa; Giuggioli, Dilia; Mascia, Maria Teresa; Marcuzzi, A; Ferri, Clodoveo
abstract

not available

2012 - Kienböck Disease in a patient with systemic sclerosis: a case report. [Abstract in Rivista]
Lumetti, F; Manfredi, Andreina Teresa; Giuggioli, D; Mascia, Maria Teresa; Marcuzzi, A; Ferri, Clodoveo
abstract

Kienböck's disease (KD), described by Robert Kienböck in 1910, is a rare disease characterized by osteonecrosis of the carpal lunate bone. The dominant hand of males in adulthood is predominantly affected, with peak of incidence between the second and fourth decade. The KD is rarely bilateral; early diagnosis is based on MRI or CT findings. The etiology of KD is uncertain, but the theory of repeated traumatism/microtraumatism associated with vascular changes is considered to be a reliable hypothesis. We describe the rare case of a patient followed in our Rheumatology Unit affected by systemic sclerosis (SSc) since 1996 and recently complicated by KD.

2012 - La capillaroscopia in reumatologia. Lesioni elementari e metodi di scoring [Monografia/Trattato scientifico]
R., De Angelis; Ferri, Clodoveo; Sebastiani, Marco; Manfredi, Andreina Teresa; W., Grassi
abstract

La capillaroscopia rappresenta una metodica d’indagine “non invasiva” di indiscusso valore nel riconoscimento delle anomalie morfologiche e funzionali del microcircolo. Il suo impiego risale agli inizi del XX secolo, ma è solo negli anni ’70 che raggiunge una collocazione precisa in ambito reumatologico con gli studi di Hildegard Maricq. Da allora, le applicazioni della capillaroscopia si sono progressivamente estese, fino a costituire un esame irrinunciabile nei pazienti con fenomeno di Raynaud e a rivestire un ruolo di primissimo piano nell’approccio diagnostico e prognostico della sclerosi sistemica. In Italia, la capillaroscopia rientra tra le metodiche che sono oggetto di apprendimento obbligatorio per tutti gli iscritti alla Scuola di Specializzazione in Reumatologia ed il training capillaroscopico è costantemente promosso nell’ambito dei progetti di formazione supportati dall’ European League Against Rheumatism (EULAR). Le future applicazioni della capillaroscopia nel campo della ricerca clinica sembrano essere promettenti. Sarà possibile monitorare l’effetto di specifiche terapie vasoattive o immunosoppressive a livello dei capillari periungueali nel contesto di appositi trial, con l’intento di sviluppare nuovi trattamenti “mirati” alla prevenzione del danno capillare.

2012 - Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: Comparison of adalimumab, etanercept and infliximab in the GISEA registry. [Articolo su rivista]
Atzeni, F; Sarzi Puttini, P; Botsios, C; Carletto, A; Cipriani, P; Favalli, Eg; Frati, E; Foschi, V; Gasparini, S; Giardina, A; Gremese, E; Iannone, F; Sebastiani, Marco; Ziglioli, T; Biasi, D; Ferri, Clodoveo; Galeazzi, M; Gerli, R; Giacomelli, R; Gorla, R; Govoni, M; Lapadula, G; Marchesoni, A; Salaffi, F; Punzi, L; Triolo, G; Ferraccioli, G.
abstract

OBJECTIVE: To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS: The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4years; mean disease duration 9.0±8.3years) enrolled in the GISEA register, who had been treated for at least 6months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS: 176 patients had experienced at least one of the 226 Sis during the 9years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS: Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

2012 - Longterm retention of tumor necrosis factor-α inhibitor therapy in a large italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors [Articolo su rivista]
Iannone, Florenzo; Gremese, Elisa; Atzeni, Fabiola; Biasi, Domenico; Botsios, Costantino; Cipriani, Paola; Ferri, Clodoveo; Foschi, Valentina; Galeazzi, Mauro; Gerli, Roberto; Giardina, Annarita; Marchesoni, Antonio; Salaffi, Fausto; Ziglioli, Tamara; Lapadula, Giovanni; Bambara, Ml; Cantini, F; Ferraccioli, G; Foti, R; Giacomelli, R; Gorla, R; Grassi, W; Mathieu, A; Olivieri, I; Passiu, G; Punzi, L; Salvarani, Carlo; Sarzi Puttini, P; Scarpa, R; Triolo, G; Trotta, F.
abstract

OBJECTIVE: To evaluate 4-year retention rates of tumor necrosis factor-α (TNF-α) inhibitors adalimumab, etanercept, and infliximab among patients with longstanding rheumatoid arthritis (RA), as derived from an Italian national registry.METHODS: The clinical records of 853 adult patients with RA in the GISEA (Gruppo Italiano Studio Early Arthritis) registry were prospectively analyzed to compare drug survival rates and the baseline factors that may predict adherence to therapy.RESULTS: In 2003 and 2004, 324 patients started treatment with adalimumab, 311 with etanercept, and 218 with infliximab. After 4 years, the global retention rate of anti-TNF-α therapy was 42%. Etanercept survival (51.4%) was significantly better than that of infliximab (37.6%) or adalimumab (36.4%; p &lt; 0.0001). Accordingly, the mean duration of therapy was significantly longer for etanercept (3.1 ± 2 yrs) than for adalimumab (2.6 ± 2 yrs) or infliximab (2.7 ± 2 yrs; p &lt; 0.05). The use of concomitant disease-modifying antirheumatic drugs, mainly methotrexate, and the presence of comorbidities significantly predicted drug continuation (p &lt; 0.01), whereas a high Disease Activity Score did not.CONCLUSION: The 4-year global drug survival of adalimumab, etanercept, and infliximab was lower than 50%, with etanercept having the best retention rate. The main positive predictor of adherence to anti-TNF-α therapy was the concomitant use of methotrexate. Our study provides further evidence that the real-life treatment of patients with RA may be different from that of randomized clinical trials.

2012 - MESENCHYMAL STEM CELLS MODULATE IN VITRO FIBROBLAST ACTIVITY IN SYSTEMIC SCLEROSIS [Abstract in Rivista]
Quirici, N; Corti, L; Scavullo, C; Maglione, W; Comina, Dp; Ferri, Clodoveo; Deliliers, Gl; Del Papa, N.
abstract

not available

2012 - PATIENTS WITH MIXED CRYOGLOBULINEMIA AND HCV INFECTION, IN PRESENCE OR ABSENCE OF AUTOIMMUNE THYROIDITIS, HAVE HIGH SERUM LEVELS OF (CXC MOTIF) LIGAND (CXCL)9 AND CXCL11 CHEMOKINES [Articolo su rivista]
Antonelli, A; Fallahi, P; Ferrari, Silvia Martina; Frascerra, S; Corrado, A; Colaci, Michele; Manfredi, Andreina Teresa; Maccheroni, M; Sansonno, D; Zignego, Al; Centanni, M; Ferri, Clodoveo
abstract

No data are present in the literature regarding chemokine (CXC motif) ligand (CXCL)9 and CXCL11 circulating levels in cryoglobulinemia associated with hepatitis C (MC+HCV), in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCL11 have been measured in 38 MC+HCV patients without AT (MCo), 38 MC+HCV patients with AT (MC+AT), and in matched controls without (control 1) or with thyroiditis (control 2). Serum CXCL9 and CXCL11 were significantly higher: in control 2 than control 1 (p&lt;0.05); in MCo than control 1 and control 2 (p&lt;0.001, for both); in MC+AT than control 1 and control 2 (p&lt;0.0001, for both), and than MCo (p=0.01, for both). Our study demonstrates markedly high serum levels of CXCL9 and CXCL11 in patients with MC+HCV compared to healthy controls; in MC+HCV patients increased CXCL9 and CXCL11 levels were significantly associated with the presence of AT. Moreover, a strong relation between circulating CXCL9 and CXCL11 in MC+HCV has been shown.

2012 - Performance of the preliminary classification criteria for cryoglobulinaemic vasculitis and clinical manifestations in hepatitis C virus-unrelated cryoglobulinaemic vasculitis [Articolo su rivista]
L., Quartuccio; M., Isola; L., Corazza; M., Maset; G., Monti; A., Gabrielli; A., Tzioufas; Ferri, Clodoveo; G., Ferraccioli; M., Ramos Casals; M., Voulgarelis; M., Lenzi; Mascia, Maria Teresa; D., Sansonno; P., Cacoub; M., Tomsic; A., Tavoni; M., Pietrogrande; A., Zignego; S., Scarpato; P., Pioltelli; S., Steinfeld; P., Lamprecht; M., Galli; S., Bombardieri; S., De Vita
abstract

Abstract: Background. Cryoglobulinaemic vasculitis (CV) is often related to hepatitis C virus (HCV) infection, but it can develop in other diseases (e.g. other infections, connective tissue diseases, malignancies) in the absence of HCV infection. A comparison of the performance of the recently published classification criteria for the CV was made between HCV-positive and HCV negative patients with serum cryoglobulins. Patient and methods. 500 patients with serum cryoglobulins were studied. Their mean age was 60.77+/-13.75 years, they were 356 females (71.2%) and 144 males (28.8%). CV was diagnosed in 272 patients (54.4%), while other diseases associated with serum cryoglobulins without CV (CwV) were diagnosed in 228 patients (45.6%). Results. 117 HCV negative patients were collected (23.4%) and they were 421272 (15.4%) among the CV group, while they were 75/228 (32.9%) among the CwV. In HCV negative patients the sensitivity and specificity of the classification criteria of CV were 89.5% CI 95% [79.5-99.5] and 90.3% CI 95% [82.8 97.8], respectively, while in HCV positive patients they were 88.3% CI 95% [83.6%-93.1%] and 96.1% CI 95% [91.8-100], respectively. The most frequent disease recognised among the HCV negative patients was Sjogren's syndrome (SS) (551117, 47.0%), and the sensitivity and the specificity of the CV classification criteria were 88.9% CI 95% [76.5-100] and 91.3% CI 95% [79.2-100], respectively. Conclusions. The classification criteria for CV showed a good performance even in HCV-unrelated patients. A slightly lower specificity was observed for the classification of HCV-unrelated CV, since some clinical manifestations included in the clinical item for the classification criteria occurred more frequently in HCV-negative rather than HCV-positive controls with CWV.

2012 - Phantom Limb Pain in Patients with Severe Cryoglobulinemic Vasculitis: Usefulness of Long-Term Pregabalin Treatment [Articolo su rivista]
Giuggioli, Dilia; Sebastiani, Marco; Ferri, Clodoveo
abstract

Background Phantom limb pain [PLP] may complicate limb amputation. This symptom has been never described in patients with mixed cryoglobulinemia [MC] syndrome. Findings. We observed three patients with hepatitis-C virus-related MC complicated by severe skin vasculitis responsible for gangrene needing limb amputation. After surgery, they developed refractory PLP and stump pain, which was successfully treated with pregabalin. Conclusions A clear improvement of PLP was observed in all patients during pregabalin; in addition, this treatment permitted an effective bed preparation and intensive medications of relapsing vasculitic ulcers in the stump, followed by complete resolution of skin lesions. At the same time, traditional analgesic therapies, potentially responsible for relevant side effects, were progressively tapered until discontinuation.

2012 - Platelet gel in the treatment of severe scleroderma skin ulcers. [Articolo su rivista]
Giuggioli, D.; Colaci, Michele; Manfredi, Andreina Teresa; Mariano, M.; Ferri, Clodoveo
abstract

Systemic sclerosis (SSc) is characterized by microvascular damage and fibrosis of the skin and internal organs. Non-healing skin ulcers, mainly non-venous leg ulcers, represent one of the most challenging complications. Platelet gel (PG) is a hemocomponent containing numerous growth factors, potentially useful for tissue reparation. This pilot open study aimed to evaluate the effect of PG in 12 SSc patients with skin ulcers resistant to conventional therapies from at least 6 months. PG was applied in the wound bed twice weekly for 2 weeks, then once a week for 12 weeks; in all cases, the ongoing treatments remained unchanged at the time of PG applications. Skin ulcers were evaluated at 0, 12 and 24 weeks; the patient's quality of life was also evaluated using the visual analogical scale (VAS) and the health assessment questionnaire (HAQ). During the 6-month follow-up, the skin ulcers consistently improved in 10/12 patients, with complete healing in 4. At the last evaluation, wound size reduced from 23.4 ± 14.9 SD to 2.3 ± 2.2 SD cm(2) (p < 0.0001). Patient's quality of life markedly improved: VAS decreased from 87.08 ± 13.5 to 57.9 ± 12.6; p < 0.0001 and HAQ from 0.73 ± 0.43 to 0.57 ± 0.22; p < 0.0001. PG may represent a novel therapeutic option for SSc skin ulcers refractory to conventional treatments.

2012 - Polymyositis following Pandemic Influenza A (H1N1) and 2009-10 Seasonal Trivalent Vaccines [Articolo su rivista]
Ferri, Clodoveo; Colaci, Michele; Manzini, Cu; Sebastiani, Marco; Giuggioli, D; Brugioni, L.
abstract

Sporadic associations between inflammatory myopathies with vaccinations were described in the literature, raising the possible trigger value of vaccines in the development of these autoimmune disorders. Here, we reported the clinical history of 3 patients who developed polymyositis complicated by interstitial lung disease (2 cases) and dermatomyositis (1 case), after influenza A (H1N1) vaccination.

2012 - Predictive role of capillaroscopic skin ulcer risk index in systematic sclerosis: a multicentre validation study [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Vukatana, G; Moscatelli, S; Riato, L; Bocci, M; Iudici, M; Principato, A; Mazzuca, S; Del Medico, P; De Angelis, R; D'Amico, Roberto; Vicini, Roberto; Colaci, Michele; Ferri, Clodoveo
abstract

Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In 2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula 'D×M/N(2'), was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation.OBJECTIVES:This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients.METHODS:CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers.RESULTS:57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514.CONCLUSIONS:The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.

2012 - PSYCHIATRIC DISORDERS IN RHEUMATOLOGY: EVALUATION OF A SCREENING PROTOCOL IN 100 HOSPITALIZED PATIENTS [Abstract in Rivista]
Lumetti, Federica; Giuggioli, Dilia; Manfredi, Andreina Teresa; Ferrari, D; Tedeschini, E; Simoni, E; Rigatelli, Marco; Ferri, Clodoveo
abstract

not available

2012 - RECRUITMENT OF CD271(+) MESENCHYMAL STEM CELLS FROM BONE MARROW TO SKIN IN ACTIVE SSc: A ROLE IN FIBROSIS DEVELOPMENT [Abstract in Rivista]
Quirici, N; Corti, L; Scavullo, C; Ferri, Clodoveo; Manfredi, Andreina Teresa; Giuggioli, Dilia; Deliliers, Gl; Del Papa, N.
abstract

not available

2012 - RET TKI: potential role in thyroid cancers. [Articolo su rivista]
Antonelli, A; Fallahi, P; Ferrari, Silvia Martina; Mancusi, C; Colaci, Michele; Santarpia, L; Ferri, Clodoveo
abstract

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (RET/PTC) or signaling kinases (vascular endothelial growth factor receptor [VEGFR]) involved in cellular growth and proliferation. Some clinical trials have been conducted showing the ability of targeted therapies able to inhibit RET(sorafenib, imatinib, vandetanib) in stabilizing the course of the disease. The aim of the introduction of these targeted therapies is to extend life duration assuring a good quality of life; however, further studies are needed to reach these goals.

2012 - Scleroderma digital ulcers complicated by infection with fecal pathogens. [Articolo su rivista]
Giuggioli, D.; Manfredi, Andreina Teresa; Colaci, Michele; Lumetti, F.; Ferri, Clodoveo
abstract

OBJECTIVE: Digital ulcers represent one of the most frequent complications of systemic sclerosis (SSc; scleroderma); they are very painful, scarcely responsive to treatment, and often responsible for marked limitations on daily activities, including patient self-care. Infectious complications may severely compromise the outcome of skin lesions in a significant percentage of patients. Numerous pathogens of different origin may be involved, including bacteria from patient endogenous flora. Here we evaluated the possible involvement of fecal pathogens in scleroderma digital ulcers.METHODS: Among a series of 82 SSc patients with digital ulcers, we retrospectively analyzed 42 subjects with clinical signs of local bacterial infection. All digital ulcers with suspected infection have been investigated by microbiologic examinations.RESULTS: Bacterial infection was confirmed in all 42 patients investigated; in particular, Staphylococcus aureus were the most frequently found (50%). Interestingly, 11 (26%) of 42 patients showed digital ulcers infected with intestinal bacteria; specifically, 7 patients were positive for Escherichia coli and 4 for Enterococcus faecalis. Diffuse cutaneous SSc patients were more numerous in this subgroup versus the other 31 patients (Fisher's P = 0.011).CONCLUSION: A number of effective measures involving health care personnel and hospital environment are essential in the management of digital ulcers and prevention of infectious complications. In addition, the prevalence of fecal pathogens in one-quarter of cases, never reported previously, suggests an important role of a patient's self-care limitations, mainly during intercurrent home medications. Consequently, methodical education on hand hygiene of both patients and relatives, frequently involved in ulcer medications, is mandatory to avoid such deleterious complications.

2012 - Serum a-Chemokine CXCL10 and b-Chemokine CCL2 Levels in HCV-Positive Cryoglobulinemia [Capitolo/Saggio]
Antonelli, A; Ferri, Clodoveo; Ferrari, Sm; Colaci, Michele; Ruffilli, I; Mancasi, C; Ferrannini, E; Fallahi, P.
abstract

illustration of the increase of serum levels of chemokines (CXCL10 and CCL2) in patients with mixed cryoglobulinemia, particularly in the case of active vasculitis

2012 - Systemic sclerosis fibroblasts show specific alterations of interferon-γ and tumor necrosis factor-α-induced modulation of interleukin 6 and chemokine ligand 2. [Articolo su rivista]
Antonelli, A; Fallahi, P; Ferrari, Silvia Martina; Giuggioli, D; Colaci, Michele; Di Domenicantonio, A; Ferri, Clodoveo
abstract

OBJECTIVE: We evaluated the effect of interferon-γ (IFN-γ) and/or tumor necrosis factor-α (TNF-α) on the secretion of prototype proinflammatory cytokine interleukin 6 (IL-6), compared to T-helper 1 [Th1; chemokine (C-X-C motif) ligand 10 (CXCL10)] or Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines, in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease.METHODS: Fibroblast cultures from 5 SSc patients (disease duration &lt; 2 yrs) and 5 healthy controls were evaluated for the production of IL-6, CXCL10, and CCL2 at the basal level and after stimulation with IFN-γ and/or TNF-α.RESULTS: SSc fibroblasts basally produced higher levels of IL-6 than controls, while no difference was observed about CCL2 and CXCL10. TNF-α was able to dose-dependently induce IL-6 and CCL2 secretion in SSc, but not in control fibroblasts. By stimulation with increasing doses of IFN-γ, SSc fibroblasts were induced to secrete CCL2 and CXCL10, while no effect was observed on IL-6. The combination of IFN-γ and TNF-α induced a strong secretion of IL-6 and CCL2 in SSc fibroblasts but not in controls. In contrast, the synergistic effect of IFN-γ and TNF-α on CXCL10 secretion was similar in SSc fibroblasts and in controls.CONCLUSION: SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, CXCL10, and CCL2 under the influence of IFN-γ and/or TNF-α. SSc fibroblasts are more active than controls in the secretion of IL-6 at baseline, and in the production of IL-6 and CCL2 under the combined IFN-γ/TNF-α stimulation.

2012 - The Expanding Spectrum of Clinical Features in HCV-Related Mixed Cryoglobulinemia [Capitolo/Saggio]
Ferri, Clodoveo; A., Antonelli; Sebastiani, Marco; Colaci, Michele; A. L., Zignego
abstract

Mixed cryoglobulinemia (MC) is a relatively rare disorder that may complicate numerous infectiousor immuno/hematological diseases. Classical MC syndrome is associated with hepatitis C virus (HCV)infection in the large majority of patients and the virus is suspected in the etiopathogenesis of the disease.MC syndrome, or cryoglobulinemic vasculitis, is characterized by a clinical triad of purpura, weakness,and arthralgias and by variable organ and, in many cases, endocrine involvement. As a late complication,some patients develop malignancies, particularly B-cell lymphomas and/or hepatocellular carcinoma.To date, there are no available diagnostic criteria for MC, but classification criteria must account for itsserological and clinical hallmarks. Leukocytoclastic vasculitis, especially of the small blood vessels,is the typical pathological finding of affected tissues. An important pathogenetic step in MC is HCVlymphotropism, which is responsible for poly/oligoclonal B-lymphocyte expansion. The consequence isa wide production of different autoantibodies and immune complexes, mainly cryoglobulins, responsiblefor organ- and non-organ-specific immunological alterations. Thus, MC, characterized by the simultaneouspresence of autoimmune and lymphoproliferative diseases, is the crossroads of these disorders andrepresents the prototype of HCV-associated pathologies. The oncogenic potential of HCV is demonstratedby several studies showing its pathogenetic link with some malignancies, particularly the hepatocellularcarcinoma and B-cell lymphomas. HCV-related disorders have a heterogeneous geographical distribution,suggesting other important genetic and/or environmental co-factors. Although the majority of individualswith chronic HCV infection exhibit hepatic manifestations only or are totally asymptomatic, a notnegligible percentage develop autoimmune and/or lymphoproliferative/neoplastic disorders through amultifactorial and multistep pathogenetic process, reflected by the name “HCV syndrome.”

2012 - The pathogenesis of the anaemia of chronic disorders. [Articolo su rivista]
Manzini, Cu; Manzini, E; Ferri, Clodoveo
abstract

Anemia of chronic disorders is a typical condition of infective, immunological and neoplastic diseases. Hepcidin and proinflammatory cytokines play a leading role in its pathogenesis. Hepcidin is a hormone produced by the liver that controls iron metabolism. It ensures that iron is retained by enterocytes (where the metal is absorbed) and by macrophages (that store the iron that results from the physiological breakdown of erythrocytes). Cytokines play a role in hepcidin synthesis, and in the proliferation and the maturation of the erythroid components within bone marrow. This paper discusses the pathogenetic mechanisms of anemia in chronic disorders.

2011 - CAPILLAROSCOPIC SKIN ULCER RISK INDEX (CSURI) IN SYSTEMIC SCLEROSIS: RESULTS FROM AN ITALIAN MULTICENTER VALIDATION STUDY [Abstract in Rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Riato, L.; Bocci, M.; Iudici, M.; Vukatana, G.; Moscatelli, S.; Principato, A.; Mazzuca, S.; Del Medico, P.; De Angelis, R.; Giuggioli, D.; Colaci, Michele; Ferri, Clodoveo
abstract

Background: Digital ulcers (DU) represent one of the most frequent complications of microangiopathy in systemic sclerosis (SSc). Recently, we developed a capillaroscopic skin ulcers risk index (CSURI), to detect patients at risk to develop DU. CSURI takes into account maximum capillary diameter (D) in a videocapillaroscopic image, number of giant capillaries (M), and number of capillaries (N), following the formula: D × M/N2. CSURI showed a sensitivity and specificity of 94.3% and 85.9% respectively, at the cut-off value of 2.94, with an area under a ROC curve of 0.926.Objectives: Aim of our multicenter study is to validate the predictive value (PV) of CSURI in a larger series of SSc patients (pts).Methods: Two hundred and fifty-nine unselected SSc pts from 10 Italian rheumatologic centers were consecutively enrolled for the study during a six-month period. Capillaroscopic parameters were defined and collected according to our previous study. With regards to their clinical history of DU, 106 pts have never experienced DU, 63 have had DU more than one year before, 42 have experienced ulcers in the last year, while 48 pts presented DU at the baseline. All pts underwent videocapillaroscopy at baseline; after three-month follow-up, they were evaluated for the possible development or persistence of DU.Results: During the follow-up period, DU were observed in 71/259 pts; in particular, 48 subjects experienced new DU, whereas 23 pts showed the persistence of ulcers already present at the baseline. The ROC curve analysis showed an area under the curve of 0.861 (95%CI 0.812-0.901) for new ulcer appearance or non-healing ulcers, with specificity and sensitivity of 78.1% (95%CI 71.6–83.8) and 92.96% (95%CI 84.3–97.6) respectively, at the cut-off value of 2.96 (the positive and negative likelihood ratios were 4.26 and 0.09 respectively).The overall PV of CSURI was 61.7%. On the other hand, the negative PV was confirmed to be very high (96.7%), considering that only 5/152 pts with CSURI ≤2.96 had DU. Among pts with recent history of DU, 58.9% of them presented DU within 3 months by NVC. In this group, CSURI had a positive PV of 78.5% and a negative PV of 92%. With regard to the healing of DU, 23 pts continued to have DU 3 months and CSURI showed a negative PV of healing of 80.8%. On the contrary, 81.8% of the pts with CSURI <2.96 showed a regression of DU. Of interest, 15/18 pts without a recent history of DU, and with DU during the follow-up, were correctly identified by CSURI.Conclusions: This multicenter study confirms the high PV of CSURI, which is able to identify SSc pts at high risk to develop new DU. The introduction of this reliable tool in the clinical practice may permit the early detection of these pts, along with a better preventive treatment strategy and reduction of morbidity and social costs.

2011 - Circulating CXCL11 and CXCL10 are increased in hepatitis C-associated cryoglobulinemia in the presence of autoimmune thyroiditis. [Articolo su rivista]
A., Antonelli; P., Fallahi; Ferrari, Silvia Martina; Sebastiani, Marco; Manfredi, Andreina Teresa; V., Mazzi; S., Fabiani; M., Centanni; S., Marchi; Ferri, Clodoveo
abstract

OBJECTIVE:No data are available about circulating levels of the CXCL11 chemokine in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) patients with or without autoimmune thyroiditis (AT). The aim of the present study, therefore, was to evaluate serum CXCL11 levels in these patients.DESIGN:Serum CXCL11 (and for comparison, CXCL10) was measured in 45 patients with MC, 45 patients with MC and AT (MC + AT), 45 sex- and age-matched controls without AT (control 1), 45 sex- and age-matched patients with AT without cryoglobulinemia (control 2), and in 45 sex- and age-matched patients with hepatitis C chronic infection without MC (HCV+).RESULTS:Serum CXCL11 and CXCL10 levels were significantly higher in control 2 than in control 1 (p < 0.01). MC patients had CXCL11 and CXCL10 significantly higher than control 1 (p < 0.01). MC + AT patients had CXCL11 and CXCL10 higher than control 2 (p < 0.01) and MC patients (p = 0.02). Serum CXCL11 levels were not associated with any of the clinical features of cryoglobulinemia in patients with MC and MC + AT, which was the same for CXCL10. CXCL10 and CXCL11 in HCV+ patients were significantly higher than in controls 1 and 2, but lower than in MC or MC+AT patients.CONCLUSION:Our study first demonstrates higher serum levels of CXCL11 chemokine in patients with MC than in HCV+ patients, and in particular in the presence of AT.

2011 - Efficacy and safety of peginterferon alfa-2b plus ribavirin for HCV-positive mixed cryoglobulinemia: a multicentre open-label study [Articolo su rivista]
Mazzaro, C; Monti, G; Saccardo, F; Zignego, Al; Ferri, Clodoveo; De Vita, S; Gabrielli, A; Lenzi, M; Donada, C; Galli, M; Pietrogrande, M; Pozzato, G.
abstract

OBJECTIVES: The aim of the present study is to provide information on clinical outcome of the patients affected by HCV-positive mixed cryoglobulinemia (MC) treated with PEG-IFN and Ribavirin for 6 or 12 months according to the HCV genotype.METHODS: Eighty-six patients (42 women and 44 men) were enrolled in 8 Italian centres. All the patients had MC in the active phase of the disease. The patients received Peginterferon alfa-2b 1.5 mcg/kg/once a week (QW) and daily oral Ribavirin (800/1,000/1,200) according to their body weight for 48 weeks for genotype 1 and 4 and for 24 weeks for genotypes 2 and 3.RESULTS: In the 44 patients who underwent 12 months of therapy, 17 cases (39%) could be considered as 'non-responders' and 11 relapsed, therefore only 16 patients (36%) obtained a sustained virological response. In the 42 patients who underwent six months of therapy only 7 cases (17%) could be considered as 'non-responders' and 8 relapsed, therefore 27 patients (64%) obtained a sustained virological response. Purpura score dropped in both group (p<5.79 x 10-17) and only 5 cases of the group A (11%) and 5 of the group B (12%) did not show any improvement. Arthralgias showed a similar behaviour. Many patients relapsed after the end of the treatment.CONCLUSIONS: This study documents a lower response rate than that observed in the clinical trials with HCV chronic hepatitis, but the presence of comorbidities and older age should be taken into consideration. Most patients (88.5%) showed a complete and persistent recovery from clinical symptoms.

2011 - Epstein-barr virus reactivation after infliximab in rheumatoid arthritis: a case report. [Articolo su rivista]
Colaci, Michele; Sebastiani, Marco; Sandri, Gilda; Meacci, M; Ferri, Clodoveo
abstract

TNF-alpha blockers represent one of the most important therapeutic strategies for rheumatoid arthritis, but their use has raised the question about their safety profile, particularly in respect to viral infections/reactivations. We describe the case of a patient who developed a symptomatic EBV reactivation 11 days after the first infusion of infliximab.

2011 - GISEA: an Italian biological agents registry in rheumatology [Articolo su rivista]
G., Lapadula; G., Ferraccioli; Ferri, Clodoveo; L., Punzi; F., Trotta
abstract

The GISEA registry is an independent database that was established by the Italian Group for the Study of Early Arthritis (GISEA) in 2008, funded by the Italian Association of Rheumatic Patients (ANMAR - ONLUS). In line with the network's epidemiological strategy, the initial protocol was designed to collect long-term follow-up data concerning patients with rheumatic diseases treated with biological agents in order to investigate the realworld characteristics in terms of disease activity, comorbidities and survival on treatment. We here describe the design and methodology used to collect patient data. Information concerning demographics, disease activity, treatment changes (including the reasons for changing and the duration of each therapy), concomitant therapies and adverse events is available to all the members of the study groups by means of a web-based interface that allows queries and the presentation of numerical data, as well as graphics to illustrate trends. Fourteen Italian rheumatology centres have contributed patients to the database which, at the time writing, includes 5145 patients (72% women) with a mean age of 53 years (range 16-88). The initial diagnoses were rheumatoid arthritis (3494 patients, 67.9%), psoriatic arthritis (833, 16.2%), ankylosing spondylitis (493, 9.6%), undifferentiated spondylo-arthritides (307, 5.9%), enteropathic arthritis (14, 0.3%) and spondylitis following reactive arthritis (4, 0.1%). These patients have been followed for up to 10 years, and 1927 (35.8%) have been treated for at least three years. The biological treatments received include etanercept, infliximab, anakinra, adalimumab, abatacept, rituximab and tocilizumab. A total of 2926 adverse events have been observed, with 1171 patients (22%) reporting at least one. Analysis of the accumulated data will provide insights into the critical early phase of the studied arthritides, and enable us to identify the clinical and laboratory profiles that may predict responsiveness to a specific therapy.

2011 - High serum levels of CXCL11 in mixed cryoglobulinemia are associated with increased circulating levels of interferon-γ. [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; I., Ruffilli; Colaci, Michele; S., Frascerra; M., Miccoli; F., Franzoni; F., Galetta; P., Fallahi
abstract

OBJECTIVE: No study has evaluated circulating chemokine C-X-C motif ligand (CXCL)11 in patients with "mixed cryoglobulinemia and chronic hepatitis C infection" (MC+HCV). We measured CXCL11, and correlated this measurement to the clinical phenotype.METHODS: Serum CXCL11, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were assayed in 97 MC+HCV patients and in 97 sex- and age-matched controls.RESULTS: MC+HCV patients showed significantly higher mean CXCL11 serum levels than controls (254 ± 295, 68 ± 16 pg/ml, respectively; p = 0.0002; ANOVA). CXCL11 was significantly increased in 36 cryoglobulinemic patients with compared to those without active vasculitis (303 ± 208 vs 179 ± 62 pg/ml, respectively; p < 0.001; ANOVA). IFN-γ levels were significantly higher in MC+HCV than in controls [6.1 (range 0.8-114.5), 1.4 (range 0.7-2.4) pg/ml, respectively; p < 0.05; Mann-Whitney U test]. Serum TNF-α mean levels were significantly higher in MC+HCV than in controls [13.4 (range 1.8-369), 1.1 (range 0.7-3.2) pg/ml, respectively; p < 0.0001; Mann-Whitney U test]. A multiple regression analysis considering CXCL11 as a dependent variable, and age, alanine aminotransferase, IFN-γ, and TNF-α as independent variables, showed in MC+HCV patients a significant association only with IFN-γ (p < 0.0001).CONCLUSION: Our study demonstrates markedly high serum levels of CXCL11 in patients with MC+HCV compared to healthy controls overall in the presence of active vasculitis. A strong relationship between circulating IFN-γ and CXCL11 was shown, strongly supporting the role of a T helper 1 immune response in the pathogenesis of MC+HCV.

2011 - IFN-γ and TNF-α induce a different modulation of interleukin-6 in systemic sclerosis fibroblasts compared to healthy controls. [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; C., Mancusi; Colaci, Michele; Sebastiani, Marco; P., Fallahi
abstract

BACKGROUND:To our knowledge, no previous study has evaluated the effect of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, or their combination on the prototype proinflammatory cytokine interleukin (IL)-6 in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease.METHODS:Fibroblast cultures from five SSc patients (disease duration < 2 years) and five healthy controls were evaluated for the basal production of IL-6, and after stimulation with TNF-α or IFN-γ, alone or combined.RESULTS:The fibroblasts from SSc patients produced higher levels of IL-6 in basal condition than controls [617 ± 173 vs. 213 ± 123 pg/mL; analysis of variance (ANOVA), p < 0.001]. TNF-α was able to dose-dependently induce IL-6 in SSc (609 ± 184, 723 ± 243, 1079 ± 297, 1436 ± 326 pg/mL, with TNF-α 0, 1, 5, 10 ng/mL, respectively) but not in control fibroblasts, whereas IFN-γ was unable to induce IL-6. Furthermore, the combination of IFN-γ and TNF-α induced a stronger secretion of IL-6 in SSc fibroblasts (ANOVA, p < 0.0001), without effect in controls.CONCLUSIONS:SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, under the influence of TNF-α and/or IFN-γ.

2011 - Lung and Breast Cancer in Systemic Sclerosis: Correlations with the Disease's Features [Abstract in Rivista]
Colaci, Michele; Giuggioli, D.; Sebastiani, Marco; Manfredi, Andreina Teresa; Vacchi, C.; Ferri, Clodoveo
abstract

Background/Purpose: Systemic sclerosis (SSc) shows an increased incidence of lung and cancer compared to general population. Chronic interstitial inflammation might have a causative role for lung cancer; while, it is very difficult to explain the breast cancer since mammalian glands are not involved in disease's processes. We aimed to investigate the possible correlations between SSc features and the development of lung or breast cancer in SSc.Methods: We retrospectively evaluated 312 consecutive SSc patients (30/282 M/F, mean age 60.6 ± 13.7 SD years, mean disease duration 10.1 ± 6.8 SD years). Besides clinical features, individual cumulative radiation dosage (measured in mSv equivalents) for radiological examinations since SSc diagnosis was calculated.Results: We found 14 cases of lung cancer (4.5%) and 12 cases of breast cancer (3.8%), which appeared 14.3 ± 6.7 SD years and a median period of 5 years (range 1–22) after the diseases onset, respectively. Statistical analysis evidenced significant correlations between pulmonary neoplasia and male sex (p=0.035), disease duration (p=0.019), presence of anti-Scl70 (p=0.001) and absence of anticentromere (p<0.0001) antibodies, lung fibrosis (p=0.011), forced vital capacity (FVC) reduction (p<0.0001), and cyclophosphamide therapy (p=0.005). Logistic regression identified only FVC as significant independent factor (OR 1.08, 95% confidence interval 1.03–1.13; p=0.02) for lung cancer. On the contrary, breast cancer did not correlate with any SSc clinical parameters. Finally, cumulative radiation dosage did not affect the appearance of both lung and breast cancer. Interestingly, this latter was inversely related to radiation cumulative dosage (p=0.022).Conclusion: The present findings suggest that a SSc patients' subset with more severe disease might have an increased risk to develop lung cancer. This malignancy mainly affects male patients, as well as subjects with longer disease duration and higher prevalence of lung fibrosis, presence of anti-Scl70 and absence of anticentromere autoantibodies. The correlation with previous cyclophosphamide therapy could be an indirect sign of severe lung involvement. Breast cancer did not show any significant correlations with SSc features; it involved women with significantly lower x-ray exposure, due to the medially shorter time interval between SSc diagnosis and the breast cancer onset, compared to SSc patients without this malignancy.

2011 - Lymphoma Prevalence in Patients with Serum Cryoglobulins with or without Cryoglobulinemic Vasculitis: Data Extrapolated From the Cryoglobulinemic Vasculitis Classification Criteria Database. [Abstract in Rivista]
Quartuccio, L.; Corazza, L.; Monti, G.; Gabrielli, A.; Tzioufas, Ag; Ferri, Clodoveo; Ferraccioli, G.; Ramos Casals, M.; Voulgarelis, M.; Lenzi, M.; Mascia, Maria Teresa; Sansonno, D.; Cacoub, P.; Tomsic, M.; Tavoni, A.; Pietrogrande, M.; Zignego, Al; Scarpato, S.; Pioltelli, P.; Steinfeld, Sd; Lamprecht, P.; Bombardieri, S.; Galli, M.; De Vita, S.
abstract

Background/Purpose: patients with cryoglobulinemic vasculitis (CV) or serum cryoglobulins without CV (CwV) a have an increased risk of lymphoma development. We compared the prevalence of lymphoma in HCV-positive or -negative patients with cryoglobulinemia.Methods: fifty hundred patients with positive serum cryoglobulins were studied. Mean age was 60.77±13.75 years, they were 356 females (71.2%) and 144 males (28.8%), and the first cryoglobulin positivity occurred thirty-four months before the last evaluation (range 3-290 months). 272 patients had CV (54.4%). The other 228 patients (45.6%) had other diseases associated with CwV. One hundred and seventeen HCV negative patients were collected and they were 42/272 (15.4%) among CV, while they were 75/228 (32.9%) among CwV. Results: globally, a lymphoma was diagnosed in thirty-two patients (32/500, 6.4%). Of them, fourteen patients were HCV negative (14/32, 43.7%). Furthermore, lymphoma was diagnosed in 18/383 HCV positive patients (4.7%), and 14/117 HCV negative patients (11.9%) (p=0.005, Pearson). Among the 18 HCV positive patients with lymphoma, a CV was present in 16/18 (88.9%), while among the 14 HCV negative patients with lymphoma, a CV was present in 10/14 (71.4%). In HCV positive, as well as in HCV negative patients, the diagnosis of a CV increases the risk of almost 5-6 times the risk of lymphoma (p=0.022, OR 5.7, 95% CI 1.3-25.1, and p=0.006, OR 5.5, 95% CI 1.6-19.0 for HCV positive and HCV negative patients, respectively). Among HCV negative patients, a Sjögren's syndrome (SS) was diagnosed in 55/117 (47%).Conclusion: CV, much more than CwV, is associated with lymphoma prevalence. Lymphoma prevalence is higher in CV without HCV infection than in CV associated with HCV infection. Thus, lymphoma should be suspected with much higher attention in HCV negative CV patients, who often suffered from SS.

2011 - PERIPHERAL ARTERIAL CHANGES IN SYSTEMIC SCLEROSIS PATIENTS ARE SIMILAR TO THOSE OBSERVED IN PATIENTS WITH CORONARY ARTERY DISEASE [Abstract in Rivista]
Colaci, Michele; Giuggioli, D.; Manfredi, Andreina Teresa; Nuzzo, A.; Rossi, Rosario; Modena, Maria Grazia; Ferri, Clodoveo
abstract

Patients with systemic sclerosis presented functional alterations of coronaries, similair to those of cardiopathic patients.

2011 - Predictors, Features and Effects of First Biologic Switch in Rheumatoid Arthritis within GISEA register: Italian 10-Year Experience [Abstract in Rivista]
Bernd, Raffeiner; Costantino, Botsios; Paolo, Sfriso; Antonio, Carletto; Domenico, Biasi; Elisa, Gremese; Gianfranco, Ferraccioli; Ferri, Clodoveo; Mauro, Galeazzi; Roberto, Gerli; Paola, Cipriani; Roberto, Giacomelli; Tamara, Ziglioli; Roberto, Gorla; Marcello, Govoni; Antonio, Marchesoni; Fausto, Salaffi; Walter, Grassi; Fabiola, Atzeni; Piercarlo, Sarzi Puttini; Annarita, Giardina; Giovanni, Triolo; Florenzo, Iannone; Giovanni, Lapadula; Leonardo, Punzi
abstract

The study investigated the predictors and the effects of treatment with a second biologic agent in rheumatoid arthritis patients. Data were collected in the GISEA register, an Italian registry that covered 10 years.

2011 - Preliminary classification criteria for the cryoglobulinaemic vasculitis [Articolo su rivista]
De Vita, S; Soldano, F; Isola, M; Monti, G; Gabrielli, A; Tzioufas, A; Ferri, Clodoveo; Ferraccioli, Gf; Quartuccio, L; Corazza, L; De Marchi, G; Ramos Casals, M; Voulgarelis, M; Lenzi, M; Saccardo, F; Fraticelli, P; Mascia, Maria Teresa; Sansonno, D; Cacoub, P; Tomsic, M; Tavoni, A; Pietrogrande, M; Zignego, Al; Scarpato, S; Mazzaro, C; Pioltelli, P; Steinfeld, S; Lamprecht, P; Bombardieri, S; Galli, M.
abstract

BACKGROUND: To develop preliminary classification criteria for the cryoglobulinaemic syndrome or cryoglobulinaemic vasculitis (CV).METHODS: Study part I developed a questionnaire for CV to be included in the formal, second part (study part II). Positivity of serum cryoglobulins was defined by experts as an essential condition for CV classification. In study part II, a core set of classification items (questionnaire, clinical and laboratory items, as agreed) was tested in three groups of patients and controls-that is, group A (new patients with the CV), group B (controls with serum cryoglobulins but lacking CV) and group C (controls without serum cryoglobulins but with features which can be observed in CV).RESULTS: In study part I (188 cases, 284 controls), a positive response to at least two of three selected questions showed a sensitivity of 81.9% and a specificity of 83.5% for CV. This questionnaire was employed and validated in study part II, which included 272 patients in group A and 228 controls in group B. The final classification criteria for CV, by pooling data from group A and group B, required the positivity of questionnaire plus clinical, questionnaire plus laboratory, or clinical plus laboratory items, or all the three, providing a sensitivity of 88.5% and a specificity of 93.6% for CV. By comparing data in group A versus group C (425 controls), the same classification criteria showed a sensitivity 88.5% and a specificity 97.0% for CV.CONCLUSION: Classification criteria for CV were developed, and now need validation.

2011 - Prevention of Digital Ulcers in Systemic Sclerosis Patients: A Proposal of Risk Chart. [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; D'Amico, Roberto; Carraro, V.; Bocci, M.; Moscatelli, S.; Iudici, M.; Colaci, Michele; Giuggioli, D.; Ferri, Clodoveo
abstract

Background/Purpose: Systemic sclerosis (SSc) is a connective tissue disease mainly characterized by fibrosis of skin and internal organs and by diffuse microangiopathy, responsible for digital ulcers (DU) in about 50% of patients. Management of DU is very challenging; it includes combined systemic and local treatments. Risk factors for the appearance of scleroderma DU are not defined and data from literature are discordant.Recently, our group proposed a capillaroscopic index (CSURI: Capillaroscopic Skin Ulcer Risk Index), able to identify patients with high risk to develop DU within 3 months from capillaroscopic evaluation, with a positive and negative predictive value of 62.3% and 97.2%, respectively.Aim of the study was to develop a predictive model, including CSURI, demographic, and clinico-serological parameters, in order to estimate the total risk of developing DU over next six months.Methods: One hundred and seventy-two unselected SSc patients (male/female 19/153, limited/diffuse cutaneous SSc 121/51, mean age 53.4 years ± 13.8 SD, mean SSc duration 108.2 months ± 97.8 SD) from 5 Italian Rheumatology Centers were consecutively enrolled. Capillaroscopic parameters were defined and collected according to our previous study. All patients underwent videocapillaroscopy at baseline; 3 and 6 months later patients were investigated for the development of DU.The main demographic, clinical, and serologic features were evaluated for the possible association with the occurrence of DU. Possible correlations among the variables and DU were investigated by multivariate logistic regression.Results: The development of DU was significantly associated with CSURI (Odds Ratio [OR] - 66.8, confidence interval [CI] 17.9 to 248.7; p <0.001), history of previous DU within the last year (OR 5.1, CI 1.7 to 14.9; p= 0.003), and male gender (OR 6.2, CI 1.1 to 34.5; p= 0.039). The proposed risk chart based on these three parameters is reported in the figure (the percentages are referred to the cumulative risk for DU). Conclusion: Among different SSc parameters CSURI, recent history of DU, and male gender showed to be strictly associated with the appearance of DU within the next six months from baseline. Our composite predictive model, which must be opportunely validated, represents an attempt to classify patients with different risk levels to develop DU; a correct patient's classification may optimize the needed pre-emptive and therapeutical strategies.

2011 - Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. [Articolo su rivista]
Pietrogrande, M; De Vita, S; Zignego, Al; Pioltelli, P; Sansonno, D; Sollima, S; Atzeni, F; Saccardo, F; Quartuccio, L; Bruno, S; Bruno, R; Campanini, M; Candela, M; Castelnovo, L; Gabrielli, A; Gaeta, Gb; Marson, P; Mascia, Maria Teresa; Mazzaro, C; Mazzotta, F; Meroni, P; Montecucco, C; Ossi, E; Piccinino, F; Prati, D; Puoti, M; Riboldi, P; Riva, A; Roccatello, D; Sagnelli, E; Scaini, P; Scarpato, S; Sinico, R; Taliani, G; Tavoni, A; Bonacci, E; Renoldi, P; Filippini, D; Sarzi Puttini, P; Ferri, Clodoveo; Monti, G; Galli, M.
abstract

OBJECTIVE: The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion.METHODS: Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements.RESULTS: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides.CONCLUSION: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.

2011 - Scleroderma Digital Ulcers Complicated by Infection with Fecal Pathogens. [Abstract in Rivista]
Giuggioli, D.; Manfredi, Andreina Teresa; Colaci, Michele; Lumetti, Federica; Sebastiani, Marco; Ferri, Clodoveo
abstract

Background/Purpose: Digital ulcers represent one of the most frequent complications in the course of systemic sclerosis (SSc); these lesions are very painful, scarcely responsive to treatment, and usually responsible for marked limitations on daily activities. Moreover, infectious complications may severely compromise the outcome of skin lesions in a significant percentage of patients. Therefore, the presence of pain and bandages, frequently used to promote the efficacy of contact medications, may limit the personal hygiene with an increased risk of local infection and difficult ulcer healing. A number of pathogens of different origin may be involved, including bacteria from patients' endogenous flora. We evaluated the possible involvement of faecal pathogens in SSc digital ulcers.Methods: Among a series of 82 SSc patients with digital ulcers, we retrospectively analyzed 42 subjects with clinical signs of local bacterial infection. All digital ulcers with typical signs of infection (increase of yellow or green exudates, pain, perilesional erythema and swelling, bad odour) have been investigated by swabs.Results: The table summarizes the main clinico-serological and microbiological features of the 42 SSc patients with digital ulcer infection. Bacterial infection was confirmed in all 42 patients investigated; in particular, Staphylococcus aureus was the most frequently found (50%). Interestingly, 11/42 (26%) patients showed digital ulcers infected by intestinal bacteria; namely, 7 subjects resulted positive for Escherichia coli and 4 for Enterococcus faecalis. A significantly higher percentage of diffuse cutaneous SSc was recorded in the subgroup of 11 patients with digital ulcers infected by faecal pathogens compared to the remaining 31 infected by other bacteria (6/11 vs. 5/31, respectively; Fisher's p=0.011). Conclusion: A number of effective measures, involving health care personnel and hospital environment, are essential in the management of digital ulcers and prevention of infectious complications. The prevalence of faecal pathogens in a quarter of cases has never been reported previously; it suggests an important role of patient's self-care limitations, generally more frequent in patients with diffuse cutaneous SSc, mainly during intercurrent home medications. Consequently, methodical patients' education on hand hygiene is mandatory to avoid such deleterious complications.

2011 - The endocrinology of liver disease [Capitolo/Saggio]
Antonelli, A; Ferri, Clodoveo; Fallahi, Poupack
abstract

discussion of endocrine disorders in patients with hepatitis

2011 - The presence of autoimmune thyroiditis in mixed cryoglobulinemia patients is associated with high levels of circulating interleukin-6, but not of tumor necrosis factor-alpha. [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Di Domenicantonio, A; Ferrari, P; Pupilli, C; Nicolini, A; Zignego, Al; Marchi, S; Fallahi, P.
abstract

OBJECTIVES: To our knowledge, no study has evaluated serum levels of interleukin-6 (IL-6), together with tumour necrosis factor-alpha (TNF-α), in a large series of patients with 'mixed cryoglobulinemia and HCV chronic infection' (MC+HCV) in relation to the presence of autoimmune thyroiditis (AT). The aims of the study were to evaluate serum levels of IL-6 in MC+HCV patients and to correlate this parameter with the presence of AT and with circulating levels of TNF-α.METHODS: Serum IL-6 and TNF-α were assayed in 41 MC+HCV patients, in 41 MC+HCV patients with autoimmune thyroiditis (MC+AT), in 41 sex- and age-matched controls, and 20 AT patients.RESULTS: MC+HCV patients showed significantly (p<0.01; Mann-Whitney U-test) higher IL-6 (median 8.1ng/l, range 0.7-651) serum levels than controls (median 0.6ng/l, range 0.5-41), or AT (median 2.8ng/l, range 0.5-67). MC+AT showed significantly (p<0.01; Mann-Whitney U-test) higher mean IL-6 (median 15.8ng/l, range 0.5-781) than controls, AT and MC+HCV. Serum TNF-α levels were significantly higher in MC+HCV (median 9.9ng/l, range 1.5-283) or MC+AT (median 11.2ng/l, range 1.6-412) than in controls (median 1.0ng/l, range 0.6-6.4), or AT (median 1.7ng/l, range 0.6-11.8) (p<0.01, for each comparison).CONCLUSIONS: Our study demonstrates significantly higher serum levels of IL-6 and TNF-α in patients with MC+HCV and MC+AT compared to healthy controls. Furthermore, the study first shows a significant increase in circulating IL-6 observed in MC+AT patients with respect to MC+HCV. Future studies in larger patients' series will be needed to evaluate the relevance of serum IL-6 and TNF-α determination as clinico-prognostic markers of MC+HCV patients and its usefulness in the therapeutic approach to these patients.

2011 - Treatment patterns of anti-TNF agents in Italy: an observational study [Articolo su rivista]
Punzi, L; Matucci Cerinic, M; Cantini, F; Bagnato, G; Fiocco, U; Ferri, Clodoveo; Bombardieri, S.
abstract

OBJECTIVE: This study aims to provide a description of real life treatment patterns of biologic anti-TNF in 23 Italian Rheumatology centers.METHODS: This was an observational, multicenter, retrospective study. Patients &gt;18 years of age, diagnosed with rheumatoid arthritis and treated with the first biologic anti-TNF agent between the 1st July 2002 to the 31st March 2004 were included. Total follow-up was 36 months.RESULTS: In total, 248 patients were first treated with infliximab, 259 with etanercept and 196 with adalimumab. First course of therapy with infliximab was associated with lower cumulative drug survival than the other two agents. At 36 months, 74.7% of patients on etanercept, 72.0% of those on adalimumab and 57.7% of subjects receiving infliximab were still on therapy. In total, 149 patients switched to a second anti-TNF agent. At 24 months of the second line treatment, 75%, 22%, and 54% of infliximab, etanercept and adalimumab recipients, respectively, had discontinued their second anti-TNF.CONCLUSIONS: Anti-TNF agents may be associated to a rather high incidence of discontinuation and dose adjustments over a 36-month period, with a possible effect on healthcare expense. In particular, infliximab was associated with a higher incidence of discontinuations compared with etanercept and adalimumab.

2011 - Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. [Articolo su rivista]
Ferri, Clodoveo; P., Cacoub; C., Mazzaro; D., Roccatello; P., Scaini; Sebastiani, Marco; A., Tavoni; A. L., Zignego; S., De Vita
abstract

OBJECTIVE:Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic.METHODS:The study included 87 patients (male/female 19/68, mean age 62.3±11.4SD years, mean disease duration 9±6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab.RESULTS:A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patient's visual analogical scale from 62±25 to 37±27; p≤.0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8±1.1SD to 1.4±0.8SD mg/dl, p≤.0001; 24-hour proteinuria from 2.2±2.1SD to 0.9±1.7SD g/24h, p≤.0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkin's B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases. The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up. On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients.CONCLUSIONS:Rituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs.

2011 - Vasculiti sistemiche [Capitolo/Saggio]
Ferri, Clodoveo; Colaci, Michele; Manfredi, Andreina Teresa
abstract

Il termine vasculiti sistemiche (VS) si riferisce ad ungruppo di condizioni morbose caratterizzate da flogosie necrosi della parete dei vasi sanguigni e da una marcataeterogeneità dal punto di vista eziopatogenetico,istopatologico e clinico-prognostico. Il processo patogeneticoalla base delle differenti VS può coinvolgere oltre allearterie di vario calibro, anche i vasi venosi ed i piccoli vasi(arteriole, capillari e venule). La vasculite è la risultante diun processo immuno-mediato a cui partecipano più costituenticellulari e fattori circolanti quali autoanticorpi, immunocomplessi,complemento ed altri mediatori della flogosi.Vi è un certo overlap (sovrapposizione) fra i differentiquadri istopatologici collegabili alle varie sindromi vasculitiche,anche se in alcuni di essi si può osservare unaprevalenza di specifici infiltrati cellulari: linfociti, monociti,granulociti neutrofili ed eosinofili, e/o cellule giganti diderivazione macrofagica. Altri aspetti riscontrabili con unacerta frequenza a livello della parete vascolare sono la necrosifibrinoide o il fenomeno della cosidetta leucocitoclasia(dissoluzione di leucociti con frammentazione nucleare),così come la formazione di tipiche lesioni granulomatose.Il danno endoteliale quasi sempre associato al processovasculitico può portare a fenomeni trombotici ed ischemicia livello dei vari organi coinvolti, mentre il danno dellaparete vascolare più o meno esteso è spesso responsabiledi lesioni aneurismatiche, a loro volta causa di manifestazioniemorragiche, o stenotiche.

2010 - Antiendothelial cell antibodies induce apoptosis of bone marrow endothelial progenitors in systemic sclerosis. [Articolo su rivista]
Del Papa, N.; Quirici, N.; Scavullo, C.; Gianelli, U.; Corti, L.; Vitali, C.; Ferri, Clodoveo; Giuggioli, D.; Manfredi, Andreina Teresa; Maglione, W.; Onida, F.; Colaci, Michele; Bosari, S.; Lambertenghi Deliliers, G.
abstract

OBJECTIVE: Patients with systemic sclerosis (SSc) have significantly fewer and functionally impaired endothelial progenitor cells (EPC) in peripheral blood and bone marrow; further, endothelial apoptosis seems to play a primary role in the pathogenesis of vascular damage. We investigated whether the failure of bone marrow EPC is related to their apoptotic phenotype and analyzed the possible mechanisms inducing apoptosis.METHODS: The presence of apoptotic cells was investigated in bone marrow aspirates taken from patients with SSc; microvessel density (MVD) and the immunohistochemical expression of vascular endothelial growth factor (VEGF) were also measured in bone marrow biopsies. A correlation between EPC apoptosis and the presence of antiendothelial cell antibodies (AECA) was also investigated.RESULTS: We confirmed the presence of bone marrow EPC dysfunction in SSc, while hematopoiesis was not impaired. Bone marrow studies showed a high percentage of apoptotic progenitors, no signs of fibrosis or an altered MVD, and an increased VEGF index. The patients' bone marrow plasma showed significant titers of AECA, and their presence correlated with that of apoptotic progenitors. These findings were further confirmed by an in vitro assay in which the apoptosis of normal progenitors was induced by the addition of AECA+ purified IgG.CONCLUSION: Our results showed that apoptosis in patients with SSc involves the source compartment of endothelial progenitors and correlates with AECA activity. These findings support the hypothesis that AECA may play a pathogenetic role by affecting the bone marrow EPC machinery that should repair the peripheral vascular lesions.

2010 - Bronchoalveolar lavage and response to cyclophosphamide in scleroderma alveolitis. [Articolo su rivista]
Colaci, Michele; Sebastiani, Marco; Giuggioli, D.; Manfredi, Andreina Teresa; Spagnolo, Paolo; Luppi, Fabrizio; Richeldi, Luca; Ferri, Clodoveo
abstract

OBJECTIVES: Systemic sclerosis (SSc) is characterized by abnormal fibrosis of the skin and internal organs, particularly the lungs. Recent reports have revealed a lack of correlation between bronchoalveolar lavage (BAL) variations and response to cyclophosphamide (CYC) in patients with scleroderma-related alveolitis. Our study aimed to evaluate whether the normalization of BAL cellularity correlates with long-term response to CYC.METHODS: We retrospectively studied 26 consecutive SSc patients with alveolitis diagnosed by BAL and treated with CYC therapy (cumulative dosage 26.5 +/- 11.7 g; 21.1 +/- 8.9 months of treatment). We evaluated high-resolution computed tomography (HRCT), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) variations before and after CYC. Radiological and functional parameters were re-evaluated in 23 patients after 1-year follow-up.RESULTS: BAL cellularity normalized after CYC therapy in 12/26 (46.2%) patients (group 1), while it remained abnormal in 14/26 (53.8%) (group 2). FVC and DLCO of group 1 slightly increased after CYC (p = 0.014 and p = 0.07, respectively) and remained stable at follow-up, whereas in group 2 they did not change after CYC and at follow-up (p = not significant). Moreover, at the end of CYC, FVC and/or DLCO showed a clinical improvement/stabilization in all patients of group 1 versus 8/14 of group 2, while at the re-evaluation 1 year after completing CYC, 2/11 patients of group 1 worsened versus 5/12 of group 2. HRCT progression was observed in 1/11 of group 1 and 8/12 of group 2 (p = 0.009).CONCLUSIONS: BAL fluid normalization after CYC therapy correlated with long-term response to treatment, contrary to what is observed in individuals with persistent alveolitis.

2010 - Chronic inflammation, including autoimmunity, and lymphomagenesis [Capitolo/Saggio]
Sa, Pileri; C., Agostinelli; C., Campidelli; F., Bacci; E., Sabattini; M., Giunti; A., Pileri; M., Piccioli; S., Righi; M., Rossi; Ferri, Clodoveo; Pp, Piccaluga
abstract

discussion of lymphomagenesis induced by infectious triggers and as evolution of autoimmune disorders.

2010 - Effects of Rituximab in a large series of patients with HCV-associated mixed cryoglobulinemia syndrome [Abstract in Rivista]
Ferri, Clodoveo; Sebastiani, Marco; P., Cacoub; D., Roccatello; P., Scaini; A., Tavoni; A. L., Zignego; S., De Vita
abstract

A multicenter retrospective study about efficacy and safety of rituximab in mixed cryoglobulinemia syndrome

2010 - High circulating levels of N-terminal pro-brain natriuretic peptide and interleukin 6 in patients with mixed cryoglobulinemia [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; E., Ghiri; F., Galetta; F., Franzoni; G., Santoro; P., Fallahi
abstract

Many patients with mixed cryoglobulinemia and chronic HCV infection experience symptoms, such as dyspnea, which sometimes do not seem to indicate the involvement of the liver but rather the symptoms of heart failure. To our knowledge, there has been no other study evaluating the serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and Interleukin 6 (IL-6) in such patients. Serum NTproBNP and IL-6 were assayed in 54 patients with mixed cryoglobulinemia and chronic HCV infection, and in 54 sex- and age-matched controls. Cryoglobulinemic-patients showed significantly higher mean NTproBNP and IL-6 levels than the controls (P = 0.005). By defining a high NTproBNP level as a value higher than 125 pg/ml (the single cut-off point for patients under 75 years of age), 30% of patients with mixed cryoglobulinemia and chronic HCV infection and 7% of controls had high NTproBNP (chi-square; P < 0.003). With a cut-off point of 300 pg/ml (used to rule out heart failure in patients under 75 years of age), 5/49 patients with mixed cryoglobulinemia and chronic HCV infection and 0/54 controls had high NTproBNP (chi-square; P < 0.04). With a cut-off point of 900 pg/ml (used for including heart failure in patients aged between 50 and 75, such as the patients in this study) 3/51 of patients with mixed cryoglobulinemia and chronic HCV infection and 0/54 controls had high NTproBNP (chi-square; P = 0.07). The study revealed high levels of circulating NTproBNP and IL-6 in patients with mixed cryoglobulinemia and chronic HCV infection. The increase in NTproBNP could indicate the presence of a subclinical cardiac dysfunction.

2010 - High levels of circulating N-terminal pro-brain natriuretic peptide in patients with hepatitis C. [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; Colaci, Michele; Sebastiani, Marco; A. L., Zignego; E., Ghiri; F., Goglia; P., Fallahi
abstract

Many patients chronically infected by hepatitis C virus (HCV) experience symptoms like fatigue, dyspnea and reduced physical activity. However, in many patients, these symptoms are not proportional to the liver involvement and could resemble symptoms of chronic heart failure. To our knowledge, no study evaluated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) in a large series of patients with HCV chronic infection (HCV+). Serum NT-proBNP was assayed in 50 patients HCV+ and in 50 sex- and age-matched controls. HCV+ patients showed significantly higher mean NT-proBNP level than controls (P = 0.001). By defining high NT-proBNP level as a value higher than 125 pg/mL (the single cut-off point for patient under 75 years of age), 34% HCV+ and 6% controls had high NT-proBNP (Fisher exact test; P < 0.001). With a cut-off point of 300 pg/mL (used to rule out chronic heart failure in patients under 75 years of age) 10% HCV+ and 0 controls had high NT-proBNP (Fisher exact test; P = 0.056). With a cut-off point of 900 pg/mL (used for ruling in chronic heart failure in patients with age 50-75) 8% HCV+ patients and 0 controls had high NT-proBNP (Fisher exact test; P = 0.12). The study demonstrates high levels of circulating NT-proBNP in HCV+ patients compared to healthy controls. The increase of NT-proBNP may indicate the presence of a sub-clinical cardiac dysfunction. Further prospective studies quantifying these symptoms in correlation with echocardiography are needed to confirm this association.

2010 - Induction of CXCL10 secretion by interferon-γ and tumour necrosis factor-α and its inhibition by peroxisome proliferator-activated receptor-γ agonists in cultured scleroderma fibroblasts. [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Colaci, Michele; Giuggioli, D; Fallahi, P.
abstract

the study illustrates the effect of PPAR-gamma agonists on the secretion of CXCL10 by scleroderma fibroblasts in vitro, stimulated by IFN-gamma and TNF-alpha

2010 - Interleukin-1beta, C-X-C Motif Ligand 10, and Interferon-Gamma Serum Levels in Mixed Cryoglobulinemia With or Without Autoimmune Thyroiditis. [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; S., De Marco; A., Di Domenicantonio; M., Centanni; C., Pupilli; Villa, Erica; F., Menichetti; P., Fallahi
abstract

The aim of this study was to evaluate serum levels of interleukin-1beta; (IL-1beta), chemokine (C-X-C motif) ligand 10 (CXCL10), and interferon-gamma (IFN-gamma;) in a series of patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC+HCV) in the presence or absence of autoimmune thyroiditis (AT) and to relate them to the clinical phenotype of these patients. Serum IL-1beta, IFN-gamma, and CXCL10 were assayed in 30 patients with MC+HCV without AT, in 30 patients with MC+HCV and AT, and in 30 sex- and age-matched controls. Cryoglobulinemic patients showed significantly higher mean IL-1beta; and CXCL10 levels than controls (P&lt;0.01). Moreover, CXCL10 was significantly increased in patients with AT patients with respect to those without AT (P&lt;0.01). Serum IFN-gamma; levels were not significantly higher in MC+HCV patients than in controls. In conclusion, our study demonstrates significantly high serum levels of IL-1beta; in patients with MC+HCV with and without AT compared with healthy controls. Further, significantly high serum levels of CXCL10 in patients with MC+HCV compared with healthy controls were confirmed, overall in the presence of AT. Moreover, a pathophysiological association between high circulating levels of IL-1beta; and CXCL10 has been suggested. A possible therapeutic role of the anti-IL-1 receptor antagonist (Anakinra) in MC remains to be evaluated.

2010 - L-Arginine in pregnant scleroderma patients [Articolo su rivista]
Giuggioli, D.; Colaci, Michele; Sebastiani, Marco; Ferri, Clodoveo
abstract

Systemic sclerosis (SSc) pregnant women show a high frequency of premature births and occurrence of renal crisis. Some evidences showed the role of L-arginine in the prevention and treatment of preeclampsia. Here, we report our experience on the effect of L-arginine treatment in four consecutive SSc pregnant women. Two patients, who have planned the pregnancy, were treated with oral L-arginine; both delivered healthy babies without any prenatal complications. The other two, with high risk of pregnancy complications because of severe lung involvement and type 1 diabetes, respectively, underwent i.v. L-arginine: patient 3 had a premature delivery of a 2-kg healthy baby, while patient 4 developed preeclampsia and, at the 28th week, delivered a 1,050-g girl. The neonate had severe respiratory distress syndrome complicated by severe infection and died at day 28. Although limited, our pilot study suggests that L-arginine may be a useful therapeutic agent in pregnant SSc women.

2010 - New targeted molecular therapies for dedifferentiated thyroid cancer [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; Sebastiani, Marco; Colaci, Michele; I., Ruffilli; P., Fallahi
abstract

Dedifferentiated thyroid cancer (DeTC) derived from follicular epithelium is often incurable because it does not respond to radioiodine, radiotherapy, or chemotherapy. In cases, RET/PTC rearrangements are found in 30%-40%, RAS mutations in about 10%, and BRAF mutations in around 40%-50%, with no overlap between these mutations results in papillary thyroid cancer, while a higher prevalence of BRAF mutations (up to 70%) has been observed in DeTC. The identification of these activating mutations in DeTC makes this malignancy an excellent model to examine the effect of tyrosine kinase inhibitors (TKIs). Clinical trials with several TKIs targeting RET, and to a lesser extent BRAF, and other TKRs have shown positive results, with about one-third of DeTC showing a reduction in tumor size up to 50%, with the longest treatment duration of approximately three-four years. Angiogenesis inhibitors have also shown promising activity in DeTC. Progress is being made toward effective targeted DeTC therapy. The possibility of testing the sensitivity of primary DeTC cells from each subject to different TKIs could increase the effectiveness of the treatment.

2010 - N-Terminal Pro-Brain Natriuretic Peptide and Tumor Necrosis Factor-alpha Both Are Increased in Patients With Hepatitis C [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; S., Marchi; N., De Bortoli; D., Sansonno; C., Chiavacci; E., Ferrannini; P., Fallahi
abstract

Many patients with hepatitis C chronic infection (HCV+ patients) experience symptoms (fatigue, dyspnea) not proportional to the liver involvement and resemble symptoms of heart failure (HF). To our knowledge, no study evaluated at the same time serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and tumor necrosis factor alpha (TNF-alpha) in HCV+ patients. Circulating NT-proBNP and TNF-alpha were assayed in 60 HCV+ patients, and in 60 sex- and age-matched controls. HCV+ patients showed significantly higher mean NT-proBNP and TNF-alpha levels than controls (P < 0.003). By defining high NT-proBNP level as a value higher than 125 pg/mL (the single cutoff point for outpatients under 75 years of age), 28% of HCV+ and 7% controls had high NT-proBNP (chi-square; P < 0.002). With a cutoff point of 900 pg/mL (that should be used for ruling in HF in patients age 50-75; such as the patients in our study), 3% HCV+ and 0 controls had high NT-proBNP. In conclusion, the study demonstrates high levels of circulating NT-proBNP and TNF-alpha in HCV+ patients. The increase of NT-proBNP may indicate the presence of a subclinical cardiac dysfunction. Further prospective studies quantifying symptoms and correlating these with echocardiographic parameters are needed to confirm this association.

2010 - Oxycodone in the Long-Term Treatment of Chronic Pain Related to Scleroderma Skin Ulcers. [Articolo su rivista]
Giuggioli, D.; Manfredi, Andreina Teresa; Colaci, Michele; Ferri, Clodoveo
abstract

Abstract Objective. To demonstrate the efficacy and safety of long-term therapy with oxycodone in severe pain of scleroderma skin ulcers. Design. Open study. Setting and Patients. Twenty-nine consecutive patients, referred to our Rheumatology Unit during 2006, affected by systemic sclerosis complicated by painful long-standing skin ulcers entered in the study. In all cases, pain was classified as severe according to World Health Organization guidelines, and oxycodone chloridrate (Oxycontin(R); Mundipharma Pharmaceuticals, Milan, Italy) was administrated at the dosage of 10-20 mg twice daily for a mean period of 7.9 +/- 3.2 standard deviation months. Outcome Measures. To evaluate the efficacy and safety of opioid therapy, the following parameters were recorded at standard time intervals: visual analog scale (VAS) pain, Pittsburgh sleep quality index (PSQI), hours of sleep per night, Health Assessment Questionnaire-Disability index, analgesics use (rescue therapy), side effects, vital signs, routine laboratory assessment. Results. After 1 month of therapy, all patients experienced relief of pain (VAS decreased from 93.8 +/- 8.72 to 56.7 +/- 10.4, P < 0.0001), and better quality of sleep (total hours of sleep increased from 3.68 +/- 1.28 to 5.27 +/- 0.75, P < 0.0001; PSQI decreased from 9.72 +/- 3.95 to 3.37 +/- 1.04, P < 0.0001). These parameters further improved after 3 months of therapy and remained stable during the follow-up; moreover, an increase of daily dosage of oxycodone was never required. The observed side effects were always transient and mild; only constipation, when present, was persistent. Conclusion. Oxycodone showed to be effective and safe in the treatment of pain due to severe scleroderma skin ulcers; contemporarily, it markedly improved the patient's compliance to local wound care procedures.

2010 - Patient preferences in the choice of anti-TNF therapies in rheumatoid arthritis. Results from a questionnaire survey (RIVIERA study). [Articolo su rivista]
S., Scarpato; M., Antivalle; E. G., Favalli; F., Nacci; S., Frigelli; F., Bartoli; L., Bazzichi; G., Minisola; M., Matucci Cerinic; Salvarani, Carlo; Altucci, P; Bombardieri, S; Battaglia, E; Ferri, Clodoveo; Pozzi, Mr; Afeltra, A; Bersi, M; Tartarelli, G; Montecucco, Cm; Altomare, E; Bambara, Lm; Bucci, R; Colombelli, Pl; Corsaro, S; Rinaldi, F; Sinigaglia, L; Trotta, F; Carrabba, M; Migliore, A; Bianchi, G; Grassi, W; Rocchetta, Pa; Altomonte, L; Coaccioli, S; Danieli Armando, G; Perpignano, G; Broggini, M; Morassi, P; Peronato, G; Canesi, B; Delsante, G; Di Giuseppe, P; Di Rosa, So; Gorla, R; Malavolta, N; Solinas, F; Todesco, S; Varcasia, G; Versace, F; Sabadini, L; Del Giacco, S; Marasini, B; Bagnato, G; Gerli, R; Modena, V; Di Piazza, V.
abstract

OBJECTIVE: To identify the determinants of anti-TNF-naive patients' preferences for the route of administration of anti-TNF agents.METHODS: The study was carried out in 50 Italian rheumatology centres (802 patients). All patients completed a 31-item questionnaire addressing their perceptions of current treatment and the preferences for treatment with anti-TNF agents. Statistical methods included analysis of variance (ANOVA), t-test and chi-square test.RESULTS: The response rate to the questionnaire was 97.6%. At the time of the survey, 310 (39.9%) patients were dissatisfied with current treatments, owing to inefficacy, side effects and inconvenience of administration. The i.v. and s.c. routes of administration were preferred by 50.2 and 49.8%, respectively. No significant difference was found in patients by gender, age, RA duration or number of drugs used. Reasons for the choice of i.v. administration were the safety of treatment at the hospital and the reassuring effect of physician presence. The s.c. administration was chosen for the convenience of treatment and in particular for home treatment. Patients dissatisfied with current therapy due to side effects preferred s.c. administration (P = 0.029), whereas patients choosing the i.v. route had slightly higher scores on 'today pain' (P = 0.047) and 'articular pain' (P = 0.023) of the Rheumatoid Arthritis Disease Activity Index (RADAI).CONCLUSIONS: Both i.v. and s.c. treatments were well accepted by patients. However, treatment choice has to be discussed with patients, as individual preference seems to be determined by personal attitudes towards safety and convenience, by past experience and by the perception of current disease status.

2010 - Recombinant human erythropoietin stimulates vasculogenesis and wound healing in a patient with systemic sclerosis complicated by severe skin ulcers. [Articolo su rivista]
Ferri, Clodoveo; Giuggioli, D.; Manfredi, Andreina Teresa; Quirici, N.; Scavullo, C.; Colaci, Michele; Gianelli, U.; Lambertenghi Deliliers, G.; Del Papa, N.
abstract

Summary Systemic sclerosis (SSc) is often complicated by severe skin ulcers that are unresponsive to traditional treatments. Vascular alterations are responsible for the ischaemic features of the disease in both the skin and visceral organs. Defective neoangiogenesis correlates with an abnormally reduced quantity of circulating endothelial progenitor cells (EPCs) caused by impaired maturation potential and proliferative capacity of bone-marrow endothelial stem cells. We report a patient with nonhealing cutaneous ulcers successfully treated with recombinant human erythropoietin (rHuEPO). The possible biological effects of this drug were also investigated. Before rHuEPO treatment, the bone-marrow sample contained reduced numbers of EPCs, which were functionally impaired. After a 6-month rHuEPO cycle, a marked increase in endothelial progenitor markers was seen, along with a significant reduction in their apoptotic rates. The clinical and laboratory data variations before and after rHuEPO treatment give new insights into the pathogenetic role of impaired endothelial stem-cell maturation and defective neoangiogenesis in patients with SSc.

2010 - Serum concentrations of interleukin 1beta, CXCL10, and interferon-gamma in mixed cryoglobulinemia associated with hepatitis C infection [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; E., Ghiri; S., Marchi; Sebastiani, Marco; P., Fallahi
abstract

OBJECTIVE: Mixed cryoglobulinemia (MC) is a systemic vasculitis of small and medium-size vessels, often associated with the hepatitis C virus. Research has shown an emerging role for chemokines and type 1 cytokines in the pathophysiology of this vasculitis. Interleukin 1 (IL-1) plays a role in initiating the cascade of immunoinflammatory responses, and levels of the interferon-gamma (IFN-gamma) inducible chemokine CXCL10 have been shown to be significantly associated with the presence of active vasculitis in patients with MC. We evaluated serum levels of IL-1beta, IFN-gamma, and CXCL10 in a series of patients with hepatitis C-related MC (MC+HCV), and correlated these measurements with clinical disease features.METHODS: Serum IL-1beta, IFN-gamma, and CXCL10 were assayed in 54 patients with MC+HCV, in 54 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 54 controls.RESULTS: MC+HCV patients showed significantly higher mean IL-1beta and CXCL10 serum levels than controls (p < 0.01) or HCV+ patients (p < 0.01). CXCL10 was significantly increased in 14 cryoglobulinemic patients with active vasculitis (necrotizing vasculitis or vasculitic skin ulcers) compared to those without (p < 0.001); IL-1beta was increased in cryoglobulinemic patients with active vasculitis (p = 0.06). No differences were observed for serum IFN-gamma levels.CONCLUSION: Serum levels of IL-1beta and CXCL10 were high in patients with MC+HCV. Increased CXCL10 and IL-1beta levels were associated with the presence of active vasculitis in MC+HCV patients.

2010 - The A, B, Cs of viral hepatitis in the biologic era. [Articolo su rivista]
Ferri, Clodoveo; M., Govoni; L., Calabrese
abstract

AbstractPURPOSE OF REVIEW: To evaluate the recent published data on the safety of biological agents, mainly anti-TNFalpha and rituximab, and diagnostic difficulties in the setting of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and inflammatory arthritides.RECENT FINDINGS: There are important differences between HBV and HCV carriers; however, clinical observations suggest that hepatotropic virus infection should not preclude the treatment with biologic agents in rheumatic diseases. Retrospective reports on limited series of HBV-infected patients with concomitant chronic arthritis convey that careful patients' clinico-virological assessment, in collaboration with the hepatologist, is necessary before starting immunosuppressive treatments, especially biological agents. Preemptive or combined antiviral treatment is mandatory, mainly in active and inactive HBV carriers. Occult HBV infection should be also carefully evaluated due to potential virus reactivation. In HCV-infected patients without chronic active hepatitis the treatment with biological agents, anti-TNFalpha or rituximab, is generally useful and well tolerated. Preliminary data suggest the possible synergic effects of combined antivirals (alpha-interferon and ribavirin) and anti-TNFalpha (or rituximab) in patients with chronic arthritis and active hepatitis C.SUMMARY: In all patients with chronic arthritis requiring immunomodulating treatments both HBV and HCV infection along with liver conditions should be evaluated before any therapeutic decisions, including differential diagnosis among virus-related autoimmune disease and simple comorbidity. Patients with HBV infection should be referred to the hepatologist and correctly classified into active, inactive, and occult carriers. Similarly, rheumatic patients with active chronic hepatitis C must be treated with sequential or combined treatment with antiviral and biological agents.

2009 - A proposal of screening for psychiatric disorders in a rheumatologic ward. [Abstract in Rivista]
C., Giubbarelli; D., Ferrari; E., Tedeschini; F., Lumetti; E., Simoni; Ferrari, Silvia; Ferri, Clodoveo; Rigatelli, Marco
abstract

XII ANNUAL MEETING OF THE EUROPEAN ASSOCIATION FORCONSULTATION-LIAISON PSYCHIATRY AND PSYCHOSOMATICS (EACLPP)

2009 - ANTI - TUMOR NECROSIS FACTOR ALPHA (ANTI-TNF) DRUGS IN RHEUMATOID ARTHRITIS: COMPARISON ON DISEASE MANAGEMENT BEFORE AND AFTER THE INTRODUCTION OF THESE BIOLOGICAL DRUGS IN MODENA, ITALY [Abstract in Rivista]
Sandri, Gilda; Ferri, Clodoveo; L., Belletti; M., Giunti; A., Caruso; S., Venturi; Mascia, Maria Teresa
abstract

Background: Anti-Tumor Necrosis Factor alpha (anti-TNF) drugs markedly improved the therapeutic approach to Rheumatoid Arthritis (RA) and consequently the quality of life of these patients.Objectives: Aim of the present study was to compare the disease progression in RA patients treated before and after 2000, when anti-TNF drugs were introduced in our Rheumatology Unit.Methods: We currently follow a standardized protocol; namely, at our RA clinic all patients were carefully monitored with clinico-serological evaluation every 3 months; only patients with DAS-28 > 5.1, unresponsive to standard treatments, are treated with anti-TNF drugs. A study was performed in 2000 on 100 consecutive patients (F 81/M 19) with RA that came to the attention of our Department and was repeated in 2007 (F 82/M 18). All patients were evaluated by Disease Activity Score (DAS-28) and by Health Assessment Questionnaire (HAQ), both tests internationally accepted.Results: Patients in the first group (year 2000) had an average age of 63.5, disease presence for 14.3 years on average, DAS-28 of 4.47±0.98, HAQ of 1.5±0.7. Only 2 patients showed a DAS-28 lower than 2.6 whereas 25 patients had a DAS-28 higher than 5.1. These data are substantially similar to those emerging from a similar study published by Pincus (1), based on American population in the same years (paper published in 2007 but referred to a comparison between patients with RA followed in the United States in 1985 and in 2000). Patients in the second group (year 2006) had an average age of 60, disease presence for 13.1 years on average, DAS-28 of 3.45±1.1, HAQ of 1.09±0.7 DAS-28 was lower than 2.6 in 27 patients (9 of them on treatment with anti-TNF) DAS-28 was higher than 5.1 in 11 patients (2 of them on treatment with anti-TNF).No statistical differences, with regard to DAS-28 or HAQ, was uncovered among patients of the second group treated with standard treatments or on therapy with anti-TNFdrugs.Conversely first and second group showed a statistically significant difference for both DAS-28 index and HAQ index (p <0,001).Conclusion: These data clearly show that in 2000 disease progression was significantly worse than in 2007. A close and careful follow-up of the disease and the inclusion in a biological-drug therapy protocol with anti-TNF drugs only when necessary (DAS-28 > 5.1) improves disease activity and quality of life; this approach has enabled a better management of RA, bringing from 2% of 2000 to 27% of 2007 the cases in which the disease can be considered in remission (DAS-28 < 2.6).

2009 - Antidepressants for the treatment of fibromyalgia. [Abstract in Rivista]
Ferrari, D; Giubbarelli, C; Giunti, M; Tedeschini, E; Ferrari, Silvia; Rigatelli, Marco; Ferri, Clodoveo
abstract

Not available

2009 - ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES (ANCA): THE RELATIONSHIP BETWEEN SEX, AGE AND ANTIGENIC SPECIFICITIES [Abstract in Rivista]
F., Lumetti; Sandri, Gilda; A., Melegari; Ferri, Clodoveo; Mascia, Maria Teresa
abstract

Background: ANCA are specific and sensitive markers for different vasculitides, i.e.Wegener granulomatosis (WG), Churg Strauss syndrome, microscopic polyangiitis (MPA), for which the term ANCA-associated systemic vasculitis (AASV) is generally used. In patients with systemic vasculitis a significant prevalence of one major antigenic specificities of ANCA, namely proteinase 3 (PR3) or myeloperoxidase (MPO), is now well established. However, the relationships between sex, age and antigenic specificities of ANCA in seropositive patients have not been adequately investigated. Some authors did not find significant difference of gender in ANCA-positive patients, while a study in the Chinese population (1) reported that female patients were younger compared to males.Objectives: to assess possible differences of age and sex in patients with serum anti-Pr3 or anti-MPO antibodies.Methods: We retrospectively evaluated 10.671 serum samples, from a total of 6015 patients, consecutively examined at the laboratory of our hospital from 2003 to 2007 using antigen-specific direct ELISA (PR3- and MPO-ANCA, Hycor company, Great Britain). A cut-off >20 units for used for both autoantibodies.Results: a total of 57 seropositive patients (28M, 29F; mean age 60.7±21yrs) were identified. Among these, 39 patients showed a classical AASV (68%), while 18 affected by other autoimmune diseases (32%). Considering specific autoantibody seropositivity, we found 29 patients with serum anti-PR3 (M/F 17/12, mean age 54±22yrs) and 28 patients with anti-MPO (M/F 11/17,average age total 67±10yrs).There is no difference in gender and the average age of females and males is similar in ANCA-positive patients. There was no correlation between mean age of females and antigenic specificity (65±20yrs vs. 63±13yrs years; respectively), while anti-PR3-positive men were significantly younger compared to anti-MPO-positives (47±20yrs vs. 73±5.yrs) p=0. 001).Conclusion: In the literature, patients with WG are younger than those with MPA, but if we consider the ANCA specificity only males anti-PR3, but not females, are younger than those anti-MPO-positive. These findings, including the results of the present study, remain very difficult to explain. Molecular biology studies on larger patients' populations could better verify their correlations with clinico-epidemiological and demographic features of AASV patients.

2009 - Arterial stiffness evaluation in patients with systemic sclerosis: an interesting correlation with right ventricular function and cardiopulmonary performance [Abstract in Atti di Convegno]
Marchese, P; Delle Donne, G; Nuzzo, A; Franchi, F; Rollini, F; Giuggioli, D; Ferri, C; Rossi, R; Modena, Mg
abstract

Arterial stiffness evaluation in patients with systemic sclerosis: an interesting correlation with right ventricular function and cardiopulmonary performance

2009 - Capillaroscopic skin ulcer risk index: a new prognostic tool for digital skin ulcer development in systemic sclerosis patients. [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Colaci, Michele; D'Amico, Roberto; Malagoli, V; Giuggioli, D; Ferri, Clodoveo
abstract

Objective. Digital ulcerations are one of the most frequent manifestations of microangiopathy in patients with systemicsclerosis (SSc; scleroderma). The early detection of SSc patients who are at high risk to develop digital ulcers could allowa preventive treatment of these complications with reduction of morbidity and social costs. The aim of our study was todevelop a capillaroscopic skin ulcer risk index (CSURI) that can predict the onset of new digital ulcers by using nailfoldvideocapillaroscopy (NVC) in patients with SSc.Methods. We performed NVC in 120 consecutive unselected patients with SSc (13 men, 107 women, mean SD age56.1 13.4 years, mean SD SSc duration 44.7 60.7 months) to assess the total number of capillaries in the distal row(N), maximum loop diameter (D), number of megacapillaries (M), and the M:N ratio.Results. Within 3 months since NVC examination, 35 of 120 patients experienced digital ulcers. A significant associationbetween ischemic lesions and the M:N ratio, N, and D was observed; the combination of these parameters allowed us todevelop the CSURI, which is characterized by the formula D M:N2. A receiver operating characteristic curve analysisshowed an area under the curve of 0.926 for ulcer appearance, with specificity and sensitivity of 85.9% and 94.3%,respectively, at the cutoff value of 2.94. Interestingly, 33 of 35 patients with new skin ulcers had a CSURI >2.94, but only2 of 35 had a CSURI <2.94.Conclusion. The proposed CSURI may represent a novel tool with the ability to predict the development of digital ulcersin patients with scleroderma.

2009 - Changes in T-Cell Responses Against Human Herpesvirus-8 Correlate with the Disease Course of Iatrogenic Kaposi's Sarcoma in a Patient with Undifferentiated Arthritis [Articolo su rivista]
Barozzi, Patrizia; Potenza, Leonardo; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Bosco, Raffaella; Morselli, M; Forghieri, F; Volzone, F; Rossi, G; Ferri, Clodoveo; Bovini, C; Ciceri, F; Bordignon, C; Whitby, D; Schulz, Tf; Torelli, Giuseppe; Luppi, Mario
abstract

OBJECTIVES: To describe the first in-depth analysis of both the T-cell responses against human herpesvirus-8 (HHV-8) and the HHV-8 viral load in 1 patient who developed iatrogenic HHV-8-associated-Kaposi's sarcoma (KS) following immunosuppressive treatment for undifferentiated arthritis and to review the literature on iatrogenic KS (IKS). METHODS: T-cell responses against HHV-8 lytic and latent antigens were analyzed by ex vivo enzyme-linked immunospot (Elispot) and HHV-8 viral load was assessed by quantitative polymerase chain reaction, in sequential peripheral blood samples from a 55-year-old woman who developed skin/mucosal and visceral KS, while receiving treatment with cyclosporine, methotrexate, and methylprednisolone for undifferentiated arthritis. RESULTS: KS may result from HHV-8 infection in patients undergoing immunosuppressive treatment for rheumatic diseases and this is the first case of IKS occurring in undifferentiated arthritis. A role for immune surveillance in the pathogenesis of IKS is supported by the observation of disease regression following discontinuation of immunosuppressive therapy. In a 4-year follow-up, we showed that variations of the virus-specific immune responses but not of the viral load correlated well with the disease course, characterized by 2 remission and subsequent relapse phases, following changes of immunosuppressive therapy. CONCLUSIONS: We have provided evidence of a clear-cut correlation between changes in immunologic markers of HHV-8 infection and the disease course of this viral associated tumor, concomitant with variations of immunosuppressive treatment. Thus, ex vivo enzyme-linked immunospot for HHV-8-specific T-cell responses represents a new tool for the clinical management of rheumatic patients with IKS.

2009 - Copernican revolution in the therapy of rheumatoid arthritis: the contribution of anti-TNFalpha drugs [Articolo su rivista]
Bombardieri, S; Ferraccioli, G; Ferri, Clodoveo; Galeazzi, M; Lapadula, G; Cerinic, Mm; Montecucco, C; Triolo, G; Trotta, F; Valentini, G.
abstract

TNFalpha has a key role in cell recruitment, proliferation and death, expression of adhesion molecules and immune responses. In RA, TNFalpha is involved in matrix degradation and osteoclastogenesis. TNFalpha inhibitors are either soluble receptors (etanercept) or monoclonal antibodies (infliximab and adalimumab; golimumab and certolizumab are in development). TNFalpha antagonists, alone or in combination with methotrexate, reduce bone erosions and thinning of cartilage, but they differ as regards ligand binding, pharmacokinetics, pharmacodynamics, and clinical indications. Etanercept is the only TNFalpha antagonist that also neutralises LFT-alpha. Infliximab and adalimumab are more immunogenic. Cytotoxicity and cellular lysis are also higher with infliximab and adalimumab. Etanercept slows progression of joint damage in recently diagnosed RA when given alone, but much more when given with methotrexate; anti-TNF monoclonal antibodies also were shown to slow progression alone and in combination with methotrexate. Patients with early and long-standing RA treated with etanercept have now shown improvement in ACR scores, inflammation and disability for up to 9 years. Outcomes with infliximab and adalimumab are similar to those with etanercept, but only in combination with methotrexate. As a result of neutralizing antibodies, increasing doses of anti-TNFalpha antibodies may be required to maintain clinical response. As regards side effects, opportunistic infections seem more frequent with monoclonal antibodies. TNFalpha antagonists produce more QALYs than traditional DMARDs, counteracting higher costs. The efficacy, safety, and quality of life benefits of TNFalpha antagonists suggest using them possibly earlier than today, even in clinically moderate RA. Thanks to its overall profile, etanercept might be considered as one of the first-choices in TNFalpha antagonism in RA management.

2009 - Cryoglobulinemia and systemic manifestations of hepatitis C virus [Capitolo/Saggio]
Ferri, Clodoveo; Mascia, Maria Teresa; Saadoun, D; Cacoub, P.
abstract

description of mixed cryoglobulinemia, etiopathogenesis, clinical manifestations, associated endocrine or neoplastic disorders, diagnosis, treatment guidelines

2009 - CXCL10 and CCL2 Chemokine Serum Levels in Patients With Hepatitis C Associated With Autoimmune Thyroiditis [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Ferrari, Silvia Martina; Frascerra, S; Pampana, A; Panicucci, E; Carpi, A; Nicolini, A; Ferrannini, E.
abstract

To evaluate CXCL10 and CCL2 in patients with hepatitis C virus chronic infection in presence/absence of autoimmune thyroiditis (AT). CXCL10 was significantly higher in: (1) patients with AT than controls without AT (control 1) (P < 0.001; ANOVA); (2) patients with hepatitis C infection than control 1 and patients with AT (P < 0.001); (3) patients with hepatitis C virus chronic infection and AT (HCV+AT) than control 1 and patients with AT (P < 0.001) and hepatitis C (P = 0.004). By defining a high CXCL10 level as a value >218 pg/mL, 2% of control 1, 14% of patients with AT, 68% of patients with hepatitis C infection, 81% of HCV+AT had high CXCL10 (P < 0.0001; chi-square). CCL2 was similar in control 1 and patients with AT. CCL2 was significantly higher in: (1) patients with hepatitis C infection than control 1 (P = 0.04; ANOVA); (2) HCV+AT than patients with AT (P = 0.03) and control 1 (P = 0.02); no difference was observed between HCV with or without AT. Our study demonstrates: (1) higher circulating CXCL10 and CCL2 in patients with hepatitis C virus chronic infection than in controls; (2) higher CXCL10 in HCV+AT than in patients with hepatitis C infection, suggesting a stronger Th1 immune response in these patients.

2009 - CXCL10 and CCL2 serum levels in patients with mixed cryoglobulinaemia and hepatitis C. [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; P., Fallahi; Ferrari, Silvia Martina; S., Frascerra; F., Franzoni; F., Galetta; A. L., Zignego; E., Ferrannini
abstract

BACKGROUND: No study evaluates serum levels of CXCL10 and CCL2 chemokines in patients with hepatitis C associated mixed cryoglobulinaemia.AIMS: To measure circulating CXCL10 and CCL2 in cryoglobulinaemic patients.PATIENTS AND METHODS: Serum CXCL10 and CCL2 were assayed in 70 consecutive cryoglobulinaemic patients, and in 2 control groups (1:1, gender- and age-matched) of healthy (controls), or of chronic hepatitis C subjects without cryoglobulinaemia.RESULTS: Cryoglobulinaemic patients showed higher CXCL10 serum levels than controls (p<0.0001), or hepatitis C patients (p=0.001) (389 +/- 141, 91 +/- 51, 311 +/- 142 pg/ml, respectively). By defining a "high CXCL10" as a value at least 2 S.D. above the mean value of the control group (>193 pg/ml), 79% of cryoglobulinaemic patients, 5% of the controls and 69% of hepatitis C patients had high CXCL10 (p<0.0001). CXCL10 levels were (p<0.01) increased in cryoglobulinaemic patients with active vasculitis, with respect to those without (445+/-108, 339 +/- 161 pg/ml, respectively). Cryoglobulinaemic patients showed significantly higher CCL2 serum level than controls (p<0.01), but not than hepatitis C patients (541 +/- 493, 387 +/- 173 and 451 +/- 281 pg/ml, respectively).CONCLUSION: Our study first demonstrates high serum levels of CXCL10 and CCL2 chemokines in cryoglobulinaemic patients. Circulating CXCL10 is higher overall in cryoglobulinaemic patients with active vasculitis, suggesting a prevalence of the Th1 immune response in this phase.

2009 - Depression in rehumatic patients [Abstract in Rivista]
Tedeschini, Enrico; D., Ferrari; M., Giunti; Ferrari, Silvia; Ferri, Clodoveo; Rigatelli, Marco
abstract

Depression in rehumatic patients

2009 - Endocrine manifestations of hepatitis C virus infection. [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; Ferrari, Silvia Martina; Colaci, Michele; D., Sansonno; P., Fallahi
abstract

Chronic infection with hepatitis C virus (HCV) can result in both hepatic and extrahepatic disease and endocrine dysfunction represents an important class of HCV-related extrahepatic disease. The most frequently occurring--and clinically important--of these endocrine disorders are thyroid disease and type 2 diabetes mellitus. In this Review, we evaluate the evidence in support of a link between HCV infection and endocrine-system dysfunction, and discuss potential pathophysiological mechanisms. A meta-analysis of the literature has revealed significant associations between chronic HCV infection, thyroid autoimmunity and hypothyroidism. Furthermore, a high prevalence of thyroid cancer has been reported in HCV-positive patients. Several clinicoepidemiological studies have demonstrated that chronic HCV infection could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. Some researchers have postulated that a type 1 T-helper -cell mediated immune response underpins the association of chronic HCV infection with endocrine disease. Indeed, the available data suggest that a common immunological, type 1 T-helper cell pattern of cytokine expression and activation (via interferon-gamma) could provide the pathophysiological basis for this association. Nonetheless, additional studies will be necessary to elucidate fully all the mechanisms involved in HCV-related endocrine dysfunction.

2009 - Hepatitis C: thyroid dysfunction in patients with hepatitis C on IFN-alpha therapy [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P.
abstract

nd

2009 - High circulating N-terminal pro-brain natriuretic peptide and tumor necrosis factor-alpha in mixed cryoglobulinemia [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Galetta, F; Franzoni, F; Santoro, G; De Marco, S; Ghiri, E; Fallahi, P.
abstract

AIM: To evaluate serum levels of N-terminal pro-brain natriuretic peptide (NTproBNP) and tumor necrosis factor alpha (TNF-alpha) in a large series of patients with hepatitis C associated with mixed cryoglobulinemia (MC+HCV).METHODS: Serum NTproBNP and TNF-alpha levels were assayed in 50 patients with MC+HCV, and in 50 sex- and age-matched controls.RESULTS: Cryoglobulinemic patients showed significantly higher mean NTproBNP and TNF-alpha levels than controls (P &lt; 0.001; Mann-Whitney U test). By defining high NTproBNP level as a value higher than 125 pg/mL (the single cut-off point for outpatients under 75 years of age), 30% of MC+HCV and 6% of controls had high NTproBNP (c2, P &lt; 0.01). With a cut-off point of 300 pg/mL (used to rule out heart failure (HF) in patients under 75 years of age), 8% of MC+HCV and 0 controls had high NTproBNP (c2, P &lt; 0.04). With a cut-off point of 900 pg/mL (used for ruling in HF in patients aged 50-75 years; such as the patients of our study), 6% of MC+HCV and 0 controls had high NTproBNP (c2, P = 0.08).CONCLUSION: The study demonstrates high levels of circulating NTproBNP and TNF-alpha in MC+HCV patients. The increase of NTproBNP may indicate the presence of a subclinical cardiac dysfunction

2009 - High interleukin-6 and tumor necrosis factor-alpha serum levels in hepatitis C infection associated or not with mixed cryoglobulinemia [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Silvia Martina; Ghiri, E; Marchi, S; Colaci, Michele; Bruschi, F; Fallahi, P.
abstract

The objective of this study is to evaluate serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) in a series of patients with hepatitis C virus (HCV)-related mixed cryoglobulinemia (HCV-MC) and to correlate these parameters with the clinical features of the disease. Serum IL-6 and TNF-a were assayed in 61 patients with HCV-MC, in 61 sex- and age-matched patients with HCV chronic hepatitis without cryoglobulinemia (HCV+), and in 61 sex- and age-matched healthy controls. HCV-MC patients showed significantly higher mean IL-6 levels than controls (p=0.005) or HCV+ patients (p = 0.02). Moreover, IL-6 was increased in cryoglobulinemic patients with active vasculitis, even if the statistical significance was not reached (p=0.056). Serum TNF-a levels were significantly higher in HCV-MC than in HCV+ or in controls (p<0.01). The study demonstrates high IL-6 and TNF-a serum levels in HCV-MC patients; moreover, IL-6 levels tended to be higher in HCV-MC patients in presence of active vasculitis.

2009 - Human Parvovirus B19 (B19V) Infection in Systemic Sclerosis Patients [Articolo su rivista]
Zakrzewska, K; Corcioli, F; Carlsen, Km; Giuggioli, D; Fanci, R; Rinieri, A; Ferri, Clodoveo; Azzi, A.
abstract

BACKGROUND: Our previous reports suggested a possible association between parvovirus B19 (B19V) infection and systemic sclerosis (SSc), based on higher prevalence of B19V DNA in SSc patients in respect to controls.METHODS: In the present study, to further evaluate the differences in the pattern of B19 infection in SSc, skin biopsies and bone marrow samples from patients and controls were analysed for B19V DNA detection, genotyping and viral expression.RESULTS: B19V DNA was detected in skin biopsies from 39/49 SSc patients and from 20/28 controls. Bone marrow showed positive in 17/29 SSc patients, 5/21 haematological patients and 0/10 healthy controls. Genotype 1 was more frequent in skin and bone marrow from patients than from controls. Simultaneous persistence of 2 genotypes was detected in SSc skin and bone marrow samples, never in controls. Viral mRNA for capsid protein was detected in the skin of genotype 1-positive patients and not in control skins.CONCLUSION: The results outline some differences in the rate of persistence of B19V DNA, in the simultaneous persistence of 2 genotypes and in the pattern of viral expression among SSc patients and controls.

2009 - Mixed cryoglobulinemia syndrome: where are we going to? [Abstract in Rivista]
Sebastiani, Marco; Colaci, Michele; Manfredi, Andreina Teresa; Elkhaldi, Nezar Moneir Fadl; Mascia, Maria Teresa; Ferri, Clodoveo
abstract

Background: Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis of small and medium-sized vessels. Its prevalence presents a large geographic heterogeneity; in particular, MC is more frequent in Southern Europe than in Northern Europe or in Northern America. Because of the striking association between hepatitis C virus (HCV) infection and MCs (up to 95-98% of cases in Italian series), the term 'essential' should be reserved only to the small number of patients without overt infectious, immuno-rheumatological or neoplastic disorders.Several strategies have been adopted to contrast HCV infection, such as the screening of hemoderivatives and the development of antiviral therapies.Objectives: we investigated the possible variations during the last years of the prevalence of HCV infection in Italian patients with overt MCs.Methods: From 2000 to 2008, MCs was diagnosed for the first time in 75 consecutive patients referred to our Rheumatology Unit (55F and 20M; mean age 65.7±11.3 SD years). At the beginning of the follow-up, all patients showed clinico-serological and pathological features sufficient for the a definite diagnosis of MCs according to the preliminary classification criteria.They were characterized by the typical clinical triad -purpura, weakness, arthralgias- in 80% of patients, mild-moderate chronic hepatitis in 52%, peripheral neuropathy in 65%, nephropathy in 9%, and severe cutaneous vasculitis in 21%.Results: in the present series of recently diagnosed patients, the percentage of HCV-positive individuals (81.3%; genotype 1b 55%, 2a/2c 38%; other 7%) was lower compared to previously observed prevalence of HCV-positives (92%) in our 168 patients screened for HCV infection. We can speculate that this reduction could be the result of several actions adopted in order to reduce the incidence of HCV infection in the general population. Furthermore, the use of combined antiviral treatment, particularly if introduced in the early stages of infection, increases the percentage of HCV eradication and, consequently, it reduces the risk of developing MCs. On the other hand, the populations with a higher prevalence of HCV infection (i.e. Africans or Asians) more often are infected with viral genotypes that seem to be scarcely involved in the pathogenesis of MCs.Another important finding of the present series is the patients' age at the diagnosis compared to that observed in our previous study (65.7±11.3 vs 56±11 SD years; p<0.0001). It could be an indirect consequence of the preventive measures adopted after HCV discovery in 1989, which lowered the incidence of viral infection in younger individuals and consequently the possible development of MCs.Conclusion: on the bases of the above considerations, we can suppose that in next years the overall incidence of the disease will show a valuable reduction; contemporarily, the relative percentage of 'essential' MCs would gradually increase. This might be particularly true for patients' populations from Italy and other Mediterranean countries, where the pathogenetic link with HCV infection is prevalent.

2009 - Serologic Profile and Mortality Rates of Scleroderma Renal Crisis in Italy [Articolo su rivista]
Codullo, V; Cavazzana, I; Bonino, C; Alpini, C; Cavagna, L; Cozzi, F; Del Papa, N; Franceschini, F; Guiducci, S; Morozzi, G; Ruffatti, A; Ferri, Clodoveo; Giacomelli, R; Matucci Cerinic, M; Valentini, G; Montecucco, C.
abstract

OBJECTIVE: To analyze clinical and serological characteristics of subjects with scleroderma renal crisis (SRC) in Italian patients with systemic sclerosis (SSc).METHODS: A retrospective analysis of medical records from 9 Italian rheumatologic referral centers was carried out. All patients with SRC and an available serum sample at the time of crisis were included. Antinuclear antibodies (ANA) by indirect immunofluorescence, anti-topoisomerase (topo) I by enzyme-linked assay (ELISA), anti-RNA polymerases (RNAP) by ELISA for the subunit III, and immunoprecipitation (IP) were performed.RESULTS: Forty-six cases (38 female; 40 diffuse cutaneous SSc) were identified. Mean age at SSc and SRC onset was 52.8 years +/- 13.2 and 55.4 years +/- 11.8, respectively. ANA were present in 44 patients (96%). Anti-topo I antibodies were detected in 30 (65%), anti-RNAP I-III in 7 (15%). No differences emerged between these 2 groups for their main clinical characteristics. The proportion of patients in the anti-RNAP I-III group developing SRC early (< 18 mo) in the course of SSc was significantly higher (p = 0.03). Cumulative survival rates were 64%, 53%, and 35% at 1, 2, and 10 years of followup, respectively. Survival rates of SSc patients significantly differed according to their autoantibody profile, being lower in the anti-topo I than in the anti-RNAP I-III group (p = 0.034).CONCLUSION: SRC is a rare manifestation of SSc in Italy but it is still associated with severe prognosis. Anti-topo I reactivity was more frequent than anti-RNAP I-III in our patients with SRC and was associated with delayed onset and high mortality rates.

2009 - Serum levels of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor alpha in mixed cryoglobulinemia [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ghiri, E; Goglia, F; Pampana, A; Bruschi, F; Fallahi, P.; Ferrari, Silvia Martina
abstract

OBJECTIVE: No single previous study has evaluated serum levels of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNFalpha) in patients with hepatitis C virus-associated mixed cryoglobulinemia (HCV-MC). This study was undertaken to evaluate serum levels of these cytokines in patients with HCV-MC.METHODS: Serum IL-1beta, IL-6, and TNFalpha were assayed in 43 patients with HCV-MC, in 43 sex- and age-matched patients with chronic HCV without cryoglobulinemia, and in 43 sex- and age-matched controls.RESULTS: HCV-MC patients showed significantly higher mean IL-1beta, IL-6, and TNFalpha levels than did the controls (P&lt;0.01) or the HCV patients (P

2009 - Staphylococcus protein A-based extracorporeal immunoadsorption and thalidomide in the treatment of skin manifestation of dermatomyositis: a case report. [Articolo su rivista]
Sebastiani, Marco; R., Puccini; Manfredi, Andreina Teresa; E., Manni; Colaci, Michele; P., Mattei; P., Barachini; Ferri, Clodoveo
abstract

Cutaneous involvement in dermatomyositis can be the prevalent component of disease, failing to respond to adequate therapies for myositis. In this case report, we describe a patient affected by dermatomyositis, characterized by prevalent skin involvement, successfully treated with Staphylococcus protein A-based extracorporeal immunoadsorption (Immunosorba, Fresenius Medical Care AG & Co. KGaA, Bad Homburg, Germany) and thalidomide. The patient showed panniculitic ulcerative lesions of the skin, difficult to treat because of side effects or ineffectiveness of various therapies. Skin manifestations rapidly improved after introduction of immunoadsorption; The association of thalidomide allowed a good maintenance of these results until the remission of skin lesions, despite several infective complications of some residual ulcers. Considering the difficulties in the management of our patient, combined therapy with Immunosorba and thalidomide has allowed a good clinical response. If confirmed, the observed beneficial effects suggest that protein A-based immunoadsorption and thalidomide can represent an alternative option in dermatomyositis, especially when cutaneous manifestations are predominant

2009 - The link between pain patient and analgesic medication is greater in migraine than in rheumatic disease patients [Articolo su rivista]
Ferrari, Anna; Leone, S.; Tacchi, R.; Ferri, Clodoveo; Gallesi, Daniela; Giuggioli, D.; Bertolini, Alfio
abstract

Our aim was to measure and compare the link between pain patients and the different kinds of analgesic medications they use by the Leeds Dependence Questionnaire (LDQ). This is a self-completion 10-item instrument to measure the severity of dependence upon a variety of substances. LDQ was administered to 200 episodic migraine patients (EM group), 77 chronic migraine patients (CM group) overusing acute medications, and 114 patients suffering from rheumatic disease (RD group), consecutively attending the Headache Centre or the Rheumatology Clinic of the University Hospital of Modena in the course of the first semester of 2007. The link with analgesics was greater in migraine patients than in patients with rheumatic disease, since the LDQ total score was significantly higher in the EM (6.65 +/- 0.32, P &lt; 0.005) and CM groups (9.61 +/- 0.59, P &lt; 0.0001) than in the RD group (5.17 +/- 0.37) (Kruskal-Wallis and Mann-Whitney U-tests). Migraine patients were significantly more linked to triptans and to combined medications than to non-steroidal anti-inflammatory drugs. The strength of the link between migraine patients and the analgesic medications they take could represent a factor of vulnerability: overusing these medications could develop medication overuse headache.

2009 - Treatment strategies for a patient with rheumatoid arthritis and hepatitis C. [Articolo su rivista]
Giannitti, C; Bellisai, F; Ferri, Clodoveo; Galeazzi, M.
abstract

BACKGROUND: The poor prognosis of rheumatoid arthritis (RA) can be aggravated by the concomitant presence of chronic hepatitis C virus (HCV) infection and there are no guidelines for the treatment of patients affected by both conditions.OBJECTIVE: To propose new therapeutic strategies for patient affected by RA and concomitant HCV chronic infection.METHODS: Review of the literature on the usage of cyclosporine-A (CsA) and anti-tumour-necrosis-factor (TNF)-alpha agents for the treatment of patients affected by RA and HCV.RESULTS/CONCLUSION: CsA exerts an inhibitory effect on HCV replication and it is safe in patients affected by RA and HCV. Anti-TNF-alpha agents are safe and efficacious in patient with RA and HCV. Anti-TNF-alpha and CsA can be safely given in combination in RA patients with HCV infection.

2008 - Alpha-chemokine CXCL10 and beta-chemokine CCL2 serum levels in patients with hepatitis C-associated cryoglobulinemia in the presence or absence of autoimmune thyroiditis. [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; P., Fallahi; Ferrari, Silvia Martina; S., Frascerra; A., Carpi; A., Nicolini; E., Ferrannini
abstract

Chemokines have been identified to play an important role in endocrine autoimmune disease and hepatitis C chronic infection. To our knowledge, no study has evaluated serum levels of CXCL10 and CCL2 in patients with "mixed cryoglobulinemia and hepatitis C virus chronic infection" (MC) in the presence or absence of autoimmune thyroiditis (AT). Serum CXCL10 and CCL2 were assayed in 60 patients with MC, in 45 patients with "MC with AT" (MC + AT), and in controls (60 without [control 1] and 45 with AT [control 2]). CXCL10 was significantly higher (1) in control 2 than in control 1 (P < .001), (2) in MC than in control 1, and (3) in MC + AT than in controls 1 and 2 and in MC (P = .002). A high CXCL10 level (>mean + SD control 1; >167 pg/mL) was present in 7% control 1, 21% control 2, 49% MC, and 78% MC + AT (P < .0001). CCL2 was significantly higher in MC and in MC + AT than in control 1 or in control 2 (P < .01). A high CCL2 level (>mean + SD control 1; >730 pg/mL) was present in 2% control 1, 1% control 2, 18% MC, and 21% MC + AT (P < .0001). The study demonstrates high CXCL10 and CCL2 serum levels in patients with MC; CXCL10 in MC + AT is significantly higher than that in MC. Future studies in larger series will be needed to evaluate the potential usefulness of serum CXCL10 and CCL2 determination as a prognostic marker in the follow-up of MC patients, also in relation to the presence of AT.

2008 - Cardiovascular risk and prostanoids in systemic sclerosis [Articolo su rivista]
Colaci, Michele; Sebastiani, Marco; Giuggioli, D.; Manfredi, Andreina Teresa; Rossi, Rosario; Modena, Maria Grazia; Ferri, Clodoveo
abstract

OBJECTIVE: Systemic sclerosis (SSc) is characterized by Raynaud's phenomenon and frequent cutaneous ulcers. In patients resistant to oral treatments, i.v. prostanoids are usefully employed. Some anecdotal reports underlined the potential risk to develop cardiovascular ischemic complications in prostanoid-treated SSc patients. METHODS: Fifty SSc patients (group 1: 44 female and 6 male, mean age 60.4 +/- 13.8SD) undergoing long-term prostanoid therapy (iloprost or alprostadil) and 42 control patients (group 2), treated with only oral drugs, were retrospectively evaluated for the cardiovascular risk and incidence of ischemic events. RESULTS: Ischemic cardiovascular complications, i.e., myocardial infarction or stroke, were recorded in a significantly higher number of patients undergoing prostanoid treatment compared to controls (group 1: 7/50, 14% vs. group 2: 1/42, 2.4%; p=0.041). Interestingly, these events were significantly more frequent in the subgroup of patients with high cardiovascular risk (group 1: 6/10, 60% vs. group 2: 1/19, 5.2%; p=0.0026).CONCLUSION: The present study suggests a possible role of prostanoid treatment in the pathogenesis of ischemic cardiovascular complications in SSc patients non-responders to oral vasodilators and high cardiovascular risk. Since prostanoids represent the first choice treatment of the most severe scleroderma ischemic cutaneous lesions, cardiovascular risk should be carefully evaluated in all patients before therapy.

2008 - Comorbid depression in rheumatic patients [Abstract in Rivista]
Ferrari, D.; Tedeschini, E; Giunti, M; Ferrari, Silvia; Rigatelli, Marco; Ferri, Clodoveo
abstract

Not available

2008 - CORRELATION OF A QUANTITATIVE VIDEOCAPILLAROSCOPIC SCORE WITH THE DEVELOPMENT OF DIGITAL SKIN ULCERS IN SCLERODERMA PATIENTS [Abstract in Atti di Convegno]
Sebastiani, Marco; Manfredi, Andreina Teresa; Colaci, Michele; Giuggioli, D.; La Sala, R.; Ferri, Clodoveo
abstract

Background: Systemic Sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs. SSc microangiopathy is early detectable in the course of the disease by nailfold videocapillaroscopy (NVC), a non-invasive technique with a high diagnostic value.Objectives: Aim of our study is to evaluate the feasibility of a novel, quantitative capillaroscopic score and its correlation with digital skin ulcers, which frequently complicate SSc microangiopathy.Methods: Two operators, in a blind manner, without knowledge of the patient's clinical history, retrospectively analyzed the NVC of 76 SSc patients (9 males, 67 females, mean age 56,3±13,3 years, mean disease duration 79±65 months, at the time of NVC), using an image analyze software (Videocap; DS MediGroup, Milan, Italy).The analysis of every available NVC image (200x) included: total number of capillaries in the distal row (N), maximum diameter (D) and number of giant capillaries (M), M/N ratio and percentage of M, micro-haemorrhages and tortuosity (counted as presence or absence). All parameters were strictly defined to reduce the inter-operator variability.Results: 22/76 SSc patients experienced digital ulcers within three months after the NVC examination. The N, D, M/N, and percentage of M significantly correlated with the appearance of ischemic ulcers. A multiple regression analysis showed a statistically significant correlation for N, D and M/N (with a coefficient of -0.634, 0.406 and 0.630, respectively), while sensitivity and specificity of these parameters were unsatisfactory. A capillaroscopic score, according to the formula DM/N2, showed a high specificity and sensibility (88.9% and 86.4% respectively, area under ROC curve 0.92) to predict the appearance of digital ulcers (mean score 5.85±12.3SD in the whole SSc population, 1.83±1.42SD in patients without ulcers, 15.72±19.74 SD in patients with ulcers; p&lt;0.0001).Conclusion: This capillaroscopic score may represent a feasible and simple tool in SSc patients' assessment. The routinely use of this parameter might permit to recognize and to preventively treat SSc patients at high risk to develop digital ulcers.

2008 - Correlation of a quantitative videocapillaroscopic score with the development of digital skin ulcers in scleroderma patients [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Colaci, Michele; Giuggioli, D.; La Sala, R.; Elkhaldi, N.; Antonelli, A.; Ferri, Clodoveo
abstract

La microangiopatia rappresenta una delle principali caratteristiche istopatologiche, della sclerosi sistemica (SSc) e giànelle sue fasi iniziali può essere evidenziata mediante la videocapillaroscopia periungueale VCP.Attraverso un’indagine retrospettiva veniva valutata la fattibilità di uno score capillaroscopico quantitativo e la suacorrelazione con l’insorgenza di ulcere digitali, una delle principali complicanze della microangiopatia sclerodermica.L’indagine veniva effettuata mediante un videocapillaroscopio a sonda ottica, equipaggiato con obiettivo 200x. In65 pazienti affetti da SSc venivano esaminati il numero totale di capillari (N) e di megacapillari (M), il diametro massimocapillare (D), il rapporto fra megacapillari e capillari totali (M/N), la presenza o l’assenza di microemorragie etortuosità. 21/65 pazienti presentavano ulcere digitali nei 3 mesi successivi. Differenze significative si evidenziavanoper D, N, M/N, M fra i pazienti che sviluppavano o meno ulcere digitali, mentre uno studio di regressione multiplaconfermava una significatività per N, M/N e D. Anche se ognuno di questi parametri correlava in maniera significativacon la comparsa di ulcere digitali uno studio delle rispettive curve ROC mostrava valori di specificità e sensibilitàscarsamente soddisfacenti. L’associazione di questi parametri, secondo la formula D×(M/N)/N consentiva invece unastretta correlazione con la comparsa di ulcere (coefficiente di correlazione 0,6183) ed elevati valori di specificità(93,2%) e sensibilità (85,7%).Questo tipo di score, anche se estremamente semplice, rappresenta uno dei primi tentativi di quantificare la microangiopatiasclerodermica e se sarà confermato potrebbe consentire una valutazione prospettica della microangiopatia, permettendoun utilizzo preventivo dei prostanoidi nei soggetti a maggior rischio ischemico.

2008 - CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis--a longitudinal study. [Articolo su rivista]
Antonelli, A.; Ferri, Clodoveo; Fallahi, P.; Ferrari, Silvia Martina; Giuggioli, D.; Colaci, Michele; Manfredi, Andreina Teresa; Frascerra, S.; Franzoni, F.; Galetta, F.; Ferrannini, E.
abstract

OBJECTIVES: To measure serum levels of CXCL10 and CCL2 chemokines in patients with SSc, and relate the findings to clinical phenotype and disease progression.METHODS: Serum CXCL10 and CCL2 were assayed in 72 consecutive newly diagnosed SSc patients and in 72 sex- and age-matched controls. In 37 SSc and 37 controls, serum CXCL10 and CCL2 were re-evaluated 5 yrs later.RESULTS: SSc at onset showed significantly higher CXCL10 serum levels than controls (216 +/- 126 vs 92 +/- 53 pg/ml; P < 0.0001), as well as CCL2 (388 +/- 172 vs 318 +/- 120 pg/ml; P = 0.01). CXCL10 was significantly increased in SSc with interstitial lung involvement or with kidney involvement (P = 0.01 and P = 0.02, respectively). A significant decrease of CXCL10 was observed from the baseline after 5 yrs in SSc (137 +/- 112 vs 270 +/- 122 pg/ml, respectively; P < 0.0001), while no significant change was observed for CCL2 (418 +/- 176 vs 405 +/- 164 pg/ml; P = NS); the CCL2/CXCL10 ratio significantly increased at the fifth year (1.7 +/- 0.8 vs 3.5 +/- 2.5; P < 0.0001). No significant variations were observed in controls from the basal to the 5-yr evaluation with regards to CXCL10, CCL2 or CCL2/CXCL10 ratio.CONCLUSIONS: Our study demonstrates high serum levels of CXCL10 (Th1) and CCL2 (Th2) chemokines in newly diagnosed SSc. High values of CXCL10 are associated with a more severe clinical phenotype (lung and kidney involvement). CXCL10 declined during the follow-up, while CCL2 remained unmodified, suggesting that the disease progresses from the early Th1 inflammatory condition to the advanced Th2-like stage.

2008 - Detection of autoimmunity in early primary Epstein-Barr virus infection by Western blot analysis [Articolo su rivista]
Mascia, Maria Teresa; Sandri, Gilda; Guerzoni, C; Roncaglia, R; Mantovani, G; Ferri, Clodoveo
abstract

AbstractObjectivesThe Epstein-Barr virus (EBV) represents a potentially important factor in the pathogenesis of certain autoimmunedisorders such as systemic lupus erythematosus (SLE), and Sjögren’s syndrome, probably through a ’s molecular mimicrymechanism. Several studies have focused on the relationship between previous EBV infection and clinically overtconnective tissue diseases (CTDs), while the aim of this study was to investigate the immunological alterations during theearly phase of primary acute EBV infection by means of ENA Western blotting (WB) analysis. This technique is able todetect a wide spectrum of anti-ENA autoantibodies, potentially directed against diverse epitopes of the same antigen.MethodsSera from 54 subjects (F/M=24/30, mean age 17±6 SD years) with primary acute EBV infection were analysed usingindirect immunofl uorescence (IF) on Hep-2 cells for ANA, and both ELISA and WB for ENA.ResultsOnly 8 ANA+ and no ENA+ were found by means of IF and ELISA techniques, respectively; however, one or more ENAautoantibodies were detected in 24/54 (44%) sera using WB. The autoantibodies were no longer present at the secondevaluation. Subjects with immunological alterations had not developed any signifi cant clinical manifestations at a 5-yearfollow-up.ConclusionsThis study demonstrated the appearance of autoantibody production in a high proportion of individuals with primaryacute EBV infection; interestingly, the observed serological subsets are quite similar to clinical SLE clusters. Moreover,the absence of immunological disorders during the follow-up reinforces the role of multiple genetic and/or environmentalco-factors in the pathogenesis of CTDs.

2008 - Eosinophilic globules in bronchoalveolar lavage fluid of patients with systemic sclerosis-related interstitial lung disease: A diagnostically useful, previously unreported finding in a retrospective and prospective study, including differential diagnosis with other idiopathic and secondary interstitial lung diseases [Articolo su rivista]
Rossi, G; Andreani, A; Morandi, P; Marchioni, A; Corradini, P; Cappiello, G; Bortolotti, M; Qosja, A; Manzini, C; Richeldi, Luca; Cavazza, A.; Ferri, Clodoveo
abstract

Bronchoalveolar lavage (BAL) is a minimally invasive method possibly representing a diagnostic tool in the evaluation of interstitial lung diseases (ILDs) of different causes. We first describe herein the morphologic, histochemical, and immunohistochemical features of previously unreported eosinophilic globular deposits of acellular amorphous material of uncertain nature in a relatively large series of 227 BAL samples obtained from patients with various ILDs. Overall, eosinophilic globules were detected in 18 cases (7.9%), 16 of which were in patients with systemic sclerosis (SSc)-related ILD (16/50 [32%]) and in 2 cases of apparently idiopathic usual interstitial pneumonia. Apart from the possible diagnostic information of this finding, in patients with SSc, the globules were significantly related to BAL neutrophilia or eosinophilia and extensive ILD in high-resolution computed tomography (P &lt; .0001). Differential diagnosis with other types of acellular globular materials observed in BAL samples is also discussed.

2008 - [Fibronectin gene polymorphisms and clinical manifestations of mixed cryoglobulinemic syndrome: increased risk of lymphoma associated to MspI DD and HaeIII AA genotypes] [Articolo su rivista]
Fabris, M; Quartuccio, L; DE RE, V; Pozzato, G; Mazzaro, C; Tavoni, A; Ferri, Clodoveo; Salvin, S; Lerussi, A; Fabro, C; Bombardieri, S; DE VITA, S.
abstract

OBJECTIVE: To analyse FN gene polymorphisms in type II mixed cryoglobulinemic syndrome (MCsn), an immune-complex mediated systemic vasculitis linked to hepatitis C virus (HCV) infection and characterized by rheumatoid factor (RF) positive B-cell proliferation at high risk for the progression into non Hogkin's lymphoma (NHL).METHODS: Samples from eighty-one patients, with MCsn (type II serum cryoglobulins and clinical signs of vasculitis were studied. Sixty-five (65/81, 80.3%) patients were HCV-positive. Twenty-one (25.9%) patients had developed a B-cell NHL during the course of MCsn. Seventy-two patients with HCV-negative and MC-unrelated NHL and 110 healthy blood donors (HBDs) were taken as controls. HaeIIIb and MspI FN gene polymorphisms were analysed by ELISA, whenever possible.RESULTS: HaeIIIb and MspI allele and genotypic frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI allele and genotype frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI (OR = 5.56; DI = 1.67-18.51, p = 0.0046) and the AA-HaeIIIb (OR = 5.54, CI = 1.64- 18.76, p = 0.0066) homozygosis appeared significantly and independently associated with the development of B-cell NHL in MCsn patients, with the HaeIIIbA allele possibly conferring an increased risk of NHL in the general population (OR = 1.72, CI = 1.128-2.635, p = 0.0133). In contrast, the major vasculitic manifestations, such as peripheral neuropathy, skin ulcers and glomerulonephritis tended to be associated with the counterpart MspI C allele. No association between FN plasma levels and FN genotypes was found.CONCLUSION: Genotyping for MspI and HaeIIIb FN gene polymorphisms may be clinically relevant to define the predisposition to the major clinical manifestations in MCsn

2008 - Fibronectin gene polymorphisms are associated with the development of B-cell lymphoma in type II mixed cryoglobulinemia. [Articolo su rivista]
Fabris, M; Quartuccio, L; Salvin, S; Pozzato, G; DE RE, V; Mazzaro, C; Ferri, Clodoveo; Baldini, C; DE VITA, S.
abstract

OBJECTIVE: To analyse fibronectin (FN) gene polymorphisms in type II mixed cryoglobulinemic syndrome (MCsn), an immune-complex mediated systemic vasculitis linked to hepatitis C virus (HCV) infection and characterised by rheumatoid factor (RF) positive B-cell proliferation at high risk for the progression into non-Hodgkin's lymphoma (NHL).METHODS: Samples from 74 patients with MCsn (type II serum cryoglobulins and clinical signs of vasculitis) were studied. In all, 58 (78.4%) patients were HCV-positive. In total, 21 (28.4%) patients developed a B-cell NHL during the course of MCsn. A total of 72 patients with HCV-negative and MC-unrelated NHL and 110 healthy blood donors (HBDs) were taken as controls. HaeIIIb and MspI FN gene polymorphisms were analysed by PCR and specific restriction enzyme digestions, following reported procedures. Plasma FN levels were analysed by ELISA, whenever possible.RESULTS: HaeIIIb and MspI allele and genotype frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI (OR = 5.99; CI 1.77-20.261, p = 0.0039) and the AA-HaeIIIb (OR = 4.82, CI 1.42-16.39, p = 0.0176) homozygosis appeared significantly associated with the development of B-cell NHL in MCsn patients, with the HaeIIIb A allele possibly conferring an increased risk of NHL in the general population (OR = 1.72, CI 1.128-2.635, p = 0.0133). None of the other MCsn-related clinical manifestations were significantly associated with a particular genetic pattern. No association between FN plasma levels and FN genotypes was found.CONCLUSION: Genotyping for MspI and HaeIIIb FN gene polymorphisms may be clinically relevant to define the risk of lymphoma development in MCsn.

2008 - HCV infection: pathogenesis, clinical manifestations and therapy. [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Galeazzi, M; Giannitti, C; Manno, D; MIELI VERGANI, G; Menegatti, E; Olivieri, I; Puoti, M; Palazzi, C; Roccatello, D; Vergani, D; SARZI PUTTINI, P; Atzeni, F.
abstract

Chronic hepatitis C virus (HCV) infection is a worldwide public health problem with a global prevalence of 2-3%. It is believed that about 170 million people are currently infected (about 3% of the world's population), and a further 3-4 million are infected each year. HCV is the main reason for liver transplantation in the developed world, and the main cause of liver-related morbidity and mortality in a number of countries, including Italy. It is not only a frequent cause of chronic liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma, but is also involved in the pathogenesis of various autoimmune and rheumatic disorders (arthritis, vasculitis, sicca syndrome, porphyria cutanea tarda, lichen planus, nephropathies, thyroid diseases, and lung fibrosis), as well as in the development of B-cell lymphoproliferative diseases. Furthermore, patients suffering from C hepatitis tend to produce rheumatoid factor, cryoglobulins and a large series of autoantibodies (ANA, anti-SSA/SSB, SAM, ATG, aCL). The use of glucocorticoids or immuno-suppressant agents in HCV infected individuals, which are needed to treat autoimmune and rheumatic disorders, leads to a risk of worsening the clinical outcome of HCV. Under these conditions, the viral infection often needs to be treated with antiviral agents, mainly pegylated interferon combined with ribavirin. However, cyclosporine A seems to be safe and effective in patients with autoimmune disease (AD) and concomitant chronic HCV infection as is documented by the reduction in viremia and transaminases, particularly in patients with high baseline levels. Finally, HCV is the main trigger of mixed cryoglobulinemia. An attempt at viral eradication is therefore indicated in most patients, and is particularly effective in the case of mild or moderate manifestations. In severe cases, rituximab is an apparently safe and effective alternative to conventional immunosuppression and, specifically, it controls B-cell proliferation.

2008 - High values of CXCL10 serum levels in mixed cryoglobulinemia associated with hepatitis C infection [Articolo su rivista]
Ferri, Clodoveo; Ferrari, Silvia Martina; Sebastiani, Marco; Ferrari, Daniela; Giunti, Marco; F., Franzoni; F., Galetta; S., Marchi; E., Ferrannini; Antonelli, A; Fallahi, P; Frascerra, S; Tolari, S
abstract

OBJECTIVES: No study has evaluated circulating CXCL10 in patients with mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) chronic infection. The aim of this study is to measure inteferon-inducible protein 10 (CXCL10/IP-10), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) (Th1 cytokines) in a series of cryoglobulinemic patients and to correlate this parameter to the clinical phenotype. METHODS: Serum CXCL10, IFN-gamma, and TNF-alpha were assayed in 102 patients with hepatitis C-associated cryoglobulinemia (MC + HCV), in 102 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 102 sex- and age-matched controls. RESULTS: Cryoglobulinemic patients showed significantly higher mean CXCL10 serum levels than controls (P &lt; 0.0001) or HCV+ patients (P &lt; 0.0001) (397 +/- 132 pg/mL, 92 +/- 53 pg/mL, 280 +/- 149 pg/mL, respectively). Moreover, CXCL10 was significantly increased in 30 cryoglobulinemic patients with active vasculitis compared to those without it (460 +/- 104 pg/mL vs 369 +/- 139 pg/mL, respectively; P &lt; 0.001). Both groups of MC + HCV patients with or without active vasculitis had serum CXCL10 significantly higher than HCV+ patients (P &lt; 0.001, P= 0.02, respectively). IFN-gamma levels were not significantly different in MC + HCV than in HCV+ patients or controls. Serum TNF-alpha levels were significantly higher in MC + HCV than in HCV+ patients or controls (median [interquartile range]: 12.0 [9.8], 5.7 [5.4], 1.3 [2.1] pg/mL, respectively; P &lt; 0.0001). CONCLUSIONS: The study demonstrates high CXCL10 and TNF-alpha serum levels in patients with hepatitis C-associated cryoglobulinemia. Moreover, in MC + HCV patients, increased CXCL10 levels were significantly associated with the presence of active vasculitis.

2008 - High values of CXCL10 serum levels in patients with hepatitis C associated mixed cryoglobulinemia in presence or absence of autoimmune thyroiditis [Articolo su rivista]
A., Antonelli; Ferri, Clodoveo; P., Fallahi; Ferrari, Silvia Martina; S., Frascerra; Sebastiani, Marco; F., Franzoni; F., Galetta; E., Ferrannini
abstract

The aim of this study was to evaluate CXCL10 serum levels in patients with hepatitis C virus chronic infection (HCV) associated mixed cyoglobulinemia (MC), in the presence or absence of autoimmune thyroiditis (AT). CXCL10 was assayed in 50 MC patients without AT, in 40 MC patients with AT (MC+AT), in 2 gender- and age-matched control groups [50 healthy controls (without HCV or AT; control); 40 controls with AT (without HCV and MC; control+AT)]. CXCL10 was significantly higher: (1) in control+AT than in control (p<0.001); (2) in MC patients than in control (p<0.001); (3) in MC+AT patients than in control (p<0.001), control+AT (p<0.001), or in MC (p=0.002). CXCL10 was significantly increased in MC+AT patients with thyroid hypoechogenicity (388+/-147 vs 302+/-112; p=0.03), or hypothyroidism (391+/-142 vs 307+/-118; p=0.04), compared to those without. By defining a high CXCL10 level as a value at least 2 SD above the mean value of the control (>167 pg/ml), 8% of control, 22% of control+AT, 47% of MC and 80% of MC+AT had high CXCL10 (p<0.0001). In conclusion, our study is the first to demonstrate high serum levels of CXCL10 in MC and that CXCL10 in MC+AT patients are significantly higher compared to MC patients.

2008 - Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Ferrari, Sm; Colaci, Michele; Fallahi, P.
abstract

Hepatitis C Virus (HCV) is known to be responsible for both hepatic and extrahepatic diseases (HCV-related extrahepatic diseases = HCV-EHDs). The most important systemic HCV-EHDs are mixed cryoglobulinemia and lymphoproliferative disorders, while the most frequent and clinically important endocrine HCV-EHDs are thyroid disorders and type 2 diabetes mellitus (T2D). From a meta-analysis of the literature a significant association between HCV infection and thyroid autoimmunity and hypothyroidism has been reported. A high prevalence of thyroid cancer has been reported, too. Furthermore, several clinical epidemiologic studies have reported that HCV infection is associated to T2D. Many studies have linked Th1 immune response with HCV infection, thyroid autoimmunity, or diabetes. These findings suggest that a possible common immunological Th1 pattern could be the pathophysiological base of the association of HCV-EHDs, with thyroid autoimmunity and T2D. In fact, HCV infection of thyrocytes or beta-cells may act by upregulating CXCL10 secretion in these cells that is responsible for Th1 lymphocyte recruitment. Th1 response leads to increased IFNgamma and TNFalpha production that in turn stimulates CXCL10 secretion by the target cells, thus perpetuating the immune cascade. This process may lead to the appearance of thyroid autoimmune disorders or T2D in genetically predisposed subjects.

2008 - Mixed cryoglobulinemia. [Articolo su rivista]
Ferri, Clodoveo
abstract

Mixed cryoglobulinemia (MC), type II and type III, refers to the presence of circulating cryoprecipitable immune complexes in the serum and manifests clinically by a classical triad of purpura, weakness and arthralgias. It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of 'essential' MC is reported as approximately 1:100,000 (with a female-to-male ratio 3:1), but this term is now used to refer to a minority of MC patients only. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as a late complication. MC may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called 'essential' MC. The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection is suggested to play a causative role, with the contribution of genetic and/or environmental factors. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjögren's syndrome. Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low C4 levels and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium- and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions. Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, Sjögren's syndrome, polyarthritis, and B-cell lymphomas. The first-line treatment of MC should focus on eradication of HCV by combined interferon-ribavirin treatment. Pathogenetic treatments (immunosuppressors, corticosteroids, and/or plasmapheresis) should be tailored to each patient according to the progression and severity of the clinical manifestations. Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies.

2008 - Patient characteristics of HCV-negative mixed cryoglobulinemia (MC) in Italy and Holland [Abstract in Rivista]
Mascia, Maria Teresa; Ferri, Clodoveo; Sandri, Gilda; Willems, H; Tervaert, Jw
abstract

A striking association between Mixed Cryoglobulinemia (MC) and Hepatitis C Virus (HCV) infection has already been established by means of clinico-epidemiological and laboratory studies. The HCV-associated MC is more common in Southern Europe than in Northern Europe or Northern America; it is probably due to the endemic presence of HCV infection, as well as to unknown environmental and/or predisposing genetic co-factors. The etiopathogenesis and epidemiology of HCV-negative MC, an heterogeneous group of diseases consisting of a small number of 'essential' MC, various autoimmune-lymphoproliferative disorders and MC associated with infectious agents of scarce clinical relevance, remain still widely unknown. While HCV represents the major etiological agent of MC in the Mediterranean area, particularly in Italy, patients with HCV-negative MC are more frequent in areas where the overall prevalence of the disease is significantly low and less frequent its association with HCV.The purpose of this study is to compare patients with HCV-negative MC type II followed in Italy with Dutch patient's series with regard to their clinical characteristics and associated disorders.Overall clinical characteristics of HCV-negative MC are similar to that recorded in different patient's series of the HCV-positive MC except a lower percentage of purpura (52% vs 81%). No differences between Italian and Dutch patients were uncovered in this study except that nephropathy is significantly more frequent in Holland. The diagnosis of essential HCV-negative MC is more frequent in Holland than in Italy (42% versus 18%). These data suggest that one or more unknown infectious agent might be implicated in the etiopathogenesis of Dutch EMC patients. Finally, ‘essential’ MC represent a charming challenge for future etiopathogenetic studies.

2008 - Safety of anti-tumor necrosis factor-alpha therapy in patients with rheumatoid arthritis and chronic hepatitis C virus infection. [Articolo su rivista]
Ferri, Clodoveo; Ferraccioli, G; Ferrari, D; Galeazzi, M; Lapadula, G; Montecucco, C; Triolo, G; Valentini, G; Valesini, G; Gisea, Group
abstract

OBJECTIVE: The prevalence of concurrent rheumatoid arthritis (RA) and hepatitis C virus (HCV) infection is probably underestimated because of the increasing spread of this virus worldwide, especially in developing countries. In these patients, anti-tumor necrosis factor-alpha (anti-TNF-alpha) therapy may aggravate hepatitis and increase viremia. We evaluated the safety of these treatments, which remain controversial.METHODS: Thirty-one HCV-positive patients (23 women, 8 men, mean age 59+/-13 yrs, mean disease duration 13+/-11.5 SD yrs) with active RA [Disease Activity Score 28 (DAS28)>3.2] unresponsive to conventional therapies were treated with TNF-alpha blockers (infliximab 11, etanercept 17, adalimumab 3) at standard dosages. Safety and efficacy were evaluated at the third month of treatment and at the patient's last observation.RESULTS: A significant clinical-serological improvement was recorded at the 3-month reevaluation. Mean values of patients assessment of general health on visual analog scale (range 0.100) decreased from 69+/-29 (SD) to 35+/-27 (p<0.0001), Ritchie index from 21.6+/-13.9 to 10.1+/-3.7 (p<0.0001), erythrocyte sedimentation rate from 36+/-25 to 28+/-22 mm/h (p=0.04), and DAS28 from 5.2+/-1.6 to 2.78+/-1.3 (p<0.0001); a DAS28<2.6 was recorded in 15/31 (48%) patients. At the last observation 19 patients (61%) continued TNF-alpha blockers, and the observed benefits persisted after 22+/-11 months of followup. Mean values of transaminases (ALT) and HCV viral load showed no significant variations; TNF-alpha blockers were discontinued in only one patient because of persistently elevated ALT not correlated to the variations of HCV viremia; this latter increased significantly (>or=2 log10) in 4 cases.CONCLUSION: Previous observations had suggested the safety of TNF-alpha blockers for treatment of RA in patients with concurrent HCV infection. Given the clinical-therapeutic implications, our results support the safety of TNF-alpha blockers in patients with HCV, provided there is close monitoring of clinical and virological data (mainly ALT and HCV viremia).

2008 - Th1 and Th2 chemokine serum levels in systemic sclerosis in the presence or absence of autoimmune thyroiditis. [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Colaci, Michele; Giuggioli, D; Ferrari, Sm; Frascerra, S; Franzoni, F; Galetta, F; Ferrannini, E.
abstract

OBJECTIVE: We evaluated contemporarily serum alpha and beta chemokines in patients with newly diagnosed systemic sclerosis (SSc) in the presence or absence of autoimmune thyroiditis (AT).METHODS: Serum levels of CXCL10 and CCL2 chemokines, prototypes of the 2 major subclasses (Th1 and Th2), were measured in patients with newly diagnosed SSc with (n = 40; SSc-II) or without (n = 50; SSc-I) AT, in comparison with 50 normal controls (control-I) and 40 AT controls without SSc (control-II) (sex- and age-matched).RESULTS: Serum CXCL10 levels were significantly higher in control-II, SSc-I, and SSc-II than in control-I (150 +/- 131, 196 +/- 137, 254 +/- 98, 83 +/- 42 pg/ml, respectively; p < 0.001 for all). SSc-I had serum CXCL10 levels significantly higher than control-II (p = 0.03), and significantly lower than SSc-II (p = 0.04). SSc-II had serum CXCL10 levels significantly higher than control-II (p = 0.002). Serum CCL2 levels were significantly higher in SSc-I and SSc-II than in control-I (378 +/- 192, 403 +/- 131, 316 +/- 113 pg/ml, respectively; p = 0.03 and p < 0.01, respectively). SSc-II had serum CCL2 levels significantly higher than control-II (327 +/- 123 pg/ml; p = 0.04).CONCLUSION: Our study demonstrates high serum levels of both CXCL10 (Th1) and CCL2 (Th2) chemokines in patients with SSc, and suggests a prevalence of Th1 immune response in the early phase of the disease. A further increase of serum CXCL10, but not of CCL2, is observed in SSc patients with AT.

2008 - Transient serum anti-Scl70 antibodies and interstitial lung involvement in acute EBV infection [Abstract in Rivista]
Mascia, Maria Teresa; Venturi, S; Ferri, Clodoveo
abstract

Among lymphotropic viruses, Epstein-Barr virus (EBV) is one of the most likely candidates for a pathogenetic role in some autoimmune rheumatic diseases by inducing a self-perpetuing activation of the immune system, in genetically predisposed individuals and is classically considered to induce systemic lupus erythematosus. Here, we describe the rare observation of transient clinico-serological alterations possibly triggered by acute EBV infection.Case report. A 13-years-old girl was referred to the Pediatric Division ofour hospital for hyperpyrexia (39 °C) and malaise. Standard chest x-ray showed a pulmonary infiltrate in the right lower lobe, followed by parenchymal consolidation, while serological tests revealed acute EBV infection with simultaneous infection by Mycoplasma pneumoniae. Diagnosis of EBV infection with bronchopneumonia was done. The patient was successfully treated with antibiotics and remained asymptomatic during the subsequent follow-up period.More recently, we retrospectively investigated the appearance of non-organ specific autoantibodies in the sera, stored at -80°C, from individuals with acute primary EBV infection, including the above patient. The analysis of her serum sample showed circulating anti-Scl70 antibodies (ELISA) and slight anti-SSB positiveness in Western Blot (WB). Past clinical history excluded any symptoms of connective tissue disease preceding EBV infection, whileclinico-serological re-evaluation 6 years later documented a moderate cold-induced acrocyanosis (started after the infectious event), serum anti-EBV IgG type, low titre of ANA (1:80, speckled), and disappearance of anti-ENA (ELISA and WB). Finally, nailfold videocapillaroscopy documented isolated neoangiogenetic phenomena, characterized by arborized capillary loops.Discussion. The diagnosis of“ EBV infection with bronchopneumonia and interstitial emphysema " was based on previous anecdotal reports on lung consolidation, characterized by interstitial infiltrate of mononuclear cells, usually observed in older individuals with ongoing EBV infection.The production of Anti-Scl70 antibodies is believed to be associated with a pathogenic process in SSc patients, since these autoantibodies are highly specific for SSc and are rarely detected in sera from individuals who do not have SSc or Raynaud’s phenomenon. In particular it is not clear whether anti–topo I antibody contribute to the pathogenesis of the disease or they should be regarded as simple epiphenomenon; however these antibodies are associated with pulmonary interstitial fibrosis and severe microvasculopathy. Studies have shown that anti–topo I antibody isotype levels are relatively stable during long-term observation in most patients, although a few patients experienced a prominent change in the antibody level.In another longitudinal analysis of autoantibody response to topoisomerase in systemic sclerosis japanese authors documented a distinct subset of anti-topo I-positive SSc patients who lose anti–topo I antibody during the disease course and have a favorable outcome.It is supposable that acute viral infection may be complicated by one or more clinical symptoms along with circulating specific autoantibodies, which may reproduce the early stage of well-defined connective tissue diseases. The transient alterations observed in the patient here described further underlined the role of different pathogenetic co-factors in the multistep process leading to chronic autoimmune disorders.

2007 - B-cells and mixed cryoglobulinemia [Articolo su rivista]
Ferri, Clodoveo; Antonelli, A; Mascia, Maria Teresa; Sebastiani, Marco; Fallahi, P; Ferrari, D; Giunti, Marco; Pileri, Sa; Zignego, Al
abstract

Mixed cryoglobulinemia (MC) is a systemic small-vessel vasculitis; B-cell expansion is the biological substrate of the disease. It can be regarded as benign lymphoproliferative condition that may evolve to frank lymphoma. HCV infection is the main causative factor of MC, as well as of other overlapping disorders, through multifactorial and multistep pathogenetic process. HCV-related B-cell proliferation represents an important model of virus-driven autoimmune/neoplastic disorder. The term HCV syndrome is referred to a wide spectrum of both hepatic and extrahepatic disorders. The present review analyzes the complex virological, clinico-pathological, and therapeutic implications of B-cell proliferation, with or without HCV infection, in MC patients.

2007 - Clinical and subclinical autoimmune thyroid disorders insystemic sclerosis [Articolo su rivista]
Alessandro, Antonelli; Ferri, Clodoveo; Poupak, Fallahi; Massimiliano, Cazzato; Ferrari, Silvia Martina; Sebastiani, Marco; Ele, Ferrannini
abstract

Objective: Several studies have reported the association of systemic sclerosis (SSc) with thyroidautoimmune disorders, but most of them have neither an appropriate control group nor include acomplete thyroid work-up.Design: The aim of our study was to evaluate the prevalence of thyroid disorders in a large number ofpatients with SSc using a complete clinical evaluation.Methods: Thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, antithyroglobulinand antithyroid-peroxidase (AbTPO) autoantibodies, thyroid ultrasonography and blood flow and fineneedle aspirationwere performed in 202 SSc patients versus 404 gender- and age-matched controls fromthe general population, with similar iodine intake, to evaluate the prevalence of clinical and subclinicalthyroid disorders.Results: Odds ratio (OR) for female SSc versus controls was: for subclinical hypothyroidism, 3.2(95% CI)Z1.8–5.7); for clinical hypothyroidism, 14.5 (95% CIZ2.3–90.9); for AbTPO positivity,2.7 (95% CIZ1.8–4.1); for hypoechoic pattern, 3.2 (95% CIZ2.2–4.7); for thyroidautoimmunity, 3.7 (95% CIZ2.6–5.4); for thyroid volume !6 ml, 1.8 (95% CIZ1.2–2.7).OR for thyroid autoimmunity in male SSc versus controls was 10.8 (95% CIZ2.2–52.4). Meanvalues of TSH in female SSc, and of AbTPO in female and male SSc were higher (P!0.01) thanin controls. We observed three cases of Graves’ disease in female SSc versus zero in controls(PZ0.0140), and two cases of papillary thyroid cancer in SSc patients.Conclusions: Thyroid function, AbTPO and ultrasonography should be tested as part of theclinical profile in SSc patients. Females, subjects with positive AbTPO and hypoechoic and smallthyroid should have thyroid function follow-up and appropriate treatment in due course.

2007 - Cytomegalovirus-associated cutaneous vasculopathy and scleroderma sans inclusion body change [Articolo su rivista]
Magro, Cm; Crowson, An; Ferri, Clodoveo
abstract

Viruses have long been held to be of pathogenetic importance in the evolution of autoimmune connective tissue disease. We describe 7 adults who developed cutaneous connective tissue disease stigmata in temporal association with recent cytomegalovirus (CMV) infection but without the classic cytopathic changes of CMV infection. We examined 7 adults with clinical presentations encompassing cutaneous vasculitis in 4 and scleroderma in 3. In all 7 patients, there was either IgM seropositivity for CMV and/or CMV DNA isolation from peripheral blood. Although no CMV inclusions were seen, in situ hybridization studies revealed very focal CMV RNA transcript expression with localization mainly to the endothelium. The patients with vasculitis treated with ganciclovir had improvement or resolution of symptoms, whereas only 1 patient with scleroderma received antiviral therapy, without benefit. Another scleroderma patient responded to infliximab therapy. Abortive/partial CMV reactivation can be associated with a syndrome complex mimicking and/or triggering a primary immune-based cutaneous microvascular injury syndrome. Antiviral therapy appears to be of therapeutic value in those cases associated with active necrotizing vasculitic changes. The role of tumor necrosis factor alpha blockers in scleroderma cases temporally associated with CMV infection requires further evaluation. (c) 2007 Published by Elsevier Inc.

2007 - Efficacia di terapia con immunoassorbimento con proteina A dello stafilococco e talidomide in un caso di dermatomiosite refrattaria. [Abstract in Rivista]
Colaci, Michele; Puccini, R; Sebastiani, Marco; Mattei, P; Manni, E; Manfredi, Andreina Teresa; Giuggioli, D; Barachini, P; Ferri, Clodoveo
abstract

descrizione dell'efficacia di una terapia combinata con talidomide e immunoassorbimento con proteina A dello stafilococco in un caso di dermatomiosite refrattaria con severo impegno cutaneo

2007 - Etanercept maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effects [Articolo su rivista]
Iannone, F; Trotta, F; Monteccuco, C; Giacomelli, R; Galeazzi, M; Matucci Cerinic, M; Ferri, Clodoveo; Cutolo, M; Bambara, Lm; Triolo, G; Ferraccioli, G; Valentini, G; Lapadula, G.
abstract

Objective: To evaluate the efficacy of switching to etanercept treatment in patients with rheumatoid arthritis who already responded to infliximab, but presented side effects. Methods: Charts of 553 patients with rheumatoid arthritis were retrospectively reviewed to select patients who responded to the treatment with infliximab and switched to etanercept because of occurrence of adverse effects. Clinical data were gathered during 24 weeks of etanercept treatment and for the same period of infliximab treatment before infliximab was stopped. Disease Activity Score computed on 44 joints (DAS-44), erythrocyte sedimentation rate (ESR) 1st hour, Visual Analogue Scale (VAS) of pain, Health Assessment Questionnaire (HAQ), and C reactive protein (CRP) were assessed every 8 weeks. Results: 37 patients were analysed. Adverse events to infliximab were mostly infusion reactions. No statistically significant difference between infliximab, before withdrawal, and etanercept, after 24 weeks, was detected in terms of DAS-44 (2.7 and 1.9, respectively), HAQ (0.75 and 0.75, respectively), ESR ( 21 and 14, respectively) and CRP (0.5 and 0.3, respectively). VAS pain decreased significantly after switching to etanercept treatment (40 and 24, respectively; p < 0.05). Conclusions: Our study shows that etanercept maintains the clinical benefit achieved by infliximab, and suggests that a second tumour necrosis factor (TNF) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNF alpha blocker has been withdrawn because of adverse events.

2007 - Extrahepatic manifestations of Hepatitis C Virus infection: a general overview and guidelines for a clinical approach. [Articolo su rivista]
Zignego, Al; Ferri, Clodoveo; Pileri, Sa; Caini, P; Bianchi, Fb; FOR THE ITALIAN ASSOCIATION OF THE STUDY OF LIVER COMMISSION ON EXTRAHEPATIC MANIFESTATIONS OF HCV, Infection
abstract

Hepatitis C Virus is associated with a wide series of extrahepatic manifestations. Based on available data the link between the virus and some of these extrahepatic diseases is only suggested and needs further confirmation. Hepatitis C Virus-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinaemia, represent the most closely related extrahepatic manifestations of Hepatitis C Virus. Other Hepatitis C Virus-associated disorders include nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, porphyria cutanea tarda, lichen planus, diabetes, chronic polyarthritis, cardiopathy and atherosclerosis. A pathogenetic link between Hepatitis C Virus and some extrahepatic manifestations was confirmed by their responsiveness to antiviral therapy, which is now deemed the first therapeutic option to consider. By contrast, there are diseases where treatment with interferon was ineffective or dangerous. The aim of the present paper is to outline the most recent evidence concerning extrahepatic disorders that are possibly associated with Hepatitis C Virus infection. Special emphasis will be given to discussion of the most appropriate clinical approaches to be adopted in order to diagnose, treat (possibly prevent) and follow-up extrahepathic diseases in patients with Hepatitis C Virus infection.

2007 - Genetic insights into the disease mechanisms of type II mixed cryoglobulinemia induced by hepatitis C virus. [Articolo su rivista]
DE RE, V; Caggiari, L; DE VITA, S; Mazzaro, C; Lenzi, M; Galli, M; Monti, G; Ferri, Clodoveo; Zignego, Al; Gabrielli, A; Sansonno, D; Dammacco, F; Libra, M; Sacchi, N; Talamini, R; Spina, M; Cannizzaro, R; Guidoboni, M; Dolcetti, R.
abstract

The ability of the immune system to distinguish between self and non-self is critical to the functioning of the immune response. A breakdown in these mechanisms can lead to the onset of autoimmune disease. Clinical and molecular data suggest that shared immunogenetic mechanisms lead to the autoimmune process. The most studied part of the autoimmune process is the human leukocyte antigen (HLA) region. Recently, progress has been made in narrowing down HLA cluster classifications based on structural and functional features of HLA alleles. Using this approach we have investigated 175 patients with hepatitis C virus (HCV)-induced type II cryoglobulinemia (MC), and compared them to a control group of 14,923 bone marrow donors. Additionally, we investigated the frequency of HLA homozygosity in the same groups of subjects. Our results provide evidence of a role for DR5 and DQ3 HLA class II clusters and a higher frequency of HLA homozygous leading to the clinical outcome of type II mixed cryoglobulinemic autoimmune disease. The DR5 cluster is characterized by a Glu in beta 9 and its polymorphism is connected with preferred anchors at beta 9 of the binding peptide, while the DQ3 cluster is characterized by Glu B86 and Leu B87, which allows the binding of large hydrophobic amino acids at p1 of the binding peptide. The mechanisms by which variations in HLA lead to autoimmunity remain unknown, although they are likely to be mediated by continuous presentation of HCV epitopes to T cells and a genetic background that limits the effective clearance of HCV. The results presented in this paper have increased our knowledge of the mechanism of autoimmune disease and B-cell lymphoproliferation during HCV infection. The work was performed in accordance with the principles of the 1983 Declaration of Helsinki. There is no conflict of interest.

2007 - Good clinical response, remission, and predictors of remission in rheumatoid arthritis patients treated with tumor necrosis factor-alpha blockers: the GISEA study. [Articolo su rivista]
L., Mancarella; F., BOBBIO PALLAVICINI; F., Ceccarelli; P. C., Falappone; A., Ferrante; D., Malesci; A., Massara; F., Nacci; M. E., Secchi; S., Manganelli; F., Salaffi; M. L., Bambara; S., Bombardieri; M., Cutolo; Ferri, Clodoveo; M., Galeazzi; R., Gerli; R., Giacomelli; W., Grassi; G., Lapadula; M., MATUCCI CERINIC; C., Montecucco; F., Trotta; G., Triolo; G., Valentini; G., Valesini; G. F., Ferraccioli
abstract

OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-alpha (TNF-alpha) drugs at outpatient clinics.METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF-alpha blockers. All patients received one TNF-alpha blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month.RESULTS: A total of 1257 patients started TNF-alpha blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male).CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA

2007 - HCV e malattie reumatiche. [Abstract in Rivista]
Ferri, Clodoveo; Sebastiani, Marco; Ferrari, D; Giunti, M; Antonelli, A; Fallahi, P; Mascia, Maria Teresa
abstract

descrizione delle manifestazioni extra-epatiche in corso di infezione da HCV, con particolare riferimento alle possibili manifestazioni di tipo autoimmune

2007 - HCV-related autoimmune and neoplastic disorders: the HCV syndrome [Articolo su rivista]
Ferri, Clodoveo; Antonelli, A; Mascia, Maria Teresa; Sebastiani, Marco; Fallahi, P; Ferrari, D; Pileri, Sa; Zignego, Al
abstract

Hepatitis C virus (HCV) chronic infection may be associated with a great number of both hepatic and extrahepatic manifestations. HCV lymphotropism is responsible for poly-oligoclonal B-lymphocyte expansion, which is the common underlying alteration in a significant percentage of HCV-infected individuals. The consequent production of different autoantibodies and immune-complexes, including cryoglobulins, may lead to organ- and non-organ-specific immunological alterations. Mixed cryoglobulinemia, a small-vessel systemic vasculitis, is characterized by the coexistence of autoimmune and lymphoproliferative alterations; therefore, it represents the prototype of HCV-associated disorders. Moreover, HCV shows an oncogenic potential; several studies support its pathogenetic link with some malignancies, mainly hepatocellular carcinoma and B-cell lymphomas. On the whole, HCV-related disorders present a heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. While the majority of HCV-infected individuals is asymptomatic or may develop only liver manifestations, a significant percentage of them may develop a variable combination of autoimmune lymphoproliferative disorders. The resulting multiform clinico-pathological condition can be termed HCV syndrome. The natural history of HCV syndrome is the expression of multifactorial and multistep pathogenetic process, which usually proceeds from mild, often isolated manifestations to systemic immune-mediated disorders, and less frequently to overt malignancies.

2007 - Hepatitis C virus-related lymphoproliferative disorders: an overview. [Articolo su rivista]
Zignego, Al; Giannini, C; Ferri, Clodoveo
abstract

Hepatitis C virus (HCV) is a global health problem affecting 3% of the world's population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV-related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies (hepatocellular carcinoma) has justified the inclusion of HCV among human cancer viruses. HCV-associated manifestations also include porphyria cutanea tarda, lichen planus, nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, diabetes, chronic polyarthritis, sexual dysfunctions, cardiopathy/atherosclerosis, and psychopathological disorders. A pathogenetic link between HCV virus and some lymphoproliferative disorders was confirmed by their responsiveness to antiviral therapy, which is now considered the first choice treatment. The aim of the present paper is to provide an overview of extrahepatic manifestations of HCV infection with particular attention to B-cell lymphoproliferative disorders. Available pathogenetic hypotheses and suggestions about the most appropriate, currently available, therapeutic approaches will also be discussed.

2007 - Indicazioni chirurgiche alla artrodesi totale di polso nei pazienti affetti da artrite reumatoide. [Abstract in Rivista]
A., Marcuzzi; S., Sartini; Mascia, Maria Teresa; Sandri, Gilda; L., Chirila; Ferri, Clodoveo
abstract

Indicazioni chirurgiche alla artrodesi totale di polso nella sinovite reumatoide

2007 - Non HCV-related mixed cryoglobulinemia [Articolo su rivista]
Mascia, Maria Teresa; Ferrari, D; Campioli, D; Sandri, Gilda; Mussini, C; Ferri, Clodoveo
abstract

A striking association (>90%) between mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) infection has been established by means of clinico-epidemiological and laboratory studies. However, little information is available as regards the etiopathogenesis and the actual percentage of HCV-negative MC. This latter seems to be more frequent in the same geographical areas where the overall prevalence of MC is low. In 195 Italian patients with serum mixed cryoglobulins consecutively analyzed at the laboratory of our hospital, during one year, the prevalence of HCV-negative MC was 15,9%. Moreover, we evaluated the clinico-serological characteristics of our whole series of 65 HCV-negative MC patients: ‘essential’ MC was present in only 25%, while the majority of cases showed different connective tissue diseases or neoplastic disorders. Interestingly, patients with Sjögren’s syndrome or lymphoma had higher levels of cryocrit with cryoglobulinemic syndrome comparable to that found in HCV-positive MC patients.MC is a multifactorial disorder; considering possible etiological factors and clinical associations the disease may present different subsets: the prevalent group of HCV-positive MC; HCV-positive MC associated to different autoimmune-lymphoproliferative disorders; two MC subsets without any apparent causative agent: those with well-known autoimmune-lymphoproliferative disorders and the rare cases of ‘essential’ MC; and finally MC associated with other infectious agents.

2007 - Percutaneous vertebroplasty as therapy for vertebral fractures: results in a series of osteoporotic patients [Articolo su rivista]
Manzini, Cu; Bernini, L; Vallone, S; Cavalleri, F; Ferri, Clodoveo
abstract

In the recent years, percutaneous vertebroplasty is available for the treatment of the vertebral fractures, primarily to relieve pain related to the lesion. In order to evaluate the efficacy and the safety of this technique, we have treated with percutaneous vertebroplasty, using polymethylmethacrylate, 22 patients, affected by one or more vertebral fractures caused by osteoporosis. All the patients satisfied the inclusion criteria of the American College of Radiology for percutaneous vertebroplasty. These patients were compared with a control group of 23 not treated subjects with vertebral fractures, using questionnaires for assessment of pain and quality of life, drug intake, use of corset, and tolerability of the surgery. In the large majority of patients, the treatment of osteoporotic vertebral fractures with percutaneous vertebroplasty resulted in a prompt, marked and sustained relief of vertebral pain with a persistent improvement of quality of life.

2007 - Role of the HLA class II: HCV-related disorders [Articolo su rivista]
DE RE, V; Caggiari, L; Simula, Mp; DE VITA, S; Mazzaro, C; Lenzi, M; Massimo, Gm; Monti, G; Ferri, Clodoveo; Zignego, Al; Gabrielli, A; Sansonno, D; Dammacco, F; Libra, M; Sacchi, N; Talamini, R; Spina, M; Tirelli, U; Cannizzaro, R; Dolcetti, R.
abstract

The paper highlights the role of different HLA class II molecules in hepatic and lymphoproliferative HCV-related disorders. HLA molecules have been reviewed, according to an in silico cluster classification, based on the sequence, the biochemical structure of the pockets, and the functional characteristics of the HLA II molecules. Thus, by reducing the complexity of HLA II polymorphism, characteristics that unite different HLA molecules with specific HCV-associated pathologies may be recognized with greater case. Results show that HLA clusters associated with better dlimination of the virus are protective against HCC development, while the same clusters are associated with a higher risk of developing cryoglobulinemic syndrome and the concomitant NHL. These data added further acknowledgements on pathogenetic mechanisms associated with HCV infection. Results also highlight differences of NHL occurring in HCV-positive subjects, with or without a concomitant type II autoimmune cryoglobulinemic syndrome, suggesting that cryoglobulinemic background associated with NHL should be considered in the evaluation of the effectiveness of new therapies in the course of HCV-associated NHLs.

2007 - Thyroid cancer in HCV-related chronic hepatitis patients: a case-control study. [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Pampana, A; Ferrari, Sm; Barani, L; Marchi, S; Ferrannini, E.
abstract

OBJECTIVE: The present study prospectively investigated prevalence and features of thyroid cancer in patients with hepatitis C virus-related chronic hepatitis (HCV+) in comparison to two samples from the general population with different iodine intake.DESIGN: We studied the prevalence of thyroid cancer in 308 unselected HCV+ patients in comparison to two population-based, gender- and age-matched control groups: 1) 616 subjects from an iodine deficient area; 2) 616 subjects from an iodine-sufficient area. Thyroid status was assessed by measurement of circulating thyroid hormones and autoantibodies, thyroid ultrasonography, and when indicated, fine-needle aspiration cytology.MAIN OUTCOME: Circulating thyrotropin, anti-thyroglobulin, and anti-thyroperoxidase antibodies levels, and the prevalence of hypothyroidism were significantly higher in HCV+ patients (p < 0.001 for all). Six patients with papillary thyroid cancer were detected among HCV+ patients, whereas no case was observed in control 1 (p = 0.001), and only one case was observed in control 2 (p = 0.003). In HCV+ patients 83% with thyroid cancer had evidence of thyroid autoimmunity vs 31% of the other HCV+ patients (p = 0.02).CONCLUSIONS: These data suggest a high prevalence of thyroid papillary cancer in HCV+ patients, overall in presence of thyroid autoimmunity; careful thyroid monitoring is indicated during the follow-up of these patients.

2007 - Trattamento con IgIV ad alte dosi in un caso di dermatomiosite con grave disfagia refrattaria alle terapie standard. [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Colaci, Michele; Manzini, C; Giuggioli, D; Ferri, Clodoveo
abstract

descrizione dell'efficacia di una terapia con immunoglobuline ad alte dosi per via endovenosa in un caso di dermatomiosite con impegno esofageo

2007 - Trattamento del dolore in reumatologia con oppioidi: nostra esperienza con ossicodone in pazienti con ulcere cutanee vasculitiche. [Abstract in Rivista]
Giuggioli, D; Manfredi, Andreina Teresa; Ferrari, D; Colaci, Michele; Sebastiani, Marco; Ferri, Clodoveo
abstract

valutazione dell'efficacia dell'ossicodone nel trattamento del dolore in pazienti con ulcere cutanee secondarie a sclerosi sistemica

2007 - Trattamento della fascite eosinofila con D-penicillamina: descrizione di 3 casi. [Abstract in Rivista]
Manzini, C; Sebastiani, Marco; Manfredi, Andreina Teresa; Colaci, Michele; Ferri, Clodoveo
abstract

descrizione di 3 casi di fascite eosinofila trattati con successo con D-penicillamina

2007 - Treatment of severe scleroderma skin ulcers with recombinant human erythropoietin [Articolo su rivista]
Ferri, Clodoveo; Giuggioli, D; Sebastiani, Marco; Colaci, Michele
abstract

Systemic sclerosis (SSc) is frequently complicated by skin ulcers, often unresponsive to traditional treatments. A preliminary evaluation of the effects of recombinant human erythropoietin (rHuEPO) was carried out in 14 patients with SSc with nonhealing, severe cutaneous ulcers. Patients received rHuEPO subcutaneously at a dosage of 150 IU/kg 3 times weekly for 2 weeks, twice weekly for the next 2 weeks, and then once weekly for 1 month. At follow-up 3-6 months from the beginning of the treatment, six patients showed complete resolution of the skin ulcers, while a significant reduction (> 60%) in lesional areas was obtained in the other eight patients (mean +/- SD ulcer area reduced from 27.6 +/- 28 to 5.3 +/- 7.8 cm(2); P<0.005). Moreover, patients' quality of life significantly improved (pain, as measured on visual analogue scale reduced from 96 +/- 5 to 46 +/- 17 points; P=0.0001; disability as measured by the Health Assessment Questionnaire-Disability Index reduced from 1.6 +/- 0.5 to 0.9 +/- 0.4 points; P=0.0001). The rHuEPO may represent a novel treatment of nonhealing scleroderma skin ulcers, suggesting some important aetiopathological implications.

2007 - Valore predittivo di uno score capillaroscopico nei pazienti sclerodermici. [Abstract in Rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Colaci, Michele; Giuggioli, D; Elkhaldi, Nezar Moneir Fadl; Ferri, Clodoveo
abstract

valutazione del valore di uno score quantitativo capillaroscopico predittivo della comparsa di ulcere digitali in corso di sclerosi sistemica

2006 - Autoimmune-like pulmonary disease in association with parvovirus B19 - A clinical, morphologic, and molecular study of 12 cases [Articolo su rivista]
C. M., Magro; R., Wusirika; G. E., Frambach; G. J., Nuovo; Ferri, Clodoveo; Ross, P. J. r.
abstract

Parvovirus B19, the agent responsible for fifth disease, has been emerging as a significant pathogenetic factor in various acute vasculitic syndromes such as Wegener's granulomatosis, Henoch-Schonlein purpura, and Kawasaki disease. It has also been implicated in more chronic vasculopathic syndromes, specifically in the context of scleroderma and dermatomyositis. The basis of this association is likely multifactorial; implicated mechanisms include the virus's affinity for endothelium, resulting in a state of neoantigenicity through varied mechanisms as well as the induction of tumor necrosis factor alpha, a factor involved in the propagation of ANCA-positive vasculitic syndromes. The authors present a series of 12 patients with interstitial lung disease including idiopathic pulmonary fibrosis, scleroderma-associated pulmonary fibrosis, lymphocytic interstitial pneumonitis, and septal capillaritis. In all cases there was evidence of chronic parvovirus B19 infection based on serologic assessment and the isolation of B19 DNA on lung samples in all patients. Furthermore, in two cases there was in situ localization of B19 RNA and tumor necrosis factor alpha to endothelium and stromal cells. On pathologic examination, there were varying degrees of both septal fibrosis and inflammation along with evidence of septal capillary injury. In those cases categorized as representing either sclerodema or idiopathic pulmonary fibrosis, the immunofluorescent studies showed evidence of anti-endothelial cell antibody formation. The ANCA-associated syndromes were, as expected, negative by fluorescent analysis. Significantly elevated factor VIII levels, a standard serologic index of endothelial cell injury, were seen in four of the six patients tested. The antiphospholipid profile revealed antiphospholipids in 7 of the 1 I patients tested. This report highlights a possible causal role for parvovirus B19 in the pathogenesis of select pulmonary disorders.

2006 - Chronic graft versus host disease a coinvolgimento cutaneo: ruolo della capillaroscopia nella diagnostica differenziale con la sclerosi sistemica. [Abstract in Rivista]
Sebastiani, Marco; Cuoghi, Aurora; Caruso, A; Bresciani, S; Venturi, S; Giuggioli, D; Ferri, Clodoveo
abstract

ruolo della capillaroscopia nella diagnostica differenziale fra sclerosi sistemica e Chronic graft versus host disease con prevalente impegno cutaneo

2006 - Cryoglobulinemia [Capitolo/Saggio]
Ferri, Clodoveo; A. L., Zignego; S. A., Pileri
abstract

descrizione della crioglobulinemia mista: definizione, manifestazioni cliniche, patofisiologia, prognosi, trattamento, diagnosi sifferenziale

2006 - Cryoglobulinemic vasculitis. [Articolo su rivista]
Ferri, Clodoveo; Mascia, Maria Teresa
abstract

PURPOSE OF REVIEW: Cryoglobulinemic vasculitis is an immune-complex-mediated systemic vasculitis involving small-medium-sized vessels. A causative role of hepatitis C virus in over 80% patients has been definitively established, with heterogeneous geographical distribution. This review focuses on recent etiopathogenetic, clinico-diagnostic, and therapeutical studies.RECENT FINDINGS: Hepatitis C virus cannot be integrated into the host genome; it may exert a chronic stimulus to the immune system. The interaction between hepatitis C virus envelope protein E2 with B-cell CD 81 receptor may increase the frequency of VDJ rearrangement in antigen-reactive B lymphocytes. One consequence is the activation of various protooncogenes, including anti-apoptotic Bcl-2. The extended B-cell survival is responsible for autoantibody and immune-complex production, including mixed cryoglobulins; some malignancies, mainly B-cell lymphomas, may complicate cryoglobulinemic vasculitis. Environmental or viral/host genetic cofactors should be relevant in the pathogenesis of hepatitis C virus-related diseases. Cryoglobulinemic vasculitis may overlap with other diseases (systemic vasculitides, Sjögren's syndrome, autoimmune hepatitis, lymphoma), which should be carefully considered for a correct diagnosis and treatment. Cumulative survival of cryoglobulinemic vasculitis is significantly lower compared with the general population. Therapeutic strategies for cryoglobulinemic vasculitis include etiologic (antiviral), pathogenetic (cyclophosfamide, rituximab), or symptomatic (steroids, plasmapheresis) treatments, which should be tailored to the individual patient according to the severity/activity of clinical symptoms.SUMMARY: Cryoglobulinemic vasculitis represents a crossroads among autoimmune and lymphoproliferative disorders; as hepatitis C virus infection is the major causative factor, cryoglobulinemic vasculitis is an important model for etiopathogenetic studies of virus-related diseases

2006 - Dactilitis and oligoarthritis after BCG immunotherapy in a patient affected by bladder cancer [Articolo su rivista]
Manzini, Cu; Bernini, L; Elkhaldi, N; Mascia, Maria Teresa; Ferri, Clodoveo
abstract

The treatment of bladder cancer with Bacillus of Calmette-Guerin (BCG) immunotherapy can induce the appearance of a reactive disorder. The Authors describe a 55-year-old male patient with bladder cancer treated with endovesical instillation of BCG immunotherapy, followed after the fifth application by asymmetric oligoarthritis and dactilitis. The observed positivity of both HLA-B27 and HLA-B51 antigens reinforces the hypothesis of a reactive form, possibly through "molecular mimicry" mechanism. The discontinuation of BCG instillation along which a therapeutic attempt with NSAD failed to improve the rheumatic manifestation, which completely remitted after a four-month course of oral steroids. No relapses of joint and tendon involvement was observed during the following five-month period. The clinico-pathogenetic implications suggested by this case are discussed.

2006 - Mixed cryoglobulinemia [Capitolo/Saggio]
Ferri, Clodoveo; Mascia, Maria Teresa
abstract

Mixed cryoglobulinemia (MC) includes:MC type II, composed by polyclonal IgGmonoclonal IgM, and MC type III, composed by polyclonal IgG-polyclonal IgM immune-complexes. MC may be secondary to various immunological,hematological, and infectiousd iseases, or it can represent a distinct disorder, the ‘essential’ MC. Following the discovery of a causative role of HCV, the term ‘essential’ is now referred to only a small percentage of patients. MC classification criteria include: serum mixed cryoglobulins, hypocomplementemia (low C4), leukocytoclastic vasculitis, typical clinical triad - purpura, weakness, arthralgias-, and multiple organ involvement.MC may share various clinico-serological features with different immunological/ neoplastic diseases; differential diagnosis should take in account other systemic vasculitides, Sjogren’s syndrome, autoimmune hepatitis, and B-cell lymphomas. MC syndrome is an immune-complex mediated systemic vasculitis (leukocytoclastic vasculitis) involving the small vessels, clinically characterized by cutaneous manifestations (orthostatic purpura, and ulcers), liver, renal, peripheral nerves, widespread vasculitis, and possible development of neoplastic disorders, mainly B-cell lymphomas.MC cumulative survival is significantly lower if compared to general population.Treatment of MC syndrome is particularly challenging because of its complex etiopathogenesis, including HCV infection, autoimmune, and lymphoproliferative alterations; it may include etiological, pathogenetic, and/or symptomatic therapies. An attempt to eradicate the HCV (interferon ribavirin) should be done in all HCV-related MC, particularly in those with active hepatitis. The immunosuppressors (cyclophosphamide or rituximab), alone or in combination with high dosage steroids and/or plasma exchange, can be usefully employed in MC patients with severe/active complications (glomerulonephritis, widespread vasculitis, sensory-motor neuropathy).

2006 - Rituximab in un caso di croglobulinemia mista complicata da glomerulonefrite e linfoma villoso. [Abstract in Rivista]
Ferrari, D; Sebastiani, Marco; Elkhaldi, Nezar Moneir Fadl; Giunti, M; Mascia, Maria Teresa; Ferri, Clodoveo
abstract

descrizione di un caso di crioglobulinemia mista complicata da glomerulonefrite e linfoma villoso.

2006 - Skin manifestations in vasculitis and erythema nodosum [Articolo su rivista]
Atzeni, F; Carrabba, M; Davin, Jc; Frances, C; Ferri, Clodoveo; Guillevin, L; Jorizzo, Jl; Mascia, Maria Teresa; Patel, Mj; Pagnoux, C; Vulpio, L; Sarzi Puttini, P.
abstract

Cutaneous lesions are frequent in medium-sized and small vessel systemic vasculitides. The classic cutaneous manifestation of vasculitis is palpable purpura; however the clinical manifestations greatly depend on the size of the vessels affected. They usually do not affect prognosis but relapsing or intractable forms have been described. When skin manifestations are only one of the clinical signs of vasculitis. treatment with corticosteroids and, when indicated, an inununosuppressant, is mandatory, which usually leads to the rapid disappearance of cutaneous lesions. Conversely, when skin lesions are isolated, the diagnosis can be snore challenging, but initial treatment may be less aggressive, e.g., dapsone or colchicine, reserving corticosteroids only for those patients in whom the former are ineffective. Erythema nodosum (EN) is the most frequent septal panniculitis. In general it is characterized by the sudden eruption of one or more erythematous and tender nodules or plaques located mainly over the extensor sides of lower extremities. EN resolves with complete '' restitutio ad integrum '' of the skin in 3-6 weeks. Relapses are uncommon but inpatients with idiophatic, streptococcal or EN associated with other upper respiratory tract infections they are more frequent. The main treatment of EN is that of the underlying associated conditions, if demonstrated. Aspirin and other NSAIDs in full doses are often sufficient.

2006 - Successful treatment with leflunomide of arthritis in systemic sclerosis patients [Articolo su rivista]
Sebastiani, Marco; Giuggioli, D; Vesprini, E; Caruso, A; Ferri, Clodoveo
abstract

Systemic sclerosis (SSc) is a connective tissue disease clinically characterized by different degrees of skin fibrosis and visceral organ involvement Joint involvement with severe synovitis during SSc is relatively uncommon. About 11% of SSc patients present with arthritis at disease onset , usually characterized by mono-oligoarthritis, responsive to steroid therapy.

2006 - Systemic sclerosis in childhood - Clinical and immunologic features of 153 patients in an international database [Articolo su rivista]
Martini, G; Foeldvari, I; Russo, R; Cuttica, R; Eberhard, A; Ravelli, A; Lehman, Tja; De Oliveira, Skf; Susic, G; Lyskina, G; Nemcova, D; Sundel, R; Falcini, F; Girschick, H; Lotito, Ap; Buoncompagni, A; Sztajnbok, F; Al Mayouf, Sm; Orban, I; Ferri, Clodoveo; At,
abstract

Objective. To determine the clinical and immunologic features of systemic sclerosis (SSc) in a large group of children and describe the clinical evolution of the disease and compare it with the adult form. Methods. Data on 153 patients with juvenile SSc collected from 55 pediatric rheumatology centers in Europe, Asia, and South and North America were analyzed. Demographic, clinical, and immunologic characteristics of children with juvenile SSc at the onset, at diagnosis, and during the disease course were evaluated. Results. Raynaud's phenomenon was the most frequent symptom, followed by skin induration in similar to 75% of patients. Musculoskeletal symptoms were present in one-third of patients, and the most frequently involved internal organs were respiratory and gastrointestinal, while involvement of renal, cerebral, and cardiovascular systems was extremely rare. Antinuclear antibodies were present in the sera of 81% of patients. Antitopoisomerase I (Scl-70) and anticentromere antibodies were found to be positive in 34% and 7.1% of patients, respectively. Involvement of the respiratory, gastrointestinal, and cardiovascular systems was more frequent and occurred earlier in patients who died than in those who survived. Compared with the adult form, juvenile SSc appears to be less s evere, with the involvement of fewer internal organs, particularly at the time of diagnosis, and has a less characterized immunologic profile. Conclusion. This study provides information on the largest collection of patients with juvenile SSc ever reported. Juvenile SSc appears to be less severe than in adults because children have less internal organ involvement, a less specific autoantibody profile, and a better long-term outcome.

2006 - The treatment of skin ulcers in systemic sclerosis: use of granulocyte-colony stimulating factor (G-CSF) in 26 patients [Articolo su rivista]
Giuggioli, D; Magistro, R; Colaci, Michele; Franciosi, U; Caruso, A; Ferri, Clodoveo
abstract

OBJECTIVES: To verify the effectiveness of G-CSF in the treatment of non-healing skin lesions in SSc patients.METHODS: 26 SSc patients (23 F and 3 M, age 54 +/-13,6 yrs) with skin ulcers were enrolled in a pilot study. Prior to the treatment with G-CSF, all ulcers failed to heal with conventional therapies carried out for a period of 1-5 years. All patients were treated with 5 microg/kg G-CSF subcutaneously for 5 days. Healing time, quality of wounds, VAS and HAQ-DI were used to evaluate the efficacy of the treatment.RESULTS: An improvement of skin ulcers was observed in 24/26 patients; in particular, 22/26 wounds completely healed, 2/26 showed a partial healing, in only 2 patients skin ulcers did not change during the 6-month follow-up. The quality of life improves as showed by VAS (from 88+/-13 to 55+/-28; p&lt;.0001) and HAQ (from 2.12 +/-0.45 to 1.28+/-0.30; p&lt;.0001). The eradication of pathogens from the infected ulcers was also observed in 12/12 patients; while no adverse side effects related to G-CSF were recorded. Our study suggests that G-CSF may be usefully employed in scleroderma skin ulcers refractory to conventional treatments.

2006 - Thymus alterations and systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; Colaci, Michele; Battolla, L.; Giuggioli, D.; Sebastiani, Marco
abstract

OBJECTIVES: The pathogenesis of systemic sclerosis (SSc) includes complex alterations to the immune system, possibly responsible for diffuse microvasculature and fibroblast dysfunction. Previous anecdotal observations suggest a possible role for thymus alterations in some autoimmune rheumatic diseases, including SSc. This study aimed to investigate the prevalence of radiological thymus alterations in SSc patients. METHODS: Thirthy-four unselected patients [28 female and 6 male, mean age (+/- S.D.) 49.7 +/- 9.5 yr, range 33-67 yr] and 34 age- and sex-matched controls were included in the study. The presence of major radiological thymus alterations, i.e. an abnormally enlarged or nodular thymus, were blindly investigated by means of unenhanced multidetector computed tomography. RESULTS: Abnormally enlarged or nodular thymuses were detected in a statistically significant percentage of SSc patients compared with controls (21 vs 0%, P = 0.011). More interestingly, radiological thymus alterations were invariably observed in patients with shorter disease duration (&lt; or =5 yr, 41% vs &gt;5 yr, 0%; P = 0.007), frequently associated with serum anti-Scl70 antibodies (P = 0.017). Among patients with thymus alterations one developed myasthenia gravis while two others showed thymus hyperplasia at histopathological evaluation after thymectomy. CONCLUSIONS: The present study suggests a possible role of thymic disorders, mainly thymus hyperplasia, in a significant number of SSc patients. Due to the limitations of radiological evaluation, the actual relevance of such an association might be underestimated. The relationship of thymus alterations with shorter disease duration, as well as with serum anti-Scl70, suggests that thymic dysfunction could play a pathogenetic role mostly in the early phases of the disease, and possibly in specific SSc patient subsets.

2006 - Thyroid disorders in chronic hepatitis C virus infection [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Ferrari, Sm; Ghinoi, A; Rotondi, M; Ferrannini, E.
abstract

The prevalence of thyroid disorders has been evaluated in patients with hepatitis C virus (HCV) infection by many studies. From a review of the published controlled studies, it is possible to observe that: (1) most investigated patients with chronic HCV hepatitis, while a minority evaluated hepatitis C virus antibody (HCVAb)- seropositive patients (the two conditions are not comparable with regards to thyroidal repercussions, in fact, HCVAb-seropositive patients do not necessarily display changes of the immune system present in chronically infected HCV patients); and (2) some authors selected as internal control hepatitis B virus (HBV)-infected patients, while others selected apparently healthy controls or HCVAb-negative subjects. Pooling all data about HCV-positive patients (with chronic hepatitis or HCVAb positivity) and using as control the sum of healthy controls, HBV-infected patients and sera negative for HCVAb, a significant increase of the prevalence has been observed both for thyroid autoimmune disorders (odds ratio [OR] = 1.6; 95% confidence interval = [C]) 1.4-1.9) as well as for hypothyroidism (OR = 2.9; 95% CI = 2.0-4.1). The results of the epidemiologic studies showing an association between HCV infection and thyroid cancer need to be confirmed. The abovementioned evidences seem sufficient to suggest careful thyroid monitoring during the follow-up of patients with HCV infection

2006 - Trattamento con Rituximab in pazienti con vasculite crioglobulinemica. [Abstract in Rivista]
Sebastiani, Marco; Ferrari, D; Colaci, Michele; Giunti, M; Mascia, Maria Teresa; Ferri, Clodoveo
abstract

Valutazione dell'efficacia e della safety del rituximab in una popolazione di pazienti con crioglobulinemia mista afferente ad un unico centro

2005 - Coexistence of non-specific and usual interstitial pneumonia in a patient with severe cystic scleroderma lung involvement and parvovirus B19 infection [Articolo su rivista]
Ghinoi, A.; Mascia, Maria Teresa; Giuggioli, D.; Magistro, R.; Barbolini, Giuseppe; Magro, C. M.; Ferri, Clodoveo
abstract

nd

2005 - Extrahepatic manifestations of hepatitis C virus: the thyroid disorders [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Ferrari, Silvia Martina; Ghinoi, A; Mascia, Maria Teresa; Ferrannini, E.
abstract

The prevalence of thyroid disorders has been studied in patients with chronic hepatitis C virus (HCV) infection by many studies. In general, thyroid dysfunction in chronic C hepatitis may include all forms of thyroid alterations, i.e. hypothyroidism and hyperthyroidism, Hashimoto's disease and isolated increases in antithyroid autoantibodies. The prevalence of various thyroid disorders and serum anti-thyroid autoantibodies is generally higher in chronic hepatitis type C than in hepatitis B or D or control series. The results of most studies in patients with hepatitis C confirm a higher prevalence of autoimmune thyroid involvement and hypothyroidism than in controls. More recently, some epidemiological studies have suggested a possible association between HCV and thyroid cancer. These last data need to be confirmed by other studies, but seem to be sufficient to suggest careful thyroid monitoring during the follow-up of patients with HCV infection.

2005 - Heart involvement and systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; Giuggioli, D.; Sebastiani, Marco; Colaci, Michele; Emdin, M.
abstract

Scleroderma heart involvement (SHI) is often manifest, and virtually always present when accurately searched and holds a significant prognostic value. Myocardial involvement by patchy fibrosis (secondary to both repeated ischaemia and inumunoinflammatory damage) leads to ventricular diastolic dysfunction, whereas right ventricle overload and failure may complicate pulmonary hypertension. Left ventricular systolic dysfunction is present in a minority of patients, namely those presenting atherosclerotic coronary artery disease and/or arterial hypertension, sometimes triggered by sclerodermic renal involvement. Dysrhythmias and conduction disturbances are considered an hallmark of SHI, facilitated by autonomic dysfunction. SHI is frequently linked to parenchimal and/or vascular lung disease; they determine symptom occurrence, particularly dyspnoea, fatigue, palpitations and chest pain when pericardium is affected. Accurate cardiologic baseline screening and subsequent follow-up are mandatory in all patients, initially consisting in some noninvasive diagnostic procedures: visit, electrocardiogram (EKG), chest X-ray, Doppler-echocardiography. When needed, these examinations should be integrated by EKG Hollter-monitoring, cardiopulmonary stress 9 tests, cardiac magnetic resonance imaging, nuclear studies of myocardial function and perfusion, cardiac catheterization to better estimate pulmonary hypertension, and cardiac natriuretic hormone evaluation. Several vasodilator approaches (prostacycline or NO/endothelin) may counteract the microvascular dysfunction at peripheral and cardiopulmonary level, and fight the sequelae of pulmonary hypertension.

2005 - Hepatitis C virus infection: evidence for an association with type 2 diabetes. [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Pampana, A; Ferrari, Sm; Goglia, F; Ferrannini, E.
abstract

non presente

2005 - Human parvovirus B19 experimental infection in human fibroblasts and endothelial cells cultures [Articolo su rivista]
Zakrzewska, K; Cortivo, R; Tonello, C; Panfilo, S; Abatangelo, G; Giuggioli, D; Ferri, Clodoveo; Corcioli, F; Azzi, A.
abstract

With the aim to detect what kind of cells; in addition to erythroid progenitors, could be involved in the pathogenesis of B 19 infection in some connective tissue diseases, primary Cultures of human fibroblasts (HF) and endothelial cells (HUVEC) were exposed to a B 19 positive serum (350 genome copies/cell). The presence of NS1 and VP1 mRNA, in both HF and HUVEC Cultures 1, 2 and 6 days after the exposure, indicated infection by B 19 virus. However, no significant increase of B 19 DNA level in the infected H[F and HUVEC cultures was detectable through the entire incubation period of 6 days. It is possible that HF and HUVEC are not permissive for B 19 virus replication or, alternatively, that few cells only get infected by B 19 virus. HF and HUVEC stimulation with different growth factors, or cytokines could be required for a B 19 productive infection to occur.

2005 - I fattori di crescita nella rigenerazione tissutale: uso di gel piastrinico nelle ulcere cutanee associate a sclerosi sistemica. [Abstract in Rivista]
Giuggioli, D; Colaci, Michele; Magistro, R; Mariano, M; Franciosi, U; Sebastiani, Marco; Caruso, A; Ferri, Clodoveo
abstract

trattamento delle ulcere digitali in corso di sclerosi sistemica con gel piastrinico

2005 - Il chimerismo nella patogenesi della sclerosi sistemica: descrizione di un caso. [Abstract in Rivista]
Sebastiani, Marco; Caruso, A; Giuggioli, D; Donelli, M; Mascia, Maria Teresa; Ferri, Clodoveo
abstract

valutazione di un caso di sclerosi sistemica insorta dopo trapianto eterologo di midollo ed evidenziazione, nelle sedi tipiche di malattia, di un quadro di chimerismo cellulare

2005 - Incidence and characteristics of non-hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias [Articolo su rivista]
Monti, G; Pioltelli, P; Saccardo, F; Campanini, M; Candela, M; Cavallero, G; DE VITA, S; Ferri, Clodoveo; Mazzaro, C; Migliaresi, S; Ossi, E; Pietrogrande, M; Gabrielli, A; Galli, M; Invernizzi, F.
abstract

Background: Some patients with cryoglobulinemic syndrome(CS) develop frank non-Hodgkin lymphoma(NHL), but the incidence and timing of this event are stillpoorly defined.Methods: A retrospective multicenter study was performedof hepatitis C virus–positive patients with CS observedin 11 Italian centers belonging to the Italian Groupfor the Study of Cryoglobulinemia.Results: The inclusion criteria were satisfied by 1255patients. During a cumulative follow-up of 8928 patientyears,59 cases of NHL were diagnosed, for an estimatedrate of 660.8 new cases per 100000 patient-years with224.1 new cases of aggressive NHL subtypes per 100000patient-years. More than 90% of the patients developingNHLs had type II cryoglobulins. The NHLs were classifiedas nonaggressive in 31 cases (53%), aggressive in 20(34%), and mucosa-associated lymphoid tissue lymphomasin 6 (10%); 2 cases were unclassifiable. The mediantime from the diagnosis of CS to the clinical onset of NHLwas 6.26 years (range, 0.81-24 years). The clinical courseand response to chemotherapy in the patients with CSwho had NHL were similar to those usually described inpatients with NHL without CS; the course of the CS onlymarginally benefited from chemotherapy.Conclusions: The overall risk of NHL in patients withCS is about 35 times higher than in the general population(12 times higher if nonaggressive lymphomas are excluded).The presence of CS did not significantly affectthe treatment of newly diagnosed lymphomas.

2005 - Parvovirus B19 and systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; A., Azzi; Cm, Magro
abstract

We read with great interest the recent article by Ohtsuka and Yamazaki reporting a significantly higher prevalence of parvovirus B19 (PV-B19) infection of the skin in patients with systemic sclerosis (SSc) compared with normal subjects and those with other immune-mediated disorders. This report further supports our previous studies suggesting a possible role of PV-B19 in the pathogenesis of SSc We would like to summarize our latest observations on this intriguing subject. Given the possible association of PV-B19 with some rheumatic disorders and its tropism for haematopoietic tissue in 1999 we first demonstrated a significantly higher prevalence of PV-B19 DNA in bone marrow biopsies from unselected patients with SSc compared with controls. Bone marrow may represent a reservoir from which the virus could spread to scleroderma target tissues.8 Thereafter, we investigated the presence of PV-B19 infection in cutaneous biopsies, as well as in skin fibroblasts and keratinocyte cultures. PV-B19 infection was demonstrated in the skin and/or bone marrow biopsies in 76% of patients with SSc. More interestingly, comparable levels of viral DNA were found in all passages of skin fibroblast cultures (from 3/3 to 6/6) using a semiquantitative polymerase chain reaction (PCR). Recently, we investigated the presence of parvoviral infection, tumour necrosis factor (TNF)- expression and C5b-9 deposition within cutaneous structures in skin biopsies from patients with SSc by means of solution-phase PCR, reverse transcriptase in situ PCR, and immunohistochemical and immunofluorescence studies. In particular, the presence of both PV-B19 DNA and TNF- mRNA was demonstrated in endothelia, fibroblasts, mast cells and perivascular inflammatory cells, along with C5b-9 deposits within the cutaneous vasculature

2005 - Parvovirus B19 as possible triggering factor of endothelial and fibroblast alterations in systemic sclerosis [Abstract in Rivista]
Ferri, Clodoveo; Magro, Cm; Nuovo, G; Giuggioli, D; Zakrewska, K; Sebastiani, Marco; Mascia, Maria Teresa; Azzi, A.
abstract

Background: Background. Numerous environmental, toxic and infectious agents have been proposed as possible triggering factors of systemic sclerosis (SSc); nevertheless its etiology remains still obscure. The disease is characterized by progressive fibrotic alterations of the skin and visceral organs. The pathogenesis may reflect a humorally mediated endothelial cell damage responsible for diffuse microangiopathy in concert with the overproduction of collagen by altered fibroblasts. Recently, two viruses, human cytomegalovirus and parvovirus B19 (B19), has been proposed as causative agents for SSc. HCMV seems to exert its pathogenetic potential through humoral immune-mediated pathogenetic mechanisms responsible for endothelial damage. While, persistent B19 infection has been demonstrated in a significant number of bone marrow and skin biopsy specimens of SSc patients.Objectives: Objectives. In order to further elucidate a role for B19 in the pathogenesis of SSc.Methods: Methods. Twelve patients who fulfilled the ACR preliminary criteria for SSc classification were randomly investigated. Patients were serologically screened for B19 infection; in addition, solution phase polymerase chain reaction (PCR) and reverse transcriptase in situ PCR (RT in situ PCR) for B19 and tumor necrosis factor-alpha (TNF-alpha) mRNA was performed on skin tissue. Two control groups were assessed for B19 and TNF-alpha expression: one with irrelevant primers and the other representing 18 cases of inflammatory skin lesions where the etiology was known and unrelated to B19 infection. In addition, frozen and paraffin-embedded tissues procured from skin lesions unrelated to B19 infection were assessed for B19 genome. In all cases, pretreatment with RNase was also performed to verify that any positive signal was indeed RNA based.Results: Results. Diffuse cutaneous involvement was seen in 7 SSc patients, and limited in five. All patients had a specific autoantibody (anticentromere, antinucleolar, anti-Scl70); 11/12 had lung involvement, whereas 8/12 had myocardial disease. Serum anti-B19 IgG antibodies were recorded in 9/12 patients, including IgM type in 2 cases. Solution phase PCR showed B19 DNA in the skin and/or bone marrow in 6 cases. In these latter, RT in situ PCR demonstrated B19 and TNF-alpha mRNA in endothelia, fibroblasts, mast cells, and perivascular inflammatory cells. Immunofluorescent studies revealed prominent deposition of C5b-9 within the cutaneous vasculature from biopsies of all patients tested. The control samples were negative for B19 DNA, TNF-alpha RNA, and C5b-9 deposition.Conclusion: Conclusion. The infection of endothelia and fibroblasts by B19, and in particular, the consequent enhanced TNF-alpha expression may be of pathogenetic importance in SSc. Moreover, the vascular deposition of C5b-9 suggests a role for humoral immunity possibly induced by a state of endothelial neoantigenicity evoked by virus-mediated cell injury.

2005 - Thyroid involvement in HCV-related cryoglobulinemic vasculitis [Abstract in Rivista]
Ferri, Clodoveo; Fallahi, P; Ghinoi, A; Nesti, C; Barali, L; Mascia, Maria Teresa; Sebastiani, Marco; Ferrannini, E; Antonelli, A.
abstract

Background: A striking association has been demonstrated between cryoglobulinemic vasculitis (CV) and hepatitis C virus (HCV) infection. CV is characterised by multiple organ involvement, secondary to immune-complex-mediated small vessel vasculitis.Objectives: The present study aimed to investigate the prevalence and characteristics of thyroid disorders (hypo- or hyperthyroidism, thyroid autoantibodies, thyroid nodules and cancer) in an unselected series of HCV-associated CV patients (HCV-CV).Methods: Ninety-nine HCV-CV (19 males and 80 females, mean age 64±9.8SD years, mean disease duration 14±7.5SD years) were studied and each one was randomly matched by sex and age (±2 years), with: 1) one subject of the general population from the same area; 2) one patient with type C chronic hepatitis (CH) without CV.Results: The prevalence of the following thyroid abnormalities was significantly higher in HCV-CV compared to the other groups: serum antithyroperoxidase autoantibody (AbTPO) (28% vs 8.7% and 14%, respectively; p<0.0022); presence of AbTPO and/or antithyroglobulin autoantibody (31% vs 12% and 19%, respectively, p<0.009); subclinical hypothyroidism (11% vs 2.3% and 7%, respectively; p<0.04). Thyroid papillary cancer was observed in 2 HCV-CV and in none of the controls.Conclusion: HCV-CV patients showed a significantly high prevalence of different thyroid disorders; thus, a careful thyroid surveillance is advisable in these individuals.

2004 - Chromosome aberrations in Raynaud's phenomenon [Articolo su rivista]
G., Porciello; R., Scarpato; F., Storino; L., Migliore; Ferri, Clodoveo; F., Cagetti; G., Morozzi; F., Bellisai; R., Marcolongo; M., Galeazzi
abstract

We evaluated the occurrence of spontaneous chromosome damage in cultured peripheral lymphocytes of subjects with idiopathic and prescleroderma Raynaud's phenomenon, by means of molecular cytogenetic analysis. Using the micronucleus assay as a marker of chromosome alteration, we studied 30 patients with pre-scleroderma Raynaud's phenomenon, 30 patients with idiopathic Raynaud's phenomenon and 30 healthy subjects. All subjects were classified as ANA-, ACA+ or Scl 70+. To identify the mechanism of micronucleus formation, fluorescence in situ hybridisation analysis was also performed. Pre-scleroderma Raynaud's phenomenon subjects showed significantly higher micronucleus frequencies than idiopathic Raynaud's phenomenon subjects and controls (37.0 +/- 11.5 vs. 11.1 +/- 3.2 and 10.7 +/- 2.7 respectively p < 0.0001). Interestingly, subjects with idiopathic Raynaud's phenomenon displayed micronucleus frequency comparable to that of healthy controls. Furthermore, ACA+ subjects showed the highest micronucleus frequencies (41.0 +/- 7.6) as compared to subjects with Scl 70+ antibody (25.0 +/- 3.5). Our results show that circulating lymphocytes of only pre-scleroderma Raynaud's phenomenon subjects undergo chromosomal damage, as detected by the micronucleus assay, at a higher rate than expected. No prevalence of aneuploidogenic or clastogenic events in micronucleus formation is revealed by fluorescence in situ hybridisation analysis.

2004 - Diffuse post-traumatic calcification of the anterior longitudinal ligamentum of cervical and dorsal spine [Articolo su rivista]
Manzini, Cu; Spina, V; Mascia, Maria Teresa; Magistro, R; Carpenito, G; Ferri, Clodoveo
abstract

Among the different conditions causing inflammation and calcification/ossification of the soft tissues of the spinal cord, single or recurrent traumatic events are included. Within the international literature, the involvement of the posterior longitudinal ligament, following spinal cord injuries is frequently reported, especially in the elders. The Authors describe here an uncommon calcification/ossification of the anterior longitudinal ligament occurred after a double traumatic event in a young man, followed clinically and radiologically for a long-term period. On the basis of clinical, laboratory and radiological findings, the differential diagnosis with other possible aetiologies, especially DISH (Diffuse idiopathic skeletal hyperostosis) and ankylosing spondylitis, is discussed.

2004 - HCV and cryoglobulinemia [Capitolo/Saggio]
Ferri, Clodoveo; Bombardieri, S.
abstract

Discussion of the etiologic role of HCV in mixed cryoglobulinemia

2004 - HCV associated cryoglobulinemic vasculitis [Abstract in Rivista]
Ferri, Clodoveo; Mascia, Maria Teresa; Ghinoi, A; Ferrari, D; Giuggioli, D; Sebastiani, Marco; Sandri, Gilda; Manzini, C; Zignego, A.
abstract

Definition: Cryoglobulinemic vasculitis (CV) is an immune-complex-mediated systemic vasculitis; its histopathological hallmark is the leukocytoclastic vasculitis involving small-sized vessels.Clinical features: Besides the typical clinical triad - purpura, weakness, arthralgias -, the most frequent manifestations of CV are peripheral neuropathy, hepatitis, glomerulonephritis, Raynaud's phenomenon, sicca syndrome, and skin ulcers (Table). Moreover, in a limited but significant percentage of individuals (10-15%) the disease can be complicated by a malignancy, i.e. B-cell lymphoma, and less frequently hepatocellular carcinoma or thyroid cancer.CV and HCV infection: A striking association between CV and hepatitis C virus (HCV) infection has been established by means of clinico-epidemiological and laboratory studies. Due to its multiform clinico-pathological features (Table), CV can be regarded as a crossing road between autoimmune disorders and malignancies (B-cell lymphomas, liver and thyroid cancer). On these bases, a pathogenetic link among HCV and other autoimmune-lymphoproliferative disorders has been also investigated; namely, Sjogren's syndrome, polyarthritis, glomerulonephritis, endocrine disorders, B-cell lymphomas, etc. There is a great geographical etherogeneity in the prevalence of different HCV-related diseases, suggesting a possible contribution of other unknown environmental and/or genetic co-factors.Pathogenesis: HCV is a lymphotropic virus; the presence of active or latent viral replication in the peripheral lymphocytes may explain the B-lymphocyte proliferation observed in HCV-related CV. Given the biological properties of HCV, viral genomic sequences cannot be integrated into the host genome. HCV could trigger the immunological alterations only indirectly by exerting a chronic stimulus to the immune system through viral proteins (E2, core, NS3, NS4, and NS5A), HCV-induced autoantigens and/or molecular mimicry phenomena. In particular, HCV envelop protein E2, able to bind CD81 molecule expressed on B-lymphocytes, might be involved in the first steps of HCV-driven autoimmune and lymphoproliferative phenomena. The interaction between HCV-E2 and CD81 may increase the frequency of VDJ rearrangement in antigen-reactive B-cell. In this context the T(14;18) translocation, demonstrated in a significantly high percentage of HCV-related CV patients, leads to the activation of anti-apoptotic Bcl-2 protoncogene responsible for extended B-cell survival. Consequently, B-lymphocyte expansion may produce a variety of autoantibodies and immune-complexes, including mixed cryoglobulins.Prognosis: Patients with CV show a relatively benign clinical course in over 50% of cases; however, the cumulative 10th year survival is significantly worse if compared to general population (56.3 vs 93.4%; p<.001). In addition, significantly lower survival rates are observed in males and in subjects with renal involvement.Treatment: For a correct therapeutic approach to HCV-related CV we must deal with conflicting conditions: HCV infection, autoimmune, and lymphoproliferative alterations. Therapeutic strategy of CV includes etiologic, pathogenetic, and/or symptomatic therapies, which should be tailored for the single patient according to the severity of clinical symptoms. Finally, a careful clinical monitoring of patients with CV is mandatory in all cases, with particular attention to neoplastic complications.References: 1. Gorevic PD, Frangione B. Mixed cryoglobulinemia cross-reactive idiotypes: implication for relationship of MC to rheumatic and lymphoproliferative diseases.

2004 - Manifestazioni autoimmuni e linfoproliferative HCV-correlate: l’esempio della crioglobulinemia mista [Articolo su rivista]
A., Ghinoi; Mascia, Maria Teresa; R., Puccini; Ferri, Clodoveo
abstract

Mixed cryoglobulinaemia (MC) is a systemic vasculitis involving small vessels (arterioles, capillaries, venules). The histological hallmark of the disease is the leukocytoclastic vasculitis secondary to the vascular deposition of circulating immune-complexes (CIC), mainly cryoglobulins and complement. The immune-mediated vasculitic lesions are responsible for different MC clinical features, including cutaneous and visceral organ involvement. Hepatitis C virus (HCV) represents the triggering factor in the large majority of MC patients (&gt;90%). Moreover, several epidemiological, clinico-pathological and laboratory investigations suggested a possible role for HCV in a wide spectrum of immuno-lymphoproliferative disorders; namely, porphyria cutanea tarda, diabetes, polyarthritis, lung fibrosis, poly-dermatomyositis, thyroiditis, thyroid cancer, B-cell non-Hodgkin's lymphomas (B-NHL), etc. Renal involvement with or without MC syndrome can be observed in HCV-infected individuals. There is great geographical etherogeneity in the prevalence of HCV-related disorders. This epidemiological observation suggests a multifactorial and multistep process in the pathogenesis of these conditions, involving other unknown genetic and/or environmental factors. HCV lymphotropism may explain the mono-oligoclonal B-lymphocyte expansion observed in HCV-infected individuals, particularly in MC patients. The 'benign' lymphoproliferative disorder, classified as monotypic lymphoproliferative disorders of undetermined significance (MLDUS), may be responsible for the wide production of CIC, including cryoglobulins, rheumatoid factor and different organ and non-organ specific autoantibodies. The consequence is the appearance of various HCV-related autoimmune diseases, including MC syndrome. This latter may be complicated by B-NHL in 10% of the cases; moreover, HCV infection has been confirmed in a significant percentage of 'idiopathic B-NHL. For a correct therapeutic approach to cryoglobulinaemic vasculitis, as well as to other HCV-related disorders, we should deal with concomitant, conflicting conditions: HCV infection, autoimmune and lymphoproliferative alterations. In this scenario, we can treat the diseases at three different levels by means of etiologic, pathogenetic and/or symptomatic therapies. The eradication of HCV by combined interferon and ribavirin therapy can be achieved in only a minority of cases. On the contrary, severe complications such as glomerulonephritis, sensory-motor neuropathy or diffuse vasculitis can be effectively treated by a combination of corticosteroids, plasma exchange and cyclophosphamide. More recently, a pathogenetic treatment with rituximab, a monoclonal chimeric antibody that binds to the B-cell surface antigen CD20 with selective B-cell blockade, was proposed in patients with HCV-related MC syndrome.

2004 - Mixed cryoglobulinemia: Demographic, clinical, and serologic features and survival in 231 patients [Articolo su rivista]
Ferri, Clodoveo; Sebastiani, Marco; Giuggioli, D; Cazzato, M; Longombardo, G; Antonelli, A; Puccini, R; Michelassi, C; Zignego, Al
abstract

BACKGROUND: Mixed cryoglobulinemia (MC) is a systemic vasculitis secondary to circulating immune complex deposition in the small vessels. In the overwhelming majority of patients, hepatitis C virus (HCV) infection represents the triggering factor of the disease. MC is characterized by multiple organ involvement, mainly skin, liver, renal, peripheral nerves, and less frequently by widespread vasculitis and cancer. OBJECTIVES: To investigate the demographic, clinical, serologic features, and survival in a large series of MC patients. METHODS: The study included 231 MC patients recruited between 1972 and 2001 at the Rheumatology Unit of the University of Pisa. All patients underwent wide clinicoserologic and virologic assessment. Cumulative survival rates were computed by the Kaplan-Meier method; moreover, the prognostic relevance of the main variables was investigated by Cox model analysis. RESULTS: In 92% of cases, the presence of HCV infection was demonstrated (anti-HCV antibody, 92%; HCV RNA, 90%), whereas hepatitis B virus (HBV) represented the possible causative agent in only 1.8% of patients (HBV DNA). Clinically, the MC syndrome followed a relatively benign clinical course in over 50% of cases, whereas a moderate-severe clinical course was observed in one third of patients whose prognosis was severely affected by renal and/or liver failure. In a limited, but significant, percentage (15%) of individuals, the disease was complicated by a malignancy, ie, B-cell lymphoma, and less frequently by hepatocellular carcinoma, or thyroid cancer. The survival study by the Kaplan-Meier method revealed a significantly lower cumulative 10th-year survival, calculated from time of diagnosis, in MC patients compared with expected death in the age- and sex-matched general population. Moreover, significantly lower survival rates were observed in males and in subjects with renal involvement. The multivariate analysis by the Cox proportional hazard regression model further supported the above findings: an increased mortality risk of 98% was observed for male gender (male/female hazard ratio, 1.978) and of 197% in patients with, compared with those without, renal involvement (hazard ratio, 2.967). At the end of the follow-up, 97 patients were deceased, and in 79 of 97 patients, the causes of death were ascertained: nephropathy (33%), malignancies (23%), liver involvement (13%), and diffuse vasculitis (13%) were the most frequent causes of death. CONCLUSIONS: Careful patient monitoring is recommended for a timely diagnosis of life-threatening MC complications, mainly nephropathy, widespread vasculitis, and B-cell lymphoma or other malignancies.

2004 - Parvoviral infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma [Articolo su rivista]
Magro, M. C.; Nuovo, G.; Ferri, Clodoveo; Crowson, A. N.; Giuggioli, D.; Sebastiani, Marco
abstract

Systemic sclerosis (SSc) is a connective tissue disease (CTD) which differs from other CTDs by progressive irreversible fibrosis in lung, kidney, skin, and heart. It has a worse prognosis compared to several other CTDs. The pathogenesis may reflect a humorally mediated microangiopathy in concert with the overproduction of collagen triggered by immune-mediated cytokine production. Having previously demonstrated parvovirus B19 (B19) DNA in bone marrow and skin biopsies of SSc patients in the absence of B19 viremia, we sought to further elucidate a role for B19 in the pathogenesis of SSc. DESIGN: Twelve patients who fulfilled American College of Rheumatology criteria for a diagnosis of SSc were encountered. Ten were serologically screened for B19 infection. Solution phase polymerase chain reaction (PCR) for B19 DNA was performed on skin tissue from six patients, and in all biopsies, reverse transcriptase in situ PCR (RT in situ PCR) for B19 and tumor necrosis factor (TNF)-alpha mRNA was performed. B19 viral protein (VP2) expression was sought by immunohistochemistry and correlated to PCR findings and to light microscopy of hematoxylin and eosin-stained sections. Frozen tissue was also available on five of the patients. Two control groups were assessed for B19 and TNF expression comprising one with irrelevant primers and the other representing 18 cases of inflammatory skin lesions where the etiology was known and unrelated to B19 infection. In addition, frozen and paraffin-embedded tissues procured from skin lesions unrelated to B19 infection were assessed for B19 genome. In all cases, pretreatment with RNase was also performed to verify that any positive signal was indeed RNA based. RESULTS: Diffuse SSc was seen in seven patients, and limited disease in five. All patients had an antinuclear antibody--specifically, an antinucleolar, anticentromere, and/or anti-Scl 70 antibody. Eleven of the 12 had lung involvement, whereas eight patients had myocardial disease. Of 12 patients tested serologically, nine had B19-specific antibodies, which included immunoglobulin M (IgM)-specific antibodies in two cases. Solution phase PCR showed B19 DNA in the skin in three cases and in the bone marrow in three cases, including two in whom skin-based B19 DNA was observed. In all cases, RT in situ PCR demonstrated B19 and TNF-alpha mRNA in endothelia, fibroblasts, mast cells, and perivascular inflammatory cells. Immunohistochemistry to assess VP2 was either negative or equivocal. Immunofluorescent studies revealed prominent deposition of C5b-9 within the cutaneous vasculature from biopsies of all patients tested. The control samples were negative for B19 and TNF RNA and DNA. CONCLUSIONS: Parasitism of endothelia and fibroblasts by B19 with resultant enhanced TNF-alpha expression may be of pathogenetic importance in SSc even in the absence of demonstrable viremia. The vascular deposition of C5b-9 suggests a role for humoral immunity possibly induced by a state of endothelial neoantigenicity evoked by virally mediated cell injury. Treatment strategies include anti-viral therapy, including in the context of intravenous gamma-globulin and anti-TNF therapy

2004 - Right ventricular overload and cardiovascular neuroendocrine derangement in systemic sclerosis [Articolo su rivista]
Michele, Emdin; Carlo, Marini; Claudio, Passino; Dilia, Giuggioli; Bruno, Formichi; Ferri, Clodoveo; Jaleh, Khabirinejad; Roberta, Poletti; Concetta, Prontera; Annalisa, Iervasi; Antonio, L'Abbate
abstract

Aim Systemic sclerosis (SSc) may be associated with right ventricular overload, secondary to pulmonary hypertension. In heart failure patients, neuroendocrine derangements can influence clinical evolution and prognosis. The aim of this study was to investigate neurohormonal control affected in SSc patients with and without right ventricular impairment. Methods and results A prospective series of 28 patients with SSc was studied. In addition to conventional evaluations, extensive neuroendocrine studies were done, including assays of both the vasoconstrictor system (plasma renin activity [PRA], aldosterone and catecholamines) and vasodilatory molecules (brain natriuretic peptide [BNP] and atrial natriuretic peptide [ANP]). A significant relation was observed between echo-Doppler estimated pulmonary systolic pressure (PAP) and neurohormonal activation, in particular between PAP and BNP (R = 0.58, p = 0.004), ANP (R = 0.65, p < 0.001) and PRA (R = 0.45, p = 0.032). Patients with right ventricular overload (i.e., PAP > 40 mmHg confirmed at cardiac catheterization) had higher levels of ANP and BNP (147 +/- 26 vs 34 +/- 6 pg/mL and 344 86 vs 30 7 pg/mL, respectively, p < 0.001), PRA (6.4 +/- 1.9 vs 1.8 +/- 0.4 ng/ mL/h, p < 0.001) and aldosterone (257 +/- 86 vs 114 +/- 22 pg/mL, p = 0.02). These patients had increased plasma noradrenaline, but not adrenaline (701 87 vs 452 66 pg/mL, p < 0.001). Conclusion SSc patients with right heart failure have a neurohormonal derangement, showing overactivity of the vasoconstrictive system, counteracted by oversecretion of cardiac natriuretic hormones. (C) 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

2004 - Storia naturale della sclerosi sistemica in Italia. [Abstract in Rivista]
Ferri, Clodoveo; Giuggioli, D; Magistro, R; Colaci, Michele; Mascia, Maria Teresa; Valentini, G; De Luca, A; La Montagna, G; Cozzi, F; Durigon, N; Tiso, F; Todesco, S; Sebastiani, Marco; Cazzato, M; Bombardieri, S; La Corte, R; Lo Monaco, A; Locaputo, A; Trotta, F.
abstract

valutazione delle caratteristiche cliniche e sierologiche di un'ampia popolazione italiana di pazienti con sclerosi sistemica

2004 - Thyroid disorders in chronic hepatitis C [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Pampana, A; Fallahi, P; Nesti, C; Pasquini, M; Marchi, S; Ferrannini, E.
abstract

PURPOSE: To explore the association of hepatitis C virus (HCV) infection with thyroid disorders.METHODS: We investigated the prevalence of thyroid disorders in 630 consecutive patients with chronic hepatitis due to HCV infection; all patients were free of cirrhosis and hepatocarcinoma, and were not on interferon treatment. Also included were a control group of 389 subjects from an iodine-deficient area, another control group of 268 persons living in an area of iodine sufficiency, and 86 patients >40 years of age with chronic hepatitis B. Levels of thyroid-stimulating hormone (TSH), free thyroxine (T(4)), and triiodothyronine (T(3)), as well as anti-thyroglobulin and anti-thyroid peroxidase antibodies, were measured.RESULTS: Mean TSH levels were higher (P = 0.001), and free T(3) and free T(4) levels were lower (P <0.0001), in patients with chronic hepatitis C than in all other groups. Patients with chronic hepatitis C were more likely to have hypothyroidism (13% [n = 82]), anti-thyroglobulin antibodies (17% [n = 108]), and anti-thyroid peroxidase antibodies (21% [n = 132]) than were any of the other groups.CONCLUSION: Both hypothyroidism and thyroid autoimmunity are more common in patients with chronic hepatitis C-even in the absence of cirrhosis, hepatocellular carcinoma, or interferon treatment-than in normal controls or those with chronic hepatitis B infection.

2004 - Thyroid involvement in patients with HCV-related mixed cryoglobulinaemia [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Giuggioli, D; Nesti, C; Longombardo, G; Fadda, P; Pampana, A; Maccheroni, M; Ferrannini, E.
abstract

BACKGROUND: Mixed cryoglobulinaemia (MC), a systemic vasculitis associated with hepatitis C virus (HCV) infection in >90% of cases, is frequently complicated by multiple organ involvement. The prevalence of thyroid disorders in MC has not yet been studied.AIM: To investigate the prevalence and clinical features of thyroid involvement in patients with HCV-associated MC (HCV + MC).DESIGN: Case-control study.METHODS: HCV + MC patients (n = 93, 17 men and 76 women, mean +/- SD age 63 +/- 10 years, mean disease duration 14 +/- 7 years) consecutively referred to the Rheumatology Unit were matched by sex and age (+/- 2 years) to (i) 93 patients with chronic C hepatitis (CH) without MC and (ii) 93 healthy (HCV-negative) controls from the local population. Measurements included prevalence of hypo- or hyperthyroidism, thyroid autoantibodies, thyroid nodules and thyroid cancer.RESULTS: By McNemar's chi(2) test, the following thyroid abnormalities were significantly more frequent in HCV + MC patients than in HCV-negative controls: serum anti-thyroperoxidase autoantibody (AbTPO) (28% vs. 9%, p = 0.001); serum AbTPO and/or anti-thyroglobulin autoantibody (31% vs. 12%, p = 0.004); subclinical hypothyroidism (11% vs. 2%, p = 0.038); thyroid autoimmunity (35% vs. 16%, p = 0.006). Serum AbTPO were also significantly more frequent in HCV + MC patients than in CH controls (28% vs. 14%, p = 0.035).DISCUSSION: The prevalence of thyroid disorders is increased in patients with HCV-related mixed cryoglobulinaemia. We suggest careful monitoring of thyroid function in these patients.

2004 - Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P; Sebastiani, Marco; Nesti, C; Barani, L; Barale, R; Ferrannini, E.
abstract

OBJECTIVES: Mixed cryoglobulinaemia (MC) is a systemic vasculitis frequently associated with hepatitis C virus (HCV) infection. A possible link between HCV infection and type 2 diabetes has been suggested. This study evaluated the prevalence and clinical phenotype of diabetes in MC-HCV+ patients. METHODS: Two hundred and twenty-nine consecutively recruited MC-HCV+ patients were compared with 217 sex- and age-matched controls without HCV infection. RESULTS: The prevalence of type 2 diabetes was significantly higher in MC-HCV+ patients than in controls (14.4 vs 6.9%, P < 0.01). Diabetic MC-HCV+ patients were leaner than diabetic patients without MC-HCV (P < 0.0001), and showed significantly lower total and low-density lipoprotein cholesterol levels (P < 0.001) and lower systolic (P = 0.01) and diastolic blood pressure (P = 0.005). MC-HCV+ diabetic patients had non-organ-specific autoantibodies more frequently (34 vs 18%, P = 0.032) than non-diabetic MC-HCV+ patients. CONCLUSIONS: The prevalence of type 2 diabetes is higher in patients with MC-HCV than in controls. Diabetic MC-HCV+ patients show an attenuated diabetic phenotype and are more likely to carry non-organ-specific autoantibodies.

2003 - Assessment of heart involvement [Articolo su rivista]
Ferri, Clodoveo; Emdin, A; Nielsen, H; Bruhlmann, P.
abstract

Cardiac involvement frequently occurs in systemic sclerosis (SSc), contributing to the occurrence of symptoms, namely dyspnoea, fatigue, palpitations, and in some instances to the clinical evolution and prognosis of the disease. A thorough baseline screening of heart functioning and appropriate follow-up monitoring is therefore mandatory in all SSc patients. This consists of various simple, non-invasive ambulatory diagnostic procedures (visit, electrocardiogram, chest X-ray, Doppler-bi-dimensional echocardiogram), which provide information on the presence of rhythm and conduction disturbances, cardiac morphology and function, as well as on the possible presence of pulmonary hypertension (PH). When needed, added tests may be carried out, including long-term ambulatory electrocardiographic recording, assessment of cardiopulmonary performance by the six-minute walking test or cardiopulmonary stress test, cardiac catheterization (mandatory to confirm and better estimate PH), cardiac magnetic resonance imaging, and nuclear studies of myocardial function and perfusion.

2003 - Autologous skin grafting in the treatment of severe scleroderma cutaneous ulcers: a case report [Articolo su rivista]
Giuggioli, D; Sebastiani, Marco; Cazzato, M; Piaggesi, A; Abatangelo, G; Ferri, Clodoveo
abstract

The result of treatment of scleroderma cutaneous ulcers is often discouraging; moreover, this complication may severely reduce the quality of life of SSc patients. The frequent concomitance of arterial and venous deficiency in the pathogenesis of leg ulcers in SSc, needing a combined (surgical and grafting) therapeutic approach, should also be taken into account. The complete, rapid recovery of malleolar ulcers observed with autograft system using Hyalograft 3D and Laserskinests suggests that this novel technology, which has been employed successfully in skin lesions of different aetiology, can also be used in refractory scleroderma skin ulcers.

2003 - Chromosome aberrations, valued as frequency of spontaneous micronuclei, in subjects with suspected presclerodermic Raynaud's phenomenon [Articolo su rivista]
Porciello, G.; Scarpato, R.; Storino, F.; Cagetti, F.; Bellisai, F.; Morozzi, G.; Marcolongo, R.; Migliore, L.; Ferri, Clodoveo; Galeazzi, M.
abstract

OBJECTIVE: To evaluate the prevalence of spontaneous chromosome damage in cultured peripheral lymphocytes of subjects with suspected presclerodermic Raynaud's phenomenon (RP), by means of molecular cytogenetic analysis.METHODS: We studied 20 suspected presclerodermic RP, 20 idiopathic RP and 25 healthy subjects. As marker of chromosome alteration we used the micronucleus assay. All subjects were also classified as ANA-, ACA+ or Scl70+. To identify the mechanism of MN formation, a MN fluorescence in situ hybridisation (FISH) analysis using a pancentromeric DNA probe was also performed.RESULTS: Suspected presclerodermic RP subjects, showed significantly higher MN frequencies than idiopathic RP and controls (39+/-15.2 vs 10+/-2.1 and 9.8+/-3.5 respectively p&lt;0.0001). Interestingly, subjects with idiopathic RP displayed MN frequency comparable to that of controls. Furthermore, ACA+ subjects showed the highest MN frequencies (44+/-8.1) as compared to subjects with different antibody pattern (26+/-7.1).CONCLUSIONS: Our results show the presence of higher levels of chromosomal damage in circulating lymphocytes of suspected presclerodermic RP. They also would suggest a key role of anti-centromere antibody in determining the observed cytogenetic anomalies. FISH analysis indicated that both aneuploidogenic and clastogenic events contribute to the formation of MN observed in suspected presclerodermic RP.

2003 - HCV-related cryoglobulinemic vasculitis: an update on its etiopathogenesis and therapeutic strategies. [Articolo su rivista]
Ferri, Clodoveo; Sebastiani, Marco; Mascia, Maria Teresa; Giuggioli, D; Cazzato, M; Zignego, Al
abstract

Cryoglobulinemic vasculitis (CV) is an immune-complex-mediated systemic vasculitis involving small-medium sized vessels. A causative role of hepatitis C virus (HCV) in over 4/5 patients has been definitely established on the basis of epidemiological, pathological, and laboratory studies. There is great geographical heterogeneity in the prevalence of CV as well as other HCV-related immuno-lymphoproliferative disorders. Thus, unknown environmental and/or genetic co-factors should contribute to the pathogenesis of these conditions. Due to the biological properties, HCV genomic sequences cannot be integrated into the host genome; the virus could trigger the immunological alterations only indirectly by exerting a chronic stimulus to the immune system. Recent laboratory observations gave us new important insights on the complex pathogenetic mechanism(s) of HCV-related CV. Firstly, the HCV envelop protein E2, able to bind CD81 molecule expressed on B-lymphocytes, might be involved in the first steps of HCV-driven autoimmune and lymphoproliferative phenomena. The interaction between HCV-E2 and CD81 may increase the frequency of VDJ rearrangement in antigen-reactive B-cell. One possible consequence may be the activation of anti-apoptotic Bcl-2 protoncogene that leads to extended B-cell survival. Interestingly, t(14, 18) translocation along with Bcl-2 activation have been demonstrated in B-lymphocytes of 80% HCV-related CV. The B-lymphocyte expansion is responsible for a wide autoantibody and immune-complex production, including mixed cryoglobulins. CV shows a relatively benign clinical course; however, its cumulative survival is significantly worse if compared to general population. For a correct therapeutic approach to HCV-related CV we must deal with conflicting conditions: HCV infection, autoimmune, and lymphoproliferative alterations. Therapeutic strategy of CV includes etiologic, pathogenetic, and/or symptomatic therapies, which should be tailored for the single patient according to the severity of clinical symptoms. A careful clinical monitoring of patients with HCV-related CV is mandatory in all cases, with particular attention to neoplastic complications.

2003 - Infezione da virus dell'epatite C e danno polmonare. [Articolo su rivista]
Fazzi, P.; Giuggioli, D.; Sebastiani, M.; Mascia, Maria Teresa; Ferri, Clodoveo
abstract

Idiopathic pulmonary fibrosis (IPF) is a relatively uncommon disease with a generally poor prognosis. Fifty per cent of patients diagnosed as having IPF may be expected to die within 4 years of the diagnosis. Although the etiology of IPF is unknown, it has been suggested that viral agents, among which hepatitis C virus (HCV), may be involved in pathogenesis of the disease. Several investigators have suggested that HCV infection is associated with various clinical conditions. These include mixed cryoglobulinemia (MC), autoimmune thyroiditis, porphyria cutanea tarda, membranoproliferative glomerulonephritis, sicca syndrome, non-Hodgkin's lymphoma, and IPF According to the available data, HCV infection appears to be main triggering factor of MC, which in rare cases may be complicated by clinically overt lungfibrosis, while the data for the association between HCV infection and IPF remain still weak. However, a number of anecdotal observations together with the example of lung fibrosis in the setting of MC are quite intriguing. Further studies including different HCV-Positive patients' subsets are necessary to ascertain the exact role of this virus in both secondary and idiopathic lung fibrosis. Here, the literature on the possible association between HCV and various immuno-mediated extrahepatic disorders, with particular attention to lung fibrosis, has been widely reviewed

2003 - Prevalence of ANCA in mixed cryoglobulinemia and chronic hepatitis C virus infection [Articolo su rivista]
Lamprecht, P; Gutzeit, O; Csernok, E; Gause, A; Longombardo, G; Zignego, Al; Gross, Wl; Ferri, Clodoveo
abstract

Objective. To determine the prevalence, target antigens and clinical associations of antineutrophil cytoplasmic antibodies (ANCA) in chronic hepatitis C without extrahepatic manifestations and in chronic hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) in two European centers. Methods. 50 sera from patients with chronic hepatitis C and 116 sera from HCV-associated MC were tested for cytoplasmic or perinuclear pattern (C-ANCA/P-ANCA) by indirect immunofluorescence test (IFT). ANCA target antigens were determined by enzyme-linked immunosorbent assay (ELISA). Results. Clinical characteristics of the patients were not different between the two centers. Cryoglobulinemic vasculitis (CV) was biopsy-proven in about 90% of the MC patients. Two patients with HCV-associated MC and I patient with chronic hepatitis C had a P-ANCA. A C-ANCA was detected in I patient with HCV-associated MC. Eight patients with a HCV-associated MC and 5 patients with chronic hepatitis C had an ANCA either directed against bactericidal/permeability increasing protein (BPI) or cathepsin G (CG). BPI- or CG-ANCA positivity was not associated with a more severe disease course. The C-ANCA titer followed disease activity in one C-ANCA positive HCV-associated MC patient. The subspecifity of the C-ANCA was not determinable in that patient. Conclusion. Two new target antigens of ANCA have been identified in HCV-associated MC and chronic hepatitis C in this study. BPI-ANCA and GC-ANCA were present in about 10% of patients with HCV-associated MC or chronic hepatitis C. ELISA proved to be more sensitive in the detection of ANCA than IFT The present study on chronic HCV infection adds to various reports on the induction of CG- and BPI-ANCA in chronic infections.

2003 - Spontaneous chromosome damage (micronuclei) in systemic sclerosis and Raynaud's phenomenon [Articolo su rivista]
Porciello, G.; Scarpato, R.; Ferri, Clodoveo; Storino, F.; Cagetti, F.; Morozzi, G.; Bellisai, F.; Migliore, L.; Marcolongo, R.; Galeazzi, M.
abstract

OBJECTIVE: To evaluate the prevalence of spontaneous chromosome damage in cultured peripheral lymphocytes of patients with systemic sclerosis (SSc), idiopathic Raynaud's phenomenon (RP), and suspected secondary RP, by means of molecular cytogenetic analysis.METHODS: We studied 43 patients with SSc, 13 with idiopathic RP, and 16 with suspected secondary RP and 25 healthy controls. As a marker of chromosome alteration we used the micronucleus (MN) assay. All subjects were also classified for antinuclear antibodies, anticentromere antibodies (ACA), or Scl70. To identify the mechanism of MN formation, we also performed MN fluorescence in situ hybridization (FISH) analysis using a pancentromeric DNA probe.RESULTS: Patients with SSc and subjects with RP showed significantly higher MN frequencies than controls (25.9 +/- 1.7 and 19.1 +/- 2.15, respectively, vs 9.4 +/- 2.2; p < 0.001). Subjects with suspected secondary RP displayed MN frequency (23.5 +/- 2.7) comparable to that of SSc patients, while spontaneous MN level in idiopathic RP subjects (13.6 +/- 3.0) did not differ significantly from controls (9.4 +/- 2.2). ACA positive subjects showed the highest MN frequencies (32.8 +/- 1.7) compared to subjects with a different antibody pattern (18.3 +/- 1.6).CONCLUSION: Our results show the presence of higher levels of micronuclei in circulating lymphocytes of patients with SSc and subjects with suspected secondary RP. They also suggest a possible role of ACA in determining cytogenetic anomalies. FISH analysis indicated that both aneuploidogenic and clastogenic events contributed to the formation of MN observed in SSc patients and subjects with suspected secondary RP

2003 - The assessment of anti-endothelial cell antibodies in scleroderma-associated pulmonary fibrosis. A study of indirect immunofluorescent and western blot analysis in 49 patients with scleroderma [Articolo su rivista]
Wusirika, R; Ferri, Clodoveo; Marin, M; Knight, Da; Waldman, Wj; Ross P., Jr; Magro, C. M.
abstract

We recently reported on the use of an indirect immunofluorescent method designated the rodent lung assay; this test assesses for the presence of circulating antibodies directed at components of the microvasculature. Serum samples from 49 patients with scleroderma were incubated with rodent lung tissue sections and visualized with fluoresceinated human anti-IgG. The assay also was performed on samples from a control group. Western blot analysis was performed with endothelial cell protein extracts using serum samples from patients with scleroderma and from healthy control subjects. The control subjects had a negative indirect immunofluorescent assay result. In the patients with scleroderma, there was a significant positive correlation between intensity of indirect immunofluorescent staining and pulmonary fibrosis (r = 0.316; P = .0347) and hypertension (r = 0.310; P = .0408). Western blot analysis revealed antibody binding to proteins in extracts of human endothelial cells in all patients in whom there was evidence of pulmonary disease. The indirect immunofluorescent rodent lung assay and Western blot data support a potential role of anti-endothelial cell antibodies in the propagation of scleroderma-associated pulmonary disease.

2003 - The dermatopathologic manifestations of hepatitis C infection: A clinical, histological, and molecular assessment of 35 cases [Articolo su rivista]
Crowson, A. N.; Nuovo, G.; Ferri, Clodoveo; Magro, Cm
abstract

Cutaneous eruptions related to hepatitis C virus (HCV), a major cause of hepatitis in the setting of blood transfusion, intravenous drug abuse, organ transplantation, and hemodialysis, are typically reported as isolated cases. We encountered 35 cases of HCV infection associated with cutaneous eruptions. The present study evaluates paraffin-embedded, formalin-fixed tissue sections stained with hematoxylin and eosin from biopsy specimens of skin lesions from 35 patients seropositive for HCV. In 20 cases, reverse transcriptase polymerase chain reaction (RT-PCR) was performed using a probe for HCV RNA; the RNA was detected through the action of alkaline phosphatase on the chromogen nitroblue tetrazolium and bromochloroindolyl phosphate. The clinical spectrum comprised dermatomyositis-like photodistributed eruptions, palpable purpura, folliculitis, violaceous and perniotic acral lesions, ulcers, nodules, and urticaria. Lesions were also classified histopathologically by the dominant reaction pattern: vasculopathies of neutrophilic, lymphocytic, and granulomatous vasculitis and pauci-inflammatory subtypes (15 patients); palisading granulomatous inflammation (3 patients); sterile neutrophilic folliculitis (5 patients); dermatitis herpetiformis (1 patient); lobular panniculitis composed of neutrophilic lobular panniculitis in 2 patients and benign cutaneous polyarteritis nodosa in 1 patient; neutrophilic dermatoses, including neutrophilic urticaria, neutrophilic eccrine hidradenitis, and pyoderma gangrenosum (3 patients); interface dermatitis (3 patients); and low-grade lymphoproliferative disease of B-cell lineage representing marginal zone lymphoma in 1 patient and a clonal plasmacellular infiltrate in another patient. In most cases, whereas 1 of the aforementioned disorders defined the dominant reaction pattern, there was an accompanying secondary reaction pattern, defining a hybrid picture. Endothelial changes including endothelial cell enlargement and effaced heterochromatin with margination of the chromatin to the nuclear membrane were seen in several cases; in some cases similar cytopathic changes also involved the supporting pericytes, eccrine ductular cells, or keratinocytes. The RT-PCR analyses in 8 of 20 cases examined revealed HCV RNA expression in a focal, weak fashion in endothelia and perivascular inflammatory cells in those cases showing vasculopathic changes. Viral parasitism of endothelia may be important in cutaneous lesional propagation in the setting of HCV infection. Cross-reactivity between endogenous and viral antigens, leading to cellular and/or type II immune reactions; viral tropism to B lymphocytes, resulting in B cell expansion with resultant autoantibody production; and circulating immune complexes containing monoclonal cryoglobulins may also be of pathogenetic importance. Tropism of the virus to B lymphocytes provides a mechanism for the development of low-grade clonal B cell lymphoproliferative disease in this setting.

2002 - Cryoglobulinaemic vasculitis as presenting manifestation of infective endocarditis. [Articolo su rivista]
La Civita, L.; Fadda, P.; Olivieri, I.; Ferri, Clodoveo
abstract

Seroimmunological alterations, including antibodies and/or cryoglobulins, are commonin infective endocarditis (IE); however, specificautoimmune disorders, such as cryoglobulinaemicvasculitis (CV) associated with IEhave seldom been described. CV is related tothe vascular deposition of circulating immunecomplexes, mainly cryoglobulins, and complement; in 70–90% of patients with CV a triggeringrole of hepatitis C virus (HCV) hasbeen suggested.We report the case of twopatients who showed a typical CV with severeneurological involvement as the presentingmanifestation of underlying IE.

2002 - Cryoglobulinemia [Articolo su rivista]
Ferri, C.; Longombardo, G.; Giuggioli, D.; Sebastiani, M.; Cazzato, M.; La Civita, L.; Fadda, P.; Porciello, G.; Storino, F.; Cecchetti, R.; Antonelli, A.
abstract

2002 - Cryoglobulins [Articolo su rivista]
Ferri, Clodoveo; Zignego, A. L.; Pileri, S. A.
abstract

Serum cryoglobulins are found in a wide spectrum of disorders but are often transient and without clinical implications. Monoclonal cryoglobulins are usually associated with haematological disorders, whereas mixed cryoglobulins are found in many infectious and systemic disorders. So called essential mixed cryoglobulinaemia shows a striking association with hepatitis C virus (HCV) infection (> 90%). It is a systemic vasculitis (leucocytoclastic vasculitis) with cutaneous and multiple visceral organ involvement. Chronic HCV infection can lead to a constellation of autoimmune and neoplastic disorders. In this review, the aetiology, diagnosis, disease heterogeneity, and treatment of cryoglobulinaemia are discussed.

2002 - Erectile dysfunction and hepatitis C virus infection. [Articolo su rivista]
Ferri, Clodoveo; Bertozzi, M. A.; Zignego, A. L.
abstract

We evaluated the prevalence of erectile dysfunction in 207 patients with HCV infection (identified by serum anti-HCV antibodies and HCV RNA), including 105 with chronic hepatitis and 102 with HCV-associated cryoglobulinemic vasculitis.2 Patients were consecutively recruited at liver and rheumatology clinics at a university hospital. Exclusion criteria were age older than 55 years, interferon alfa treatment in the last year, or presence of diabetes, renal failure, hypothyroidism, human immunodeficiency virus infection, or concurrent cardiovascular or psychiatric disorders. All patients gave informed consent for the study, which was approved by the local ethics committee..All patients were asked to complete the International Index of Erectile Failure (IIEF).4 Those with erectile dysfunction based on this evaluation underwent nocturnal penile tumescence testing for 3 nights. We also measured serum hormone levels including total and free testosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, and estradiol-17β in all patients. Finally, we compared the prevalence of erectile dysfunction in our patients with its occurrence in a sample of 207 age-matched men who were randomly selected from a larger group of 2010 Italian men previously investigated for complaints of erectile dysfunction.5 We performed prostate transrectal ultrasonography to exclude neoplastic disorders of the prostate and seminal vesicles in all HCV-positive patients with erectile dysfunction. Statistical analysis was performed using the χ2 test with Yates correction and unpaired t test; P<.05 was considered significant.Erectile dysfunction was diagnosed in 80 (39%) HCV-positive patients and in 29 (14%) control subjects (P<.001) on the basis of IIEF score and nocturnal penile tumescence testing. Erectile dysfunction was more common in patients with cryoglobulinemic vasculitis than in those with chronic HCV infection (44% vs 33%), although this difference was not statistically significant (Table 1). Erectile dysfunction was significantly more common in both HCV groups than in control subjects (P<.001).Plasma levels of total and free testosterone were generally lower in HCV-positive patients, but they were significantly lower in patients with erectile dysfunction vs those without (Table 1). In addition, neither erectile dysfunction nor testosterone level was significantly correlated with the severity of liver involvement, as defined on the basis of ultrasound examination (ie, irregular margins of the liver, coarse echoic pattern, and hypertrophy of caudate lobus) and laboratory tests (ie, low levels of serum albumin and pseudo-cholinesterase and prolonged prothrombin time).It has been speculated that neurovascular and hormonal effects of chronic HCV infection may contribute to the pathogenesis of erectile dysfunction. We found that hepatic failure and interferon alfa therapy were unrelated to erectile dysfunction, thus suggesting that chronic HCV infection itself may play a causal role. Nonetheless, both liver failure and interferon alfa may also contribute to erectile dysfunction, and treatment should be individualized. It is also possible, however, that antiviral treatment may improve erectile function in some HCV-positive patients, and this should be evaluated in prospective clinical trials. Finally, given the increasing prevalence of HCV, the possibility of HCV infection should be considered in the differential diagnosis of erectile dysfunction.

2002 - HCV and cryoglobulinemic vasculitis. [Articolo su rivista]
Ferri, Clodoveo; Zignego, Al; Giuggioli, D; Sebastiani, Marco; Cazzato, M; Antonelli, A; La Civita, L; Fadda, P; Longombardo, G; Pileri, S.
abstract

munoglobulinemia)or more immunoglobulins (mixedcryoglobulinemia), which precipitate at temperaturesbelow 37 °C and redissolve on re-warming is termed“cryoglobulinemia.” This is an in vitro phenomenon; theactual mechanism(s) of cryoprecipitation remains obscure.It could be secondary to intrinsic characteristics ofboth mono- and polyclonal immunoglobulin (Ig) components;it can be caused as well by the interaction amongsingle components of the cryoprecipitate.

2002 - Hepatitis C virus infection and arthritis. A clinico-serological investigation of arthritis in patients with or without cryoglobulinemic syndrome. [Articolo su rivista]
Fadda, P.; La Civita, L.; Zignego, A. L.; Ferri, Clodoveo
abstract

OBJECTIVE: To compare the clinico-serological features of arthritis from two HCV+ patient groups characterized by mixed cryoglobulinemia (MC) or chronic hepatitis (CH).METHODS: We retrospectively studied 157 MC patients (119 females, mean age 64.8 yrs, range 36-88) and 155 CH patients (103 females, mean age 58.8 yrs, range 30-81). Patients with HBV and/or HIV co-infections and a follow-up shorter than 1 year were excluded. MC was classified according to standard criteria, while CH classification was based on Desmet's criteria.RESULTS: No differences in epidemiology were demonstrated between the two series of patients. Although significantly prevalent in MC patients, extra-hepatic manifestations including nephropathy, neuropathy, pneumopathy, mixed cryoglobulins, RF positivity and hypocomplementemia were detected in both patient groups. Arthritis was present in 23 CH (15%) and 12 MC (8%) patients. A symmetrical polyarthritis was observed in 87% of 23 CH patients, while cryoglobulinemic arthritis was invariably asymmetrical and pauciarticular. Unlike MC patients, who had a constantly non-erosive arthritis, in 7/23 CH patients arthritis was erosive. Steroids and/or hydroxycloroquine or D-penicillamine were safe and useful in controlling the arthritis over the short-medium time, although clinical response was more evident in MC patients. Instead, in 5/23 CH and 3/12 MC patients, interferon-alpha treatment was able to trigger or exacerbate the arthritis despite a good control of liver function.CONCLUSIONS: HCV infection seems to be, possibly in genetically predisposed patients, responsible for arthritis at times similar to rheumatoid arthritis. In these patients a careful assessment of the interferon-alpha treatment is mandatory owing to the potential "arthritogenic effect" due to its immunoregulatory properties.

2002 - Parvovirus B19 infection of cultured skin fibroblasts from systemic sclerosis patients: comment on the article by Ray et al [Articolo su rivista]
Ferri, Clodoveo; Giuggioli, D.; Sebastiani, Marco; Panfilo, S.; Abatangelo, G.; Zakrzewska, K; Azzi, A.
abstract

We read with interest the recent article by Ray and coworkers reporting that human parvovirus B19 infection can induce in vitro invasive properties in normal human synovial fibroblasts . Their study further supports previous observations suggesting that B19 infection could be involved in the pathogenesis of rheumatoid arthritis and other rheumatic disorders, including systemic sclerosis (SSc) . SSc is a connective tissue disease of unknown etiology; its pathogenesis involves overproduction of collagen by altered fibroblasts and alterations of the microvasculature and immune system . Numerous genetic, environmental, and infectious agents have been proposed as possible etiologic factors

2002 - Prevalence of bcl-2 rearrangement in patients with hepatitis C virus-related mixed cryoglobulinemia with or without B-cell lymphomas [Articolo su rivista]
Zignego, Al; Ferri, Clodoveo; Giannelli, F.; Giannini, C.; Caini, P.; Monti, M.; Marrocchi, Me; Di Pietro, E.; La Villa, G.; Laffi, G.; Gentilini, P.
abstract

BACKGROUND: Hepatitis C virus (HCV) infection is strictly associated with mixed cryoglobulinemia, a benign B-cell lymphoproliferative disorder that may evolve to lymphoma. An increased prevalence of bcl-2 rearrangement (the t(14;18) translocation) has been shown in patients infected with HCV.OBJECTIVE: To evaluate the prevalence of bcl-2 rearrangement in patients with HCV-related mixed cryoglobulinemia and patients with chronic hepatitis but no cryoglobulinemia.DESIGN: Prospective study.SETTING: Two university hospitals.PATIENTS: 37 consecutively recruited patients with HCV-related mixed cryoglobulinemia and 101 patients with chronic HCV infection but without mixed cryoglobulinemia.MEASUREMENTS: Clinical and serologic characteristics; liver biopsy; bcl-2 rearrangement, Bcl-2 expression, and the ratio of Bcl-2 to Bax in total peripheral blood mononuclear cells and cell subgroups; and sequence analysis of the junction of bcl-2 and IgH joining segments in positive samples.RESULTS: Rearrangement of bcl-2 was observed in 28 of 37 (75.7%) patients with mixed cryoglobulinemia (65% of those with type III disease and 85% of those with type II disease, including 3 of 4 patients with lymphoma) and in 38 of 101 (37.6%) patients with chronic HCV infection but not mixed cryoglobulinemia (P < 0.001). Overexpression of Bcl-2 protein and a high ratio of Bcl-2 to Bax were observed in samples from patients with bcl-2 rearrangement. In 2 patients followed over time, peripheral blood cells bearing the t(14;18) translocation disappeared after antiviral therapy.CONCLUSIONS: Rearrangement of bcl-2 was found with increased frequency in patients with chronic HCV infection and mixed cryoglobulinemia. The frequency was greatest in patients with type II mixed cryoglobulinemia. The high ratio of Bcl-2 to Bax in patients with bcl-2 rearrangement and disappearance of the rearrangement with antiviral therapy suggest that the translocation is associated with the antiapoptotic function of Bcl-2 and that HCV infection is linked to inhibition of B-cell apoptosis.

2002 - Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients [Articolo su rivista]
Ferri, Clodoveo; Valentini, G.; Cozzi, F.; Sebastiani, Marco; Michelassi, C.; La Montagna, G.; Bullo, A.; Cazzato, M.; Tirri, E.; Storino, F.; Giuggioli, D.; Cuomo, G.; Rosada, M.; Bombardieri, S.; Todesco, S.; Tirri, G.
abstract

Demographic and clinical features of 1,012 Italianpatients evaluated at the beginning and at the end offollow-up (mean, 7.1 yr 5.7 SD) are shown in Table3. At the last evaluation, 636 (62.8%) patients werealive, 279 (27.6%) were known to have died, and 97(9.6%) were considered lost to follow-up. These lattershowed the same clinico-serologic characteristics ofthe 915 patients evaluated for survival study. The female/male ratio rose from 7.8 of the entire SSc populationat first visit to 10.4 of the surviving 636 patients.At the time of diagnosis lcSSc was the most frequentcutaneous subset; its rather high prevalence was significantlymore pronounced at the end of follow-up(p .01). Similarly, the prevalence of various clinicalfeatures referring to both living and deceased patients(n 915) significantly increased, with the exceptionof Raynaud, calcinosis, and renal involvement; onlyarthritis was less frequently observed.

2002 - Systemic sclerosis following human cytomegalovirus infection [Articolo su rivista]
Ferri, Clodoveo; Cazzato, M; Giuggioli, D; Sebastiani, Marco; Magro, C.
abstract

Systemic sclerosis (SSc) is a connective tissue diseasecharacterised by skin and visceral organ involvement.The cause of SSc is still unknown; it has been suggestedthat one or more factors may be responsible for the diseasethrough a complex pathogenic mechanism. Immune systemdysregulation, collagen hyperproduction by altered fibroblasts,and vascular alterations can variably contribute to SScdevelopment. The presence of Raynaud’s phenomenon anddiffuse microangiopathy suggests that endothelial injury mayrepresent the first step in the pathogenesis of the disease.4Numerous genetic, environmental, and infectious agents havebeen proposed as possible triggering factors. Among these,human cytomegalovirus infection may play a part inthe pathogenesis of the SSc owing to its ability to infect bothendothelial and monocyte/macrophage cells.

2002 - The high frequency of spontaneous micronuclei observed in lymphocytes of systemic sclerosis patients: preliminary results. [Articolo su rivista]
Porciello, G.; Scarpato, R.; Storino, F.; Cagetti, F.; Marcolongo, R.; Migliore, L.; Ferri, Clodoveo; Galeazzi, M.
abstract

OBJECTIVE: Aim of the study is to assess the presence of spontaneous chromosome damage in patients affected by limited (lSSc) or diffuse (dSSc) Systemic Slerosis, using the micronucleus (MN) assay.METHODS: We evaluated MN frequency in cultured peripheral lymphocytes of 18 SSc and in a group of 20 healthy controls. Patients were also classified as ACA+, Scl70+, FAN+ according to the presence of the specific anti-nuclear antibodies. We also explored the hypothesis that the extent of cytogenetic alteration might be related to the severity of the pathological condition and/or to the immunological profile.RESULTS: Compared to controls, the patient group as a whole showed significantly higher MN frequencies (10.8+/-4.5 vs. 27.8+/-13.7, p&lt;0.001). No correlation was found between spontaneous chromosome damage and severity of the disease, being MN frequency 33.1+/-17.0 and 19.8+/-2.7 in lSSc and dSSc, respectively. Interestingly, ACA+ subjects displayed the highest MN frequency (36.9+/-15.0), as compared to patients with different antibody pattern (Scl70+, FAN+; 19.7+/-8.2).CONCLUSIONS: Our results confirm the presence of chromosomal damage in circulating lymphocytes of SSc patients and would suggest a key role of antibodies to the centromere in determining the observed cytogenetic anomalies.

2001 - European multicentre study to define disease activity criteria for systemic sclerosis. I. Clinical and epidemiological features of 290 patients from 19 centres [Articolo su rivista]
Della Rossa, A.; Valentini, G.; Bombardieri, S.; Bencivelli, W.; Silman, A. J.; D`angelo, S.; Cerinic, M. M.; Belch, J. F.; Black, C. M.; Becvar, R.; Bruhlman, P.; Cozzi, F.; Czirjak, L.; Drosos, Aa; Dziankowska, B.; Ferri, Clodoveo; Gabrielli, A.; Giacomelli, R.; Hayem, G.; Inanc, M.
abstract

OBJECTIVE: To investigate the existence of differences among European referral centres for systemic sclerosis (SSc) in the pattern of attendance and referral and in the clinical and therapeutical approaches.METHODS: In 1995 the European Scleroderma Study Group initiated a multicentre prospective one year study whose aim was to define the disease activity criteria in SSc. During the study period each participating European centre was asked to enroll consecutive patients satisfying American College of Rheumatology criteria for SSc and to fill out for each of them a standardised clinical chart. Patients from various centres were compared and differences in epidemiological, clinical, and therapeutical aspects were analysed.RESULTS: Nineteen different medical research centres consecutively recruited 290 patients. The patients could be divided into two subgroups: 173 with the limited (lSSc) and 117 with the diffuse (dSSc) form of the disease. The clinical and serological findings for the series of 290 patients seemed to be similar to data previously reported. However, when the data were analysed to elicit any differences between the participating centres, a high degree of variability emerged, in both epidemiological and clinical features and in the diagnostic and therapeutic approaches to the disease.CONCLUSIONS: The clinical approach to SSc, not only in different countries but also in different centres within the same country, is not yet standardised. To overcome this problem, it will be necessary for the scientific community to draw up a standardised procedure for the management of patients with SSc. This would provide a common research tool for different centres engaged in research on this complex disease.

2001 - European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes. [Articolo su rivista]
Valentini, G.; Della Rossa, A.; Bombardieri, S.; Bencivelli, W.; Silman, A. J.; D`angelo, S.; Cerinic, M. M.; Belch, J. F.; Black, C. M.; Bruhlmann, P.; Czirjak, L.; De Luca, A.; Drosos, A. A.; Ferri, Clodoveo; Gabrielli, A.; Giacomelli, R.; Hayem, G.; Inanc, M.; Mchugh, N. J.; Nielsen,
abstract

AbstractOBJECTIVE: To develop criteria for disease activity in systemic sclerosis (SSc) that are valid, reliable, and easy to use.METHODS: Investigators from 19 European centres completed a standardised clinical chart for a consecutive number of patients with SSc. Three protocol management members blindly evaluated each chart and assigned a disease activity score on a semiquantitative scale of 0-10. Two of them, in addition, gave a blinded, qualitative evaluation of disease activity ("inactive to moderately active" or "active to very active" disease). Both these evaluations were found to be reliable. A final disease activity score and qualitative evaluation of disease activity were arrived at by consensus for each patient; the former represented the gold standard for subsequent analyses. The correlations between individual items in the chart and this gold standard were then analysed.RESULTS: A total of 290 patients with SSc (117 with diffuse SSc (dSSc) and 173 with limited SSc (lSSc)) were enrolled in the study. The items (including Delta-factors-that is, worsening according to the patient report) that were found to correlate with the gold standard on multiple regression were used to construct three separate 10-point indices of disease activity: (a) Delta-cardiopulmonary (4.0), Delta-skin (3.0), Delta-vascular (2.0), and Delta-articular/muscular (1.0) for patients with dSSc; (b) Delta-skin (2.5), erythrocyte sedimentation rate (ESR) &gt;30 mm/1st h (2.5), Delta-cardiopulmonary (1.5), Delta-vascular (1.0), arthritis (1.0), hypocomplementaemia (1.0), and scleredema (0.5) for lSSc; (c) Delta-cardiopulmonary (2.0), Delta-skin (2.0), ESR &gt;30 mm/1st h (1.5), total skin score &gt;20 (1.0), hypocomplementaemia (1.0), scleredema (0.5), digital necrosis (0.5), Delta-vascular (0.5), arthritis (0.5), TLCO &lt;80% (0.5) for all patients with SSc. The three indexes were validated by the jackknife technique. Finally, receiver operating characteristic curves were constructed in order to define the value of the index with the best discriminant capacity for "active to very active" patients.CONCLUSIONS: Three feasible, reliable, and valid preliminary indices to define disease activity in SSc were constructed.

2000 - Hepatitis C Virus, B-cell Disorders, and Non-Hodgkin’s Lymphoma [Capitolo/Saggio]
Ferri, Clodoveo; Pileri, S; Zignego, Al
abstract

Discussion of the etiologic role of HCV in the development of haematological cancers

2000 - Isolated pulmonary hypertension in diffuse cutaneous systemic sclerosis successfully treated with long-term plasma exchange. [Articolo su rivista]
Ferri, Clodoveo; Emdin, M.; Storino, F. A.; Giuggioli, D.; Longombardo, G.; Greco, F.; Fertig, N.; Medsger, T. A.
abstract

Isolated pulmonary hypertension (PHT) in patients with diffuse cutaneous systemic sclerosis (dSSc) is one of the most severe complication. Here we report the case of a 22 year-old white woman with anti-U3RNP antibody-positive dSSc complicated by severe, isolated PHT successfully treated with long-term plasma exchange. This beneficial effect persisted for two years, even after plasma exchange discontinuation. This is the first observation of isolated PHT in dSSc responsive to plasma exchange therapy.

2000 - Relation between infection and autoimmunity in mixed cryoglobulinemia [Articolo su rivista]
Ferri, Clodoveo; Zignego, A. L.
abstract

Mixed cryoglobulinemia (MC) is a systemic vasculitis of small to medium-sized vessels due to the vascular deposition of circulating immune-complexes (CIC) and complement. A leukocytoclastic vasculitis is the histologic hallmark of cutaneous manifestations of the disease, while a clonal B lymphocyte expansion in blood, bone marrow, liver, and spleen represents the underlying pathologic alteration responsible for the production of cryo-CIC and non-cryo CIC with rheumatoid factor activity. A causative role of hepatitis C virus (HCV) infection has been demonstrated in the large majority of MC patients. Hepatitis C virus is both a hepatotropic and a lymphotropic virus; due to this latter biological peculiarity, HCV may trigger a constellation of autoimmune-lymphoproliferative disorders. Besides MC, other important HCV-related diseases are porphyria cutanea tarda, autoimmune hepatitis, membranoproliferative glomerulonephritis, and B cell neoplasias. Hepatitis C virus-related MC represents a link between autoimmune and lymphoproliferative disorders; moreover, MC is an important model to study the complex relation between infections and immune system alterations in humans. During the last years many other autoimmune manifestations have been correlated with HCV infection; namely, sicca syndrome, chronic polyarthritis, polydermatomyositis, fibromyalgia, autoimmune thyroiditis, lung fibrosis, and diabetes mellitus. It is often difficult to verify whether the above associations are coincidental or a pathogenetic link actually exists. At least for particular patients' subsets and in some geographic areas, a causative role of HCV seems to be likely. The geographically heterogeneous distribution of HCV-related autoimmune diseases suggests the contribution of important environmental and genetic factors in the pathogenesis of such conditions. In clinical practice, patients with recent-onset, atypical rheumatic and autoimmune disorders should be carefully investigated for possible HCV infection; this is particularly advisable for correct diagnosis and adequate therapeutic strategy.

2000 - T(14;18) translocation in chronic hepatitis C virus infection [Articolo su rivista]
Zignego, Al; Giannelli, F.; Marrocchi, Me; Mazzocca, A.; Ferri, Clodoveo; Giannini, C.; Monti, M.; Caini, P.; Villa, Gl; Laffi, G.; Gentilini, P.
abstract

Pathogenic mechanisms of B-cell lymphoproliferative disorders in chronic hepatitis C virus (HCV) infection are unclear. We studied t(14;18) translocation by polymerase chain reaction in peripheral blood mononuclear cells from 50 patients with HCV-related liver disease (group A), 7 with mixed cryoglobulinemia syndrome (group B), 55 with HCV-negative liver disease (group C), and 30 with HCV-negative chronic rheumatic disorders or chronic infection by nonhepatotropic agents (group D). T(14;18) was significantly more frequent in group A (13/50 patients = 26 %) and group B (5/7 = 71.4%) patients than in group C (1/55 = 3.6%) and group D (1/30 = 3.3%) ones. Immunoblot analysis showed bcl-2 over-expression in all t(14;18)-positive samples. In group A, 10/13 (77%) patients with t(14;18) and 13/37 (35%) without t(14;18) had serum cryoglobulins in the absence of mixed cryoglobulinemia symptoms (P <.05). These data indicate that t(14;18) and bcl-2 over-expression in lymphoid cells are frequent in chronic HCV infection and suggest that this event may contribute to the pathogenesis of HCV-related lymphoproliferative disorders.

1999 - From essential mixed cryoglobulinemia to virus-induced autoimmunity: ten years of research on mixed cryoglobulinemia. [Capitolo/Saggio]
Della Rossa, A; Ferri, Clodoveo; Bombardieri, S.
abstract

the chapter illustrates the history of clinical and laboratoristic research about the etiopathogenesis of mixed cryoglobulinemia, firstly considered "essential", that is idiopathic, and than related to infection of HCV.

1999 - Hepatitis C virus (HCV) in cryoglobulinaemic leukocytoclastic vasculitis (LCV): could the presence of HCV in skin lesions be related to T CD8+ lymphocytes, HLA-DR and ICAM-1 expression? [Articolo su rivista]
Bernacchi, E; La Civita, L; Caproni, M; Zignego, Al; Bianchi, B; Monti, M; Fabbri, P; Pasero, G; Ferri, Clodoveo
abstract

An association between mixed cryoglobulinaemia (MC) and hepatotropic viruses, chiefly hepatitis C virus (HCV), has been widely reported. The presence of HCV genomic sequences or HCV-related viral proteins in the serum, purified cryoglobulins, peripheral blood mononuclear cells and into several tissues has suggested an important triggering role for HCV in MC patients. However, only few reports investigated the presence of HCV in cutaneous vasculitis and its potential pathogenetic role. Biopsies of cutaneous purpuric lesions from 5 MC female patients (aged from 40 to 80 years) were carried out for virological and histopathological evaluation. A leukocytoclastic vasculitis pattern was found in 4/5 subjects, while the presence of HCV RNA was detected in 3/5. In only 3 cases biopsy specimens were sufficient for immunohistochemical and direct immunofluorescence (DIF) studies. Immunohistochemical evaluation was performed by means of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) immune-complexes. In the same skin specimen APAAP and DIF findings were compared with the presence/absence of HCV genomic sequences (PCR technique). In 1 MC patient, the detection of HCV-RNA was associated to a prevalent CD8+ T suppressor pattern with a perivascular and subjunctional distribution as well as an intense expression of second class (HLA-DR) and intercellular adhesion (ICAM-1) molecules on basal keratinocytes, endothelial cells and perivascular infiltrate. These findings suggest a marked inflammatory activation that spreads from endothelial cells to keratinocytes and Langerhans cells. In the 2 HCV-RNA negative specimens the scanty immunopathological staining could indicate a residual activity due to the previous inflammatory event triggered by cryoglobulins. The deposition of circulating HCV-containing immune complexes (CIC) in the skin could be the initial pathogenic event for cryoglobulinemic vasculitis; subsequently CIC could spread from the vascular bed to the perivascular tissue and then could be very rapidly eliminated. If confirmed in larger patients' series these findings could definitely demonstrate a direct role of HCV in the pathogenesis of cryoglobulinemic vasculitis.

1999 - Parvovirus B19 and systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; Longombardo, G; Azzi, A; Zakrzewska, K.
abstract

the article raises the potential trigger role of parvovirus in the pathogenesis of systemic sclerosis

1999 - Parvovirus B19 infection of bone marrow in systemic sclerosis patients. [Articolo su rivista]
Ferri, Clodoveo; Zakrzewska, K; Longombardo, G; Giuggioli, D; Storino, Fa; Pasero, G; Azzi, A.
abstract

OBJECTIVE: To investigate the prevalence of human parvovirus B19 (B19) infection in the bone marrow of systemic sclerosis (SSc) patients.METHODS: Twenty-one consecutive SSc patients and 15 sex- and age-matched subjects without immunological rheumatic diseases were studied for: (i) the presence of circulating anti-B19 antibodies (anti-B19 IgG and IgM type and anti-B19 NS1 IgG) detected by means of standard methodologies, and (ii) B19 genomic sequences in sera and bone marrow biopsy specimens using a nested-PCR technique.RESULTS: The presence of B19 DNA was demonstrated in a significant percentage of bone marrow biopsies from SSc patients (12/21; 57%) and was never detected in the control group (p < 0.01). In no case was the B19 viremia observed, while serum anti-B19 NS1 antibodies, possible markers of B19 persistent infection, were more frequently detected in SSc patients than in controls (33% vs 13%). SSc patients with bone marrow B19 infection showed a shorter mean disease duration than B19-negative patients (5.6 +/- 4.2 vs 12.7 +/- 7.8 yrs; p < 0.01).CONCLUSIONS: This is the first demonstration of bone marrow B19 infection in a significant percentage of SSc patients. The possible etiopathogenetic role of B19 should be verified in a larger patients series and further investigated by means of molecular biology studies.

1999 - Thyroid cancer in patients with hepatitis C infection [Articolo su rivista]
Antonelli, A; Ferri, Clodoveo; Fallahi, P.
abstract

the report illustrates the increased incidence of thyroid cancer in patients with HCV

1999 - Ultrasonic videodensitometric analysis in scleroderma heart disease [Articolo su rivista]
Di Bello, V; Ferri, Clodoveo; Giorgi, D; Bianchi, M; Bertini, A; Martini, A; Storino, Fa; Paterni, M; Pasero, G; Giusti, C.
abstract

OBJECTIVES: Symptomatic cardiac involvement is a frequent visceral complication of systemic sclerosis that can affect the overall prognosis of the disease. The aim of the present study was to detect preclinical myocardial alterations in patients with systemic sclerosis using ultrasonic videodensitometric analysis.METHODS: Fifty patients with systemic sclerosis [five men, aged 48.8 +/- 11 years (mean +/- SD), range 22-65 years] with normal left ventricular function and 25 age- and sex-matched healthy controls were investigated. Exclusion criteria were the presence of positive maximal exercise stress, arterial hypertension, renal involvement and diabetes. Echocardiographic images were digitized using a real-time video-digitizer Quantitative texture analysis was performed on data from the septum and posterior wall, and mean gray level (MGL) histograms at both end-diastole (d) and end-systole (s) were obtained. The cyclic variation index (CVI) was calculated according to the formula [(MGLd - MGLs)/MGLd] x 100. Left ventricular mass, body surface corrected, was calculated according to the Penn convention.RESULTS: The pattern of variations of mean gray level during the cardiac cycle was totally different from that of the controls; this finding, probably related to myocardial fibrosis, was detected in the large majority of patients with systemic sclerosis (90%). In particular, CVI, which is the expression of the intrinsic myocardial structural function, was significantly lower than in controls (septum -31 +/- 38% versus 36 +/- 9%, P < 0.0001; and posterior wall -19 +/- 33% versus 51 +/- 20%, P < 0.0001).CONCLUSIONS: Ultrasonic videodensitometric analysis is a non-invasive, feasible method of detecting myocardial alterations in patients with systemic sclerosis, which could be related to both fibrosis and microcirculatory abnormalities. The potential role of these abnormalities in the pathogenesis of ventricular dysfunction should be investigated further.

1998 - Heart involvement in systemic sclerosis: an ultrasonic tissue characterisation study [Articolo su rivista]
Ferri, Clodoveo; Di Bello, V; Martini, A; Giorgi, D; Storino, Fa; Bianchi, M; Bertini, A; Paterni, M; Giusti, C; Pasero, G.
abstract

BACKGROUND: Clinicoepidemiological findings indicate that symptomatic heart involvement in patients with systemic sclerosis (SSc) predicts a very poor prognosis. At necropsy studies, SSc heart involvement without significant coronary lesions is characterised by patchy myocyte necrosis and contraction band necrosis with collagen replacement leading to myocardial fibrosis. There is a discrepancy between the frequency of clinically evident myocardial disease (25%) and autoptical myocardial fibrosis (81%).OBJECTIVE: The aim of this study was to detect preclinical myocardial alterations in SSc patients by ultrasonic videodensitometric analysis.METHODS: Thirty five SSc patients (three male, aged 48.6 (11) SD years, range 22-65) with normal ventricular function and 25 age and sex matched healthy controls were studied. All patients had a negative maximal exercise stress; in all cases arterial hypertension, renal involvement, and diabetes were excluded. Echocardiographic images were digitised by a real time videodigitiser (Tomtec Imaging Systems). Quantitative texture analysis was performed on data from the septum and the posterior wall, obtaining mean gray level histogram (MGL) at both end-diastole (d) and end-systole (s). The cyclic variation index (CVI), was calculated according to the formula ((MGLd-MGLs)/MGLd) x 100. Left ventricular mass (LVM), body surface corrected, was calculated according to Penn convention.RESULTS: Comparable systolic and diastolic blood pressure, LVM, diastolic and systolic function were recorded in both SSc patients and controls. In contrast, in SSc patients the CVI, which is the expression of the intrinsic myocardial structural function, was significantly lower than in controls (septum: -18 (28)% v 35 (10)%, p < 0.0001; and posterior wall: -13 (32)% v 50 (20)%, p < 0.0001). Changes in cyclic echo amplitude, probably related to myocardial fibrosis, were detected in the large majority of SSc patients (88%).CONCLUSIONS: Ultrasonic videodensitometric analysis represents a non-invasive, feasible method that can detect early myocardial changes in SSc patients, which could be related to both fibrosis and microcirculatory abnormalities. Their potential evolution towards ventricular dysfunction and their link with cardiac sudden death, because of severe conduction system or rhythm disturbances, should be further investigated.

1998 - Hepatitis E virus and systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; Longombardo, G; Mugnaini, P.
abstract

discussion of the possible link between systemic sclerosis and the virus HEV

1998 - Immune response to an epitope of the NS4 protein of hepatitis C virus in HCV-related disorders [Articolo su rivista]
Longombardo, G; Ferri, Clodoveo; Marchi, S; Costa, F; Lombardini, F; Vacri, L; Bombardieri, S; Migliorini, P.
abstract

NS4, a nonstructural protein of HCV, is a frequent target of antibodies in infected subjects. According to recent data, the antibodies frequently recognize the sequence 1921-40 of the NS4 protein. The aim of this work was to analyze antibody reactivity with the sequence 1921-40 in different HCV-related disorders. Although this sequence is located in a relatively invariant region of viral genome, two strain-specific sequences are described. Thus, three NS4 1921-1940 peptides were synthesized: the BK shared by most viral strains, the J6 (strain 2a), and the J8 (strain 2b). The peptides were used as antigens in the solid phase for measuring serum IgG antibodies in an ELISA assay. Antibodies reactive with the 1921-40 BK peptide were detected in 64% of sera from patients with autoimmune hepatitis (AIH), 51% from chronic hepatitis C (CHC), and 22% from mixed cryoglobulinemia (MC). The frequency of positive sera in MC was significatively lower than in AIH (P < 0.0001) or CHC (P < 0.0021). Similar results were obtained with the J6 and J8 peptides. All sera that did not react with the BK peptide were negative on J6 and J8 and conversely most sera reacting with the BK peptide also bound the J6 and the J8 peptides. No correlation was found between the genotype of the infecting virus and the presence of antibodies to any of the NS4 peptides. These results indicate that many HCV-infected subjects produce antibodies to the NS4 sequence 1921-40. The immune response to this sequence is not strain specific and varies with the different disorders associated with HCV infection.

1998 - L’interessamento polmonare nella sclerosi sistemica [Articolo su rivista]
Ferri, Clodoveo; Fazzi, P; Storino, Faa; Cazzato, M; Martini, A; Giuggioli, D; Pasero, G.
abstract

descrizione del coinvolgimento del polmone nei pazienti con sclerosi sistemica (interstiziopatia polmonare, sindrome restrittiva, ipertensione arteriosa polmonare)

1998 - microvascular involvement in systemic sclerosis: laser doppler evaluation of reactivity to acetylcholine and sodium nitroprusside by iontophoresis [Articolo su rivista]
LA CIVITA, L; Rossi, M; Vagheggini, G; Storino, Faa; Ferri, Clodoveo
abstract

OBJECTIVES: To investigate the skin vasodilatory response to iontophoretically applied acetylcholine (Ach), an endothelium dependent vasodilator, and to sodium nitroprusside (SNP), an endothelium independent vasodilator, in patients with systemic sclerosis (SSc).METHODS: Eleven SSc patients were preliminarily studied (10 females, mean age 40.5; mean disease duration 6.5 years), and 16 age and sex matched control subjects. By means of laser Doppler flowmetry skin blood flow was evaluated at third finger, at baseline, and after postischaemic hyperaemia test and during iontophoretically transcutaneous application of 1% solution of Ach and SNP.RESULTS: No significant differences in basal skin blood flow were detected between SSc patients and controls. Cutaneous vasodilatory response to ischaemia, Ach, and SNP was significantly less pronounced in SSc patients compared with controls (p < 0.001). Moreover, among SSc patients a lower (p < 0.05) vasodilatory response to Ach compared with ischaemia and SNP was recorded.CONCLUSIONS: These data confirm a reduction of skin digital vasodilatory reserve in SSc patients and suggest a defect of both endothelial dependent arteriolar relaxation and wall compliance in the pathogenesis of this dysfunction.

1998 - Mixed cryoglobulinaemia: a cross-road between autoimmune and lymphoproliferative disorders [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Longombardo, G; Zignego, Al; Pasero, G.
abstract

Mixed cryoglobulinaemia (MC) is a systemic vasculitis, secondary to the deposition in small and medium-sized blood vessels of circulating immune complexes, mainly the cryoglobulins, and complement. MC is characterised by a typical clinical triad (purpura, weakness, arthralgias) and by one or more organ involvement: chronic hepatitis, glomerulonephritis, peripheral neuropathy, skin ulcers and diffuse vasculitis. In a limited number of MC patients, a malignancy, that is B-cell non-Hodgkin's lymphoma or hepatocellular carcinoma, may also develop. Hepatitis C virus (HCV) infection has been found in the majority of patients with MC; the frequency of HCV markers (91%) was significantly higher than other rheumatic diseases (6.4%), namely systemic lupus, Sjögren's syndrome, rheumatoid arthritis and systemic sclerosis, or healthy controls (1.2%). The HCV infection of lymphoid tissues may represent the remote event leading to B-lymphocyte proliferation responsible for autoantibodies and immune-complex production. In a similar way, HCV infection may also be involved in the pathogenesis of other autoimmune (glomerulonephritis, thyroiditis, lung fibrosis, autoimmune hepatitis, porphyria cutanea tarda) and lymphoproliferative disorders (monoclonal gammopathies, B-cell lymphomas). MC shares numerous clinico-serological and pathological features with the above disorders. HCV seems to be their common etiological agent; however, a variable combination of unknown co-factors (infectious, genetic, environmental) should be determinant for the appearance of different clinical patterns.

1998 - Progressive sensorineural hearing impairment in systemic vasculitides [Articolo su rivista]
Berrettini, S; Ferri, Clodoveo; Ravecca, F; La Civita, L; Bruschini, L; Riente, L; Mosca, M; Sellari Franceschini, S.
abstract

OBJECTIVES: A large series of patients with various forms of systemic vasculitis were evaluated to analyze the prevalence of progressive sensorineural hearing loss (PSNHL), its characteristics and evolution, and the effects of different therapies.METHODS: A total of 673 patients were questioned about the presence of subjective audiovestibular disturbances. Of those, 80 subjects complained of subjective audiological disturbances and underwent oto-rhino-laryngological and audiovestibular evaluation. Those patients with progressive hearing impairment were selected and studied carefully.RESULTS: A PSNHL was observed in 14 patients. The hearing loss was bilateral and asymmetrical in most subjects. It was usually sensorineural, with a cochlear lesion. Unsteadiness was the most frequent vestibular symptom and canal paresis or palsy was noted in most patients. Systemic corticosteroids and cyclophosphamide were useful treatments; in unresponsive patients, satisfactory results were obtained with methotrexate and plasma exchange.CONCLUSIONS: PSNHL is a rare complication of systemic vasculitis, but occasionally is one of the presenting symptoms. Its clinical evolution is variable, but timely clinical assessment and treatment can positively affect prognosis.

1998 - Severe urinary bladder involvement in systemic sclerosis. Case report and review of the literature [Articolo su rivista]
La Civita, L; Fiorentini, L; Tognetti, A; Pasero, G; Ferri, Clodoveo
abstract

Lower urinary tract involvement is an uncommon manifestation of systemic sclerosis; however, it may represent a troublesome disturbance affecting the quality of life in systemic sclerosis patients. Here we report the case of a middle-aged woman with a 5-year history of systemic sclerosis, who developed severe and progressive urinary bladder sclerosis. This report is particularly interesting because of the severity of the bladder involvement, which required surgical treatment.

1997 - Autonomic dysfunction in systemic sclerosis: time and frequency domain 24 hour heart rate variability analysis [Articolo su rivista]
Ferri, Clodoveo; Emdin, M; Giuggioli, D; Carpeggiani, C; Maielli, M.
abstract

To evaluate the autonomic nervous control of the heart in patients with systemic sclerosis (SSc), spontaneous heart rate variability was investigated by means of time-domain and spectrum analysis of 24 h ECG ambulatory recordings in 30 SSc patients (four males, aged 45.2 +/- 9 yr, mean +/- S.D., range 27-60) and 30 age-matched healthy subjects. A significantly higher heart rate (P < 0.01) and lower circadian and spectral indices of heart rate variability (P < 0.01) were observed in SSc patients, compared with controls. A predictive value of age (P = 0.002), tachycardia (P = 0.002), circadian heart rate variability (P = 0.0025) and spectral power values (P = 0.005) for patient mortality was found. Moreover, the relative risk of death was higher (P = 0.05) in older subjects with circulating anti-Scl70. These abnormalities, detectable by a feasible, non-invasive diagnostic approach, indicate the presence of autonomic cardiac neuropathy in SSc patients

1997 - Could HGV infection be implicated in lymphomagenesis? [Articolo su rivista]
Zignego, Al; Giannini, C; Gentilini, P; Bellesi, G; Hadziyannis, S; Ferri, Clodoveo
abstract

discussion of the potential pathogenic effect of HGV on the development of lymphomas

1997 - Frequency of bcl-2 rearrangement in patients with mixed cryoglobulinemia and HCV-positive liver diseases [Articolo su rivista]
Zignego, Al; Giannelli, F; Marrocchi, Me; Giannini, C; Gentilini, P; Innocenti, F; Ferri, Clodoveo
abstract

the paper illustrates the high frequency of bcl-2 rearrangement in patients affected by HCV-related mixed cryoglobulinemia, prospecting a role for the virus in the oncogenesis

1997 - Hepatitis C virus infection in mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma: evidence for a pathogenetic role. [Articolo su rivista]
Zignego, Al; Ferri, Clodoveo; Giannini, C; La Civita, L; Careccia, G; Longombardo, G; Bellesi, G; Caracciolo, F; Thiers, V; Gentilini, P.
abstract

We investigated the pathogenetic relevance of hepatitis C virus (HCV) infection in mixed cryoglobulinemia (MC) with or without complicating B-cell Non-Hodgkin's lymphoma (NHL) in comparison with other immunological and lymphoproliferative disorders. The following groups of patients were studied: A) 25 patients with MC in 7 cases evolved into B-cell NHL; B) 25 healthy subjects; C) 22 patients with different systemic immune diseases; D) 24 patients with chronic HCV infection without MC; E) 25 patients with B-cell idiopathic NHL. Methods used included: i) Polymerase chain reaction (PCR) for HCV RNA detection in serum and peripheral blood mononuclear cells (PBMC) (uncultured or mitogen-stimulated); ii) Branched DNA (b-DNA) for HCV RNA quantification; iii) HCV genotyping by genotype-specific primers localized in the core region and by hybridization of amplification products of the 5' untranslated region (5'UTR), obtained with universal primers, using genotype-specific probes. Serum anti-HCV and HCV RNA were detected in 88% and 73% of MC patients, respectively, and in a significantly lower percentage of healthy controls and patients with autoimmune diseases. HCV RNA concentration was significantly lower in supernatants than in corresponding whole sera (p < 0.001). Plus-strand HCV RNA was detected in 81% of peripheral blood mononuclear cell (PBMC) samples and minus-strand in the majority of fresh or mitogen stimulated cells. All MC patients with NHL had HCV RNA sequences in PBMC. HCV genotype 2a/III was detected in MC patients with a prevalence that was significantly higher than in HCV infected patients without MC. Surprisingly, HCV markers (anti-HCV and/or HCV RNA) were found in 32% of patients with idiopathic NHL. These data suggest that HCV infection is involved in the pathogenesis of MC through both direct participation in the immune complex related vasculitis and by triggering the lymphoproliferative disorder underlying the disease. This latter disorder seems to be related to HCV lymphotropism which could also be responsible for the evolution of MC to malignant lymphoma. This study also suggests that HCV infection may be involved in the pathogenesis of idiopathic B-cell NHL through a similar pathogenetic mechanism.

1997 - Hepatitis-C-virus infection and cancer [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Zignego, Al; Pasero, G.
abstract

discussion of the pathogenic role of HCV in the development of haematological and liver cancers

1997 - Interstitial lung fibrosis and rheumatic disorders in patients with hepatitis C virus infection. [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Fazzi, P; Solfanelli, S; Lombardini, F; Begliomini, E; Monti, M; Longombardo, G; Pasero, G; Zignego, A. L.
abstract

A possible aetiopathogenetic role of hepatitis C virus (HCV) has been reported in various immune-mediated disorders, such as mixed cryoglobulinaemia, which may be complicated by interstitial lung involvement; moreover, different viruses, including HCV, have been correlated with idiopathic pulmonary fibrosis. Here, a cohort of eight HCV-positive patients (M/F = 4/4, mean age 61 +/- 8 S.D. yr) with interstitial lung fibrosis and a variable number of rheumatic disorders are described. Interstitial lung involvement appeared medially 4.5 +/- 3.2 S.D. yr after the clinical onset of chronic hepatitis. During the clinical follow-up, some rheumatic symptoms were also recorded: articular involvement (four patients): mild sicca syndrome (one patient); severe polymyositis and cranial neuropathy (one patient); serum cryoglobulins and/or autoantibodies (eight patients). In all patients, a moderate (four patients) or severe (four patients) lung fibrosis was evaluated by means of high-resolution computed tomography. The presence of parenchymal radiotracer uptake on 67Ga scan (7/7 patients) and increased percentages of neutrophils (4/4 patients) and lymphocytes (2/4) at bronchoalveolar lavage suggested an active lung involvement. Different degrees of reduction of single breath diffusing capacity for carbon monoxide (DLco) (mean value 57.6 +/- 15%, range 37-80) were observed in all cases, while spirometric abnormalities, consistent with a global restrictive pattern, were less frequently found. In all cases, anti-HCV antibodies and HCV viraemia were demonstrated: viral genome was also detected in peripheral lymphocytes from 4/4 subjects and in one case in lung biopsy specimens. A desquamative interstitial pneumonia pattern was demonstrated in two cases by lung biopsy. The present work supports the hypothesis that HCV chronic infection could represent a trigger factor for interstitial lung fibrosis and various rheumatic disorders.

1997 - Lack of preferential localization of tumoral mass in B-cell non-Hodgkin's lymphoma associated with hepatitis C virus infection. [Articolo su rivista]
Zignego, Al; Ferri, Clodoveo; Innocenti, F; Giannini, C; Monti, M; Bellesi, G; Gentilini, P.
abstract

report of clinical features of 150 HCV+ patients with B-cell lymphoma

1997 - Lymphotropic virus infection of peripheral blood mononuclear cells in B-cell non-Hodgkin's lymphoma. [Articolo su rivista]
Ferri, Clodoveo; Lo Jacono, F; Monti, M; Caracciolo, F; La Civita, L; Barsanti, La; Longombardo, G; Lombardini, F; Careccia, G; Zignego, Al
abstract

Some lymphotropic viruses such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been proposed as causative agents of B cell non-Hodgkin's lymphoma (NHL). More recently, the presence of hepatitis C virus (HCV), which is both a hepatotropic and lymphotropic virus, has been reported in one third of B cell NHL patients. The aim of this study was to investigate in a series of B cell NHL the prevalence of three lymphotropic viruses, i.e. EBV, HHV-6 and HCV, in peripheral blood mononuclear cells (PBMC). Eighteen unselected B cell NHL patients (10 men, 8 women; mean age 62 +/- 12 years, range 31-77 years; mean disease duration 1.8 +/- 1.4 years) and 40 age- and sex-matched healthy controls were included in the study. In all cases, an acquired-immunodeficiency-syndrome-related lymphoma was excluded. By means of the polymerase chain reaction technique, EBV DNA, HHV-6 DNA and HCV RNA were detected in PBMC. HCV genomic sequences were significantly more frequent in PBMC of NHL patients than in controls (33 vs. 2.5%; p < 0.01); on the other hand, in the same two groups EBV DNA (39 vs. 60%; p = not significant) and HHV-6 DNA (22 vs. 32%; p = not significant) were present in a comparable percentage of individuals in the same two groups. The infection of PBMC by HCV alone was present in the majority (5 of 6) of HCV-positive NHL. These data support the implication of HCV infection in a statistically significant number of B cell NHL, whereas a possible co-operation between HCV and other well-known lymphotropic viruses seems to be excluded.

1997 - Viruses and cancers: possible role of hepatitis C virus [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Zignego, Al; Pasero, G.
abstract

Oncogenesis is a multifactorial process in which environmental, genetic and infectious factors are variably involved. A possible role of specific viruses has been suggested in at least 15% of human cancers. Hepatitis C virus (HCV), which is both hepato- and lymphotropic, is responsible for various liver disorders, i.e. chronic hepatitis, cirrhosis and hepatocelluar carcinoma, as well as for a constellation of extrahepatic immune-mediated manifestations, among which is mixed cryoglobulinaemia. This is a systemic disorder secondary to a chronic, benign B-lymphocyte proliferation, which in some subjects may evolve to a malignant non-Hodgkin's lymphoma (NHL). Interestingly, recent studies reported the appearance of malignant B-cell neoplasias in patients with type C chronic hepatitis; moreover, in a significant number (from 22% to 50%) of 'idiopathic' NHLs, the presence of HCV infection has been demonstrated. The presence of a geographical etherogeneity in the prevalence of HCV-positive NHL suggests that other co-factors, i.e. genetic and environmental, could be involved in the lymphomagenesis. HCV may exert its oncogenic potential in two different directions, leading to liver cancer or B-cell lymphoma.

1996 - Bone involvement in Gaucher's disease: 'bone crisis' or disease complication? [Articolo su rivista]
La Civita, L; Mariani, G; Porciello, G; Molea, N; Viacava, P; Lazzeri, E; Pasero, G; Ferri, Clodoveo
abstract

Bone involvement can represent the inaugural symptom of Gaucher's disease (GD). Here, we report the case of a 68-year old man diagnosed as having GD since 1963. In June 1994 the patient was referred to our Rheumatology Unit because of a long-lasting coxalgia on the left hip and progressive walking impairment following traumatic fracture of the left femur. Multicystic osseous changes at standard X-ray and hyper-gamma-globulinemia with an elevated ESR (122 mm, 1st hour) suggested the diagnosis of either osteonecrosis of the femoral head or multiple myeloma. On bone marrow biopsy examination, Gaucher's cell infiltrates were detected and an increased uptake in the distal left femur and proximal tibia were demonstrated by lipophilic tracer scan (99mTc-Sestamibi). Subsequently, the patient suffered another femoral fracture at a site of Gaucher's infiltrates previously documented by bone scan. We conclude that in patients with GD, 99mTc-Sestamibi bone scan can selectively evaluate the presence of bone lipid deposits, and could indirectly differentiate this bone condition from other serious skeletal complications of the disease.

1996 - Chronic hepatitis C and B-cell non-Hodgkin's lymphoma [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Monti, M; Giannini, C; Cecchetti, R; Caracciolo, F; Longombardo, G; Lombardini, F; Zignego, Al
abstract

Hepatitis C virus (HCV), a hepatotropic and lymphotropic virus, is the major causative agent of nonA-nonB chronic hepatitis; moreover, it is frequently associated with benign and malignant lymphoproliferative disorders such as mixed cryoglobulinaemia and B-cell non-Hodgkin's lymphoma (NHL). We investigated the clinical and virological features of B-cell NHL complicating chronic hepatitis C in a series of 10 patients (M/F 1/9; mean age 63 +/- 6SD years). The malignancy appeared after median 8 +/- 4SD years from onset and was low-grade in six patients, intermediate in three, and high-grade in one. 'One-tube nested' PCR detected serum HCV RNA and viral ongoing replication in both fresh and cultured peripheral lymphocytes in all ten. Analysis of HCV genotypes showed a relatively higher prevalence of 2a/III type compared with unselected chronic hepatitis C (50% vs. 15%). In one patient, HCV RNA was also found in the neoplastic bone marrow and lymph-node specimens. B-cell NHL can complicate chronic hepatitis C and affect the overall prognosis of the disease. The increasing frequency of chronic hepatitis C worldwide suggests that the actual prevalence of this complication may be underestimated. Careful clinical work-up at diagnosis and during follow-up is particularly recommendable.

1996 - Effect of isradipine on endothelin-1 plasma concentrations in patients with Raynaud's phenomenon. [Articolo su rivista]
La Civita, L; Giuggioli, D; Del Chicca, Mg; Longombardo, G; Pasero, G; Ferri, Clodoveo
abstract

This study has demonstrated the favourableeffects of isradipine on patients withRaynaud's phenomenon; moreover, it is thefirst to demonstrate a significant reductionin plasma concentrations of ET-1 duringcalcium antagonist treatment.

1996 - Exacerbation of peripheral neuropathy during alpha-interferon therapy in a patient with mixed cryoglobulinemia and hepatitis B virus infection [Articolo su rivista]
La Civita, L; Zignego, Al; Lombardini, F; Monti, M; Longombardo, G; Pasero, G; Ferri, Clodoveo
abstract

An association between hepatotropic viruses, chiefly hepatitis C virus (HCV), occasionally hepatitis B virus (HBV), and mixed cryoglobulinemia has been widely reported. Alpha-interferon (IFN-alpha) has usefully been employed in the treatment of mixed cryoglobulinemia, particularly for liver and renal involvement. IFN-alpha treatment may be associated with neurological complications, including peripheral neuropathy. We describe an HBV positive patient with mixed cryoglobulinemia with recurrent purpura, mild sensory peripheral neuropathy, and active hepatitis treated with IFN-alpha. Rapid improvement of the purpura, liver enzymes, and cryocrit, and disappearance of serum HBV DNA were observed after a 4 week treatment period. However, concomitant worsening of the neuropathy prompted us to discontinue IFN-alpha. Although in this case, a positive effect of IFN-alpha on the clinico-serological and virological variables was confirmed, due to the possible exacerbation of neurological manifestations, a careful patient evaluation is necessary before starting IFN-alpha in patients with mixed cryoglobulinemia.

1996 - Extrahepatic manifestations of hepatitis C virus infection [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Zignego, Al
abstract

discussion of possible extrahepatic manifestations in patients infected by HCV (i.e. lymphoma, thyroiditis, arthritis)

1996 - Hepatitis C virus and lymphoproliferative disorders. [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Caracciolo, F; Bellesi, G; Zignego, Al
abstract

the study focuses on the trigger role of HCV on immune system, inducing alterations and stimulating the onset of lymphoproliferative disorders, possibly due to variable combinations of unknown infectious, environmental, and genetic factors.

1996 - Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia [Articolo su rivista]
Zignego, Al; Ferri, Clodoveo; Giannini, C; Monti, M; La Civita, L; Careccia, G; Longombardo, G; Lombardini, F; Bombardieri, S; Gentilini, P.
abstract

OBJECTIVE: To investigate the possible role of HCV variants in the pathogenesis of mixed cryoglobulinemia.SETTING: Medical service (rheumatology and hepatology units) of urban, university-affiliated teaching hospitals.DESIGN: Analysis of viral genotypes in a cohort of patients with hepatitis C virus (HCV) infection and mixed cryoglobulinemia.PATIENTS: 90 unselected HCV-positive (anti-HCV antibody-positive and HCV RNA-positive) patients consecutively recruited at routine ambulatory visits: 29 with and 61 without (control group) mixed cryoglobulinemia.MEASUREMENTS: Clinical and histologic data; HCV RNA detection in serum and peripheral blood mononuclear cells by polymerase chain reaction (PCR); HCV genotype determination by two methods based on genotype-specific primer PCR and genotype-specific probe hybridization, respectively.RESULTS: Persistent aminotransferase increases were found in 55% of patients with mixed cryoglobulinemia. Peripheral blood mononuclear cells were infected in 80% of cases. In serum samples, HCV genotype 2a/III was detected with a higher prevalence in patients with mixed cryoglobulinemia than in controls (41% compared with 15%). The overall prevalence of genotype 2a/III in mixed cryoglobulinemia increased to 52% when findings in peripheral blood mononuclear cells were also considered. Among patients with mixed cryoglobulinemia, this genotype was more frequent in those without clinical and biochemical signs of liver disease (85%) or with serum autoantibodies (75%).CONCLUSIONS: Mixed cryoglobulinemia may be related, at least in part, to the HCV genotype infecting the host.

1996 - Hepatitis C virus in patients with lymphoproliferative disorders [Articolo su rivista]
FERRI, Clodoveo; La Civita, L; Zignego, AL
abstract

correlation between HCV and lymphoproliferative disorders

1996 - Hepatitis C virus infection and cutaneous vasculitis in mixed cryoglobulinemia [Articolo su rivista]
La Civita, L; Zignego, Al; Bernacchi, E; Monti, M; Fabbri, P; Ferri, Clodoveo
abstract

the paper discusses the skin manifestations of HCV-related mixed cryoglobulinemia

1996 - Hepatocellular carcinoma in mixed cryoglobulinemia patients [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Zignego, Al; Lombardini, F; Longombardo, G; Gentilini, P; Pasero, G.
abstract

the manuscript raises the pathogenetic role of HCV virus in the carcinoma of the liver

1996 - Mixed cryoglobulinemia: the role of HCV and organ-specific antibodies [Capitolo/Saggio]
Bombardieri, S; Tavoni, A; Mosca, M; La Civita, L; Dolcher, Mp; Lombardini, F; Migliorini, P; Ferri, Clodoveo
abstract

The chapter illustrates the pathogenesis of mixed cryoglobulinemia, namely the trigger role of HCV and the pathogenic role of auto-antibodies

1996 - Polymyositis, lung fibrosis, and cranial neuropathy in a patient with hepatitis C virus infection. [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Fazzi, P; Pasero, G; Zignego, Al
abstract

description of a case report of a patient with HCV infection, who developed polymyositis, lung fibrosis, and cranial neuropathy

1996 - Scintigraphic findings on 99mTc-MDP, 99mTc-sestamibi and 99mTc-HMPAO images in Gaucher's disease. [Articolo su rivista]
Mariani, G; Molea, N; La Civita, L; Porciello, G; Lazzeri, E; Ferri, Clodoveo
abstract

Gaucher s disease is an autosomal recessive lysosomal storage disease characterized by the specific deficiency of glucocerebrosidase that leads to accumulation of insoluble glucocerebroside in the reticuloendothelial system, particularly the bone marrow, liver, spleen and lymph nodes. Direct scintigraphic visualization of lipid deposits in Gaucher s disease has recently been described, based on the use of the lipid-soluble xenon-133. We report here on the use of the lipophilic cationic complex technetium-99m sestamibi (99mTc-MIBI), employed as an indicator of increased cellular density and metabolic activity, to evaluate Gaucher cell infiltrates in the bone marrow; 99mTc-hexametazime (99mTc-HMPAO) was also employed, as a pure indicator of lipidic infiltration in the bone marrow. A 67-year-old patient with known type 1 Gaucher s disease presented with a painful left hip and knee and difficulty in gait subsequent to traumatic fracture of the left femoral neck that had required implant of a fixation screw-plaque. Bone scan with 99mTc-methylene diphosphonate revealed reduced uptake at the distal metaphyseal-epiphyseal femoral region. In addition, whole-body maps and spot-view acquisitions of the thighs and legs were recorded at both 30 min and 2.5 h after the injection of 99mTc-MIBI: the scintigraphic pattern clearly showed increased uptake at several sites involved by Gaucher deposits in the bone marrow (both knees, with variable intensity in different areas), matching the bone changes detected by conventional x-ray. The target to non-target ratios slowly decreased with time, from an average value of 2.25 in the early scan to an average value of 2 in the delayed scan. The lipid-soluble agent 99mTc-HMPAO exhibited a superimposable scintigraphic pattern of accumulation at the involved sites, though with lower target to non-target ratios (1.27-1.48). The results obtained in this patient suggest a potential role of 99mTc-MIBI in the scintigraphic evaluation of Gaucher s lipid deposits in the bone marrow. If the results are confirmed in other patients, this radiopharmaceutical would offer clear advantages over 133Xe because of its wider availability and greater practicality (i.v. administration of 99mTc-MIBI versus inhalation of 133Xe, and use of a single gamma camera instead of two as with 133Xe).

1996 - Type C hepatitis and chronic lymphocytic leukemia [Articolo su rivista]
La Civita, L; Zignego, Al; Monti, M; Longombardo, G; Greco, F; Pasero, G; Ferri, Clodoveo
abstract

discussion of the possible link between the infection by HCV and the chronic lymphocytic leukemia

1995 - Can type C hepatitis be complicated by B-cell malignant lymphoma? [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Monti, M; Longombardo, G; Greco, F; Pasero, G; Zignego, Al
abstract

the article discusses the pathogenic role of the hepatitis C virus in the development of B-cell lymphoma

1995 - CRYOGLOBULINEMIAS - A MULTICENTER STUDY OF THE EARLY CLINICAL AND LABORATORY MANIFESTATIONS OF PRIMARY AND SECONDARY DISEASE [Articolo su rivista]
Monti, G; Galli, M; Invernizzi, F; Pioltelli, P; Saccardo, F; Monteverde, A; Pietrogrande, M; Renoldi, P; Bombardieri, S; Bordin, G; Candela, M; Ferri, Clodoveo; Gabrielli, A; Mazzaro, C; Migliaresi, S; Mussini, C; Ossi, E; Quintiliani, L; Tirri, G; Vacca, A; Da,
abstract

In a multi-centre retrospective study, we compared clinical and laboratory data in 913 patients with cryoglobulinaemias, divided as: (i) essential cryoglobulinaemias; (ii) cryoglobulinaemias secondary to connective tissue diseases (CTD), lymphoproliferative or other haematological diseases (LPD), chronic liver diseases (CLD), and 'other diseases'. Purpura was the commonest presenting feature in all groups and was more common in essential cryoglobulinaemias (p < 0.0001). Meltzer's triad (purpura, arthralgia, weakness) was less frequent, but similarly distributed. Renal involvement was randomly distributed. Neurological impairment was less frequent in cryoglobulinaemias secondary to CLD (p < 0.002). Raynaud's phenomenon, arthritis and sicca syndrome were more frequent in cryoglobulinaemias secondary to CTD. Essential cryoglobulinaemias had a significantly higher percentage of serum complement C4 < 8 mg/dl (p < 0.004), of detectable rheumatoid factor activity (p < 0.0002), and of type II cryoglobulins (p < 0.0001). Liver involvement was evident at presentation in 32.6% of essential cryoglobulinaemias, 27.1% of cryoglobulinaemias secondary to LPD and 12.2% of cryoglobulinaemias secondary to CTD. Antibodies to hepatitis B surface (HBsAg) and core (HBc) antigens were more frequent in cryoglobulinaemias secondary to CLD; anti-HBs antibodies were randomly distributed. Antibodies to hepatitis C (HCV) were tested for in 224 patients, and prevalence was high in all the groups, but lower in cryoglobulinaemias secondary to CTD (p < 0.0001). Type II and type III essential cryoglobulinaemias differed significantly in renal involvement (p < 0.0001), cryocrit > 3% (p < 0.0001), C4 < 15 mg/dl (p < 0.001), HBsAg prevalence (p < 0.01) and purpura (p < 0.05). Despite the high prevalence of HCV markers in all groups, the role of HCV in essential cryoglobulinaemia is not well defined; HBV seems to pray only a marginal role.

1995 - Etiopathogenetic role of hepatitis C virus in mixed cryoglobulinemia, chronic liver diseases and lymphomas [Articolo su rivista]
Ferri, Clodoveo; Zignego, Al; Bombardieri, S; La Civita, L; Longombardo, G; Monti, M; Lombardini, F; Greco, F; Pasero, G.
abstract

Hepatitis C virus (HCV) infection has been found in the majority of patients with mixed cryoglobulinemia (MC) in studies conducted in different countries. In our series of 110 MC patients the frequency of HCV markers was significantly high (91%) compared with other rheumatic diseases (6.4%) and with healthy Italian controls (1.2%). Moreover, HCV RNA was detected in 81% of the peripheral lymphocytes from MC patients. Comparable percentages of HCV infection were detectable in other disorders, i.e. porphyria cutanea tarda (77%) and autoimmune hepatitis type 1 (77%). The HCV infection of peripheral lymphocytes suggests that this virus could be the triggering factor for the lymphoproliferation underlying MC. In a number of patients with MC the evolution from a benign lymphoproliferation to frank B-cell lymphoma was observed. In these subjects HCV RNA in the sera and in fresh and cultured peripheral lymphocytes was constantly detected. The same phenomenon has been observed in patients with long-lasting type C chronic hepatitis. Interestingly, HCV infection has also been recorded in 32% of idiopathic B-cell non-Hodgkin's lymphomas. Taken together, the above findings suggest that HCV can cause benign B-cell proliferation with the consequent production of various autoantibodies, including rheumatoid factor and mixed cryoglobulins. These serological abnormalities characterise different clinical disorders, including the appearance of lymphoma in a not negligible number of individuals

1995 - From internal medicine to rheumatolgy and back: the example of mixed cryoglobulinemia [Articolo su rivista]
Pasero, G; Bombardieri, S; Ferri, Clodoveo
abstract

A report about the trouble in the clinical practice in patients with mixed cryoglobulinemia.

1995 - Guidelines for the management of essential mixed cryoglobulinemia [Articolo su rivista]
Tavoni, A; Mosca, M; Ferri, Clodoveo; Moriconi, L; La Civita, L; Lombardini, F; Bombardieri, S.
abstract

The principal therapeutic procedures and when they are clinically indicated in the management of essential mixed cryoglobulinemia (EMC) have been the subject of much debate. This paper reviews current knowledge and our experience in the treatment of this complex disease. It is generally agreed that patients with purpura, the primary symptom of EMC, should avoid long periods of sitting or standing in the same position. Non-steroidal antiinflammatory drugs can be used for the management of arthralgias and/ or arthritis. Low dose steroids (0.5-0.3 mg/kg/die) are usually sufficient to control the purpura, arthralgias, arthritis and weakness, while larger doses (0.5-1.5 mg/kg/die) are needed to treat the renal involvement, peripheral neuropathy and serositis. Since the discovery of the association between EMC and viral infections, the appropriateness of cytotoxic drugs has been re-evaluated and they are no longer used. With the low antigen content diet, a regimen designed to restore a saturated mononuclear phagocytic system, good results have been obtained in the treatment of purpura, arthralgias, weakness and peripheral neuropathy. Furthermore, this dietary regimen may play a steroid sparing role. Plasma exchange is widely used in the management of severe renal involvement, hyperviscosity syndrome, sensory motor neuropathy and liver involvement in EMC

1995 - Hepatitis C virus as a lymphotropic agent: evidence and pathogenetic implications [Articolo su rivista]
Zignego, Al; Ferri, Clodoveo; Monti, M; La Civita, L; Giannini, C; Careccia, G; Pasero, G; Bombardieri, S; Gentilini, P.
abstract

Hepatitis C virus has been proven to be the major cause of NANB hepatitis, cirrhosis and hepatocellular carcinoma worldwide. Based on the genome similarities between HCV and flavivirus or pestivirus, this agent has been included within the family Flaviviridae as a separate genus. Among the analogies between HCV and the other members of the same family there is the possibility of infecting blood cells. In particular, significant evidence obtained through studies performed in vivo and in vitro support the concept that HCV is not only a hepatotropic but also a lymphotropic virus. This suggests that, in addition to playing a role in inducing hepatic diseases (both of a non-tumoral and a neoplastic nature), HCV infection may also play a role in extrahepatic pathologies. The striking association observed between HCV infection and some autoimmune-lymphoproliferative disorders of either benign or neoplastic nature is consistent with this hypothesis. However, in analogy with what has been observed in the case of liver disease, the mechanisms involved in the pathogenesis of HCV-related extra-hepatic manifestations have to be more deeply analysed and clarified

1995 - Inner ear involvement in mixed cryoglobulinaemia patients [Articolo su rivista]
Berrettini, S; Ferri, Clodoveo; La Civita, L; Segnini, G; Lombardini, F; Bruschini, P; Longombardo, G; Sellari Franceschini, S.
abstract

In order to evaluate the nature and prevalence of audiovestibular disturbances in mixed cryoglobulinaemia (MC), 32 consecutive MC patients were studied by a wide audiological and vestibular examination. Pure tone audiometry, impedance audiometry, brainstem response audiometry and vestibular function were performed. Patients with a previous history of ear damage due to other well-known agents were excluded from the study. In MC patients we found a rather frequent audiovestibular involvement (34.3%). Bilateral sensorineural hearing loss was found in seven MC patients (22%) and altered vestibular function test values in other seven subjects (22%). Moreover, anamnestic and clinical data revealed a high incidence of benign positional paroxysmal vertigo in our MC series. We can suppose that immune complex-mediated microvascular involvement of the labyrinthine vessels may be responsible for inner ear damage in MC. Thus, audiovestibular disturbances may be included among various organ involvement of the MC.

1995 - Mixed cryoglobulinemia as a possible preneoplastic disorder [Articolo su rivista]
La Civita, L; Zignego, Al; Monti, M; Longombardo, G; Pasero, G; Ferri, Clodoveo
abstract

the article fucosed on the potential evolution of mixed cryoglobulinemia in neoplastic disorders

1995 - Reduced bone mass and normal calcium metabolism in systemic sclerosis with and without calcinosis [Articolo su rivista]
Di Munno, O; Mazzantini, M; Massei, P; Ferdeghini, M; Pitaro, N; Latorraca, A; Ferri, Clodoveo
abstract

Forty-three female patients with systemic sclerosis divided into subgroups based on the extent of skin involvement and the presence of calcinosis, and 50 sex and age-matched healthy controls were investigated for bone mineral density (BMD) on the basis of radial (dual photon absorptiometry, Osteograph, NIM), lumbar, and total body measurements (dual energy X-ray absorptiometry, Lunar DPX, Lunar Corp.), and for parameters of calcium metabolism. The patients showed a lower BMD (mean +/- SD; mg/cm2) than the controls at the radial (313 +/- 69 vs 347 +/- 73; p < 0.005), lumbar (974 +/- 143 vs 1081 +/- 154; p < 0.005), and total body (997 +/- 82 vs 1075 +/- 109; p < 0.05) determinations. The patients with the diffuse form of skin involvement had lower values than those with the limited form. There was a negative correlation between BMD and the duration of the disease. The presence of calcinosis was not found to have any effect on BMD. Calcium metabolism was found to be normal in each subgroup. It may be concluded that generalized osteoporosis is a feature of systemic sclerosis, with and without calcinosis. The extent and duration of the disease may play a role in determining bone loss.

1995 - Type C chronic hepatitis complicated by B-cell non-Hodgkin's lymphoma [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Giannini, C; Cecchetti, R; Longombardo, G; Zignego, Al
abstract

the article illustrated the pathogenic role of HCV in lymphomagenesis

1995 - Wegener's granulomatosis of the elderly: a case report of uncommon severe gangrene of the feet [Articolo su rivista]
La Civita, L; Jeracitano, G; Ferri, Clodoveo; Pedrinelli, R; Dell'Omo, G; Catapano, G.
abstract

description of a case report: a patient affected by Wegener's granulomatosis complicated by severe skin ulcers

1994 - Audiovestibular involvement in systemic sclerosis [Articolo su rivista]
Berrettini, S; Ferri, Clodoveo; Pitaro, N; Bruschini, P; Latorraca, A; Sellari Franceschini, S; Segnini, G.
abstract

In order to evaluate the nature and association of audiovestibular disturbances and systemic sclerosis (SSC), 37 unselected SSC patients were studied with a detailed audiological and vestibular examination since November, 1987. Pure-tone audiometry, speech audiometry, impedance audiometry, brainstem response audiometry and vestibular function using electronystagmographic recording were performed. We found a rather frequent audiovestibular involvement (41%). A hearing loss was found in 14 SSC patients; hearing loss was sensorineural in 10 cases and mixed in 4 cases. The latter revealed a finding similar to tympanosclerosis. Four patients showed altered vestibular test values and only one of these had normal hearing. Sensorineural deafness was the more frequent pathological finding and in all cases the site of lesion was cochlear. SSC appears to be directly responsible for audiovestibular damage, since in 12 out of 15 patients with such involvement, no other apparent cause could be revealed. SSC may be included among the autoimmune diseases which may cause audiovestibular disturbances

1994 - Autoantibodies from mixed cryoglobulinemia patients bind glomerular antigens [Articolo su rivista]
Dolcher, Mp; Marchini, B; Sabbatini, A; Longombardo, G; Ferri, Clodoveo; Riente, L; Bombardieri, S; Migliorini, P.
abstract

Mixed cryoglobulinaemia (MC) is a disorder characterized by the presence of large amounts of cryoprecipitating IgM-IgG complexes. An immune complex glomerulonephritis develops in one third of all patients, but its occurrence does not seem related to the amount of cryoglobulins in the sera, nor to their complement-fixing ability. In this study we investigated the presence of IgG antibodies reactive with kidney antigens in 33 MC patients (11 with glomerulonephritis, 22 without renal involvement). A total glomerular extract was run on a 10% acrylamide gel, blotted to nitrocellulose and probed with the patients' sera. Sera from half of the patients without renal involvement reacted with several glomerular antigens whose molecular weight ranged between 200 and 29 kD. In the group with renal involvement, sera from 7/11 patients reacted with an antigen of 50 kD, which is also expressed in thymus, but not in the heart or liver. In a follow-up study of four patients with renal involvement, the amount of serum antibody specific for the 50-kD antigen fluctuated, either spontaneously or in response to therapy. These results show that antibodies specific for glomerular antigens are detectable in MC sera. The immune response against a 50-kD antigen expressed in the kidney and thymus seems to be restricted to a subset of MC patients with renal involvement. Circulating autoantibodies specific for glomerular antigens might contribute to the induction of glomerulonephritis in MC forming immune complexes in situ.

1994 - Hepatitis C virus and mixed cryoglobulinaemia [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Longombardo, G; Zignego, Al
abstract

A report on Hepatitis C virus and mixed cryoglobulinaemia

1994 - Hepatitis C virus as common cause of mixed cryoglobulinemia and autoimmune liver disease [Articolo su rivista]
Ferri, Clodoveo; Longombardo, G; La Civita, L; Greco, F; Lombardini, F; Cecchetti, R; Cagianelli, Ma; Marchi, S; Monti, M; Zignego, Al; Manns, Mp
abstract

AbstractOBJECTIVES: Mixed cryoglobulinaemia (MC) and autoimmune chronic hepatitis (AI-CH) are frequently associated with hepatitis C virus (HCV) chronic infection. Because HCV represents a possible common aetiological factor, the aim of the present study is to investigate the clinico-serological alterations of both MC and AI-CH and to verify a possible overlap between these disorders.SETTING: Patients from three tertiary referral centres.SUBJECTS: Two Italian series of 88 MC patients and 30 AI-CH type 1 were studied.RESULTS: MC and AI-CH share several clinico-serological features. The patients' mean age (MC vs. AI-CH: 60 +/- 9 vs. 57 +/- 13 years), disease duration (10.5 +/- 5 vs. 9.6 +/- 6 years), and female/male ratio (3.4 vs. 3.3) were very similar in the two series. Typical hallmarks of MC, i.e. purpura, arthralgias, and weakness, circulating mixed cryoglobulins with rheumatoid factor activity, and hypocomplementemia were also recorded in a significant number of AI-CH patients. Similarly, chronic active hepatitis was found in 68% of MC patients and its histological and serological alterations were comparable with those of AI-CH; moreover, amongst various autoantibodies, antinuclear antibodies and/or anti-smooth-muscle antibodies were detected in half of the cases of MC. Anti-HCV antibodies, detected by second-generation Chiron ELISA and RIBA, were present in a high percentage of both MC and AI-CH (94 vs. 80%), and frequently associated with HCV viraemia (86 vs. 77%). Finally, anti-GOR, the HCV-related autoantibodies, were found in half cases of MC and AI-CH.CONCLUSIONS: On the whole, these data suggest that HCV in combination with other infectious and environmental and genetic factors can trigger a complex immunological disorder with different clinical patterns

1994 - Hepatitis C virus in mixed cryoglobulinemia and B-cell lymphoma [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Longombardo, G; Lombardini, F; Pasero, G; Zignego, Al; Monti, M; Mazzaro, C; Greco, F; Mazzoni, A.
abstract

A report on Hepatitis C virus in mixed cryoglobulinemia and B-cell lymphoma

1994 - Hepatitis C virus infection and B-cell lymphomas [Articolo su rivista]
Ferri, Clodoveo; Caracciolo, F; La Civita, L; Monti, M; Longombardo, G; Greco, F; Zignego, Al
abstract

A report on the development of B-cell lymphomas in patients with hepatitis C virus infection

1994 - Hepatitis C virus infection in non-Hodgkin's B-cell lymphoma complicating mixed cryoglobulinaemia [Articolo su rivista]
Ferri, Clodoveo; Monti, M; La Civita, L; Careccia, G; Mazzaro, C; Longombardo, G; Lombardini, F; Greco, F; Pasero, G; Bombardieri, S; Zignego, Al
abstract

A report on Hepatitis C virus infection in non-Hodgkin's B-cell lymphoma complicating mixed cryoglobulinaemia

1994 - Hepatitis C Virus Infection in Patients with non-Hodgkin's Lymphoma [Articolo su rivista]
Ferri, Clodoveo; Caracciolo, F; Zignego, Al; La Civita, L; Monti, M; Longombardo, G; Lombardini, F; Greco, F; Capochiani, E; Mazzoni, A; Mazzaro, C; Pasero, G.
abstract

Hepatitis C virus (HCV), which is both a hepatotropic and a lymphotropic virus, has been proposed as a possible causative agent of mixed cryoglobulinaemia. This 'benign' lymphoproliferative disorder can switch over to a malignant B-cell non-Hodgkin's lymphoma (NHL). Therefore HCV infection has been investigated in a series of 50 unselected Italian patients with B-cell NHL. Antibodies against HCV were found in 30% of NHL and HCV viraemia in 32% of cases. HCV-related markers were detected in 34% (17/50) of our NHL patients; this prevalence is particularly significant when compared with HCV seropositivity in Hodgkin's lymphoma (3%) and healthy controls (1.3%).

1994 - Hypercomplementaemia as a marker of the evolution from benign to malignant B-cell proliferation in patients with type II mixed cryoglobulinaemia [Articolo su rivista]
Vitali, C; Ferri, Clodoveo; Nasti, P; La Civita, L; Mazzantini, M; Longombardo, G; Bombardieri, S.
abstract

A report about the usefulness of hypercomplementaemia as a marker of the evolution from benign to malignant B-cell proliferation in patients with type II mixed cryoglobulinaemia

1994 - Nailfold capillary microscopy in lacunar infarction [Articolo su rivista]
Ferri, Clodoveo; Pitaro, N; Giuggioli, D; Martini, A; Carabelli, E; Giraldi, G; Muratorio, A.
abstract

A report about nailfold capillary microscopy in lacunar infarction

1994 - Non-Hodgkin's lymphoma: a possible role of hepatitis C virus infection [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Caracciolo, F; Zignego, Al
abstract

A reporto on the possible role of hepatitis C virus infection in non-Hodgkin's lymphoma.

1994 - Plasma levels of endothelin-1 in mixed cryoglobulinaemia patients [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Zignego, Al; Longombardo, G; Del Chicca, Mg; Pedrinelli, R; Greco, F; Pasero, G; Bombardieri, S.
abstract

A report on the plasma levels of endothelin-1 in mixed cryoglobulinaemia patients

1994 - Recent developments in the therapy of localized and systemic sclerosis. [Articolo su rivista]
Ferri, Clodoveo; Amer, M; Bombardieri, S.
abstract

A review on the therapies of localized and systemic sclerosis

1993 - Amlodipine in the treatment of Raynaud's phenomenon [Articolo su rivista]
La, Civita; Pitaro, N; Rossi, M; Gambini, I; Giuggioli, D; Cini, G; Ferri, Clodoveo
abstract

A report on the use of Amlodipine in the treatment of Raynaud's phenomenon

1993 - Cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus [Articolo su rivista]
Pasquariello, A; Ferri, Clodoveo; Moriconi, L; La Civita, L; Longombardo, G; Lombardini, F; Greco, F; Zignego, Al
abstract

A striking association between hepatitis C virus (HCV) and mixed cryoglobulinemia (MC) has been reported by various authors, regardless of the presence of chronic hepatitis. The aim of this study is to evaluate the prevalence of HCV-related markers in cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) which is one of the most severe complications of MC. Antibodies against HCV have been detected by second-generation Chiron ELISA and RIBA in 26/26 (100%) cryoglobulinemic MPGN. In addition, serum HCV RNA, expression of the ongoing viral replication, was present in 7/7 patients by the polymerase chain reaction technique. The high percentage of anti-HCV seropositivity suggests that this virus may play an important role in the pathogenesis of this immunemediated glomerulonephritis.

1993 - Effect of alpha-Interferon on hepatitis C virus chronic infection in mixed cryoglobulinemia patients [Articolo su rivista]
Ferri, Clodoveo; Zignego, Al; Longombardo, G; Monti, M; La Civita, L; Lombardini, F; Greco, F; Mazzoni, A; Pasero, G; Gentilini, P; Bombardieri, S; Manns, M.
abstract

Since a striking association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia has been demonstrated, the aim of this study is to investigate the effect of alpha-interferon (alpha-IFN) on HCV viraemia and clinico-serological manifestations of 15 patients (ten female and five male, mean [+/- SD] age 53 +/- 7 years). In 14/15 patients pre-study steroid dosage remained unchanged during treatment. alpha-IFN was administered at a dose of 2 x 10(6) IU daily for a month, then every other day for five months. On the whole, a statistically significant improvement of purpura (p < 0.001), serum transaminases (p < 0.001), and cryocrit (p < 0.01) was observed after alpha-IFN treatment. HCV viraemia was detected by polymerase chain reaction technique in 13/15 patients with mixed cryoglobulinemia and anti-GOR antibodies, expression of HCV-related autoimmunity, were present in 8/15. After alpha-IFN treatment, HCV RNA levels showed a clear-cut reduction in five persons and disappeared in another, while anti-HCV antibodies (Chiron ELISA and RIBA II) did not change after the six-month period of therapy. These data further support the possible etiopathogenetic role of HCV in patients with mixed cryoglobulinemia and suggest that alpha-IFN may be regarded as the elective treatment in this disease

1993 - Hepatitis C virus and mixed cryoglobulinemia (review) [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Longombardo, G; Greco, F; Bombardieri, S.
abstract

A review on the relationship between hepatitis C virus and mixed cryoglobulinemia

1993 - Hepatitis C virus-related autoimmunity in patients with porphyria cutanea tarda [Articolo su rivista]
Ferri, Clodoveo; Baicchi, U; La Civita, L; Greco, F; Longombardo, G; Mazzoni, A; Careccia, G; Bombardieri, S; Pasero, G; Zignego, Al; Manns, Mp
abstract

Hepatitis C virus (HCV) infection is frequently found in autoimmune hepatitis and mixed cryoglobulinaemia. In these conditions HCV could be responsible for immuno-mediated organ alterations. The aim of this study was to evaluate the presence of immunological alterations in PCT patients, in which HCV infection has been frequently found. Twenty-three PCT patients were evaluated for clinical and serological alterations, including: chronic hepatitis, other systemic symptoms, serum cryoglobulins and rheumatoid factor (RF), haemolytic complement, serum immunoglobulins, anti-nuclear (ANA), anti-smooth muscle (ASMA), anti-liver-kidney-microsomal (anti-LKM1), anti-soluble-liver-antigen (SLA), anti-mitochondrial (AMA), anti-GOR antibodies, anti-HCV and HCV RNA. Abnormal serum ALT were present in the majority of cases (20/23, 87%), while liver biopsy revealed a chronic persistent hepatitis or chronic active hepatitis in 15/20 (75%) PCT patients. In a high percentage of subjects (91%) the presence of anti-HCV was detected by ELISA and RIBA II (Chiron, Emeryville CA, USA). In 17/22 (77%) cases the ongoing HCV replication in the serum was demonstrated by the detection of HCV genomes (polymerase chain reaction). The prevalence of both anti-HCV and HCV RNA in PCT was significantly higher if compared to 22 systemic immunological diseases (P < 0.001) and 47 healthy subjects (P < 0.001). A possible HCV-induced autoimmunity in PCT was suggested by the presence of the following immunological parameter alterations: anti-GOR in 13/23 (57%), ANA in 4/23 (17%), ASMA in 18/23 (78%), anti-LKM1 in 1/23 (4%), RF in 23/23 (100%), mixed cryoglobulins in 4/23 (17%), complement consumption in 10/23 (43%).(ABSTRACT TRUNCATED AT 250 WORDS)

1993 - Increased plasma endothelin-1 immunoreactive levels in vasculitis: a clue to the use of endothelin-1 as a marker of vascular damage? [Articolo su rivista]
Ferri, Clodoveo; Latorraca, A; Catapano, G; Greco, F; Mazzoni, A; Clerico, A; Pedrinelli, R.
abstract

A report about the use of endothelin-1 as a marker of vascular damage

1993 - Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia [Articolo su rivista]
Ferri, Clodoveo; Monti, M; La Civita, L; Longombardo, G; Greco, F; Pasero, G; Gentilini, P; Bombardieri, S; Zignego, Al
abstract

A striking association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia (MC) has been shown; thus, HCV seems to play an important etiopathogenetic role in this lymphoproliferative disorder. Because HCV is both a hepatotropic and lymphotropic virus, this study aimed to investigate the prevalence of HCV infection of peripheral blood mononuclear cells (PBMCs) in a series of 16 patients with type II (IgMk) MC. Antibodies against HCV were detected by commercially available kits (Second Generation Chiron enzyme-linked immunosorbent assay [ELISA] and recombinant-based immunoblot assay [RIBA]), and the presence of HCV RNA was evaluated in both sera and isolated PBMCs using the polymerase chain reaction technique. A previous exposure to HCV was shown by ELISA and confirmed by RIBA in all cases (100%). Moreover, HCV RNA was present in the sera of 8 of 16 patients (50%), whereas its frequency markedly increased (13 of 16 [81%]) when genomic sequences were detected in peripheral lymphocytes. HCV RNA was never detected in the PBMCs of 20 control subjects. These findings showed that HCV infection, alone or in combination with other factors, may be responsible for the clonal B-cell expansion underlying the systemic manifestations of MC, and may explain the appearance of a malignant non-Hodgkin's lymphoma in some subjects

1993 - Interferon Alfa-2b in Mixed Cryoglobulinemia: a controlled crossover trial [Articolo su rivista]
Ferri, Clodoveo; Marzo, E; Longombardo, G; La Civita, L; Lombardini, F; Giuggioli, D; Vanacore, R; Liberati, Am; Mazzoni, A; Greco, F; Bombardieri, S.
abstract

To confirm the positive results of a preliminary trial, 26 patients with mixed cryoglobulinaemia were enrolled in a controlled, randomised, crossover trial with interferon alfa-2b. A significant improvement was seen in the purpura score and alanine aminotransferase activities during six months' treatment, and was associated with a significant decrease in cryocrit and a returning to normal of the lymphocyte CD4/CD8 ratio (in eight of nine patients). No significant variations were seen during the six month period without interferon. Only six patients withdrew from treatment, three because of side effects and three because of poor compliance.

1993 - Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial [Articolo su rivista]
Ferri, Clodoveo; Marzo, E; Longombardo, G; Lombardini, F; La Civita, L; Vanacore, R; Liberati, Am; Gerli, R; Greco, F; Moretti, A; Monti, M; Gentilini, P; Bombardieri, S; Zignego, Al
abstract

The effects of interferon-alpha (IFN-alpha) on clinical and serologic manifestations of mixed cryoglobulinemia (MC) were investigated by randomized, crossover-controlled trial in 26 patients. The trial alternated 6 months with and 6 months without IFN-alpha therapy (2 x 10(6) IU daily for a month, then every other day for 5 months). In 22 patients, pretreatment steroid dosage remained unchanged during the study. Six patients dropped out (three because of side effects), whereas another 20 patients experienced a significant improvement of purpura (P < .02) and serum transaminases (P < .005) during IFN-alpha treatment. The presence of clinical improvement was supported by the outcome measurements of several immunologic parameters. In particular, serum cryoglobulins were significantly reduced (P < .04) during IFN-alpha therapy. A rebound phenomenon of clinical and serologic parameters was observed after IFN-alpha discontinuation. In addition, no variations were recorded during 6 months without therapy. Hepatitis C virus (HCV) RNA was detected in 91% (20/22) of our MC patients; in 2/13 cases HCV RNA was no longer detectable in serum samples after IFN-alpha therapy. Thus, IFN-alpha could be considered as treatment for MC in patients with HCV seropositivity.

1993 - Low-antigen-content diet in the treatment of patients with IgA nephropathy [Articolo su rivista]
Ferri, Clodoveo; Puccini, R; Longombardo, G; Paleologo, G; Migliorini, P; Moriconi, L; Pasero, G; Cioni, L.
abstract

Since dietary macromolecular antigens can be involved in the pathogenesis of IgA nephropathy (IgAN), the effect of a low-antigen-content diet was evaluated in 21 patients (10 women, 11 men, mean age 27.7 +/- 10 years) with immunohistochemical findings of active IgAN. The diet was followed for a 14-24-week period (mean 18.8 +/- 6); in all cases the effects of the treatment were evaluated by clinical and serological parameters, and in 11 patients also by repeat renal biopsy. After dietetic therapy a significant reduction of urinary proteins was recorded (P < 0.001); in particular, heavy proteinuria (> 1 g/day), present in 12 cases during the 6 months preceding the treatment, was markedly reduced or disappeared in 11. At post-treatment control biopsy mesangial and parietal deposits of immunoglobulins, complement C5 fraction and fibrinogen were significantly reduced. The improvement of the objective parameters such as heavy proteinuria, a strong predictor of a poor prognosis, and of immunohistochemical alterations indicate that a low-antigen diet can positively affect patients with IgAN. These results could be ascribed to a reduction of nephritogenic food antigen input and to a putative functional restoration of the mononuclear phagocytic system

1992 - Antinuclear antibody profile in Italian patients with connective tissue diseases [Articolo su rivista]
Neri, R; Tavoni, A; Cristofani, R; Levanti, C; Sodini, G; D'Ascanio, A; Vitali, C; Ferri, Clodoveo; Bombardieri, S.
abstract

In the present work we report data on the specificity of antinuclear antibodies (ANA) in a large series of Italian patients suffering from a broad spectrum of connective tissue diseases (CTD), by using a series of homogeneous and validated techniques. The present study confirms, on the one hand, generally accepted concepts, i.e. that certain autoantibodies are strictly associated to certain disease states (such as anti-PCNA and anti-Sm in systemic lupus erythematosus, Jo 1 in polymyositis, and ACA and Scl-70 in scleroderma); the presence of 'marker' antibodies is, however, restricted to a relative minority of CTD patients. The application of a new methodological approach that considers the entire profile of ANA can greatly augment their diagnostic relevance and may provide useful indications for their interpretation, allowing us to establish for the first time the diagnostic usefulness not only of marker autoantibodies but also of certain associations between non-marker autoantibodies. Finally, the application of a more appropriate and powerful statistical tool (multiple correspondence analysis) has further emphasized the clear relationship existing between antibody specificities and certain disease states.

1992 - Hepatitis C virus, autoimmune liver diseases and cryoglobulinemic hepatitis [Articolo su rivista]
Ferri, Clodoveo; Longombardo, G; La Civita, L; Bombardieri, S; Greco, F; Highfield, P; Corbishley, T.
abstract

The Authors showed an association between Hepatitis C virus, autoimmune liver diseases and mixed cryoglobulinemia

1992 - IgA nephropathy: preliminary results of low-antigen-content diet treatment [Articolo su rivista]
Ferri, Clodoveo; Puccini, R; Paleologo, G; Longombardo, G; Migliorini, P; Moriconi, L.
abstract

IgA nephropathy is recognized as the most common form of glomerulonephritis. Circulating IgA-IC, found in one third of the patients, seems to play a relevant role. On this bases, we applied a dietetic regimen in five patients with IgA nephropathy to reduce the input of potential nephritogenic dietary antigens

1992 - Low antigen content diet in the management of immuno-mediated diseases [Relazione in Atti di Convegno]
Bombardieri, S; Ferri, Clodoveo
abstract

Circulating IgA-IC seems to play a relevant role in several autoimmune diseases, as mixed cryoglobulinemia. On this bases, we applied a dietetic regimen in patients with mixed cryoglobulinemia to reduce the input of potential dietary antigens

1992 - Lung involvement in systemic sclerosis sine scleroderma treated by plasma exchange [Articolo su rivista]
Ferri, Clodoveo; Bernini, Luigi; Gremignai, G; Latorraca, A; Fazzi, P; Tavoni, A; Solfanelli, S; Bombardieri, S.
abstract

Systemic sclerosis sine scleroderma can present in some patients as pulmonary interstitial fibrosis. Until now ten cases with this particular clinical variant, all men, have been reported in the literature. The knowledge of systemic sclerosis sine scleroderma presenting as lung interstitial involvement is important in clinical practice for an early diagnosis and correct therapeutic strategy. This work reports the clinico-serological features of two further cases, one a woman, of systemic sclerosis sine scleroderma with prevalent lung involvement, and describes the effects of therapeutic plasma exchange.

1992 - Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiological investigations [Articolo su rivista]
Ferri, Clodoveo; La Civita, L; Cirafisi, C; Siciliano, G; Longombardo, G; Bombardieri, S; Rossi, B.
abstract

Peripheral neuropathy has been described in different rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus and systemic vasculitis, but usually in limited numbers of patients. Nerve injury is more frequently reported in mixed cryoglobulinemia. In earlier studies generally performed in small series of patients, prevalence of peripheral neuropathy varied widely. We evaluated prevalence of peripheral neuropathy in 33 unselected patients with mixed cryoglobulinemia (25 women, 8 men, aged from 45-71 years). Neurologic involvement was detected using a complete clinical and electrophysiologic assessment, including sensory motor conduction velocities, F wave and H reflex. Neurologic examination revealed a neuropathy in 48% of subjects, while electrophysiologic variables were altered in 82%; a percentage similar to that of subjective symptoms (91%). Among electrophysiologic investigations, F wave was altered in 22/33 subjects (67%); therefore, this variable seems to be the most reliable for the detection of neurologic involvement. Cryocrit levels were significantly higher in patients with peripheral neuropathy: abnormal examination (p less than 0.01), sensory motor conduction (p less than 0.04), and F wave alterations (p less than 0.008). In addition, hemorheological abnormalities seem to contribute to the pathogenesis of nerve injury. Our results indicate that peripheral neuropathy, to a variable degree, is present in the majority of patients with mixed cryoglobulinemia, and a complete clinical and electrophysiologic investigation can be useful for an early and correct diagnosis

1992 - Slow-releasing nicardipine in the treatment of Raynaud's phenomena without underlying diseases [Articolo su rivista]
Ferri, Clodoveo; Cecchetti, R; Cini, G; Gambini, I; La Civita, L; Latorraca, A; Bernini, Luigi; Bombardieri, S; Pasero, G.
abstract

Calcium channel blockers have been used in the treatment of primary and secondary Raynaud's phenomenon (RP), and a beneficial effect was often recorded. The efficacy of slow-releasing nicardipine was assessed in a clinically homogeneous series of RP without underlying diseases in a randomized, double blind, cross-over and placebo controlled trial. Out of twenty-one selected patients (18 women and 3 men, mean age 46 +/- 12 yrs) eighteen completed the study and three dropped out, one for inadequate compliance and two due to headache. After a three-week period, slow-releasing nicardipine (20 mg two times daily) was significantly more useful than placebo: the number of RP episodes per week decreased (p less than 0.02), severity of discomfort and hand disability scores, evaluated after single RP attack, clearly improved (p less than 0.005 and p less than 0.02, respectively). According to clinical improvement, time of peak flow after postischemic reactive hyperaemia test was significantly reduced only after nicardipine (p less than 0.01). These results show that slow-releasing nicardipine is generally well tolerated and can provide effective improvement in RP patients without underlying diseases.

1991 - Alpha-interferon in the treatment of mixed cryoglobulinemia patients [Articolo su rivista]
Ferri, Clodoveo; Marzo, E; Longombardo, G; Lombardini, F; Greco, F; Bombardieri, S.
abstract

A report about the use of Alpha interferon in the treatment of mixed cryoglobulinaemia patients

1991 - Antibodies against hepatitis C virus in mixed cryoglobulinemia patients. [Articolo su rivista]
Ferri, Clodoveo; Greco, F; Longombardo, G; Palla, P; Marzo, E; Moretti, A; Fosella, Pv; Pasero, G; Bombardieri, S.
abstract

The prevalence of antibodies against hepatitis C virus (anti-HCV) in an unselected series of 45 mixed cryoglobulinemia patients was assessed by an enzyme linked immunosorbent assay (Chiron ELISA HCV, Second Generation). The anti-HCV specificity was evaluated by a recombinant based immunoblot assay (Chiron RIBA HCV, Second Generation Assay). HBV-related markers and HIVAb were detected in the same samples. The prevalence of anti-HCV observed in mixed cryoglobulinemia was compared with 80 patients with other immunological systemic diseases. Anti-HCV were found in 91% of mixed cryoglobulinemia patients, and confirmed by RIBA in all cases; on the other hand, anti-HCV were practically absent in other control diseases. HBV markers were recorded in 49% of mixed cryoglobulinemia subjects; while HIVAb were constantly absent. These data give us new insights into the etiopathogenesis of mixed cryoglobulinemia.

1991 - Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. [Articolo su rivista]
Ferri, Clodoveo; Greco, F; Longombardo, G; Palla, P; Marzo, E; Moretti, A; Fosella, Pv; Pasero, G; Bombardieri, S.
abstract

The prevalence of antibodies to hepatitis C virus (HCVAb) was investigated in 52 unselected patients with mixed cryoglobulinemia and in 84 patients with other systemic immunologic diseases. HCVAb were detected by an enzyme-linked immunosorbent assay, and their specificity was evaluated by a recombinant-based immunoblot assay. The presence of HBV-related markers was investigated in the same samples. HCVAb were found in 54% of mixed cryoglobulinemia patients, and the finding was confirmed by recombinant-based immunoblot assay in all cases. HCVAb and/or HBV markers were present in 70% of the patients. HCVAb seropositivity was significantly more frequent in mixed cryoglobulinemia patients with biopsy-proven liver involvement (P less than 0.01) and with increased serum transaminase levels (P less than 0.01). HCVAb were virtually absent in control patients with other immunologic diseases. These results support the notion that viral agents, i.e., HCV and possibly HBV, have a role in the pathogenesis of mixed cryoglobulinemia patients.

1991 - Association between hepatitis C virus and mixed cryoglobulinemia. [Articolo su rivista]
Ferri, Clodoveo; Greco, F; Longombardo, G; Palla, P; Marzo, E; Moretti, A; Mazzoni, A; Pasero, G; Bombardieri, S; Highfield, P; Corbishley, T.
abstract

The prevalence of hepatitis C virus (HCV) RNA and of antibodies to HCV in an unselected series of 42 mixed cryoglobulinemia patients was investigated in this study. HCV RNA was detected by the polymerase chain reaction technique, and HCV antibodies by two enzyme-linked immunosorbent assays (Chiron ELISA HCV, Second Generation, Emeryville CA, USA; Wellcome Diagnostic, England). HCV RNA was found in 86% of the mixed cryoglobulinemia patients. Using either the Chiron ELISA or the Wellcome ELISA, HCV antibodies were present in 90% of the same samples; anti-HCVAb seropositivity was confirmed in all cases by immunoblot assay (Chiron RIBA HCV, Second Generation Assay). A striking correlation between HCV RNA and anti-HCV antibody seropositivities was recorded. HCV RNA in mixed cryoglobulinemia patients was not correlated with the presence or absence of biopsy-proven liver involvement. These results suggest that the association between HCV and mixed cryoglobulinemia is not fortuitous, and therefore that HCV may have an etiopathogenetic role in this disorder.

1991 - Cutaneous and serological subsets of systemic sclerosis [Articolo su rivista]
Ferri, C.; Bernini, L.; Cecchetti, R.; Latorraca, A.; Marotta, G.; Pasero, G.; Neri, R.; Bombardieri, S.
abstract

The relevance of the extent of skin sclerosis and of other clinicoserological features in diagnosis, severity and prognosis of disease was studied in a large number of unselected patients with systemic sclerosis (SSc). One hundred and fifty-one patients with SSc (126 F and 25 M, mean age 48 +/- 14 SD) followed for 5.3 +/- 3.2 years were included. Patients were divided into 3 cutaneous subsets: limited (68), intermediate (46) and diffuse SSc (37). Serological markers were detected in 288 patients with Raynaud's phenomenon and other connective tissue diseases (CTD). Limited and intermediate SSC prevailed in female patients while the diffuse subset was more frequent in males (p less than 0.0001). Duration of Raynaud's phenomenon before disease onset was shorter in the diffuse variant (p less than 0.0001). A wider cutaneous involvement was associated with more severe forms of SSc. Diffuse subset showed the poorest prognosis at 10 years of followup compared with intermediate (p less than 0.05) and limited variant (p less than 0.001). Intermediate SSc seems a distinct variant of SSc on the basis of clinical manifestations and survival. Among serological markers, anticentromere, anti-Scl-70 and antinucleolar antibodies were found in 21, 40 and 27% of the cases, respectively; these were statistically less frequent (p less than 0.0001) in other CTD. In 83.5% of patients with SSc at least one of these specific markers was recorded. Anticentromere antibodies were correlated to sex (female), limited SSc, calcinosis and telangiectasia. On the contrary anti-Scl-70 was associated with diffuse and intermediate subsets and with more severe SSc manifestations

1991 - Hepatitis C virus antibodies in mixed cryoglobulinemia [Articolo su rivista]
Ferri, Clodoveo; Greco, F; Longombardo, G; Palla, P; Marzo, E; Moretti, A.
abstract

A report about the association about hepatitis C virus and mixed cryoglobulinemia

1990 - Blood viscosity and filtration abnormalities in mixed cryoglobulinemia patients. [Articolo su rivista]
Ferri, Clodoveo; Mannini, L; Bartoli, V; Gremignai, G; Genovesi Ebert, F; Cristofani, R; Albanese, B; Pasero, G; Bombardieri, S.
abstract

Blood, plasma and serum viscosity and blood filtration were investigated in 43 unselected mixed cryoglobulinemia patients. A hyperviscosity syndrome was present in only one patient, and rapidly improved after plasma exchange and cyclophosphamide therapy. A clear-cut increase in blood viscosity was infrequently observed in mixed cryoglobulinemia, although significant differences were present in the plasma and serum viscosity of patients and controls. In contrast, blood filtration was severely impaired in a high percentage of cases (51 and 72% of the values recorded at 37 degrees and 25 degrees C, respectively), and was on the average significantly higher in patients than in controls. Indirect evidence suggests that blood viscosity is at least in part related to cryoglobulins. In 19 patients studied before and after cryoglobulin removal, serum viscosity significantly decreased when the serum was deprived of cryoglobulins. In addition, the cryocrit correlated with all the hemorheological parameters with the exception of blood filtration. The hemorheological findings were compared with multisystemic features of the disease, i.e. liver, renal, lung, neurologic, vascular and funduscopic alterations. The potential clinical relevance of the hemorheological parameters was stressed by the close correlation between blood filtration parameters and serum creatinine. Furthermore, by discriminant analysis, viscosity and blood filtration changes were the serological parameters most significantly associated with the presence of renal, liver and neurological involvement. Thus, hemorheological parameters are frequently abnormal in mixed cryoglobulinemia patients, and seem to play a significant clinical role; they should therefore be included in the work-up of these patients.

1990 - La terapia aferetica in reumatologia. [Capitolo/Saggio]
Pasero, G; Ferri, Clodoveo
abstract

il testo illustra le indicazioni terapeutiche della terapia aferetica nelle varie malattie reumatiche

1989 - Changes of the putative antigen/antibody ratio of circulating immune complexes folowing selected removal of macromolecules in mixed cryoglobulinemia and systemic lupus erythematosus [Articolo su rivista]
Bombardieri, S; Caponi, L; Pilo, A; Moriconi, L; Ferri, Clodoveo; Puccetti, A.
abstract

the paper reported the changes of the putative antigen/antibody ratio of circulating immune complexes folowing selected removal of macromolecules in mixed cryoglobulinemia and systemic lupus erythematosus

1989 - Double filtration plasmapheresis in the treatment of cryoglobulinemic glomerulonephritis [Articolo su rivista]
Moriconi, L; Ferri, Clodoveo; Puccini, R; Casto, G; Baronti, R; Cecchetti, R; Gremignai, G; Cioni, L; Bombardieri, S.
abstract

the paper discussed the effects of double filtration plasmapheresis in the treatment of cryoglobulinemic glomerulonephritis

1989 - Low-antigen-content diet in the treatment of mixed cryoglobulinemia patients [Articolo su rivista]
Ferri, Clodoveo; Pietrogrande, M; Cecchetti, C; Tavoni, A; Cefalo, A; Buzzetti, G; Vitali, C; Bombardieri, S.
abstract

PURPOSE: The effects of a low-antigen-content diet (LAC diet) versus a standard normocaloric diet on the signs and symptoms of mixed cryoglobulinemia (MC) were compared in a crossover randomized study.PATIENTS AND METHODS: The study consisted of 24 outpatients with MC, and was carried out in a 48-week period. After 18 weeks of either the LAC or the placebo diet, patients returned to a totally unrestricted diet for 12 weeks (washout period) and crossed over to the second half of the study for the other 18 weeks.RESULTS: After three weeks of the restricted LAC diet, the cryocrit decreased from 3.5 +/- 3.4% (mean +/- SD) to 2.3 +/- 2.0% (p less than 0.01), and the circulating immune complex levels decreased from 48 +/- 30% to 39 +/- 34% (p less than 0.01). At the same time, the purpura score (p less than 0.05), glutamic pyruvic transaminase level (p less than 0.01), and gamma glutamyl transferase level (p less than 0.001) significantly improved. Splenic reticuloendothelial function, measured as the half-life of heat-damaged autologous red cells, decreased from 41 +/- 21 minutes to 21 +/- 10 minutes (p less than 0.005). In contrast, no significant parallel clinical, biochemical, and immunologic changes occurred in the same patients during the placebo (standard normocaloric) diet.CONCLUSION: These data show that an LAC diet decreases the amount of circulating immune complexes in MC and can modify certain signs and symptoms of the disease. These effects of the LAC diet may be explained by postulating a functional restoration of the mononuclear phagocytic system.

1989 - Lung function in essential mixed cryoglobulinemia: a short-term follow-up [Articolo su rivista]
Viegi, G; Fornai, E; Ferri, Clodoveo; Di Munno, O; Begliomini, E; Vitali, C; Melocchi, F; Bombardieri, S; Paoletti, P.
abstract

Lung involvement in essential mixed cryoglobulinemia (EMC) has been recently described. In order to assess whether patients with EMC experience an accelerated deterioration of lung function, nineteen patients (17 females, 2 males; 49.6 +/- 6.6 years) underwent a short-term follow-up of lung function, chest X-ray and serologic investigations. Reduction of forced expiratory flows and presence of roentgenologic signs of interstitial involvement were confirmed in the baseline evaluation. In addition, a decrease of diffusing capacity was shown. After a mean interval of 15 months, no significant change in lung function was found, with the exception of decrease in maximal expiratory flow at 50% of forced vital capacity, total lung capacity, functional residual capacity, coefficient of transfer of CO. A slight decrease of hemolitic complement (CH50) and of complement fraction (C3) was also observed. This study suggests that patients with EMC tend to have an involvement of pulmonary interstitial space, possibly related to immune complex deposition, but they do not show a severe decline of lung function. Periodical assessment of lung function and chest X-ray is, however, worthwhile

1989 - T cell subset modifications induced by apheretic therapy of immunological diseases [Articolo su rivista]
Pecori, F; Ferri, Clodoveo; Moriconi, L; Casto, G; Grazzini, R; Cecchetti, R; Bombardieri, S; Gremignai, G; Barbani, N; Chelli, E; Foselle, Pv
abstract

the paper reported the T cell subset modifications induced by apheretic therapy of immunological diseases

1989 - The evaluation of certain biocompatibility parameters during apheretic therapy of immunological diseases [Articolo su rivista]
Puccini, R.; Ferri, Clodoveo; Neri, R; Palmieri, L; Pecori, F; Gremignai, G; Gazzetti, P; Cioni, L; Bombardieri, S; Moriconi, L.
abstract

The article evaluated the biocompatibility of certain parameters during apheretic therapy in course of immunological diseases

1986 - Cryoglobulins and immune complexes in essential mixed cryoglobulinemia [Articolo su rivista]
Bombardieri, S; Ferri, Clodoveo; Migliorini, P; Pontrandolfo, A; Puccetti, A; Vitali, C; Pasero, G.
abstract

The authors review the role, clinico-serological correlations and the putative pathogenetic relevance of a number of immunological parameters in essential mixed cryoglobulinemia. On the whole, in spite of the fact that levels of cryoglobulins, immune complexes, complement as well as reticuloendothelial splenic function are frequently abnormal in this condition, they are generally poorly correlated with clinical features. Therefore, it is postulated that this apparent discrepancy may either be due to the contemporary presence in the same serum of many types of immune complexes with different toxicity, or to the influence of rheumatoid factor on the nature of circulating immune complexes

1986 - Long-term griseofulvin treatment for progressive systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; Bernini, Luigi; Bombardieri, S; Pasero, G.
abstract

Thirty-three patients with progressive systemic sclerosis (PSS) (24 women and 9 men, 27 with diffuse scleroderma and 6 with CREST syndrome) were treated with griseofulvin alone (375-500 mg/day) for 12-84 months (mean 33). Clinical and functional assessment of the results included: a self-evaluation (general status, skin toughness, cold sensitivity, dysphagia), a physical examination (fingerprint areas, chest expansion, mouth widening, grip strength) routine laboratory tests, electrocardiogram, glomerular filtration rate (GFR), esophagus and chest X-rays. After griseofulvin, a significant improvement was noted in 28/33 patients (85%) regarding subjective condition and skin thickening and elasticity, particularly in the trunk and proximal limbs (p less than 0.05 for chest expansion), and of GFR (p less than 0.01). Lung and esophageal involvement, on the whole, remained unchanged during the treatment, which does not appear to modify the progression of PSS myocardiopathy. No patient stopped using griseofulvin because of side effects. The present results show that griseofulvin is a safe drug for PSS treatment and that it can influence the skin and renal involvement.

1986 - Lung function abnormalities in different connective tissue diseases [Articolo su rivista]
Vitali, C.; Viegi, G. Tassoni S.; Tavoni, A.; Paoletti, P.; Bibolotti, E.; Ferri, Clodoveo; Bombardieri, S.
abstract

Lung volumes, forced expiratory flow-volume curves, diffusing capacity indexes, and arterial blood gases were measured in 72 non-smoking patients with various connective tissue diseases (13 with rheumatoid arthritis, 17 with systemic lupus erythematosus, 25 with progressive systemic sclerosis, 10 with primary Sjögren's syndrome, 4 with polymyositis, and 3 with mixed connective tissue disease). Small airways disease and a diffusion capacity impairment were the most frequent and marked functional abnormalities in the whole group, and were often present in asymptomatic patients. Different lung function defects seemed to be present in each disease group. In fact, large airway obstruction was prevalent in progressive systemic sclerosis, diffusion capacity impairment in systemic lupus erythematosus, and small airways disease in rheumatoid arthritis. In contrast, primary Sjögren's syndrome appeared to be the connective tissue disease in which lung function abnormalities were less frequent and less pronounced.

1986 - Lymphocyte subpopolation in essential mixed cryoglobulinemia [Articolo su rivista]
Barbieri, P.; Benedettini, G.; Ferri, Clodoveo; Campa, M.; Bombardieri, S.
abstract

Lymphocyte subpopulations were evaluated in 31 patients affected by essential mixed cryoglobulinemia, using OKT3, OKT4, and OKT8 monoclonal antibodies in a cytotoxic assay. The patients with essential mixed cryoglobulinemia had a normal number of OKT3+ and OKT4+ cells but significantly lower values of OKT8+ cells compared to healthy controls. When the OKT4+/OKT8+ ratio was considered, patients could be subdivided into 3 main subgroups: 6 patients had a low OKT4+/OKT8+ ratio, 10 patients had a normal ratio, and 15 had a high ratio. This ratio did not correlate with age, sex, disease duration, low corticosteroid therapy or serological hallmarks of the disease. In contrast, purpura and liver involvement were more prevalent in patients with a normal or high OKT4+/OKT8+ ratio, while lung involvement was more prevalent in patients with a low ratio.

1986 - Plasma exchange and renal prostaglandins in lupus nephritis. [Capitolo/Saggio]
Moriconi, L.; Di Munno, O.; Pugliese, F.; Ferri, Clodoveo; Tartarelli, G.; Gremignai, G.; Ciabattoni, G.; Cioni, L.; Bombardieri, S.
abstract

discussion of the therapeutic role of plasma exchange in patients with lupus complicated by nephritis

1986 - Plasma-exchange in mixed cryoglobulinemia. Effects on renal, liver and neurologic involvement [Articolo su rivista]
Ferri, Clodoveo; Gremignai, G; Bombardieri, S; Moriconi, L; Pontrandolfo, A; Vitali, C; Fosella, Pv; Pasero, G.
abstract

Prolonged plasma-exchange without addition of cytotoxic agents was employed in 16 patients with mixed cryoglobulinemia and kidney, liver or neurologic involvement. Patients with rapidly progressive renal failure or active and reversible lesions generally improved after plasma-exchange, as well as those with a recently occurring sensory-motor peripheral neuropathy. In 4 out of 6 patients with mixed cryoglobulinemia and chronic active hepatitis, plasma-exchange was followed by either normalization or significant reduction of liver enzymes and bromosulfophthalein retention. In all cases responding to plasma-exchange the beneficial effects were evident after the first 2-3 weeks of treatment, while symptoms did not generally recur when the procedures were either slowly tapered or discontinued. Although the pathogenetic mechanism(s) of action of plasma-exchange remains largely unknown, preliminary data indicate that these procedures induce quantitative as well as qualitative changes in the immune system.

1986 - Treatment of renal involvement in essential mixed cryoglobulinemia with prolonged Plasma Exchance [Articolo su rivista]
Ferri, Clodoveo; Moriconi, L; Gremignai, G; Migliorini, P; Paleologo, G; Fosella, Pv; Bombardieri, S.
abstract

Nine patients with mixed cryoglobulinemia and severe membranoproliferative glomerulonephritis were treated with plasma exchange alone or in combination with medium to low amounts of corticosteroids, but never with cytotoxic drugs. In 5 patients renal function and/or proteinuria improved after plasma exchange, and no clinical relapse usually occurred when the procedures were reduced or discontinued. These procedures seemed of particular effect in the presence of histologically active and not irreversible lesions and rapid deterioration of renal function. While cryocrit almost invariably decreased, circulating immune complex or complement levels were unpredictably affected by plasma exchange. Cryocrit, but not immune complex or complement levels, was the serological parameter which most often closely correlated with signs of renal involvement (i.e., proteinuria and/or serum creatinine). Thus, plasma exchange might be a safe and useful tool in the treatment of an often drug-resistant and rapidly progressive renal involvement occurring in patients with mixed cryoglobulinemia.

1985 - Acute effect of plasma exchange on arterial blood pressure and plasma renin activity [Articolo su rivista]
Moriconi, L; Palombo, C; Fommei, E; Meconi, P; Puccini, R; Innocenti, M; Ferri, Clodoveo; Pecori, F; Ghione, S.
abstract

Blood pressure (BP) decreases significantly in patients with immune complex nephritis and hypertension in the course of therapeutic plasma exchange (TPE). To investigate possible underlying mechanisms of this effect, the variations of supine and upright BP and plasma renin activity (PRA) acutely induced by PE (performed by isovolumetric replacement of plasma with 4% albumin in saline solution) were analyzed in six patients. On the average, both supine and upright BP decreased after TPE; however, statistical significance was obtained only for upright systolic BP. Supine and upright PRA did not change significantly, although a clearly blunted response to posture was observed in three patients. The changes of BP induced by TPE were apparently not due to a functional depression of the renin-angiotensin system, since the more marked decrements in BP were observed in the patients with lower basal PRA.

1985 - Association of anti-centromere and anti-Scl 70 antibodies in scleroderma. Report of two cases. [Articolo su rivista]
Ruffatti, A; Calligaro, A; Ferri, Clodoveo; Bombardieri, S; Gambari, Pf; Todesco, S.
abstract

In testing for antinuclear antibodies the sera of 121 patients affected with scleroderma, we found in 2 of them the concurrent presence of anti-centromere and anti-Scl 70 antibodies. Since the association of these antibodies has never been reported, to the best of our knowledge, we report the clinical and serological features of the 2 patients. Both subjects were women with an incomplete CREST syndrome (RST), a relatively limited involvement of the skin, a mild pulmonary fibrosis without apparent signs of other visceral involvement. On the other hand, the clinical course of the disease was different in the 2 cases. One patient had a longer disease duration and up to date the clinical features appear to be unchanged; the other had a shorter disease duration, when suddenly she died of cardiac arrest

1985 - Hypotensive effect of plasma exchange in immune complex nephritis. [Articolo su rivista]
Puccini, R; Fommei, E; Meconi, P; Moriconi, L; Palombo, C; Pasquariello, A; Ferri, Clodoveo; Cioni, L; Ghione, S.
abstract

The effect of plasma exchange (PE) on blood pressure (BP) in 20 hypertensive patients (9 with mixed cryoglobulinemia, 7 with systemic lupus erythematosus, and 4 with idiopathic glomerulonephritis) was evaluated retrospectively. In each PE 1.5-2.5 L of plasma was replaced with an equal volume of 4% albumin polysaline solution. The frequency of PE was three times per week for the first 2 weeks and twice per week subsequently. Sixteen patients were on hypotensive treatment at the onset of PE. Their systolic/diastolic BP was 171 +/- 4.7/102 +/- 3.0 mm Hg (mean +/- 1 SEM). After 4 weeks, BP decreased to 141 +/- 2.8/89 +/- 2.3 mm Hg (p less than 0.001), although in 10 patients antihypertensive drug therapy had been reduced or discontinued. The most marked decrease of BP occurred after the first week (152 +/- 5.3/92 +/- 2.9 mm Hg), and this decrement correlated remarkably well with pressure levels before PE despite the great heterogeneity of the individual patients (for diastolic BP, r = 0.87, p less than 0.001; for systolic BP, r = 0.60, p less than 0.01). A mild decrease of serum creatinine was observed during PE, but its time course was different from that of BP, and did not correlate with this parameter.

1985 - Immune complex behaviour during prolonged plasma exchange in essential mixed cryoglobulinemia and systemic lupus erythematosus [Articolo su rivista]
Bombardieri, S; Ferri, Clodoveo; Migliorini, P; Puccetti, A; Vitali, C; Moriconi, L; Fosella, Pv
abstract

A number of immunological parameters were measured in 9 patients with essential mixed cryoglobulinemia and 12 patients with systemic lupus erythematosus undergoing plasma exchange alone or without cytotoxic drugs. Only cryocrit significantly decreased in the majority of patients with essential mixed cryoglobulinemia. In contrast, immune complex levels, measured in two different ways, did not change on the whole, although variable and unpredictable changes were often present in individual patients. Thus, these data do not support the view that the mechanism(s) of action of plasma exchange in these diseases is only due to the quantitative removal of circulating immune complexes, and qualitative changes in the immune complex moiety may also occur.

1985 - Noninvasive evaluation of cardiac dysrhythmias and their relationship with multisystemic symptoms, in progressive systemic sclerosis patients [Articolo su rivista]
Ferri, Clodoveo; Bernini, Luigi; Bongiorni, M. G.; Levorato, D.; Bravi, P.; Viegi, G.; Contini, C.; Pasero, G.; Bombardieri, S.
abstract

Fifty-three patients (34 who had diffuse scleroderma, and 19 who had CREST syndrome [calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias]) were studied by noninvasive procedures, including resting electrocardiogram (ECG), continuous 24-hour Holter ECG monitoring, M-mode echocardiography, and 2-dimensional echocardiography. Only 22 patients (42%) had abnormalities such as conduction defects, supraventricular or ventricular arrhythmias, or ST-T changes detected on resting ECG. In contrast, using Holter monitoring, the number of conduction abnormalities seen increased from 10 to 16 patients and transient ST-T changes increased from 2 to 18 patients. Forty-eight patients had ventricular arrhythmias, with multiform ventricular premature beats in 21 (40%), pairs of runs of ventricular tachycardia in 15 patients (28%), and 1 or more runs of ventricular tachycardia in 7 (13%). Echocardiography detected asymmetric septal hypertrophy in 10 patients, impaired ventricular function in 9 patients, congestive cardiomyopathy in 2, mitral prolapse in 4, and pericardial effusion in 3 patients. Multiform and/or repetitive ventricular premature beats occurred more frequently in patients with echocardiographic abnormalities, but were also present in patients who had normal findings on echocardiographic examination. Cardiac involvement was not correlated with clinical variants of scleroderma (CREST syndrome or diffuse scleroderma), nor with other signs and symptoms of the disease. Thus, cardiac involvement is found much more frequently than would be expected from clinical symptoms or from results of resting ECG alone; therefore, Holter monitoring and echocardiography should be included in the routine workup of patients who have scleroderma

1985 - Plasma exchange in unusual forms of rapidly progressive glomerulonephritis [Abstract in Rivista]
Paleologo, G.; Moriconi, L.; Puccini, R.; Pasquariello, A.; Innocenti, M.; Lippi, A.; Gadducci, P.; Marianetti, G.; Ferri, Clodoveo; Cioni, L.
abstract

the paper illustrated the plasma exchange in unusual forms of rapidly progressive glomerulonephritis

1985 - The blood pressure lowering effects of plasma exchange [Articolo su rivista]
Ghione, S.; Meconi, P.; Fommei, E.; Palombo, C.; Pecori, F.; Moriconi, L.; Ferri, Clodoveo; Mezzasalma, L
abstract

the article focused on the effect of plasma exchangeon blood pressure

1984 - Inhibitory effect of IgM rheumathoid factor on the immune complex solubilization capacity and on the inhibition of immune precipitation [Articolo su rivista]
Balestrieri, G; Tincani, A; Migliorini, P; Ferri, Clodoveo; Cattaneo, R; Bombardieri, S.
abstract

Purified IgM rheumatoid factors (RF; 3 monoclonal and 2 polyclonal) were shown to inhibit, in a dose-dependent manner, 2 complement-mediated functions, i.e., the immune complex solubilization capacity and the inhibition of immune precipitation. Inhibition of immune complex solubilization capacity occurred only if RF was added at the same time as, but not after, addition of the complement source. Experimental evidence suggests that the effects of RFs were not related to their anticomplementary activity, but rather required the attachment of RF to the Fc region of the IgG molecule. Although no clinical data are available so far, it might be plausible that these newly described properties of RF have biologic relevance

1983 - Plasma exchange in the treatment of Lupus nephritis [Articolo su rivista]
Moriconi, L.; Ferri, Clodoveo; Fanara, G.; Migliorini, P.; Vitali, C.; Cioni, L.; Gremignai, G.; Bombardieri, S.
abstract

Seven women with severe Systemic Lupus Erythematosus Nephritis were treated with Plasma Exchange, without any additional therapy with cytotoxic agents. All patients had failed to respond to high doses of corticosteroids and, in 3 cases, to 6-methylprednisolone pulses. In 4 patients the indication for plasma exchange treatment was a rapid deterioration of renal function, and in the others a need to better control symptoms without using toxic corticosteroid dosages. The total number of plasma exchange sessions ranged from 14 to 57 depending on the patient. After PE treatment, serum creatinine values significantly decreased in all 4 patients with rapidly developing, nephritis while in the others it remained unchanged. No major side effects were recorded and no relapse of renal disease occurred whenever Plasma Exchange treatment was gradually tapered or discontinued. These data suggest that prolonged Plasma Exchange treatment without the concomitant administration of cytotoxic agents may be effective in the treatment of steroid resistant severe lupus nephritis

1983 - Prolonged Plasma-exchange in the treatment of renal involvement in essential mixed cryoglobulinemia [Articolo su rivista]
Bombardieri, S.; Ferri, Clodoveo; Paleologo, G.; Bibolotti, E.; Camici, M.; Fosella, P. V.; Pasero, G.; Moriconi, L.
abstract

Four men and 2 women with Essential Mixed Cryoglobulinemia and a membrano-proliferative glomerulonephritis were treated with prolonged Plasma Exchange without the addition of cytotoxic agents. All patients had Nephrotic Syndrome and Renal Insufficiency. Three of them presented a rapid deterioration of renal function just prior to Plasma Exchange treatment. Total number of procedures varied for each patients from 24 to 105. Serum creatinine decreased significantly in those patients with rapid deterioration of renal function, while it was not modified in the 3 with stable chronic renal failure. In no instance major side effects were recorded, and relapses of the disease did not occur, after gradually tapering of Plasma Exchange sessions. These data suggest that Plasma Exchange alone, if early instituted, may be an effective and safe treatment of Essential Mixed Cryoglobulinemia Glomerulonephritis

1981 - Plasma exchange in systemic lupus erythematosus [Articolo su rivista]
Moriconi, L; Ferri, Clodoveo; Paleologo, M; Migliorini, P; Fanara, G; Gremignai, G; Cioni, L; Bombardieri, S.
abstract

Seven women with severe Systemic Lupus Erythematosus Nephritis were treated with Plasma Exchange, without any additional therapy with cytotoxic agents. All patients had failed to respond to high doses of corticosteroids and, in 3 cases, to 6-methylprednisolone pulses. In 4 patients the indication for plasma exchange treatment was a rapid deterioration of renal function, and in the others a need to better control symptoms without using toxic corticosteroid dosages. The total number of plasma exchange sessions ranged from 14 to 57 depending on the patient. After PE treatment, serum creatinine values significantly decreased in all 4 patients with rapidly developing, nephritis while in the others it remained unchanged. No major side effects were recorded and no relapse of renal disease occurred whenever Plasma Exchange treatment was gradually tapered or discontinued. These data suggest that prolonged Plasma Exchange treatment without the concomitant administration of cytotoxic agents may be effective in the treatment of steroid resistant severe lupus nephritis.

1980 - Minor connectivitis and the mixed connective tissue disease [Articolo su rivista]
Pasero, G; Di Munno, O; Ferri, Clodoveo; Riente, L.
abstract

A report about the different expressions of connective tissue diseases

1979 - Liver involvement in essential mixed cryoglobulinemia [Articolo su rivista]
Bombardieri, S; Ferri, Clodoveo; Di Munno, O; Pasero, G.
abstract

A report about the liver involvement in essential mixed cryoglobulinemia

1979 - Lung involvement in essential mixed cryoglobulinemia [Articolo su rivista]
Bombardieri, S.; Paoletti, P.; Ferri, Clodoveo; Di Munno, O.; Fornai, E.; Giuntini, C.
abstract

non presente in pubmed

1978 - Quantitative evaluation of 99mTc-pyrophosphate muscle uptake in patients with inflammatory and noninflammatory muscle diseases [Articolo su rivista]
Bellina, CR; Bianchi, R; Bombardieri, S; FERRI, Clodoveo; Mariani, G; Muratorio, A; Rossi, B.
abstract

non presente su pubmed