DILIA GIUGGIOLI - personale UniMoRe

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DILIA GIUGGIOLI

Professore Ordinario
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

Pubblicazioni

2024 - Assessing hand grasp in patients with systemic sclerosis using the 16-grasp test: Preliminary results from a multidisciplinary study group [Articolo su rivista]
Sandri, Gilda; Spinella, Amelia; Sartini, Silvana; Caselgrandi, Francesco; Schiavi, Margherita; Bettelli, Valentina; Gherardini, Francesco; Amati, Gabriele; Lumetti, Federica; Mascia, Maria Terasa; Secchi, Ottavio; Giuggioli, Dilia
abstract

Background: Reports on hand dysfunction and rehabilitation in SSc are quite scarce in the literature and mainly focus on functional assessment tools, such as the Duruoz Hand Index and the HAMIS test for evaluating hand mobility by simulating specific grasps with nine different objects. Purpose of the study: This study aimed to provide an adequate assessment methodology for hand grasp dysfunctions in patients suffering from systemic sclerosis (SSc) through the 16-grasp test. Study design: Case-control study. Methods: Ninety-seven consecutive SSc patients were recruited at our Scleroderma Unit, where a 16-grasp test was performed by all patients and supervised by an experienced hand therapist. Sixteen different patterns of grasp have been divided into power grasps and precision pinch and two more modalities: static and dynamic prehension evaluation on scale from 0 to 4. We also compared previous evaluations on 19 of patients recruited. Results: The majority of SSc patients (84 females and 13 males; mean age 56.0±12.0 years; mean disease duration 8.0±6.0 years) displayed grasp dysfunctions; in particular 48% and 54% reported slight difficulty in the right and left grasps respectively, 6% medium difficulty in both hands, and only 3% and 1% experienced severe difficulty respectively, while 31.5% had no issues in either hand. Our results showed that the limited cutaneous subset (lcSSc) scored a lower deficit for either grasp compared to diffuse form (dcSSc). No statistically significant differences in total grasp deficit had been noticed when comparing patients having a disease duration < 5 years or longer. In the retrospective study on 19 of these patients, 8 out of 10 lcSSc patients showed no significant changes, while in 2 out of 10, slight improvements were observed in both hands. However, in the dcSSc group, 4 out of 9 worsened bilaterally while the grasp scores for 5 of them remained unchanged. Conclusion: Our study reported hand involvement in both lcSSc and dcSSc forms, more significantly in dcSSc patients. This test is intended to be a more objective means of assessing grasp alterations linked to scleroderma hand deformities. Furthermore, thanks to its intuitiveness, the test may be useful for engineers designing personalized ergonomic assistive devices.

2023 - AB1310 UTILIZATION AND ATTITUDES TOWARDS NAILFOLD VIDEOCAPILLAROSCOPY FOR THE ASSESSMENT OF MICROVASCULAR STATUS IN PATIENTS WITH LONG-COVID: A MULTICENTER ONLINE SURVEY [Abstract in Rivista]
Gotelli, E.; Ingegnoli, F.; De Angelis, R.; Guiducci, S.; Giuggioli, D.; Pizzorni, C.; Riccieri, V.; Sebastiani, M.; Sulli, A.; Smith, V.; Cutolo, M.
abstract

2023 - Correction to: Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC) (Clinical Rheumatology, (2023), 42, 2, (359-370), 10.1007/s10067-022-06391-w) [Articolo su rivista]
Quartuccio, L.; Bortoluzzi, A.; Scirè, C. A.; Marangoni, A.; Del Frate, G.; Treppo, E.; Castelnovo, L.; Saccardo, F.; Zani, R.; Candela, M.; Fraticelli, P.; Mazzaro, C.; Renoldi, P.; Scaini, P.; Filippini, D. A.; Visentini, M.; Scarpato, S.; Giuggioli, D.; Mascia, M. T.; Sebastiani, M.; Zignego, A. L.; Lauletta, G.; Fiorilli, M.; Casato, M.; Ferri, C.; Pietrogrande, M.; Pioltelli, P. E.; De Vita, S.; Monti, G.; Galli, M.
abstract

2023 - Lung vascular changes as biomarkers of severity in systemic sclerosis–associated interstitial lung disease [Articolo su rivista]
Bruni, Cosimo; Occhipinti, Mariaelena; Pienn, Michael; Camiciottoli, Gianna; Bartolucci, Maurizio; Laura Bosello, Silvia; Payer, Christian; ́ lint, Zolta ́ n Ba; Rita Larici, Anna; Tottoli, Alessandra; Tofani, Lorenzo; De Lorenzis, Enrico; Lepri, Gemma; Bellando-Randone, Silvia; Spinella, Amelia; Giuggioli, Dilia; Masini, Francesco; Cuomo, Giovanna; Lavorini, Federico; Colagrande, Stefano; Olschewski, Horst; Matucci-Cerinic, Marco
abstract

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.

2023 - One-year clinical experience on the use of Nintedanib in Systemic Sclerosis [Articolo su rivista]
Magnani, Luca; Spinella, Amelia; Testoni, Sofia; Lumetti, Federica; Scelfo, Chiara; Dardani, Lucia; Bajocchi, Gianluigi; Clini, Enrico; Salvarani, Carlo; Giuggioli, Dilia
abstract

AIM- Systemic Sclerosis (SSc) is a complex autoimmune disease characterized by vascular damage, immune activation and fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is one of the most common causes of death. In 2019 Nintedanib was approved for SSc-related ILD, due to randomized clinical trials (RCTs) demonstrating a reduction in the annual rate of decline in Forced Vital Capacity (FVC). METHODS We reviewed eleven patients with SSc-related ILD from January 2020 to January 2021 and who started Nintedanib 150 mg twice a day. RESULTS- Non-Specific Interstitial Pneumonia (NSIP) was the most frequent HRCT pattern, followed by Usual Interstitial Pneumonia (UIP) and UIP/NSIP pattern. The mean of Modified Rodnan Skin Score (mRSS) at baseline was 9.23 (±10SD) points without any significant improvement during the follow-up. Patients continued their ongoing therapy for lung involvement. Mean FVC was 2233.6 ml [+/- 1066 ml] (61.3% predicted) at beginning and remained stable during the follow-up period. The mean modified British Council Medical Questionnaire (mmRC) decreased from 3 at baseline to 2.5 at the end of follow up and the mean of the Borg scale of dyspnea ameliorated from 7.27 at baseline to 6 at twelve months. Both the differences were not significant. Two patients stop therapy: one for partial intestinal obstruction and one for incoercible diarrhea. CONCLUSION- Nintedanib was generally well tolerated and we did not record any serious adverse event

2023 - Topical Cannabidiol in the Treatment of digital ulcers in patients with Scleroderma: comparative Analysis and Literature Review [Articolo su rivista]
Spinella, Amelia; DE PINTO, Marco; Baraldi, Carlo; Galluzzo, Claudio; Testoni, Sofia; Lumetti, Federica; Parenti, Luca; Guerzoni, Simona; Salvarani, Carlo; Giuggioli, Dilia
abstract

OBJECTIVE To explore the effect of topical cannabidiol (CBD) in treating digital ulcers in patients with systemic sclerosis (SSc). METHODS In total, 45 patients with SSc who had digital ulcers were consecutively enrolled between January 2019 and December 2019. Of the participants, 25 were treated with CBD during surgical debridement and 20 were treated with standard local therapy. A numeric rating scale for pain and Health Assessment Questionnaire Disability Index were administered at the baseline and at the end of treatment. RESULTS Local treatment with CBD was significantly associated with lower pain scores, higher health assessment scores, and an increase in participants' total hours of sleep. Patients in the control group more frequently required additional analgesic therapy. CONCLUSIONS Topical CBD may be a valuable tool to treat pain related to digital ulcers in patients with SSc.

2022 - AN OVERVIEW OF NAILFOLD CAPILLAROSCOPY IN ITALY: RESULTS FROM A NATIONAL SURVEY [Abstract in Rivista]
Ingegnoli, F; Cornalba, M; De Angelis, R; Guiducci, S; Giuggioli, D; Pizzorni, C; Riccieri, V; Sebastiani, M; Sulli, A; Cutolo, M
abstract

2022 - Absent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseases [Articolo su rivista]
Giuggioli, Dilia
abstract

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients’ setting, tailored vaccination and/or therapeutic strategy are highly advisable.

2022 - Analysis of cryoproteins with a focus on cryofibrinogen: a study on 103 patients [Articolo su rivista]
Natali, Patrizia; Debbia, Daria; R Cucinelli, Maria; Trenti, Tommaso; Amati, Gabriele; Spinella, Amelia; Giuggioli, Dilia; Mascia, Maria Teresa; Sandri, Gilda
abstract

2022 - From Raynaud Phenomenon to Systemic Sclerosis in COVID-19: A Case Report [Articolo su rivista]
Giuggioli, Dilia; Spinella, Amelia; De, Pinto; Mascia, Maria TeresA; Salvarani, Carlo
abstract

ABSTRACT: In 2019, the novel SARS-CoV-2 infection emerged, causing the disease called COVID-19, which primarily affects the respiratory tract and lung at alveolar and interstitial levels. Systemic sclerosis (SSc) is an autoimmune connective disease characterized by vascular abnormalities and diffuse and progressive fibrosis of the skin and internal organs. Raynaud phenomenon (RP) occurs in virtually all patients affected by SSc and, in most cases, is an onset symptom of the disease; that is, RP may appear several years before overt illness. Although the exact pathophysiologic pathways leading to RP and SSc are still unknown, several infectious agents, especially viruses, have been suggested as possible triggering factors. Here, the authors describe the first case of RP secondary to SSc following SARS-CoV-2 infection.

2022 - Geographical heterogeneity of clinical and serological phenotypes of systemic sclerosis observed at tertiary referral centres. The experience of the Italian SIR-SPRING registry and review of the world literature [Articolo su rivista]
Giuggioli, Dilia; Bajocchi, Gianluigi
abstract

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. Materials and methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities.

2022 - Nailfold capillaroscopy in the rheumatological current clinical practice in Italy: results of a national survey [Articolo su rivista]
Ingegnoli, F; Cornalba, M; De Angelis, R; Guiducci, S; Giuggioli, D; Pizzorni, C; Riccieri, V; Sebastiani, M; Sulli, A; Cutolo, M
abstract

: This cross-sectional online study was designed by the study group on Capillaroscopy and Microcirculation in Rheumatic Diseases (CAP) of the Italian Society of Rheumatology (SIR) to provide an overview of the management of nailfold capillaroscopy in Italian rheumatology centers. Therefore, SIR distributed the survey to its members in July 2021, and each center's physician with the most expertise in capillaroscopy completed the questionnaire. The survey was completed by 102 centers, with at least one representative from each Italian region. Ninety-three centers perform capillaroscopy, and 52 (56) conduct more than 200 investigations annually. Seventy-eight (84%) of respondents have more than five years of experience with the technique, and 75 centers (80.6%) have received certification from specific national or international training courses. In 85 centers, a videocapillaroscope with 200x magnification is employed (91.4%). The average waiting period for the examination is 2.4 months, and less than 3 months in 64 of the locations (68.8%). The study demonstrates that capillaroscopy is an integral part of both the diagnostic phase of Raynaud's phenomenon and the monitoring of autoimmune connective tissue diseases (CTDs). However, the reporting methods and timing of patient followup are heterogeneous.

2022 - Peripheral Microangiopathy Changes in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Data From a Multicenter Observational Study [Articolo su rivista]
Giuggioli, D.; Riccieri, V.; Cipolletta, E.; Del Papa, N.; Ingegnoli, F.; Spinella, A.; Pellegrino, G.; Risa, A. M.; de Pinto, M.; Papa, S.; Armentaro, G.; De Angelis, R.
abstract

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10-15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the "late" pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

2022 - Photobiomodulation Therapy: A New Light in the Treatment of Systemic Sclerosis Skin Ulcers [Articolo su rivista]
Spinella, Amelia; de Pinto, Marco; Galluzzo, Claudio; Testoni, Sofia; Macripò, Pierluca; Lumetti, Federica; Parenti, Luca; Magnani, Luca; Sandri, Gilda; Bajocchi, Gianluigi; Starnoni, Marta; De Santis, Giorgio; Salvarani, Carlo; Giuggioli, Dilia
abstract

Introduction: Skin ulcers (SU) represent one of the most frequent manifestations of systemic sclerosis (SSc), occurring in almost 50% of scleroderma patients. SSc-SU are often particularly difficult to treat with conventional systemic and local therapies. In this study, a preliminary evaluation of the role and effectiveness of blue light photobiomodulation (PBM) therapy with EmoLED® in the treatment of scleroderma skin ulcers (SSc-SU) was performed. Methods: We retrospectively analyzed 12 consecutive SSc patients with a total of 15 SU on finger hands. All patients were treated with adequate systemic therapy and local treatment for SU; after a standard skin ulcer bed preparation with debridement of all lesions, EmoLED® was performed. All patients were locally treated every week during 2 months of follow-up; SU data were collected after 4 weeks (T4) and 8 weeks (T8). Eight SSc patients with comparable SU were also evaluated as controls. Results: The application of EmoLED® in addition to debridement apparently produced faster healing of SU. Complete healing of SU was recorded in 41.6% cases during EmoLED® treatment. Significant improvements in SU area, length, and width, wound bed, and related pain were observed in EmoLED® patients from T0 to T8. Control subjects treated with standard systemic/local therapies merely showed an amelioration of SU area and width at the end of the follow-up. No procedural or post-procedural adverse events were reported. Conclusions: The positive clinical results and the absence of side effects suggest that EmoLED® could be a promising tool in the management of SSc-SU, with an interesting role to play in the healing process in addition to conventional systemic and local treatments.

2022 - Prevalence and Death Rate of COVID-19 in Autoimmune Systemic Diseases in the First Three Pandemic Waves. Relationship with Disease Subgroups and Ongoing Therapies [Articolo su rivista]
Giuggioli, Dilia
abstract

Objective: Autoimmune systemic diseases (ASD) represent a predisposing condition to COVID-19. Our prospective, observational multicenter telephone survey study aimed to investigate the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients. Methods: The study included 3,918 ASD pts (815 M, 3103 F; mean age 59±12SD years) consecutively recruit-ed between March 2020 and May 2021 at the 36 referral centers of COVID-19 and ASD Italian Study Group. The possible development of COVID-19 was recorded by means of a telephone survey using a standardized symptom assessment questionnaire. Results: ASD patients showed a significantly higher prevalence of COVID-19 (8.37% vs. 6.49%; p<0.0001) but a death rate statistically comparable to the Italian general population (3.65% vs. 2.95%). Among the 328 ASD patients developing COVID-19, 17% needed hospitalization, while mild-moderate manifestations were observed in 83% of cases. Moreover, 12/57 hospitalized patients died due to severe interstitial pneumonia and/or cardiovascular events; systemic sclerosis (SSc) patients showed a significantly higher COVID-19-related death rate compared to the general population (6.29% vs. 2.95%; p=0.018). Major adverse prognostic factors to develop COVID-19 were: older age, male gender, SSc, pre-existing ASD-related interstitial lung involvement, and long-term steroid treatment. Of note, patients treated with conventional synthetic disease-modifying an-tirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs. 46.99%; p=0.000), as well as the SSc patients treated with low dose aspirin (with 5.57% vs. without 27.84%; p=0.000). Conclusion: During the first three pandemic waves, ASD patients showed a death rate comparable to the general population despite the significantly higher prevalence of COVID-19. A significantly increased COVID-19-related mortality was recorded in only SSc patients’ subgroup, possibly favored by preexisting lung fibrosis. Moreover, ongoing long-term treatment with csDMARDs in ASD might usefully contribute to the generally positive outcomes of this frail patients’ population.

2022 - Sex-related Differences in Systemic Sclerosis: A Multicenter Cross-sectional Study From the National Registry of the Italian Society for Rheumatology [Articolo su rivista]
De Angelis, R.; Giuggioli, D.; Bajocchi, G.; Dagna, L.; Zanframundo, G.; Foti, R.; Cacciapaglia, F.; Cuomo, G.; Ariani, A.; Rosato, E.; Guiducci, S.; Girelli, F.; Riccieri, V.; Zanatta, E.; Bosello, S.; Cavazzana, I.; Ingegnoli, F.; Santis, M.; Murdaca, G.; Abignano, G.; Romeo, N.; Della Rossa, A.; Caminiti, M.; Iuliano, A.; Ciano, G.; Beretta, L.; Bagnato, G.; Lubrano, E.; De Andres, I.; Giollo, A.; Saracco, M.; Agnes, C.; Lumetti, F.; Spinella, A.; Magnani, L.; Campochiaro, C.; De Luca, G.; Codullo, V.; Visalli, E.; Masini, F.; Gigante, A.; Bellando-Randone, S.; Pellegrino, G.; Pigatto, E.; Dall'Ara, F.; Lazzaroni, M. G.; Generali, E.; Mennillo, G.; Barsotti, S.; Mariano, G. P.; Calabrese, F.; Furini, F.; Vultaggio, L.; Parisi, S.; Peroni, C. L.; Risa, A. M.; Rozza, D.; Zanetti, A.; Carrara, G.; Landolfi, G.; Scire, C. A.; Bianchi, G.; Fusaro, E.; Sebastiani, G. D.; D'Angelo, S.; Cozzi, F.; Doria, A.; Iannone, F.; Salvarani, C.; Matucci-Cerinic, M.; Ferri, C.; Govoni, M.
abstract

OBJECTIVE: There is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics. METHODS: A multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared. RESULTS: The overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs. CONCLUSION: Our study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

2021 - Autologous fat grafting in the treatment of a scleroderma stump-skin ulcer: a case report [Articolo su rivista]
Giuggioli, Dilia; Spinella, Amelia; Cocchiara, Emanuele; de Pinto, Marco; Pinelli, Massimo; Parenti, Luca; Salvarani, Carlo; De Santis, Giorgio
abstract

Here we describe the case of a 60-year-old-woman with systemic sclerosis sent to our Scleroderma Unit to treat digital stumps. The stumps were successfully treated with autologous fat grafting (crown-shape infiltration). Our technique of autologous lipotransfer improved wound healing in a scleroderma patient with stump-digital ulcers where all other options failed.

2021 - CLINICAL AND PATHOLOGICAL FEATURES OF BREAST CANCER IN PATIENTS WITH SYSTEMIC SCLEROSIS: PRELIMINARY DATA FROM THE SCLERO-BREAST STUDY [Abstract in Rivista]
Toss, Angela; Spinella, Amelia; Isca, Chrystel; Vacchi, Caterina; Ficarra, Guido; Fabbiani, Luca; Iannone, Anna; Magnani, Luca; Castrignanò, Paola; Macripo', Pierluca; Gasparini, Elisa; Piana, Simonetta; Cortesi, Laura; Maiorana, Antonino; Salvarani, Carlo; Dominici, Massimo; Giuggioli, Dilia
abstract

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients.

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 - Clinical and Pathological Features of Breast Cancer in Systemic Sclerosis: Results from the Sclero-Breast Study [Articolo su rivista]
Toss, Angela; Spinella, Amelia; Isca, Chrystel; Vacchi, Caterina; Ficarra, Guido; Fabbiani, Luca; Iannone, Anna; Magnani, Luca; Castrignanò, Paola; Macripò, Pierluca; Gasparini, Elisa; Piana, Simonetta; Cortesi, Laura; Maiorana, Antonino; Salvarani, Carlo; Dominici, Massimo; Giuggioli, Dilia
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 vaccine hesitancy in systemic sclerosis [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, Mp; Ferri, C; Meliconi, R; Ursini, F.
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 - Infections of scleroderma digital ulcers: A single center cohort retrospective study [Articolo su rivista]
Giuggioli, Dilia; Magnani, Luca; Spinella, Amelia; Bajocchi, Gianluigi; Palermo, Adalgisa; Lumetti, Federica; Cocchiara, Emanuele; Salvarani, Carlo
abstract

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 - Invited Response on: Comments on "Autologous Fat Grafting for the Oral and Digital Complications of Systemic Sclerosis: Results of a Prospective Study" [Articolo su rivista]
Pignatti, Marco; Spinella, Amelia; Cocchiara, Emanuele; Boscaini, Giulia; Lusetti, Irene Laura; Citriniti, Giorgia; Lumetti, Federica; Setti, Giacomo; Dominici, Massimo; Salvarani, Carlo; De Santis, Giorgio; Giuggioli, Dilia
abstract

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 - Management of Systemic Sclerosis Patients in the COVID-19 Era: The Experience of an Expert Specialist Reference Center [Articolo su rivista]
Spinella, A.; Magnani, L.; De Pinto, M.; Marvisi, C.; Parenti, L.; Bajocchi, G.; Salvarani, C.; Mascia, M. T.; Giuggioli, D.
abstract

Objective: COVID-19 pandemic represents a serious health emergency that severely compromised our Public Health system, resulting in a rapid and forced reorganization and involved the management of chronic diseases too. The Scleroderma Unit of Modena and Reggio Emilia follows more than 600 patients suffering from systemic sclerosis (SSc) and recently became the referral center (HUB) in Emilia-Romagna for this rare connective tissue disease. The aim of the present study was to evaluate the extent by which the lockdown and the pandemic has impacted the activity of admissions to Scleroderma Unit of Modena and Reggio Emilia. Methods: Our daily clinical activity is characterized by outpatient visits, videocapillaroscopy exam, ulcers treatment, therapeutic infusions in day hospital regimen, multidisciplinary visits following our dedicated SSc care pathway, and clinical trials. Our activity has been quickly rescheduled to ensure the proper assistance to our SSc patients during the COVID-19 pressure. Results: The use of telemedicine has certainly assured a robust continuity of health care. Furthermore, telephone pre-triage, nurse/medical triage, proper physical distancing and use of PPE/DPI allowed us to re-organize and continue SSc daily activity. Specifically, therapeutic infusions in day hospital regimen and outpatient visits, including ulcers treatment, was guaranteed and maximized. Conclusion: The management of scleroderma patients by an expert specialist reference center is crucial in order to ensure continuity of care and pursue the best SSc practice.

2021 - POS0837 THE USE OF CANNABIDIOL IN THE TREATMENT OF PAIN RELATED TO SCLERODERMA DIGITAL ULCERS [Poster]
Giuggioli, D.; De Pinto, M.; Parenti, L.; Magnani, L.; Castrignanò, P.; Salvarani, C.; 2, ; Spinella, A.
abstract

Background: Systemic Sclerosis-SSc is an autoimmune disease, characterized by fibrosis due to immune-mediated microangiopathy. Digital ulcers-DUs represent frequent complications, they are recurrent, painful and often resistant to traditional treatments. Standard therapy, in particular oral opioids, is often inadequate or limited by side effect. Cannabidiol-CBD, is the major non-psychotropic component of the Cannabis sativa, recent studies on its effectiveness as an anxiolytic, anti-inflammatory, and antipsychotic drug showed promising results, in the setting of chronic pain too. Objectives: We evaluated the efficacy of CBD drop in pain management in a cohort of SSc patients using standard rating scale VAS, PSQI and HAQ. We further assessed the safety profile and the potential use as opioid-sparing. Methods: From January to November 2019 we consecutively enrolled 31 SSc patients (F/M 26/5, mean age 53.0 …

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 …

2021 - Resilience of systemic sclerosis patients following the first COVID-19 wave in Italy [Articolo su rivista]
Ciaffi, J.; Giuggioli, D.; Spinella, A.; Meliconi, R.; Ursini, F.; Ferri, C.
abstract

2021 - Systemic sclerosis cutaneous expression: Management of skin fibrosis and digital ulcers [Articolo su rivista]
Starnoni, M.; Pappalardo, M.; Spinella, A.; Testoni, S.; Lattanzi, M.; Femino, R.; De Santis, G.; Salvarani, C.; Giuggioli, D.
abstract

Systemic sclerosis is a connective tissue disease with cutaneous involvement. Clinical manifestations result from the balance of inflammations/autoimmunity process and fibrogenesis. Patients suffer from skin ulcers, non-ulcerative lesions including digital pitting scars, telangiectasias, subungual hyperkeratosis, abrasions, fissures, and subcutaneous calcinosis. A review about the pathophysiology of the disease, the physical examination of the patients, the instrumental assessment, and possible treatments is performed.

2020 - AB0611 STRAIN ANALYSIS OF THE RIGHT VENTRICLE USING 2D-SPECKLE TRACKING ECHOCARDIOGRAPHY IN A COHORT OF PATIENTS WITH SYSTEMIC SCLEROSIS [Abstract in Rivista]
Spinella, A; Macripo, P; Cocchiara, E; Galli, E; Lumetti, F; Magnani, L; Coppi, F; Mattioli, Av; Rossi, R; Boriani, G; Salvarani, C; Giuggioli, D
abstract

Background: Systemic Sclerosis (SSc) is a rare and life-threatening connective tissue disease with multiple organ impairment. Cardio-pulmonary involvement is common: pulmonary fibrosis, pulmonary hypertension (PH), and electrical disorders are the most serious complications and causes of increased mortality. Objectives: We evaluated features related with the onset and development of PH in a cohort of SSc patients. We further studied ecocardiographic abnormalities, by means of 2D-speckle tracking echocardiography (STE) with specific reference to the right ventricular strain measure (RV-strain). Methods: We analyzed data from 50 SSc patients (pts) referred to our University-based Rheumatology Centre and SSc Unit from January 2007 to June 2019 (F/M 45/5; lc/dcSSc 45/5; mean age 59.20±14.357 years; mean disease duration 12.08±8.75 years). All pts underwent general and cardio-pulmonary …

2020 - Autologous Fat Grafting for the Oral and Digital Complications of Systemic Sclerosis: Results of a Prospective Study [Articolo su rivista]
Pignatti, Marco; Spinella, Amelia; Cocchiara, Emanuele; Boscaini, Giulia; Lusetti, Irene Laura; Citriniti, Giorgia; Lumetti, Federica; Setti, Giacomo; Dominici, Massimo; Salvarani, Carlo; De Santis, Giorgio; Giuggioli, Dilia
abstract

Background: Systemic sclerosis is a connective tissue disease. Skin involvement of the mouth and hand may compromise function and quality of life. Autologous fat grafting has been described as a specific treatment of these clinical features. We report the results of our prospective study designed to treat and prevent skin complications in systemic sclerosis. Materials and methods: We treated 25 patients with mouth and/or hand involvement (microstomia, xerostomia, skin sclerosis, Raynaud's phenomenon and long-lasting digital ulcers) with autologous fat grafting, according to the Coleman's technique, around the mouth and/or at the base of each finger. The surgical procedures were repeated in each patient every 6 months for a total of two or three times. Clinical data were collected before the first surgery and again 6 months after each surgical procedure. Pain, skin thickness, saliva production and disability were assessed with validated tests. Results: Overall we performed 63 autologous fat grafting sessions (either on the mouth, on the hands or on both anatomical areas). Results at 6 moths after the last session included improvement of xerostomia evaluated with a sialogram, reduction of the skin tension around the mouth and, in the hands, reduction of the Raynaud phenomenon as well as skin thickness. Pain was reduced while the perception of disability improved. Digital ulcers healed completely in 8/9 patients. Conclusions: Our results confirm the efficacy and safety of autologous fat grafting for the treatment of skin complications and digital ulcers due to systemic sclerosis. In addition, the patients' subjective well-being improved. Level of evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . Keywords: Autologous fat grafting; Digital ulcers; Microstomia; Stem cell transplantation; Systemic sclerosis; Xerostomia.

2020 - COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series [Articolo su rivista]
Ferri, C.; Giuggioli, D.; Raimondo, V.; L'Andolina, M.; Tavoni, A.; Cecchetti, R.; Guiducci, S.; Ursini, F.; Caminiti, M.; Varcasia, G.; Gigliotti, P.; Pellegrini, R.; Olivo, D.; Colaci, M.; Murdaca, G.; Brittelli, R.; Mariano, G. P.; Spinella, A.; Bellando-Randone, S.; Aiello, V.; Bilia, S.; Giannini, D.; Ferrari, T.; Caminiti, R.; Brusi, V.; Meliconi, R.; Fallahi, P.; Antonelli, A.
abstract

Introduction: Covid-19 infection poses a serious challenge for immune-compromised patients with inflammatory autoimmune systemic diseases. We investigated the clinical-epidemiological findings of 1641 autoimmune systemic disease Italian patients during the Covid-19 pandemic. Method: This observational multicenter study included 1641 unselected patients with autoimmune systemic diseases from three Italian geographical areas with different prevalence of Covid-19 [high in north (Emilia Romagna), medium in central (Tuscany), and low in south (Calabria)] by means of telephone 6-week survey. Covid-19 was classified as (1) definite diagnosis of Covid-19 disease: presence of symptomatic Covid-19 infection, confirmed by positive oral/nasopharyngeal swabs; (2) highly suspected Covid-19 disease: presence of highly suggestive symptoms, in absence of a swab test. Results: A significantly higher prevalence of patients with definite diagnosis of Covid-19 disease, or with highly suspected Covid-19 disease, or both the conditions together, was observed in the whole autoimmune systemic disease series, compared to “Italian general population” (p =.030, p =.001, p =.000, respectively); and for definite + highly suspected diagnosis of Covid-19 disease, in patients with autoimmune systemic diseases of the three regions (p =.000, for all comparisons with the respective regional general population). Moreover, significantly higher prevalence of definite + highly suspected diagnosis of Covid-19 disease was found either in patients with various “connective tissue diseases” compared to “inflammatory arthritis group” (p <.000), or in patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs treatments (p =.011). Conclusions: The finding of a higher prevalence of Covid-19 in patients with autoimmune systemic diseases is particularly important, suggesting the need to develop valuable prevention/management strategies, and stimulates in-depth investigations to verify the possible interactions between Covid-19 infection and impaired immune-system of autoimmune systemic diseases.Key Points• Significantly higher prevalence of Covid-19 is observed in a large series of patients with autoimmune systemic diseases compared to the Italian general population, mainly due to patients’ increased susceptibility to infections and favored by the high exposure to the virus at medical facilities before the restriction measures on individual movement.• The actual prevalence of Covid-19 in autoimmune systemic diseases may be underestimated, possibly due to the wide clinical overlapping between the two conditions, the generally mild Covid-19 disease manifestations, and the limited availability of virological testing.• Patients with “connective tissue diseases” show a significantly higher prevalence of Covid-19, possibly due to deeper immune-system impairment, with respect to “inflammatory arthritis group”.• Covid-19 is more frequent in the subgroup of autoimmune systemic diseases patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs, mainly hydroxyl-chloroquine and methotrexate, which might play some protective role against the most harmful manifestations of Covid-19.

2020 - COVID-19 in Italian patients with rheumatic autoimmune systemic diseases [Articolo su rivista]
Ferri, C.; Giuggioli, D.; Raimondo, V.; Fallahi, P.; Antonelli, A.; Spinella, A.; Brittelli, R.; Aiello, V.; Caminiti, R.; L'Andolina, M.; Tavoni, A.; Bilia, S.; Giannini, D.; Mariano, G. P.; Cecchetti, R.; Guiducci, S.; Bellando-Randone, S.; Ursini, F.; Brusi, V.; Meliconi, R.; Caminiti, M.; Mariano, G. P.; Varcasia, G.; Ferrari, T.; Gigliotti, P.; Pellegrini, R.; Olivo, D.; Colaci, M.; Murdaca, G.
abstract

2020 - HHV-6A infection and systemic sclerosis: Clues of a possible association [Articolo su rivista]
Caselli, E.; Soffritti, I.; D'accolti, M.; Bortolotti, D.; Rizzo, R.; Sighinolfi, G.; Giuggioli, D.; Ferri, C.
abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, excessive extracellular matrix deposition, and fibrosis of the skin and internal organs. Several infectious agents, including human herpesvirus-6 (HHV-6), have been suggested as possible triggering factors, but a direct association is still missing. We characterized 26 SSc patients for the presence of HHV-6 in tissues and blood, the anti-HHV-6 response, HLA-G plasma levels, and KIR typing. Given the prominent role of endothelial cells (EC) in SSc pathogenesis, along with HHV-6 tropism for EC, we also investigated the expression of pro-fibrosis factors in HHV-6 infected EC. Results showed the presence of HHV-6A in skin biopsies, and an increased virus load was associated with disease severity and poor natural killer (NK) response against the virus, particularly in subjects exhibiting a KIR2 phenotype. HLA-G plasma levels were significantly higher in HHV- 6A/B-KIR2 positive SSc patients and in vitro HHV-6A infection-induced pro-fibrosis factors expression in EC, supporting its role in the development of the fibrosing process. Our data suggest an association between virus infection/reactivation and disease, opening the way to future studies to understand the mechanisms by which HHV-6A might contribute to the multifactorial pathogenesis of SSc.

2020 - Living with arthritis: a “training camp” for coping with stressful events? A survey on resilience of arthritis patients following the COVID-19 pandemic [Articolo su rivista]
Ciaffi, J.; Brusi, V.; Lisi, L.; Mancarella, L.; D'Onghia, M.; Quaranta, E.; Bruni, A.; Spinella, A.; Giuggioli, D.; Landini, M. P.; Ferri, C.; Meliconi, R.; Ursini, F.
abstract

Resilience is defined as “the capacity of individuals to cope successfully with significant change or adversity”. The challenge posed by the COVID-19 pandemic may potentially represent an overwhelmingly stressful event for patients with chronic diseases. Aim of our study was to investigate the levels of resilience in individuals with inflammatory arthritis living in Emilia Romagna, the third hardest-hit Italian region during the ongoing COVID-19 pandemic. To this purpose, we developed a survey consisting of four different sections assessing demographic characteristics, the 14-item resilience scale (RS14) and questionnaires evaluating depression and anxiety. Consecutive patients with inflammatory arthritis were recruited over a short time frame immediately after the end of national lockdown and compared with control individuals from the general population. One hundred twenty-two patients and 173 controls were included. Levels of resilience, as measured by RS14 score, were significantly higher in patients with inflammatory arthritis (82.6 ± 14.0 vs 79.0 ± 12.8, p = 0.018). After stratification for gender, the difference in RS14 score was maintained in women (p = 0.045), but not in men (p = 0.252). High resilience, defined as having a RS14 score > 90, was significantly more prevalent in patients than in controls (30% vs 16%, p = 0.009). In arthritis patients, no significant differences in RS14 were observed after stratification for specific diagnosis, age, or disease duration and activity. Our findings suggest that patients with inflammatory arthritis may be more resilient than the general population towards unexpected stressful events such as the ongoing COVID-19 pandemic.• Living with inflammatory arthritis may foster resilience.• After COVID-19, patients with inflammatory arthritis were more resilient than the general population.

2020 - OP0063 QUANTITATIVE COMPUTED TOMOGRAPHY PREDICTS 10-YEAR MORTALITY IN INTERSTITIAL LUNG DISEASE RELATED TO SYSTEMIC SCLEROSI [Abstract in Rivista]
Ariani, A; Bravi, E; De Santis, M; Hax, V; Parisi, S; Lumetti, F; Girelli, F; Saracco, M; De Gennaro, F; Giollo, A; Abdel Jaber, M; Bozzao, F; Silva, M; Ditto, Mc; Lomater, C; Mozzani, F; Santilli, D; Di Donato, E; Becciolini, A; Pucciarini, F; Canziani, L; Bodini, Fc; Arrigoni, E; Bredemeier, M; Mendonça Da Silva Chakr, R; Spinella, A; Idolazzi, L; Bortolotti, R; Tomietto, P; Baratella, E; Tollot, S; Giuggioli, D.; Fischetti, F; Fusaro, E; Sverzellati, N; Scirè, Ca
abstract

Background: Interstitial lung disease (ILD) is the main cause of death in Systemic Sclerosis (SSc). Chest CT is the gold standard in detecting ILD although it is not easy to understand its prognostic value. ILD qualitative assessment is almost worthless. Goh et al. semi quantitative score of ILD extent is related to mortality risk but it is burdened by relevant inter/intra-readers variability. An operator independent algorithm based on voxel-wise analysis proved to identify SSc patients with an increased risk of mortality according to prediction models. Objectives: To verify if quantitative analysis of chest CT (QCT) predict 10 years-mortality in SSc patients. Methods: SSc patients with availability of a chest CT were enrolled in 13 different centers. The CT voxel-wise analysis with a free software (www.horosproject.com) provided QCT indexes: kurtosis, skewness, mean lung attenuation and standard deviation. Patients …

2020 - OP0181 FUNCTIONAL CUT-OFFS TO DISTINGUISH PULMONARY VASCULAR AND PARENCHYMAL INVOLVEMENT IN SYSTEMIC SCLEROSIS (SSC): A QUANTITATIVE ANALYSIS OF IMAGING FEATURES AT CHEST COMPTED TOMOGRAPHY (CT) . [Abstract in Rivista]
Bruni, C; Occhipinti, M; Camiciottoli, G; Bartolucci, M; Lepri, G; Fabbrizzi, A; Tottoli, A; Bassetto, A; Ciardi, G; Giuggioli, D; Cuomo, G; Masini, F; Lavorini, F; Calistri, L; Matucci-Cerinic, M
abstract

2020 - Pulmonary arterial hypertension: Guidelines and unmet clinical needs [Articolo su rivista]
Giuggioli, D.; Bruni, C.; Cacciapaglia, F.; Dardi, F.; De Cata, A.; Del Papa, N.; Iannone, F.; Lunardi, C.; Maglione, W.; Molinaro, F.; Palazzini, M.; Spinella, A.; Tinazzi, E.; Matucci Cerinic, M.
abstract

The term pulmonary arterial hypertension (PAH) identifies a heterogeneous group of diseases characterized by a progressive increase in pulmonary arterial resistance (PVR), which causes a significant burden in terms of quality of life, right heart failure and premature death. The pathogenesis of PAH is not completely clear: the remodeling of the small pulmonary vessels is crucial, causing an increase in the resistance of the pulmonary circle. Its diagnosis is based on cardiac catheterization of the right heart. According to the present hemodynamic definition of pulmonary hypertension (PH) proposed by the Guidelines of the European Society of Cardiology/European Respiratory Society (ESC-ERS), the mean pulmonary arterial pressure (mPAP) values are ≥25 mmHg. In case of PAH, apart from an mPAP value ≥25 mmHg, patients must have a >3 Wood units increase in PVR and normal pressure values of the left heart. PH is a pathophysiological condition observed in more than 40 different diseases, while PAH is a primary disease of the pulmonary bloodstream potentially treatable with specific drugs. PAH is a severe complication of systemic sclerosis (SSc) affecting about 10% of the patients. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. In fact, despite awareness of the negative impact of SSc-PAH on quality of life and survival, as well as on the severity of lung function, at the moment standardized and shared guidelines and/or screening programs for the diagnosis and the subsequent early treatment of PAH in SSc are not available. The aim of the present paper is to highlight the lights and shadows of SSc-PAH, unraveling the unmet clinical needs on this topic with a proposal of clinical-diagnostic and therapeutic guidelines.

2020 - Quantitative analysis of pulmonary vasculature in systemic sclerosis at spirometry-gated chest CT [Articolo su rivista]
Occhipinti, M.; Bruni, C.; Camiciottoli, G.; Bartolucci, M.; Bellando-Randone, S.; Bassetto, A.; Cuomo, G.; Giuggioli, D.; Ciardi, G.; Fabbrizzi, A.; Tomassetti, S.; Lavorini, F.; Pistolesi, M.; Colagrande, S.; Matucci-Cerinic, M.
abstract

Objective To prospectively investigate whether differences in pulmonary vasculature exist in systemic sclerosis (SSc) and how they are distributed in patients with different pulmonary function. Methods Seventy-four patients with SSc undergoing chest CT scan for interstitial lung disease (ILD) screening or follow-up were prospectively enrolled. A thorough clinical, laboratory and functional evaluation was performed the same day. Chest CT was spirometry gated at total lung capacity and images were analysed by two automated software programs to quantify emphysema, ILD patterns (ground-glass, reticular, honeycombing), and pulmonary vascular volume (PVV). Patients were divided in restricted (FVC% <80, DLco%<80), isolated DLco% reduction (iDLco-FVC%≥80, DLco%<80) and normals (FVC%≥80, DLco%≥80). Spearman ρ, Mann-Whitney tests and logistic regressions were used to assess for correlations, differences among groups and relationships between continuous variables. Results Absolute and lung volume normalised PVV (PVV/LV) correlated inversely with functional parameters and positively with all ILD patterns (ρ=0.75 with ground glass, ρ=0.68 with reticular). PVV/LV was the only predictor of DLco at multivariate analysis (p=0.007). Meanwhile, the reticular pattern prevailed in peripheral regions and lower lung thirds, PVV/LV prevailed in central regions and middle lung thirds. iDLco group had a significantly higher PVV/LV (2.2%) than normal (1.6%), but lower than restricted ones (3.8%). Conclusions Chest CT in SSc detects a progressive increase in PVV/LV as DLco decreases. Redistribution of perfusion to less affected lung regions rather than angiogenesis nearby fibrotic lung may explain the results. Further studies to ascertain whether the increase in PVV/LV reflects a real increase in blood volume are needed.

2020 - SAT0553 QUANTITATIVE ANALYSIS OF IMAGING FEATURES AT CHEST CT OF PULMONARY ARTERIAL AND VENOUS COMPONENTS IN SYSTEMIC SCLEROSIS-INTERSTITIAL LUNG DISEASE (SSc-ILD). [Abstract in Rivista]
Bruni, Cosimo; Occhipinti, Mariaelena; Camiciottoli, Gianna; Bartolucci, M; Pienn, M; Lepri, G; Fabbrizzi, A; Tottoli, A; Ciardi, G; Giuggioli, D; Cuomo, G; Masini, F; Olschewski, H; Lavorini, F; Calistri, L; Matucci-Cerinic, M
abstract

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.

2020 - THU0600 a case of systemic sclerosis complicated by renal crisis: potential etiopathogenetic role of cytomegalovirus and treatment [Abstract in Rivista]
Palermo, A; Galli, E; Spinella, A; Cocchiara, E; Lumetti, F; Klinowski, G; Giovanella, S; Manzini, Cu; Salvarani, C; Giuggioli, D
abstract

Background: Scleroderma renal crisis (SRC) is a rare complication of systemic sclerosis (SSc), which can be triggered by viruses, such as Cytomegalovirus (CMV). SRC presents as a new-onset accelerated-phase hypertension with/without rapidly progressive renal failure. Objectives: Here we describe the case of a patient developing SSc complicated by the appearance of SRC after a recent episode of acute Cytomegalovirus infection. Methods: A 66-year-old male was referred to our Scleroderma Unit in March 2019. He presented with widespread skin rash, exertional dyspnoea and peripheral oedemas. He reported a myocarditis due to CMV occurred in October 2018. Antibodies anti-CMV IgM were detected in his serum. The patient developed a progressive cutaneous involvement characterized by diffuse oedema, sclerosis and melanoderma. Subsequently, Raynaud’s phenomenon, puffy hands and pitting scars …

2020 - Ultrasonography involvement of carotid, upper and lower limb arteries in a large cohort of systemic sclerosis patients [Articolo su rivista]
Caimmi, C.; De Marchi, S.; Bosello, S. L.; Giuggioli, D.; Caramaschi, P.; Di Giorgio, A.; Spinella, A.; Astorino, G.; Canestrari, G.; Cocchiara, E.; Gremese, E.; Viapiana, O.; Rossini, M.
abstract

Objectives: Data on macrovascular involvement in systemic sclerosis (SSc) are still debatable. The aim of this study was to estimate its prevalence and possible determinants in a large cohort. Methods: One hundred and fifty-five outpatients with SSc were enrolled. Data about disease characteristics and cardiovascular risk factors were collected and patients underwent ecocolor Doppler ultrasonography of arteries of the neck and lower (LL) and upper (UL) limbs. Results: Mean age was 57.9 ± 14.5 years and most were female (88.4%) with a limited subset (63.2%). Mean disease duration was 11.4 ± 8.1 years. Twenty-three (14.8%) had hypertension, 7 (4.8%) diabetes, 64 (41.3%) hypercholesterolemia and 63 (40.6%) were active/past smokers. Seventy-nine (49%) patients had plaques at carotids, 49 (32.9%) at LL and 7 (4.9%) at UL. In multivariate analysis, patients with carotid plaques had more often a limited pattern (P =.001), patients with distal LL plaques pulmonary arterial hypertension (P =.006) and patients with proximal LL plaques lower diffusing capacity for carbon monoxide adjusted to hemoglobin and its ratio to alveolar volume (P =.004). In patients with UL plaques traditional cardiovascular risk factors were not more common, while forced vital capacity was lower (P =.023). Finally, upper limb and proximal LL plaques were as common in early disease patients as in longstanding ones, although the former were younger. Conclusions: This study shows that macrovascular involvement is quite common in SSc and that some disease characteristics linked to microvascular involvement are associated with atherosclerotic plaques, which can be present even in early disease. Our study suggests that a complete evaluation of macrocirculation is mandatory for rheumatologists treating SSc patients.

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 - AB0645 CANNABINOIDS IN THE TREATMENT OF PAIN RELATED TO SYSTEMIC SCLEROSIS SKIN ULCERS: OUR EXPERIENCE [Abstract in Rivista]
Cocchiara, Emanuele; Spinella, Amelia; Magnani, Luca; Lumetti, Federica; Palermo, Adalgisa; Baiocchi, Gianluigi; Salvarani, Carlo; Giuggioli, Dilia
abstract

2019 - Effects of Parvovirus B19 In Vitro Infection on Monocytes from Patients with Systemic Sclerosis: Enhanced Inflammatory Pathways by Caspase-1 Activation and Cytokine Production [Articolo su rivista]
Zakrzewska, K.; Arvia, R.; Torcia, M. G.; Clemente, A. M.; Tanturli, M.; Castronovo, G.; Sighinolfi, G.; Giuggioli, D.; Ferri, C.
abstract

Parvovirus B19 (B19V) has been proposed as a triggering agent for some autoimmune diseases including systemic sclerosis (SSc). In this study, we investigated whether B19V infection in vitro differently activates inflammatory pathways, including those dependent on caspase-1 activation, in monocytes from patients with SSc and healthy controls. We showed that B19V can infect both THP-1 cells and primary monocytes but is not able to replicate in these cells. B19V infection increases the production of tumor necrosis factor-α and induces NLRP3-mediated caspase-1 activation in both THP-1 cells differentiated with phorbol 12-myristate 13-acetate and in monocytes from patients with SSc but not from healthy controls. B19V infection was sufficient for THP-1 to produce mature IL-1β. Monocytes from patients with SSc required an additional stimulus, here represented by lipopolysaccharides, to activate cytokine genes. Following B19V infection, however, lipopolysaccharide-activated monocytes from patients with SSc strongly increased the production of IL-1β and tumor necrosis factor-α. Altogether, these data suggest that viral components might potentiate the response to endogenous and/or exogenous toll-like receptor 4 ligands in monocytes from patients with SSc. The B19V-mediated activation of inflammatory pathways in monocytes might contribute to the disease progression and/or development of specific clinical phenotypes.

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 - Overall mortality in combined pulmonary fibrosis and emphysema related to systemic sclerosis [Articolo su rivista]
Ariani, A.; Silva, M.; Bravi, E.; Parisi, S.; Saracco, M.; De Gennaro, F.; Caimmi, C.; Girelli, F.; De Santis, M.; Volpe, A.; Lumetti, F.; Hax, V.; Bredemeier, M.; Alfieri, V.; Santilli, D.; Bodini, F. C.; Lucchini, G.; Mozzani, F.; Seletti, V.; Bacchini, E.; Arrigoni, E.; Giuggioli, D.; Chakr, R.; Idolazzi, L.; Bertorelli, G.; Imberti, D.; Michieletti, E.; Paolazzi, G.; Fusaro, E.; Chetta, A. A.; Scire, C. A.; Sverzellati, N.
abstract

Objectives: This multicentre study aimed to investigate the overall mortality of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) and to compare CPFE-SSc characteristics with those of other SSc subtypes (with interstitial lung disease - ILD, emphysema or neither). Methods: Chest CTs, anamnestic data, immunological profile and pulmonary function tests of patients with SSc were retrospectively collected. Each chest CT underwent a semiquantitative assessment blindly performed by three radiologists. Patients were clustered in four groups: SSc-CPFE, SSc-ILD, SSc-emphysema and other-SSc (without ILD nor emphysema). The overall mortality of these groups was calculated by Kaplan-Meier method and compared with the stratified log-rank test; Kruskal-Wallis test, t-Student test and χ 2 test assessed the differences between groups. P<0.05 was considered statistically significant. Results: We enrolled 470 patients (1959 patient-year); 15.5 % (73/470) died during the follow-up. Compared with the SSc-ILD and other-SSc, in SSc-CPFE there was a higher prevalence of males, lower anticentromere antibodies prevalence and a more reduced pulmonary function (p<0.05). The Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with SSc-CPFE (HR vs SSc-ILD, vs SSc-emphysema and vs other-SSc, respectively 1.6 (CI 0.5 to 5.2), 1.6 (CI 0.7 to 3.8) and 2.8 (CI 1.2 to 6.6). Conclusions: CPFE increases the mortality risk in SSc along with a highly impaired lung function. These findings strengthen the importance to take into account emphysema in patients with SSc with ILD.

2019 - SAT0285 EVALUATION OF CHRONIC PAIN IN PATIENTS WITH SYSTEMIC SCLEROSIS COMPARED TO THOSE WITH CHRONIC HEADACHE AND RHEUMATOID ARTHRITIS [Abstract in Rivista]
Magnani, Luca; Lumetti, Federica; Cocchiara, Emanuele; Spinella, Amelia; Baraldi, Carlo; Pini, Luigialberto; Pellesi, Lanfranco; Baiocchi, Gianluigi; Salvarani, Carlo; Giuggioli, Dilia
abstract

2019 - SAT0301 THE USE OF 16 GRIPS TEST TO EVALUATE HAND IMPAIRMENT IN SYSTEMIC SCLEROSIS (SSC): PRELIMINARY TO CONSTRUCTION OF PERSONALIZED DEVICES [Abstract in Rivista]
Tonelli, Roberto; Anastasio, Chiara; Schiavi, Margherita; Lucia, Zingarello; Giuggioli, Dilia; Mascia, Maria Teresa
abstract

2019 - Thu0349 autologous fat grafting in the treatment of patients with systemic sclerosis: current experience and future prospects [Abstract in Rivista]
Spinella, Amelia; Pignatti, Marco; Citriniti, Giorgia; Lumetti, Federica; Cocchiara, Emanuele; Palermo, Adalgisa; Sighinolfi, Gianluca; Pacchioni, Lucrezia; Zaccaria, Giovanna; Lusetti, Irene Laura; DE SANTIS, Giorgio; Salvarani, Carlo; Giuggioli, Dilia
abstract

2019 - Use of Neem oil and Hypericum perforatum for treatment of calcinosis-related skin ulcers in systemic sclerosis [Articolo su rivista]
Giuggioli, D.; Lumetti, F.; Spinella, A.; Cocchiara, E.; Sighinolfi, G.; Citriniti, G.; Colaci, M.; Salvarani, C.; Ferri, C.
abstract

Objective: This study evaluated Neem oil and Hypericum perforatum (Holoil®) for treatment of scleroderma skin ulcers related to calcinosis (SU-calc). Procedure: We retrospectively analyzed 21 consecutive systemic sclerosis (SSc) patients with a total of 33 SU-calcs treated daily with Holoil® cream compared with a control group of 20 patients with 26 SU-calcs. Holoil® was directly applied to skin lesions, while the control group received only standard medication. Results: Application of Holoil® either resulted in crushing and complete resolution of calcium deposits or facilitated sharp excision of calcinosis during wound care sessions in 27/33 cases (81.8%). Complete healing of SU-calc occurred in 15/33 (45%) of cases within a time period of 40.1 ± 16.3 (mean ± SD) days, while 18/33 (55%) of lesions improved in terms of size, erythema, fibrin and calcium deposits. Patients reported a reduction of pain (mean numeric rating scale 7.3 ± 1.9 at baseline versus 2.9 ± 1.4 at follow-up) The control group had longer healing times and a higher percentage of infections. Conclusions: The efficacy of local treatment with neem oil and Hypericum perforatum suggest that Holoil® could be a promising tool in the management of SSc SU-calc.

2018 - A paradigmatic interplay between human cytomegalovirus and host immune system: Possible involvement of viral antigen-driven CD8+ T cell responses in systemic sclerosis [Articolo su rivista]
Arcangeletti, M. -C.; Maccari, C.; Vescovini, R.; Volpi, R.; Giuggioli, D.; Sighinolfi, G.; De Conto, F.; Chezzi, C.; Calderaro, A.; Ferri, C.
abstract

Human cytomegalovirus (HCMV) is a highly prevalent opportunistic agent in the world population, which persists as a latent virus after a primary infection. Besides the well-established role of this agent causing severe diseases in immunocompromised individuals, more recently, HCMV has been evoked as a possible factor contributing to the pathogenesis of autoimmune diseases such as systemic sclerosis (SSc). The interplay between HCMV and immune surveillance is supposed to become unbalanced in SSc patients with expanded anti-HCMV immune responses, which are likely involved in the exacerbation of inflammatory processes. In this study, blood samples from a cohort of SSc patients vs. healthy subjects were tested for anti-HCMV immune responses (IgM, IgG antibodies, and T cells to peptide pools spanning the most immunogenic HCMV proteins). Statistically significant increase of HCMV-specific CD8+ T cell responses in SSc patients vs. healthy subjects was observed. Moreover, significantly greater HCMV-specific CD8+ T cell responses were found in SSc patients with a longer disease duration and those with higher modified Rodnan skin scores. Given the known importance of T cells in the development of SSc and that this virus may contribute to chronic inflammatory diseases, these data support a relevant role of HCMV-specific CD8+ T cell responses in SSc pathogenesis.

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 - AB0760 Advanced oxidation protein products in serum of patients with systemic sclerosis: a possible indicator of clinical evolution [Abstract in Rivista]
Sighinolfi, G; Colaci, M; Spinella, Amelia; Lumetti, Federica; Artoni, Erica; Salvarani, C; Giuggioli, Dilia
abstract

2018 - Advanced oxidation protein products in serum of patients with systemic sclerosis: a possible indicator of clinical evolution [Abstract in Atti di Convegno]
Sighinolfi, GIAN LUCA; Colaci, M; Spinella, Amelia; Lumetti, Federica; Artoni, Erica; Salvarani, C; Giuggioli, Dilia
abstract

Background Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disease characterised by by immune dys-regulation, obliterative microvasculopathy and fibrosis. Endothelial dysfunction, immune system imbalance and fibroblast activation constitute the three major factors of the pathogenetic process. In this context, oxidative stress could play a significant role through direct damage of endothelial cells and the persistent activation of the immune system.1,2 Objectives This study investigated the presence of advanced protein oxidation products (AOPP) in serum of patients with SSc and its correlation with disease’s features. Methods 50 patients with SSc (M:F 1:7, mean age 57.3±11.2 SD, mean duration of disease 10±9.1 SD years), were screened for AOPP in the serum, using the AOPP OxiSelect Kit of CELL BIOLABS (San Diego, Ca, USA). Among 50 SSc patients, 39 had limited cutaneous subset, while 11 had the diffuse one. Anamnestic and clinical data were collected for all SSc patients. As a control group 50 consecutive healthy subjects, sex and age matched, were recruited. Results We found serum levels of AOPP increased in the SSc group compared with the controls (p<0.0001) with mean values of 336.9±167.8 mmol/L and 167.5±59.2 mmol/L, respectively. In addition, higher levels of AOPP directly correlated with the diffuse cutaneous subset (p=0.0242), presence of digital ulcers (p=0.005), esophagopathy (p=0.006) and pulmonary fibrosis (p=0.0128). Conclusions Serum AOPP levels are significantly higher in patients with SSc than in controls. In addition, the correlations of AOPP with SSc diffuse cutaneous subset, digital ulcers, and pulmonary involvement (indicative of progressive disease and worse prognosis) suggest a possible role of this marker in the identification of the cases with worse clinical evolution. The data of this preliminary study should be confirmed on larger case series and analysed in prospective studies, in order to understand its eventual usefulness during the follow-up of SSc patients.

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 - Endocrine disorders associated with hepatitis C virus chronic infection [Articolo su rivista]
Colaci, M.; Malatino, L.; Antonelli, A.; Fallahi, P.; Giuggioli, D.; Ferri, C.
abstract

The term “HCV syndrome” encompasses several organ- and systemic pathophysiological states, which often recognize autoimmunity or neoplastic evolution in their pathophysiology, as well as chronic HCV infection as trigger. The clinical features of HCV patients are heterogenous, and may include endocrine or metabolic disorders, namely autoimmune thyroiditis, type 2 diabetes mellitus, and erectile/sexual dysfunctions. In this review, we summarize current knowledge on the endocrine/metabolic diseases associated with chronic HCV infection, focusing on the main concepts emerged in the recent literature in this field. The application of this knowledge in everyday clinical practice may be relevant, in order to reinforce a holistic vision of the patient with chronic HCV infection, stimulating in turn a multi-disciplinary approach, thus increasing the probability of early diagnosis, more effective treatments, and a better prognostic outcome.

2018 - Erratum to "From Localized Scleroderma to Systemic Sclerosis: Coexistence or Possible Evolution" [Articolo su rivista]
Giuggioli, Dilia; Colaci, Michele; Cocchiara, Emanuele; Spinella, Amelia; Lumetti, Federica; Ferri, Clodovero
abstract

[This corrects the article DOI: 10.1155/2018/1284687.].

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 - FRI0651 Quantitative chest ct predicts 8-years-mortality and comorbidity in systemic sclerosis [Abstract in Rivista]
Ariani, A; Silva, M; Bravi, E; Saracco, M; Parisi, S; De Gennaro, F; Idolazzi, L; De Santis, M; Girelli, F; Lumetti, F; Volpe, A; Santilli, D; Mozzani, F; Lucchini, G; Giuggioli, D; Seletti, V; Bacchini, E; Benini, C; Arrigoni, E; Bodini, Fc; Paolazzi, G; Imberti, D; Fusaro, E; Scirè, Ca; Sverzellati, N
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 - The safety of iloprost in systemic sclerosis in a real-life experience [Articolo su rivista]
Bellando-Randone, S.; Bruni, C.; Lepri, G.; Fiori, G.; Bartoli, F.; Conforti, Ml; Moggi-Pignone, A.; Guiducci, S.; Giuggioli, D.; Colaci, M.; Spinella, A.; Ferri, C.; Matucci-Cerinic, M.
abstract

Iloprost (ILO) is employed intravenously for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in systemic sclerosis (SSc). The aim of this study was to evaluate the safety and tolerability of the intravenous treatment with ILO in different phases of SSc. Eighty-one consecutive non-selected SSc patients, all on nifedipine, with moderate RP, treated with ILO infusion, were retrospectively evaluated. Patients were sub classified according to the edematous or fibrotic/atrophic cutaneous phase of the disease. ILO was infused with a progressive increase of the dosage up to the achievement of patient’s tolerance, 1 day/week. In cases of slower infusion regimen due to adverse events (AE) at the beginning of the administration, patients received a lower dose of the drug (not possible to quantify precisely the final cumulative dosage). 16/81 SSc patients presented digital edema, 5 developed diarrhea, and 9 developed transient hypotension during the infusion at 20 ml/h that ameliorated when the drug was withdrawn. Moreover, 10/16 edematous patients experienced significant and painful digital swelling, unlike patients in the fibrotic group (p < 0.0001); 11/16 patients reported flushing and 7/16 headache, always controlled with dose tapering below 10 ml/h. In the atrophic/fibrotic phase patients (65/81), 10 developed diarrhea and 24 hypotension at infusion rate of 20 ml/h that led to temporary withdrawal of the drug. When ILO was restarted and kept below 10 ml/h, no side effects were experienced. 23/65 patients experienced flushing and 8/65 headache, all controlled with infusion reduction below 10 ml/h. In these patients, adverse events were significantly less frequent than in the edematous group (p = 0.023 and p = 0.008, respectively). Our data suggest that calcium channel blockers should be transitorily stopped while using ILO and that a pre-treatment approach might reduce or control adverse events. In patients with digital edema, ILO infusion should be carefully employed after the evaluation of patient’s drug tolerance.

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 - 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 - 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<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 - 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<0.001), gender (p=0.002), the presence of purpura (p=0.005), arthralgia (p=0.009), liver abnormalities (p<0.001), sicca syndrome (p<0.001), lymphadenopathy (p=0.003), splenomegaly (p=0.002), and rheumatoid factor titres (p<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<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 - 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 - 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 < 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 < 0.001). CONCLUSIONS: In addition to HCV infection, MPs and NPs might play an important role in the aetiopathogenesis of MC.

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 ± 15.1 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 ± 4.1 ng/ml vs. 26 ± 8.1 ng/ml of group B); in particular, 88/91 (97%) patients showed vitamin D deficiency (<20 ng/ml), with very low vitamin D levels (<10 ng/ml) in 40 (44%) subjects. Only 15/49 (30.6%) patients of group B reached normal levels of 25-OH-vitD (≥30 ng/ml), whereas vitamin D deficiency persisted in 12/49 (24.5%) individuals. Parathormone levels inversely correlated with 25-OH-vitD (r = −0.3, p < 0.0001). Of interest, hypovitaminosis D was statistically associated with autoimmune thyroiditis (p = 0.008), while calcinosis was more frequently observed in patients of group A (p = 0.057). Moreover, we found significantly higher percentage of serum anticentromere antibodies in group B patients with 25-OH-vitD level ≥30 ng/ml (8/15 vs. 6/34; p = 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 - 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 - 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 - 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 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 - 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 - 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 - 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 >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 - 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 - 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 - 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 - Cryoglobulinemic Vasculitis [Capitolo/Saggio]
Ferri, C.; Giuggioli, D.; Sebastiani, M.
abstract

Cryoglobulinemic vasculitis, also termed mixed cryoglobulinemic syndrome, is a rare systemic small vessel vasculitis due to the vascular deposition of immune- complexes, mainly mixed IgG-IgM cryoglobulins. It is associated with hepatitis C virus infection, immunological, and neoplastic diseases. Cryoglobulinemic vasculitis is characterized by the classical triad of purpura, weakness and arthralgia, frequent multiple organ involvement, and with infrequent late lymphatic and hepatic malignancies. The etiopathogenesis of cryoglobulinemic vasculitis is not completely understood. However, hepatitis C viral infection and associated lymphotropism, genetic and environmental factors play important roles in cryoglobulin and immune-complex production that deposit in blood vessels, and in B-lymphocyte expansion. The diagnosis is suggested by clinical evidence of purpura, circulating mixed cryoglobulinemia and low C4 levels, and pathologically evident leukocytoclastic vasculitis in skin biopsy lesions. The prognosis is poor in patients with renal disease, liver failure, and malignancy. Treatment is directed toward eradicating hepatitis C viral infection employing combination PEGylated- interferon-alpha and ribavirin treatment, immunomodulatory and immunosuppressant medications as warranted by the level of clinical severity.

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

non presente in quanto trattasi di Lettera all'editore

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 - [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 - [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 - [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.

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

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 - 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 - 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 >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) <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 - 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<0.001) and sPAP >40 mmHg (HR 18.03, 95%CI 9.01-36.06; p<0.001) were associated with an increased risk to develop PAH. SystolicPAP >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 - 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 - 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 - 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 (>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<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 >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 (<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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 < 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.

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 - 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 - 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 - 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 - 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.

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 - 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 - 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 - 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 - 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.

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 - 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 - 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 < 0.005) and CM groups (9.61 +/- 0.59, P < 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 - Use of complementary and alternative medicine (CAM) by patients with chronic non-malignant pain: comparison between primary headache and rheumatic disease [Poster]
Spaccapelo, L.; Giuggioli, D.; Tacchi, R.; Ferrari, Anna
abstract

Complementary and alternative medicine (CAM) is frequently used by patients with chronic non-malignant pain. However, little is known about the use of CAM according to the kind and origin of the pain. Our aim was to compare the rate, pattern, and motivation of complementary and alternative medicine (CAM) use between two clinical populations: primary headache and rheumatic disease patients. Method: we studied 307 primary headache patients (F: 81%; M: 19%; mean age±SD: 38.9±9.0 years; migraine: 90%; tension-type headache: 7%; cluster headache: 3%) and 303 rheumatic disease patients (F: 79%, M: 21%; mean age±SD: 52.0±13.6 years; disorders of connective tissue: 61%; rheumatoid arthritis: 25%; fibromyalgia: 14%) consecutively attending the out-patients services respectively of the Headache Centre and of the Rheumatology Clinic of the University Hospital of Modena for a follow-up visit from October 2008 to March 2009. The investigation was carried out by a standardized physician-administered questionnaire. The data collected were inserted into a specially prepared data base. A descriptive analysis of the frequencies of all parameters collected was made, as well as a comparison between primary headache and rheumatic disease patients. Statistical differences were analysed by Fisher’s exact test to compare percentages and by Student’s t test for unpaired data to compare mean values between groups. A “P” lower than 0.05 was chosen as significant for all the tests. Results: the majority of the patients in both groups had never used CAM. The headache patients’ group had used at least one kind of CAM significantly more (n=138, 45%) than the rheumatic disease group (n=104, 34%) (P= 0.008, Fisher’s exact test). The first three kinds of most used CAM were the same in the two groups: homeopathy, phytotherapy and acupuncture. However, a significantly larger number of headache patients (n=57, 41%) than of rheumatic disease patients (n=22, 21%) had used acupuncture (P= 0.000; Fisher’s exact test). The most common source of recommendation of CAM was a friend or a relative in both groups (headache patients: 70%; rheumatic disease patients: 55%). The chemist had been a source of advice significantly more for headache (n=32, 23%) than for rheumatic patients (n=4, 4%) (P= 0.000; Fisher’s exact test). Most patients, without any differences between the two groups (headache patients: 67%; rheumatic disease patients: 71%), had informed their general practitioner that they were using CAM. The first reason for the use of CAM was different in the two groups: lack of efficacy of traditional drugs in the case of headache patients (49% vs rheumatic disease group: 6%; P= 0.000; Fisher’s exact test) and idea of using a more natural treatment, less dangerous than traditional drugs, in the case of rheumatic disease patients (59% vs headache patients: 33%; P= 0.000; Fisher’s exact test). Most rheumatic patients had only used one kind of CAM (52% vs headache patients: 37%; P= 0.026; Fisher’s exact test). A higher percentage of headache patients (20%) than of rheumatic patients (5%) had used three or more kinds of CAM (P= 0.000; Fisher’s exact test). Less headache patients (45%) than rheumatic patients (61%) reported to have improved thanks to the use of CAM (P= 0.019; Fisher’s exact test). However, only a minority (5-7%) in both groups thought that CAM treatments were more effective than traditional pharmacological treatments. In spite of this, most patients (headache patients: 74%; rheumatic disease patients: 68%) considered the use of CAM a positive experience and thought that CAM therapy should be chargeable to the National Health Service (headache patients: 82%; rheumatic disease patients: 73%). Conclusion: the use of CAM suggests an active behaviour and seems to answer chronic non-malignant pain patients’ fully justified needs, considering the limitations of the drugs presently available for their treatment.

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<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 - 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 - 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 - 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 - Improvement of endothelial function and its relationship with exercise capacity and hemodynamic profile in patients with pulmonary hypertension. A randomized study comparing bosentan and sildenafil [Abstract in Atti di Convegno]
Nuzzo, A; Rossi, R; Rossi, E; Franchi, F; Giuggioli, D; Ferri, C; Modena, Mg
abstract

Improvement of endothelial function and its relationship with exercise capacity and hemodynamic profile in patients with pulmonary hypertension. A randomized study comparing bosentan and sildenafil

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.

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 - 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 - 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 - 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 - 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 - 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<.0001) and HAQ (from 2.12 +/-0.45 to 1.28+/-0.30; p<.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 (< or =5 yr, 41% vs >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.

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

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 - 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 - 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.

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 - 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 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.

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 - 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

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 - 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 - 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 - 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 - 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.

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.

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.

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)

1997 - Amlodipine in the treatment of Raynaud's phenomenon. A double blind placebo-controlled crossover study [Articolo su rivista]
La Civita, L.; Pitaro, N.; Rossi, M.; Giuggioli, D.; Gambini, I.; Cini, G.; Pasero, G.; Ferri, C.
abstract

Treatment with calcium antagonists has been shown to be beneficial in patients with primary and secondary Raynaud's phenomenon. A double-blind placebo-controlled crossover trial was performed to assess the efficacy of amlodipine, a new long-acting calcium antagonist, in patients with Raynaud's phenomenon without underlying disease. 20 of the 24 patients enrolled (20 women and 4 men, mean age 45 years) completed the trial. The number of episodes of Raynaud's phenomenon per week and the severity of discomfort significantly improved during amlodipine (p < 0.0001 and p < 0.0004, respectively) but not placebo treatment. Perfusion-pressure index, evaluated with Doppler sonography using a postischaemia reactive hyperaemia test, significantly improved (p < 0.04) after treatment with amlodipine but not placebo. These results indicate that amlodipine is a useful treatment for primary and suspected secondary Raynaud's phenomenon, at least in the short term.

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

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.

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

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 - 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.

Università degli studi di Modena e Reggio Emilia

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