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Marco SEBASTIANI

Ricercatore Universitario presso: Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa


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Pubblicazioni

2020 - Combination Therapy with Nintedanib and Sarilumab for the Management of Rheumatoid Arthritis Related Interstitial Lung Disease [Articolo su rivista]
Vacchi, Caterina; Manfredi, Andreina; Cassone, Giulia; Salvarani, Carlo; Cerri, Stefania; Sebastiani, Marco
abstract

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease characterized by joint and extra-articular involvement. Among them, interstitial lung disease (ILD) is one of the most common and severe extra-articular manifestations, with a negative impact on both therapeutic approach and overall prognosis. ILD can occur at any point of the natural history of RA, sometimes before the appearance of joint involvement. Since no controlled studies are available, the therapeutic approach to RA-ILD is still debated and based on empirical approaches dependent on retrospective studies and case series. Here, we report the case of a 75-year-old patient affected by RA complicated by ILD successfully treated with a combination therapy of an antifibrotic agent, nintedanib, and an inhibitor of IL-6 receptor, sarilumab. We obtained a sustained remission of the joint involvement and, simultaneously, a stabilization of the respiratory symptoms and function, with a good safety profile. To date, this is the first report describing a combination therapy with nintedanib and a disease-modifying antirheumatic drug (DMARD) for the management of RA complicated by ILD. Future prospective studies are needed to better define efficacy and safety of this approach in the treatment of these subjects.


2020 - Drug retention, inactive disease and response rates in 1860 patients with axial spondyloarthritis initiating secukinumab treatment: routine care data from 13 registries in the EuroSpA collaboration [Articolo su rivista]
Michelsen, Brigitte; Lindström, Ulf; Codreanu, Catalin; Ciurea, Adrian; Zavada, Jakub; Loft, Anne Gitte; Pombo-Suarez, Manuel; Onen, Fatos; Kvien, Tore K; Rotar, Ziga; Santos, Maria Jose; Iannone, Florenzo; Hokkanen, Anna-Mari; Gudbjornsson, Bjorn; Askling, Johan; Ionescu, Ruxandra; Nissen, Michael J; Pavelka, Karel; Sanchez-Piedra, Carlos; Akar, Servet; Sexton, Joseph; Tomsic, Matija; Santos, Helena; Sebastiani, Marco; Österlund, Jenny; Geirsson, Arni Jon; Macfarlane, Gary; van der Horst-Bruinsma, Irene; Georgiadis, Stylianos; Brahe, Cecilie Heegaard; Ørnbjerg, Lykke Midtbøll; Hetland, Merete Lund; Østergaard, Mikkel
abstract

To explore 6-month and 12-month secukinumab effectiveness in patients with axial spondyloarthritis (axSpA) overall, as well as across (1) number of previous biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), (2) time since diagnosis and (3) different European registries.


2020 - Efficacy, Safety, and Tolerability of Treatments for Systemic Sclerosis-Related Interstitial Lung Disease: A Systematic Review and Network Meta-Analysis [Articolo su rivista]
Erre, Gian Luca; Sebastiani, Marco; Fenu, Maria Antonietta; Zinellu, Angelo; Floris, Alberto; Cavagna, Lorenzo; Renzoni, Elisabetta; Manfredi, Andreina; Passiu, Giuseppe; Woodman, Richard John; Mangoni, Arduino Aleksander
abstract

There is a paucity of head-to-head comparisons of the efficacy and harms of pharmacological treatments for systemic sclerosis-related interstitial lung disease (SSc-ILD).


2020 - Epidemiology and management of interstitial lung disease in ANCA-associated vasculitis [Articolo su rivista]
Sebastiani, M.; Manfredi, A.; Vacchi, C.; Cassone, G.; Faverio, P.; Cavazza, A.; Sverzellati, N.; Salvarani, C.; Luppi, F.
abstract

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is a group of systemic vasculitides that predominantly affect small vessels, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Pulmonary involvement is frequently observed in AAV patients, with various possible phenotypes in the different diseases. In the last years, among the possible types of lung involvement, a growing interest has been addressed to the interstitial lung disease (ILD). Prevalence of ILD is higher in MPA than in GPA; in fact, ILD has been reported in up to 45% of MPA patients and in 23% of GPA. Anti-MPO antibodies are the main ANCA subtype associated to ILD, in about 46-71% of cases, while anti-PR3 antibodies are reported in 0-29% of patients. High resolution computed tomography (HRCT) frequently detects interstitial lung abnormalities in AAV, up to 66% of patients with MPA, even if with an unclear clinical relevance, specifically in asymptomatic patients. Ground glass opacities, mainly consistent with diffuse alveolar hemorrhage (DAH), are the most frequent finding in MPA patients, but reticulations, interlobular septal thickening and honeycombing are also reported. ILD significantly affects quality of life and survival, with mortality increased 2 to 4 times, particularly higher in MPA patients with pulmonary fibrosis. Currently, immunosuppressive therapy is considered also as a possible treatment of ILD. However, a careful evaluation of progression and severity of lung involvement, should guide the treatment decision in the single patient. In this review, we discuss the available evidence on clinical features, diagnostic work-up, prognosis and management of AAV-ILD.


2020 - Factors Predicting Early Failure of Etanercept in Rheumatoid Arthritis: An Analysis From the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis) Registry [Articolo su rivista]
Sebastiani, M; Manfredi, A; Iannone, F; Gremese, E; Bortoluzzi, A; Favalli, E; Bazzani, C; Salaffi, F; Fusaro, E; Foti, R; Giannitti, C; Caporali, R; Gauli, A; Cassone, G; Lopalco, G; Petricca, L; Ferraccioli, G; Lapadula, G
abstract

Objectives: This study aims to investigate the factors associated with early discontinuation (within one year) of etanercept (ETA) in rheumatoid arthritis (RA) patients who began ETA as first biologic disease-modifying antirheumatic drug (bDMARD) and who were entered into the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis; GISEA) registry.Patients and methods: This registry-based cohort study included 477 RA patients (95 males, 382 females; median age 53 years; range 18 to 83 years) who began ETA as first bDMARD. Patient demographics, disease features and drugs were re-evaluated after 12 months. Baseline predictors of ETA discontinuation were estimated by univariate and multivariate analyses using Cox regression model.Results: Seventy patients (14.7%) discontinued ETA during the first year (for inefficacy in 55.8%, adverse events in 28.6%, and other reasons in 6.5%). Concurrent conventional synthetic DMARDs (csDMARDs) were reported in 54.3% of patients, mainly methotrexate (MTX), while 52.4% of subjects took low doses of glucocorticoids. Patients stopping ETA more frequently showed one or more comorbidities, mainly cardiovascular diseases (28.6% vs. 15.7% in patients stopping and continuing ETA, respectively, p=0.009). The presence of comorbidities and a combination therapy with csDMARDs other than MTX were independent factors associated with early discontinuation of ETA at multivariate Cox analysis.Conclusion: Although ETA demonstrated a high persistence in biologic-naive RA patients, about 15% of patients discontinued the treatment within 12 months. The presence of comorbidities and a combination therapy with csDMARDs other than MTX were the main factors for an early withdrawal of the drug.


2020 - Functional Progression in Patients with Interstitial Lung Disease Resulted Positive to Antisynthetase Antibodies: A Multicenter, Retrospective Analysis [Articolo su rivista]
Dei, Giulia; Rebora, Paola; Catalano, Martina; Sebastiani, Marco; Faverio, Paola; Pozzi, Maria Rosa; Manfredi, Andreina; Cameli, Paolo; Salton, Francesco; Salvarani, Carlo; Cavagna, Lorenzo; Confalonieri, Marco; Bargagli, Elena; Luppi, Fabrizio; Pesci, Alberto
abstract

Antisynthetase syndrome (ASSD) is a rare autoimmune disease characterized by serologic positivity for antisynthetase antibodies. Anti-Jo1 is the most frequent, followed by anti PL-7, anti PL-12, anti EJ, and anti OJ antibodies. The lung is the most frequently affected organ, usually manifesting with an interstitial lung disease (ILD), which is considered the main determinant of prognosis. Some evidences suggest that non-anti-Jo-1 antibodies may be associated with more severe lung involvement and possibly with poorer outcomes, while other authors do not highlight differences between anti-Jo1 and other antisynthetase antibodies. In a multicenter, retrospective, "real life" study, we compared lung function tests (LFTs) progression in patients with ILD associated with anti-Jo1 and non-anti-Jo1 anti-synthetase antibodies to assess differences in lung function decline between these two groups. Therefore, we analyzed a population of 57 patients (56% anti-Jo1 positive), referred to the outpatient Clinic of four referral Centers in Italy (Modena, Monza, Siena, and Trieste) from 2008 to 2019, with a median follow-up of 36 months. At diagnosis, patients showed a mild ventilatory impairment and experienced an improvement of respiratory function during treatment. We did not observe statistically significant differences in LFTs at baseline or during follow-up between the two groups. Moreover, there were no differences in demographic data, respiratory symptoms onset (acute vs. chronic), extrapulmonary involvement, treatment (steroid and/or another immunosuppressant), or oxygen supplementation. Our study highlights the absence of differences in pulmonary functional progression between patients positive to anti-Jo-1 vs. non anti-Jo-1 antibodies, suggesting that the type of autoantibody detected in the framework of ASSD does not affect lung function decline.


2020 - INTERSTITIAL LUNG DISEASE RELATED TO RHEUMATOID ARTHRITIS. WHAT DO WE DON’T KNOW? THE LIRA STUDY (LUNG INVOLVEMENT IN RHEUMATOID ARTHRITIS) [Poster]
Sebastiani, M.; Vacchi, C.; Cassone, G.; Salvarani, C.; Atzeni, G. Sandri F.; Biggioggero, M.; Carriero, A.; Erre, G. L.; Fedele, A. L.; Furini, F.; Tomietto, P.; Venerito, V.; Atienza-Mateo, B.; Della Casa, G.; Cerri, S.; Palermo, A.; Galli, E.; Pancaldi, F.; González-Gay, M. A.; Manfredi on behalf of LIRA Study Group, A.
abstract

Background: Interstitial lung disease (ILD) is one of the more frequent and potentially severe extra-articular manifestation of rheumatoid arthritis (RA). ILD significantly decreases the survival and quality of life of patients and influences the treatment approach to the patient. Despite its clinical relevance, the prevalence, incidence and survival of RA-ILD is unknown and supposed on the base of retrospective data or registry-based studies. Objectives: For the first time, the Lung Involvement in Rheumatoid Arthritis (LIRA) study aims to investigate epidemiology, features and prognosis of RA-ILD patients in a prospective international multicentre study. Methods: All RA patients referring to the involved centres will be evaluated every six months with a digital stethoscope and a software able to identify velcro crackles with a diagnostic accuracy of 83.9% (VECTOR). In fact, velcro crackles are virtually identified in all stages of fibrosing alveolitis like RA-ILD, and their search is as a simple and reliable method to screening patients to be undergone to high resolution computed tomography (HRCT). For each patient, clinical and serological data are recorded at baseline and every six months; when velcro crackles or other conditions suspicious for ILD, such as cough or dyspnoea, are detected, a HRCT is requested to confirm ILD. Patients with ILD periodically perform pulmonary function tests to monitor lung function evolution. Results: At now, 205 RA patients have been enrolled (female/male 161/44, mean age 64.8±12.9 years, mean disease duration 14.2±8.9 years), anti-citrullinated peptides antibodies (ACPA) and rheumatoid factor (RF) were positive in 77.1% and 78.1%, respectively. The prevalence of ILD was 21% (43 patients). In other 13 patients the HRCT is ongoing; therefore, we could suppose up to a prevalence of 27.3%. Patients with ILD were symptomatic in 53.5% of cases (23 patients), they are more frequently males and were older than patients without ILD (mean age 73.2±7.4 and 62.7±13.2; p<0.0001, female/male ratio 139/23 vs 22/21; p<0.0001) without significant differences regarding disease duration, positivity for ACPA or RF. Conclusion: The prevalence and the incidence of RA-ILD is still not well defined. Preliminary data of our study confirm a prevalence of ILD higher than 20%, patients are asymptomatic in almost the half of cases and more frequently males and elderly. Our study can help to define the clinical history of these patients, the possible association with clinical and serological features and the supposed role of some drugs.


2020 - Interstitial lung disease in Sjögren's syndrome: a clinical review [Articolo su rivista]
Luppi, Fabrizio; Sebastiani, Marco; Silva, Mario; Sverzellati, Nicola; Cavazza, Alberto; Salvarani, Carlo; Manfredi, Andreina
abstract

Interstitial lung disease (ILD) is considered the most frequent and serious pulmonary complication in primary Sjögren's syndrome (pSS), with the majority of the studies indicating a prevalence of about 20%, and resulting in significant morbidity and mortality. Although ILD was historically described as a late manifestation of pSS, more recently, a high variability of the time of onset of pSS-ILD has been observed and from 10 to 51% of patients can develop ILD years before the onset of pSS. Lymphocytic interstitial pneumonia is highly typical for SS, but it occurs only in a few cases, while the most common ILD pattern is nonspecific interstitial pneumonia, followed by usual interstitial pneumonia and organising pneumonia. Multidisciplinary discussion can be necessary in pSS cases with ambiguous clinical findings, when differential diagnosis with IIPs might be very difficult. Up to date, available data do not allow to establish an evidence-based treatment strategy in pSS-ILD. Glucocorticoids are empirically used, usually in association to immunosuppressive drugs, such as cyclophosphamide and mycophenolate mofetil. A better understanding of the molecular mechanisms involved in the pathogenesis of pSS should facilitate the development of new therapies. Recently, a trial showed the efficacy of the antifibrotic drug nintedanib in slowing progression of various interstitial lung diseases, including patients with connective tissue diseases. The aims of this review are to describe clinical features, imaging, pathology, together with diagnostic criteria, prognosis and management of pSS-ILD patients.


2020 - Interstitial pneumonia with autoimmune features: A single center prospective follow-up study [Articolo su rivista]
Sebastiani, M.; Cassone, G.; De Pasquale, L.; Cerri, S.; Della Casa, G.; Vacchi, C.; Luppi, F.; Salvarani, C.; Manfredi, A.
abstract

Background and objective: Recently the term “interstitial pneumonia with autoimmune features” (IPAF) has been proposed to identify patients with interstitial lung disease and autoimmune characteristics, not fulfilling the criteria for specific connective tissue diseases (CTD). Only few data are available about the clinical and serological features of IPAF patients, their survival and the possible evolution in a CTD. The aims of the study were to investigate the demographic and clinico-serologic features of patients with IPAF, their relationship to survival, and the possible evolution in a definite CTD. Patients and methods: Fifty-two patients were consecutively enrolled and prospectively followed for 45 ± 31.6 months. Data about disease onset, serological, clinical and therapeutic features, pulmonary function tests and high-resolution computed tomography were periodically repeated. The survival of patients with IPAF was compared with that of 104 patients with idiopathic pulmonary fibrosis (IPF). Results: The clinical domain for IPAF was satisfied in 44 patients, serological domain in 49 and the morphological domain in 29 patients. During the follow-up, a definite CTD was diagnosed in 7 patients, in particular Sjogren's syndrome in 4 patients, rheumatoid arthritis in 2, and polymyositis in the last. The estimated 5-year survival of IPAF patients 69.5 ± 7.8%, significantly higher than survival observed in IPF patients, and the baseline value of FVC and DLCO were the only factors associated to death. Conclusions: IPAF seems to a distinct entity, with a low tendency to evolve in a definite CTD. Nevertheless, further studies are needed to better define the clinical evolution and the outcome of IPAF.


2020 - Lung complications of Sjogren syndrome [Articolo su rivista]
Luppi, F.; Sebastiani, M.; Sverzellati, N.; Cavazza, A.; Salvarani, C.; Manfredi, A.
abstract

Primary Sjogren syndrome (pSS) is a systemic autoimmune disease characterised by lymphocytic infiltration of exocrine glands and by a number of systemic manifestations, including those regarding the lung. Pulmonary involvement in pSS includes interstitial lung disease (ILD) and airway disease, together with lymphoproliferative disorders.Patients with pSS-ILD report impaired health-related quality of life and a higher risk of death, suggesting the importance of early diagnosis and treatment of this type of pulmonary involvement. In contrast, airway disease usually has little effect on respiratory function and is rarely the cause of death in these patients.More rare disorders can be also identified, such as pleural effusion, cysts or bullae.Up to date, available data do not allow us to establish an evidence-based treatment strategy in pSS-ILD. No data are available regarding which patients should be treated, the timing to start therapy and better therapeutic options. The lack of knowledge about the natural history and prognosis of pSS-ILD is the main limitation to the development of clinical trials or shared recommendations on this topic. However, a recent trial showed the efficacy of the antifibrotic drug nintedanib in slowing progression of various ILDs, including those in pSS patients.


2020 - Methotrexate and rheumatoid arthritis associated interstitial lung disease [Articolo su rivista]
Juge, Pierre-Antoine; Lee, Joyce S; Lau, Jessica; Kawano-Dourado, Leticia; Rojas Serrano, Jorge; Sebastiani, Marco; Koduri, Gouri; Matteson, Eric; Bonfiglioli, Karina; Sawamura, Marcio; Kairalla, Ronaldo; Cavagna, Lorenzo; Bozzalla Cassione, Emanuele; Manfredi, Andreina; Mejia, Mayra; Rodríguez-Henriquez, Pedro; González-Pérez, Montserrat I; Falfán-Valencia, Ramcés; Buendia-Roldán, Ivette; Pérez-Rubio, Gloria; Ebstein, Esther; Gazal, Steven; Borie, Raphaël; Ottaviani, Sébastien; Kannengiesser, Caroline; Wallaert, Benoît; Uzunhan, Yurdagul; Nunes, Hilario; Valeyre, Dominique; Saidenberg-Kermanac'h, Nathalie; Boissier, Marie-Christophe; Wemeau-Stervinou, Lidwine; Flipo, René-Marc; Marchand-Adam, Sylvain; Richette, Pascal; Allanore, Yannick; Dromer, Claire; Truchetet, Marie-Elise; Richez, Christophe; Schaeverbeke, Thierry; Lioté, Huguette; Thabut, Gabriel; Deane, Kevin D; Solomon, Joshua; Doyle, Tracy; Ryu, Jay H; Rosas, Ivan; Holers, V Michael; Boileau, Catherine; Debray, Marie-Pierre; Porcher, Raphaël; Schwartz, David A; Vassallo, Robert; Crestani, Bruno; Dieudé, Philippe
abstract

Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD.


2020 - Pathogenesis and treatment of idiopathic and rheumatoid arthritis-related interstitial pneumonia. The possible lesson from COVID-19 pneumonia [Articolo su rivista]
Manfredi, A; Luppi, F; Cassone, G; Vacchi, C; Salvarani, C; Sebastiani, M
abstract

Main clinical manifestations of SARS-CoV-2 infection are characterized by fever, cough, dyspnoea and interstitial pneumonia frequently evolving in an acute respiratory distress syndrome (ARDS).


2020 - Pirfenidone for the treatment of interstitial lung disease associated to rheumatoid arthritis: a new scenario is coming? [Articolo su rivista]
Cassone, G.; Sebastiani, M.; Vacchi, C.; Cerri, S.; Salvarani, C.; Manfredi, A.
abstract

Introduction: Interstitial lung disease (ILD) is a frequent extra-articular manifestation of Rheumatoid arthritis (RA), but nowadays there are no randomized controlled clinical trials to support therapeutic guidelines. RA-ILD, especially with UIP pattern, shares some similarities with idiopathic pulmonary fibrosis, suggesting a possible role of antifibrotic therapy in these patients. To date, there are no published data supporting the use of pifenidone in RA-ILD. We describe for the first time two patients with a diagnosis of RA-ILD successfully treated with hydroxychloroquine and pirfenidone, without adverse events. Case presentation: Patient 1 and patient 2 were first diagnosed with IPF (UIP pattern at high-resolution computed tomography, no other signs or symptoms suggesting other forms of ILD, routine laboratory examinations and immunological texts negative). Patients started pirfenidone 2403 mg daily. Few months later, they referred to our multidisciplinary outpatient for arthritis. ACPA and RF were positive. A diagnosis of RA was performed and treatment with corticosteroids and hydroxychloroquine was started, in association with pirfenidone. In both cases we assessed the stabilization of articular and lung manifestations, without adverse events. Discussion: In absence of randomized controlled trials, the optimal treatment of RA-ILD has not been determined and remains challenging. When considering therapeutic options for RA-ILD, both pulmonary and extra-thoracic disease manifestations and degrees of activity should be assessed and taken into consideration. Future prospective research might change RA-ILD management, moving to a more personalized approach based on the identification of different phenotypes of the disease or to a combination of immunosuppressive and antifibrotic treatment.


2020 - Safety and effectiveness of biosimilar of Rituximab CT-P10 in the treatment of cryoglobulinemic vasculitis: the MARBLe study (Mixed cryoglobulinemiA Rituximab BiosimiLar) [Articolo su rivista]
Vacchi, C.; Visentini, M.; Gragnani, L.; Fraticelli, P.; Tavoni, A.; Filippini, D.; Saccardo, F.; Lauletta, G.; Colantuono, S.; Atzeni, F.; Pioltelli, P.; Manfredi, A.; Casato, M.; Zignego, A. L.; Monti, G.; Pietrogrande, M.; Galli, M.; Sebastiani, M.
abstract

Rituximab (RTX) represents a milestone in the treatment of mixed cryoglobulinemic vasculitis (MCV). Despite usually well-tolerated, RTX may induce different types of adverse drug reactions, including exacerbation of vasculitis. Recently, RTX biosimilar CT-P10 has been approved in Europe for the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of CT-P10 in the treatment of MCV. In this multicenter open-label study, we analyzed the safety of CT-P10 in patients with MCV treated in first-line or after a shift by RTX originator. Fifty-one consecutive MCV patients (females/males 35/16, median age 68 years, median disease duration 42 months, 51% HCV positive) were included in the study between July and December 2018 and were treated with CT-P10 (group 1). Safety and effectiveness of CT-P10 were compared with a retrospective group (group 2) including 75 consecutive patients treated with RTX originator between July 2017 and July 2018. Thirty-six patients were treated with CT-P10 for the first time, while the other 15 switched from RTX originator. RTX was administrated with high or dosage schemes (375 mg/m2 four times a week apart/1000 mg twice one week apart or 250 mg/m2 twice one week apart). During a month period after the last infusion, 13/51 adverse events (AE) were observed in group 1 and 17/75 in group 2 (p not significant). Among them, 7/13 and 6/17 (in group 1 and 2, respectively) could be considered immune-mediated AE (p not significant). At univariate analysis patients with IM-AE were more frequently males (p = 0.04) and with a lower disease duration (p = 0.03), but both the parameters were not significant at logistic regression. About clinical response after 6 months by the end of the treatment, no differences were observed between patients treated with originator and CT-P10 regarding the response to the therapy. No differences were observed in safety and effectiveness between patients naïve at RTX or switching from originator. Despite the higher prevalence of immune-mediated AE among patients treated with CT-P10 than originator, we have observed no significant differences between the 2 groups. The use of a low-dosage regimen is more common in group 1 than in group 2, representing a possible bias of the study, possibly influencing the appearance of AE. Considering the cost/efficacy ratio of biosimilars, their use could be helpful to treat a large number of MCV patients with an effectiveness and safety comparable to originator. Multicenter studies including a large number of patients and the new RTX biosimilars could be useful to fully elucidate the possible risk of immune-mediated adverse events with biosimilar drugs. Considering the cost/efficacy ratio of CT-P10, its use could help to treat a large number of MCV patients with an effectiveness and safety comparable to originator.


2020 - Safety of Abatacept in Italian Patients with Rheumatoid Arthritis and Interstitial Lung Disease: A Multicenter Retrospective Study [Articolo su rivista]
Cassone, Giulia; Manfredi, Andreina; Atzeni, Fabiola; Venerito, Vincenzo; Vacchi, Caterina; Picerno, Valentina; Furini, Federica; Erre, Gian Luca; Tomietto, Paola; Fedele, Anna Laura; Della Casa, Giovanni; Nucera, Valeria; Giannitti, Chiara; Salvarani, Carlo; Sebastiani, Marco
abstract

Treatment of rheumatoid arthritis (RA)-related interstitial lung disease (ILD) is challenging, and many conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) have been associated with ILD development or progression. The aim of this multicentric retrospective study was to analyze the evolution of ILD in Italian RA-ILD patients treated with abatacept (ABA).


2020 - Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review [Articolo su rivista]
Vacchi, Caterina; Sebastiani, Marco; Cassone, Giulia; Cerri, Stefania; Della Casa, Giovanni; Salvarani, Carlo; Manfredi, Andreina
abstract

Interstitial lung disease (ILD) is one of the most serious pulmonary complications of connective tissue diseases (CTDs) and it is characterized by a deep impact on morbidity and mortality. Due to the poor knowledge of CTD-ILD's natural history and due to the difficulties related to design of randomized control trials, there is a lack of prospective data about the prevalence, follow-up, and therapeutic efficacy. For these reasons, the choice of therapy for CTD-ILD is currently very challenging and still largely based on experts' opinion. Treatment is often based on steroids and conventional immunosuppressive drugs, but the recent publication of the encouraging results of the INBUILD trial has highlighted a possible effective and safe use of antifibrotic drugs as a new therapeutic option for these subjects. Aim of this review is to summarize the available data and recent advances about therapeutic strategies for ILD in the context of various CTD, such as systemic sclerosis, idiopathic inflammatory myopathy and Sjogren syndrome, systemic lupus erythematosus, mixed connective tissue disease and undifferentiated connective tissue disease, and interstitial pneumonia with autoimmune features, focusing also on ongoing clinical trials.


2020 - Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows [Articolo su rivista]
Cassone, Giulia; Manfredi, Andreina; Vacchi, Caterina; Luppi, Fabrizio; Coppi, Francesca; Salvarani, Carlo; Sebastiani, Marco
abstract

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease affecting 0.5-1% of the population worldwide. Interstitial lung disease (ILD) is a serious pulmonary complication of RA and it is responsible for 10-20% of mortality, with a mean survival of 5-8 years. However, nowadays there are no therapeutic recommendations for the treatment of RA-ILD. Therapeutic options for RA-ILD are complicated by the possible pulmonary toxicity of many disease modifying anti-rheumatic drugs (DMARDs) and by their unclear efficacy on pulmonary disease. Therefore, joint and lung involvement should be evaluated independently of each other for treatment purposes. On the other hand, some similarities between RA-ILD and idiopathic pulmonary fibrosis and the results of the recent INBIULD trial suggest a possible future role for antifibrotic agents. From this perspective, we review the current literature describing the pulmonary effects of drugs (immunosuppressants, conventional, biological and target synthetic DMARDs and antifibrotic agents) in patients with RA and ILD. In addition, we suggest a framework for the management of RA-ILD patients and outline a research agenda to fill the gaps in knowledge about this challenging patient cohort.


2019 - AB0472 PRIMARY SJOGREN SYNDROME ASSOCIATED INTERSTITIAL LUNG DISEASE: FEATURES, TREATMENT AND OUTCOME OF A MONOCENTRIC COHORT [Abstract in Rivista]
Manfredi, Andreina; Sebastiani, Marco; Vacchi, Caterina; Luppi, Fabrizio; Cerri, Stefania; Cassone, Giulia; Salvarani, Carlo
abstract


2019 - AB0624 SAFETY OF RITUXIMAB BIOSIMILAR FOR THE TREATMENT OF CRYOGLOBULINEMIC VASCULITIS [Abstract in Rivista]
Vacchi, Caterina; Visentini, Marcella; Cicco, Maria DI; Angelotti, Francesca; Lauletta, Gianfranco; Manfredi, Andreina; Filippini, Davide; Tavoni, Antonio; Casato, Milvia; Castelnovo, Laura; Monti, Giuseppe; Pietrogrande, Maurizio; Salvarani, Carlo; Galli, Massimo; Sebastiani, Marco
abstract


2019 - AB1157 VALIDATION OF VECTOR (VELCRO CRACKLES DETECTOR) FOR THE DIAGNOSIS OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH CONNECTIVE TISSUE DISEASES [Abstract in Rivista]
Manfredi, Andreina; Cassone, Giulia; Pancaldi, Fabrizio; Vacchi, Caterina; Cerri, Stefania; Casa, Giovanni Della; Salvarani, Carlo; Sebastiani, Marco
abstract


2019 - Acute exacerbation of interstitial lung diseases secondary to systemic rheumatic diseases: A prospective study and review of the literature [Articolo su rivista]
Manfredi, A.; Sebastiani, M.; Cerri, S.; Vacchi, C.; Tonelli, R.; Casa, G. D.; Cassone, G.; Spinella, A.; Fabrizio, P.; Luppi, F.; Salvarani, C.
abstract

Acute exacerbation (AE) is a possible manifestation of interstitial lung diseases (ILD) associated to very high mortality. It’s defined as clinically significant respiratory deterioration with evidence of new widespread alveolar abnormalities on computed tomography scan. AE is better described in idiopathic pulmonary fibrosis (IPF) but also reported in ILD secondary to connective tissue diseases (CTD) and vasculitis. The main features and the real clinical impact of this severe complication in these patients are not well defined. Aim of our study was to prospectively investigate the incidence, clinical features and outcome of AE in a population of patients with ILD related to CTD and vasculitis. We consecutively enrolled all patients, with ILD secondary to rheumatic systemic diseases, referring to our multidisciplinary outpatient clinic for rare lung diseases. All patients were followed for at least 12 months (range, 12–36 months). At baseline, all patients underwent to a core set of laboratory investigations and periodically followed; data about demographic, disease onset, clinical, serological and therapeutic features were also recorded. AE occurred in 9/78 patients, with an incidence of 5.77/100 patients/year, and 5/9 patients died because of AE. The baseline value of DLCO was significantly associated to the risk of AE at Cox regression. In patients with ILD related to rheumatic systemic diseases AE can occur with an incidence similar to IPF. Rheumatologists should carefully consider this life-threatening complication as a possible natural course of all patients with ILD secondary to systemic rheumatic disease.


2019 - Diagnostic accuracy of a velcro sound detector (VECTOR) for interstitial lung disease in rheumatoid arthritis patients: The InSPIRAtE validation study (INterStitial pneumonia in rheumatoid ArThritis with an electronic device) [Articolo su rivista]
Manfredi, A.; Cassone, G.; Cerri, S.; Venerito, V.; Fedele, A. L.; Trevisani, M.; Furini, F.; Addimanda, O.; Pancaldi, F.; Della Casa, G.; D'Amico, R.; Vicini, R.; Sandri, G.; Torricelli, P.; Celentano, I.; Bortoluzzi, A.; Malavolta, N.; Meliconi, R.; Iannone, F.; Gremese, E.; Luppi, F.; Salvarani, C.; Sebastiani, M.
abstract

Background: Interstitial lung disease (ILD) is a severe systemic manifestation of rheumatoid arthritis (RA). High-resolution computed tomography (HRCT) represents the gold standard for the diagnosis of ILD, but its routine use for screening programs is not advisable because of both high cost and X-ray exposure. Velcro crackles at lung auscultation occur very early in the course of interstitial pneumonia, and their detection is an indication for HRCT. Recently, we developed an algorithm (VECTOR) to detect the presence of Velcro crackles in pulmonary sounds and showed good results in a small sample of RA patients. The aim of the present investigation was to validate the diagnostic accuracy of VECTOR in a larger population of RA patients, compared with that of the reference standard of HRCT, from a multicentre study. Methods: To avoid X-ray exposure, we enrolled 137 consecutive RA patients who had recently undergone HRCT. Lung sounds of all patients were recorded in 4 pulmonary fields bilaterally with a commercial electronic stethoscope (ES); subsequently, all HRCT images were blindly evaluated by a radiologist, and audio data were analysed by means of VECTOR. Results: Fifty-nine of 137 patients showed ILD (43.1%). VECTOR correctly classified 115/137 patients, showing a diagnostic accuracy of 83.9% and a sensitivity and specificity of 93.2 and 76.9%, respectively. Conclusions: VECTOR may represent the first validated tool for the screening of RA patients who are suspected for ILD and who should be directed to HRCT for the diagnosis. Moreover, early identification of RA-ILD could contribute to the design of prospective studies aimed at elucidating unclear aspects of the disease.


2019 - FRI0613 THERAPEUTIC STRATEGIES AND SURVIVAL IN PATIENTS WITH INTERSTITIAL PNEUMONIA WITH AUTOIMMUNE FEATURES [Abstract in Rivista]
Sebastiani, Marco; Vacchi, Caterina; Pasquale, Lisa De; Cerri, Stefania; Cassone, Giulia; Casa, Giovanni Della; Garofalo, Martina; Salvarani, Carlo; Manfredi, Andreina
abstract


2019 - Factors predicting early discontinuation of methotrexate as a first-line treatment for rheumatoid arthritis in Italy: Results from the GISEA registry [Articolo su rivista]
Manfredi, A.; Sebastiani, M.; Iannone, F.; Gremese, E.; Bortoluzzi, A.; Favalli, E.; Gorla, R.; Salaffi, F.; Fusaro, E.; Foti, R.; Cantarini, L.; Caporali, R.; Cauli, A.; Cantatore, F. P.; Cantatore, F.; Carletto, A.; Conti, F.; D'Angelo1, S.; Epis, O.; Ramonda, R.; Marchesoni, A.; Ferraccioli, G.; Lapadula, G.
abstract

Objective: Despite the well-established efficacy of methotrexate (MTX) in rheumatoid arthritis (RA), monotherapy is not sufficient in almost half of patients. The aim of this registry-based study was to detect possible predictive factors for the early failure of MTX as a first-line treatment in early RA patients. Materials and Methods: Five-hundred and ninety RA patients beginning MTX as the first-line treatment were included. Persistence on therapy was re-evaluated after 12 months. Baseline features of disease were evaluated by means of univariate Cox regression, and parameters significantly associated to the outcome were included in multivariate model. Results: One hundred and forty-nine patients (25.3%) failed MTX during the 1st year, for inefficacy in 43.6% and adverse events in 37.5% of cases, respectively. At univariate analysis, patients who discontinued or failed treatment showed lower mean age, higher prevalence of anti-citrullinated peptide antibodies (ACPAs), and higher number of tender/swollen joints. The dose of MTX was correlated with the efficacy and the tolerance of the drug. In particular, patients treated with 7.5 mg of MTX weekly showed a higher rate of discontinuation for inefficacy than adverse events, and the contrary was detected for higher doses. On multivariate analysis, age, ACPA, and number of tender joints were directly associated with MTX discontinuation or failure. Conclusions: More than 25% of RA patients treated with MTX as a first-line therapy failed treatment at 12 months. ACPA positivity, age, and number of tender joints were associated with early withdrawal of MTX in RA patients, while the dose of MTX was correlated to the efficacy and safety of the drug.


2019 - Incidence of cancer in patients with spondyloarthritis treated with anti-TNF drugs [Articolo su rivista]
Atzeni, F.; Carletto, A.; Foti, R.; Sebastiani, M.; Panetta, V.; Salaffi, F.; Bonitta, G.; Iannone, F.; Gremese, E.; Govoni, M.; Marchesoni, A.; Giulio Favalli, E.; Gorla, R.; Ramonda, R.; Sarzi-Puttini, P.; Ferraccioli, G.; Lapadula, G.
abstract


2019 - Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course [Articolo su rivista]
Cavagna, Lorenzo; Trallero-Araguás, Ernesto; Meloni, Federica; Cavazzana, Ilaria; Rojas-Serrano, Jorge; Feist, Eugen; Zanframundo, Giovanni; Morandi, Valentina; Meyer, Alain; Pereira da Silva, Jose Antonio; Matos Costa, Carlo Jorge; Molberg, Oyvind; Andersson, Helena; Codullo, Veronica; Mosca, Marta; Barsotti, Simone; Neri, Rossella; Scirè, Carlo; Govoni, Marcello; Furini, Federica; Lopez-Longo, Francisco Javier; Martinez-Barrio, Julia; Schneider, Udo; Lorenz, Hanns-Martin; Doria, Andrea; Ghirardello, Anna; Ortego-Centeno, Norberto; Confalonieri, Marco; Tomietto, Paola; Pipitone, Nicolò; Rodriguez Cambron, Ana Belen; Blázquez Cañamero, María Ángeles; Voll, Reinhard Edmund; Wendel, Sarah; Scarpato, Salvatore; Maurier, Francois; Limonta, Massimiliano; Colombelli, Paolo; Giannini, Margherita; Geny, Bernard; Arrigoni, Eugenio; Bravi, Elena; Migliorini, Paola; Mathieu, Alessandro; Piga, Matteo; Drott, Ulrich; Delbrueck, Christiane; Bauhammer, Jutta; Cagnotto, Giovanni; Vancheri, Carlo; Sambataro, Gianluca; De Langhe, Ellen; Sainaghi, Pier Paolo; Monti, Cristina; Gigli Berzolari, Francesca; Romano, Mariaeva; Bonella, Francesco; Specker, Christof; Schwarting, Andreas; Villa Blanco, Ignacio; Selmi, Carlo; Ceribelli, Angela; Nuno, Laura; Mera-Varela, Antonio; Perez Gomez, Nair; Fusaro, Enrico; Parisi, Simone; Sinigaglia, Luigi; Del Papa, Nicoletta; Benucci, Maurizio; Cimmino, Marco Amedeo; Riccieri, Valeria; Conti, Fabrizio; Sebastiani, Gian Domenico; Iuliano, Annamaria; Emmi, Giacomo; Cammelli, Daniele; Sebastiani, Marco; Manfredi, Andreina; Bachiller-Corral, Javier; Sifuentes Giraldo, Walter Alberto; Paolazzi, Giuseppe; Saketkoo, Lesley Ann; Giorgi, Roberto; Salaffi, Fausto; Cifrian, Jose; Caporali, Roberto; Locatelli, Francesco; Marchioni, Enrico; Pesci, Alberto; Dei, Giulia; Pozzi, Maria Rosa; Claudia, Lomater; Distler, Jorg; Knitza, Johannes; Schett, George; Iannone, Florenzo; Fornaro, Marco; Franceschini, Franco; Quartuccio, Luca; Gerli, Roberto; Bartoloni, Elena; Bellando Randone, Silvia; Zampogna, Giuseppe; Gonzalez Perez, Montserrat I; Mejia, Mayra; Vicente, Esther; Triantafyllias, Konstantinos; Lopez-Mejias, Raquel; Matucci-Cerinic, Marco; Selva-O'Callaghan, Albert; Castañeda, Santos; Montecucco, Carlomaurizio; Gonzalez-Gay, Miguel Angel
abstract

Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.


2019 - Italian consensus recommendations for the management of hepatitis C infection in patients with rheumatoid arthritis [Articolo su rivista]
Sebastiani, Marco; Atzeni, Fabiola; Milazzo, Laura; Quartuccio, Luca; Scirè, Carlo; Gaeta, Giovanni Battista; Lapadula, Giovanni; Armignacco, Orlando; Tavio, Marcello; Olivieri, Ignazio; Meroni, Pierluigi; Bazzichi, Laura; Grassi, Walter; Mathieu, Alessandro; Mastroianni, Claudio; Sagnelli, Evangelista; Santantonio, Teresa; Foppa, Caterina Uberti; Puoti, Massimo; Sarmati, Loredana; Airò, Paolo; Epis, Oscar Massimiliano; Scrivo, Rossana; Gargiulo, Miriam; Riva, Agostino; Manfredi, Andreina; Ciancio, Giovanni; Zehender, Gianguglielmo; Taliani, Gloria; Meroni, Luca; Sollima, Salvatore; Sarzi-Puttini, Piercarlo; Galli, Massimo
abstract

Objectives: The recent introduction of direct-acting antiviral agents (DAAs) which can eliminate Hepatitis C virus (HCV) had revolutionized the treatment of HCV infections also in a complex clinical setting such as the patients with rheumatoid arthritis (RA). HCV elimination is also opportune due to the availability of more efficient immunosuppressive drugs, whose effect on the course of HCV infection is largely unknown. Methods: Consensus process was endorsed by the Italian Society of Rheumatology (SIR) and the Italian Society of Infectious and Tropical Diseases (SIMIT) to review the available evidence and produce practical, hospital-wide recommendations. The consensus panel consisted of 18 infectious diseases consultants, 20 rheumatologists and one clinical epidemiologist, who used the criteria of the Oxford Centre for Evidence-based Medicine to assess the quality of the evidence and the strength of their recommendations. Results: A core-set of statements about management of patients with RA and infection by HCV have been developed to help clinicians in their clinical practice. Conclusions: A screening for HCV should be performed in all RA patients and it is mandatory before starting an immunosuppressive therapy. Finally, a DAA treatment should be considered in all HCV-infected patients.Significance and Innovations HCV antibodies should be investigated at the time of diagnosis of RA and, in any case, before starting immunosuppressive therapy with disease-modifying antirheumatic drugs (DMARDs). HCV eradication with DAA should be attempted as soon as possible, depending on patient conditions allowing a continuous oral treatment lasting 8–12 weeks Conventional and biological DMARDs are allowed in patients with HCV infection, but they should be used cautiously in presence of advanced liver disease.


2019 - Nailfold Capillaroscopy Characteristics of Antisynthetase Syndrome and Possible Clinical Associations: Results of a Multicenter International Study [Articolo su rivista]
Sebastiani, Marco; Triantafyllias, Konstantinos; Manfredi, Andreina; González-Gay, Miguel Angel; Palmou-Fontana, Natalia; Cassone, Giulia; Drott, Ulrich; Delbrück, Christiane; Rojas-Serrano, Jorge; Bertolazzi, Chiara; Nuño, Laura; Giannini, Margherita; Iannone, Florenzo; Vicente, Esther F; Castañeda, Santos; Selva-O'Callaghan, Albert; Araguas, Ernesto Trallero; Emmi, Giacomo; Iuliano, Annamaria; Bauhammer, Jutta; Miehle, Nikolaus; Parisi, Simone; Cavagna, Lorenzo; Codullo, Veronica; Montecucco, Carlomaurizio; Lopez-Longo, Francisco Javier; Martínez-Barrio, Julia; Nieto-González, Juan Carlos; Vichi, Silvia; Confalonieri, Marco; Tomietto, Paola; Bergner, Raoul; Sulli, Alberto; Bonella, Francesco; Furini, Federica; Scirè, Carlo Alberto; Bortoluzzi, Alessandra; Specker, Christof; Barsotti, Simone; Neri, Rossella; Mosca, Marta; Caproni, Marzia; Weinmann-Menke, Julia; Schwarting, Andreas; Smith, Vanessa; Cutolo, Maurizio
abstract

TOBJECTIVE: To describe nailfold videocapillaroscopy (NVC) features of patients with antisynthetase syndrome (AS) and to investigate possible correlations with clinical and serological features of the disease. METHODS: We retrospectively analyzed NVC images of 190 patients with AS [females/males 3.63, mean age 49.7 ± 12.8 yrs, median disease duration 53.7 mos (interquartile range 82), 133 anti-Jo1 and 57 non-anti-Jo1-positive patients]. For each patient, we examined number of capillaries, giant capillaries, microhemorrhages, avascular areas, ramified capillaries, and the presence of systemic sclerosis (SSc)-like pattern. Finally, we correlated NVC features with clinical and serological findings of patients with AS. Concomitantly, a historical cohort of 75 patients with antinuclear antibody-negative primary Raynaud phenomenon (RP) and longterm followup was used as a control group (female/male ratio 4.13/1, mean age 53.9 ± 17.6 yrs) for NVC measures. RESULTS: NVC abnormalities were observed in 62.1% of AS patients compared with 29.3% of primary RP group (p < 0.001). An SSc-like pattern was detected in 67 patients (35.3%) and it was associated with anti-Jo1 antibodies (p = 0.002) and also with a longer disease duration (p = 0.004). Interestingly, there was no significant correlation between the presence of SSc-like pattern and RP, and only 47% of patients with SSc-like pattern had RP. CONCLUSION: NVC abnormalities are commonly observed in AS, independently from the occurrence of RP. The presence of an SSc-like pattern could allow identification of a more defined AS subtype, and prospective studies could confirm the association with clinical and serological features of AS.


2019 - PROPOSAL OF CORE OUTCOME DOMAINS IN MIXED CRYOGLOBULINEMIC VASCULITIS [Abstract in Rivista]
Guerrini, G; Scire, CA; Vultaggio, L; Giambalvo, S; Sebastiani, M; Vacchi, C; Quartuccio, L; Pietrogrande, M
abstract


2019 - Predictors of DAPSA28 Remission at 6 Months in Bio-Naive Patients with Psoriatic Arthritis Starting a TNF Inhibitor in Clinical Practice-Results from the EuroSpA Collaboration [Abstract in Rivista]
Ornbjerg, LM; Georgiadis, S; Jacobsson, L; Loft, AG; Iannone, F; Moeller, B; Sexton, J; Mann, H; Santos, MJ; Pombo-Suarez, M; Eklund, KK; Tomsic, M; Gudbjornsson, B; Erten, S; Codreanu, C; van der Horst-Bruinsma, I; Wallman, J; Sebastiani, M; Nissen, MJ; Kristianslund, E; Pavelka, K; Vieira-Sousa, E; Sanchez-Piedra, C; Trokovic, N; Rotar, Z; Love, TJ; Yolbas, S; Ionescu, R; van de Sande, M; Jones, G; Michelsen, B; Ostergaard, M; Hetland, ML
abstract


2019 - Rate of serious infections in spondyloarthropathy patients treated with anti-tumour necrosis factor drugs: a survey from the Italian registry GISEA [Articolo su rivista]
Atzeni, F; Sarzi-Puttini, P; Sebastiani, M; Panetta, V; Salaffi, F; Iannone, F; Carletto, A; Foti, R; Gremese, E; Govoni, M; Marchesoni, A; Favalli, E; Gorla, R; Ramonda, R; Ferraccioli, G; Lapadula, G
abstract

ObjectiveTo determine the incidence of serious infections (SIs) among the spondyloarthropathy (SpA) patients from the "Gruppo Italiano per lo Studio delle Early Arthritis" (GISEA) registry and treated with tumour necrosis factor (TNF) inhibitors (TNFIs), and to identify the factors associated with the development of the infections.MethodsThis observational study on 3321 GISEA-registered SpA patients collected real-world demographic and clinical data relating to their biological drug treatments. The overall incidence of infections was analysed by type of SpA.ResultsA total of 3321 SpA patients (1731 males, 52.2%; mean age 47 +/- 13 years; median disease duration 3 years, interquartile range [IQR] 0-8) were eligible for inclusion in the analysis. Two hundred and fifty-nine patients experienced at least one of 391 microbiologically diagnosed SIs, 32% of which were recorded during the first 12 months of treatment. The overall incidence of SIs was 43.9/1000 patient-years of follow-up (95% confidence interval [CI] 39.6-48.4): 29.9/1000 (95% CI 23.1-38.1) among those treated with adalimumab (ADA); 36.1/1000 (95% CI 30.0-43.1) among those treated with etanercept (ETN); and 61.4/1000 (95% CI 53.3-70.5) among those treated with infliximab (INF). The highest incidence was observed among the patients with psoriatic arthritis (PsA), but the difference was statistically significant only in comparison with the patients with undifferentiated SpA (p=0.002), whose incidence of SIs was also lower than in the patients with ankylosing spondylitis (AS) (p=0.034). Multivariate models showed that the number of comorbidities (hazard ratio [HR] 1.29, 95% CI 1.2-1.4; p<0.001), age at the start of TNFi treatment (HR 0.99, 95% CI 0.97-0.99; p=0.030), steroid use (HR 1.40, 95% CI 1.1-1.8; p=0.012) and male sex (HR 0.72, 95% CI 0.5-0.9; p=0.012) were all statistically significant predictors of infection. The factors independently associated with a lower risk of SIs were the use of ETN (HR 0.52, 95% CI 0.4-0.7; p<0.001) or ADA (HR 0.59, 95% CI 0.4-0.8; p=0.002) rather than INF.ConclusionThe incidence of SIs was higher among patients with PsA or AS than among those with undifferentiated SpA, and among patients treated with INF than among those treated with ADA or ETN. Male sex, steroid use and the number of comorbidities were all factors predictive of SIs.


2019 - Recommendations for managing the manifestations of severe and life-threatening mixed cryoglobulinemia syndrome [Articolo su rivista]
Galli, M.; Monti, G.; Marson, P.; Scaini, P.; Pietrogrande, M.; Candela, M.; Castelnovo, L.; Faggioli, P.; Novati, P.; Zani, R.; Mascia, M. T.; Saccardo, F.; Mazzaro, C.; Sarzi-Puttini, P.; Sebastiani, M.; Quartuccio, L.; De Vita, S.
abstract

Objective: Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion.Methods: The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews.Results: Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patients condition allows the use of direct-acting antivirals.


2019 - SAT0391 REMISSION AND DRUG RETENTION RATES OF SECUKINUMAB IN 1549 PATIENTS WITH PSORIATIC ARTHRITIS TREATED IN ROUTINE CARE – POOLED DATA FROM THE OBSERVATIONAL EUROSPA RESEARCH COLLABORATION NETWORK [Abstract in Rivista]
Michelsen, Brigitte; Brahe, Cecilie Heegaard; Jacobsson, Lennart T. H.; Nissen, Michael; Pombo-Suarez, Manuel; Mann, Heřman; Rotar, Ziga; Sexton, Joe; Santos, Maria Jose; Nordström, Dan; Codreanu, Catalin; Gudbjornsson, Björn; Yilmaz, Sema; Iannone, Florenzo; Lindström, Ulf; Loft, Anne Gitte; Moeller, Burkhard; Sánchez-Piedra, Carlos; Pavelka, Karel; Tomsic, Matija; Kristianslund, Eirik; Santos, Helena; Hokkanen, Anna-Mari; Ionescu, Ruxandra; Love, Thorvardur Jon; Pehlivan, Yavuz; Sebastiani, Marco; Jones, Gareth T.; van der Horst-Bruinsma, Irene; Hyldstrup, Lise; Krogh, Niels Steen; Hetland, Merete L.; Östergaard, Mikkel
abstract


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


2019 - Therapeutic Strategies and Survival in Patients with Interstitial Pneumonia with Autoimmune Features [Abstract in Rivista]
Sebastiani, M; Cassone, G; Vacchi, C; De Pasquale, L; Cerri, S; Della Casa, G; Salvarani, C; Manfredi, A
abstract


2019 - Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicenter retrospective study [Articolo su rivista]
Manfredi, Andreina; Cassone, Giulia; Furini, Federica; Gremese, Elisa; Venerito, Vincenzo; Atzeni, Fabiola; Arrigoni, Eugenio; Della Casa, Giovanni; Cerri, Stefania; Govoni, Marcello; Petricca, Luca; Iannone, Florenzo; Salvarani, Carlo; Sebastiani, Marco
abstract

Interstitial lung disease (ILD) is the most severe extra-articular manifestation of rheumatoid arthritis (RA). Although it is responsible of 10-20% of all RA mortality, no controlled studies are available for the treatment of RA-ILD and its therapeutic approach is still debated.


2019 - Vasculitis in a patient with mixed cryoglobulinemia treated with rituximab biosimilar CT-P10: a case report [Articolo su rivista]
Vacchi, Caterina; Manfredi, Andreina; Salvarani, Carlo; Sebastiani, Marco
abstract

Rituximab represents a milestone in the treatment of mixed cryoglobulinemic vasculitis. Despite usually well-tolerated, rituximab may induce different types of adverse drug reactions, including exacerbation of vasculitis. Rituximab biosimilar have been recently approved in Europe in the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of rituximab biosimilar in the treatment of mixed cryoglobulinemic vasculitis. We describe a severe skin vasculitis reactivation in a patient affected by rheumatoid arthritis and mixed cryoglobulinemic vasculitis treated with rituximab biosimilar. After 7 days from the first infusion, a severe purpuric rash at lower limbs appeared, that resolved in about 2 weeks with high dose-corticosteroid. Rituximab-induced vasculitis has also been described since 2001, but its pathophysiology is still controversial due to the anecdotical descriptions in literature and the variability of the time between the rituximab infusion and the onset of skin lesions. Up to date, this is the first report describing a vasculitic flare in a patient affected by mixed cryoglobulinemic vasculitis treated with rituximab biosimilar.


2018 - Analysis of pulmonary sounds for the diagnosis of interstitial lung diseases secondary to rheumatoid arthritis [Articolo su rivista]
Pancaldi, Fabrizio; Sebastiani, Marco; Cassone, Giulia; Luppi, Fabrizio; Cerri, Stefania; Della Casa, Giovanni; Manfredi, Andreina
abstract

The diagnosis of interstitial lung diseases in patients affected by rheumatoid arthritis is fundamental to improving their survival rate. In particular, the average survival time of patients affected by rheumatoid arthritis with pulmonary implications is approximately 3 years. The gold standard for confirming the diagnosis of this disease is computer tomography. However, it is very difficult to raise diagnosis suspicion because the symptoms of the disease are extremely common in elderly people. The detection of the so-called velcro crackle in lung sounds can effectively raise the suspicion of an interstitial disease and speed up diagnosis. However, this task largely relies on the experience of physicians and has not yet been standardized in clinical practice. The diagnosis of interstitial lung diseases based on thorax auscultation still represents an underexplored field in the study of rheumatoid arthritis. In this study, we investigate the problem of the automatic detection of velcro crackle in lung sounds. In practice, the patient is auscultated using a digital stethoscope and the lung sounds are saved to a file. The acquired digital data are then analysed using a suitably developed algorithm. In particular, the proposed solution relies on the empirical observation that the audio bandwidth associated with velcro crackle is larger than that associated with healthy breath sounds. Experimental results from a database of 70 patients affected by rheumatoid arthritis demonstrate that the developed tool can outperform specialized physicians in terms of diagnosing pulmonary disorders. The overall accuracy of the proposed solution is 90:0%, with negative and positive predictive values of 95:0% and 83:3%; respectively, whereas the reliability of physician diagnosis is in the range of 60-70%. The devised algorithm represents an enabling technology for a novel approach to the diagnosis of interstitial lung diseases in patients affected by rheumatoid arthritis.


2018 - Incidence of cancer in patients with spondyloarthritis treated with anti-TNF drugs [Articolo su rivista]
Atzeni, F; Carletto, A; Foti, R; Sebastiani, M; Panetta, V; Salaffi, F; Bonitta, G; Iannone, F; Gremese, E; Govoni, M; Marchesoni, A; Favalli, Eg; Gorla, R; Ramonda, R; Sarzi-Puttini, P; Ferraccioli, G; Lapadula, G
abstract

Objective: To determine the incidence of cancer in TNF inhibitor (TNFi)-treated spondyloarthritis (SpA) patients entered in the GISEA registry, and identify the factors associated with its development. Methods: This observational study involved an open cohort of 3321 SpA patients selected from the GISEA registry, designed to collect real-world clinical data concerning patients with RA or SpA treated with biological drugs. The baseline information includes demographics and clinical parameters. The overall incidence of neoplasias was compared to this observed in the general population according to the Italian Association of Medical Oncology. Results: Of the 3321 SpA patients (1731 males, 52.2%; mean age 47 ± 13 years; median disease duration three years, interquartile range [IQR] 0–8), 50 developed at least one of 56 malignancies during the follow-up period of up to 12 years of treatment with TNFi. The overall incidence was 6.3/1000 patient-years of follow-up (95% confidence interval [CI] 4.7–8.2): 7.3/1000 patient-years (95% CI 4.1–11.8) in those treated with ADA; 6.1/1000 patient-years (95% CI 3.8–9.4) in those treated with ETN; and 5.8/1000 patient-years (95% CI 3.5–9.1) in those treated with INF while in the general population was 5.1/1000 patient-years. Univariate analysis showed that age at the time of starting TNFi (P = 0.001), the presence of comorbidities (P = 0.012), the number of comorbidities (P < 0.001), and HAQ-DI score (P = 0.002) were associated with a higher risk of malignancies. Stepwise regression models showed that only previous neoplasia was a significant predictor of a new malignancy. The type of drug was not associated with the risk of malignancy. Conclusions: The incidence of malignancies among SpA patients treated with the three TNFi was higher than in general population; having had a previous solid cancer is predictive of a new malignancy.


2018 - Italian consensus guidelines for the management of hepatitis B virus infections in patients with rheumatoid arthritis [Articolo su rivista]
Sebastiani, M.; Atzeni, F.; Milazzo, L.; Quartuccio, L.; Scire, C.; Gaeta, G. B.; Lapadula, G.; Armignacco, O.; Tavio, M.; Olivieri, I.; Meroni, P.; Bazzichi, L.; Grassi, W.; Mathieu, A.; Mastroianni, C.; Sagnelli, E.; Santantonio, T.; Uberti Foppa, C.; Puoti, M.; Sarmati, L.; Airo, P.; Epis, O. M.; Scrivo, R.; Gargiulo, M.; Riva, A.; Manfredi, A.; Ciancio, G.; Zehender, G.; Taliani, G.; Meroni, L.; Sollima, S.; Sarzi-Puttini, P.; Galli, M.
abstract


2018 - Nailfold videocapillaroscopy in antisynthetase syndrome [Articolo su rivista]
Cassone, G.; Sebastiani, M.; Cavagna, L.; Triantafyllias, K.; Codullo, V.; Salvarani, C.; Manfredi, A.
abstract

A 57-year-old woman with a diagnosis of antisynthetase syndrome (ASSD) underwent a nailfold videocapillaroscopy (NVC) showing a scleroderma pattern. Alterations in capillary morphology have been reported in adults with inflammatory myositis (IM) but only recently have the differences in NVC findings between these two diseases been established. ASSD is currently classified as a subset of IM, for which reason only a few studies in literature evaluate its specific hallmarks, showing nonspecific features of NVC in patients with polymyositis and dermatomyositis (DM) and antisynthetase antibodies. To our knowledge, this is the first description of ASSD capillaroscopy features, and the first report of NVC in ASSD with evidence of scleroderma pattern. Further studies are needed to define clearly frequency, typical features, and possible correlation with clinical and serological data of NVC changes in ASSD, differences between microangiopathy in ASSD and systemic sclerosis or DM.


2018 - The profiling of axial spondyloarthritis patient candidate to a biologic therapy: Consensus from a Delphi-panel of Italian experts [Articolo su rivista]
Favalli, Eg; Becciolini, A; Caporali, R; Todoerti, M; Iannone, F; Dinoia, L; Sebastiani, M; Spinella, A; Gremese, E; Cianci, F; Atzeni, F; Bandinelli, F; Ferraccioli, G; Lapadula, G
abstract

The project aimed to collect expert consensus statements for the profiling of patients with axial spondyloarthritis (axSpA) candidate to biologic agents (bDMARDs) treatment, in order to better define the drivers for the best treatment choice. METHODS: The 6 more interesting topics about axSpA patient profiling were identified by the project steering committee and a panel of axSpA Italian experts. A systematic literature review (SLR) was performed for each of the selected topics according to the PICO format. Two rounds of a modified Delphi process were conducted. In the 1st round, the steering committee evaluated the results of the SLR in order to formulate statements for each topic. In the 2nd round, the experts panel discussed, rephrased when needed, and voted the level of agreement (on a 5-point Likert-type scale) for each statement. Consensus was defined as ≥66% agreement. RESULTS: The topics selected for the analysis were the differential efficacy of available bDMARDs on enthesitis/dactylitis, uveitis, radiographic progression and cardiovascular involvement, and the clinical response in non radiographic-axSpA and in patients receiving a second-line bDMARD. The Delphi rounds formulated 19 statements, all reaching the defined level of consensus in a second round including 25 rheumatologists highly skilled in the management of axSpA. CONCLUSION: Identified consensus statements can help clinicians to apply to routine-care settings the results from clinical studies and international recommendations, providing a guide for individualization of treatment strategy in axSpA patients.


2018 - Timing of onset affects arthritis presentation pattern in antisyntethase syndrome [Articolo su rivista]
González-Gay, Ma; Montecucco, C; Selva-O'Callaghan, A; Trallero-Araguas, E; Molberg, O; Andersson, H; Rojas-Serrano, J; Perez-Roman, Di; Bauhammer, J; Fiehn, C; Neri, R; Barsotti, S; Lorenz, Hm; Doria, A; Ghirardello, A; Iannone, F; Giannini, M; Franceschini, F; Cavazzana, I; Triantafyllias, K; Benucci, M; Infantino, M; Manfredi, M; Conti, F; Schwarting, A; Sebastiani, G; Iuliano, A; Emmi, G; Silvestri, E; Govoni, M; Scirè, Ca; Furini, F; Lopez-Longo, Fj; Martínez-Barrio, J; Sebastiani, M; Manfredi, A; Bachiller-Corral, J; Sifuentes Giraldo, Wa; Cimmino, Ma; Cosso, C; Belotti Masserini, A; Cagnotto, G; Codullo, V; Romano, M; Paolazzi, G; Pellerito, R; Saketkoo, La; Ortego-Centeno, N; Quartuccio, L; Batticciotto, A; Bartoloni Bocci, E; Gerli, R; Specker, C; Bravi, E; Selmi, C; Parisi, S; Salaffi, F; Meloni, Federica; Marchioni, E; Pesci, A; Dei, G; Confalonieri, M; Tomietto, P; Nuno, L; Bonella, F; Pipitone, N; Mera-Valera, A; Perez-Gomez, N; Gerzeli, S; Lopez-Mejias, R; Matos-Costa, Cj; Pereira da Silva, Ja; Cifrian, J; Alpini, C; Olivieri, I; Blázquez Cañamero, Má; Rodriguez Cambrón, Ab; Castañeda, S; Cavagna, L
abstract

OBJECTIVES: To evaluate if the timing of appearance with respect to disease onset may influence the arthritis presentation pattern in antisynthetase syndrome (ASSD). METHODS: The patients were selected from a retrospective large international cohort of ASSD patients regularly followed-up in centres referring to AENEAS collaborative group. Patients were eligible if they had an antisynthetase antibody testing positive in at least two determinations along with arthritis occurring either at ASSD onset (Group 1) or during the course of the disease (Group 2). RESULTS: 445 (70%; 334 females, 110 males, 1 transsexual) out of the 636 ASSD we collected had arthritis, in the majority of cases (367, 83%) from disease onset (Group 1). Patients belonging to Group 1 with respect to Group 2 had an arthritis more commonly polyarticular and symmetrical (p=0.015), IgM-Rheumatoid factor positive (p=0.035), erosions at hands and feet plain x-rays (p=0.036) and more commonly satisfying the 1987 revised classification criteria for rheumatoid arthritis (RA) (p=0.004). Features such as Raynaud's phenomenon, mechanic's hands and fever (e.g. accompanying findings) were more frequently reported in Group 2 (p=0.005). CONCLUSIONS: In ASSD, the timing of appearance with respect to disease onset influences arthritis characteristics. In particular, RA features are more common when arthritis occurs from ASSD onset, suggesting an overlap between RA and ASSD in these patients. When arthritis appears during the follow-up, it is very close to a connective tissue disease-related arthritis. Also, the different prevalence of accompanying features between these two groups is in line with this possibility.


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

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

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


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

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


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

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


2017 - Comparison of efficacy of first- versus second-line adalimumab in patients with rheumatoid arthritis: experience of the Italian biologics registries [Articolo su rivista]
Codullo, Veronica; Iannone, Florenzo; Sinigaglia, Luigi; Favalli, Ennio Giulio; Sarzi Puttini, Piercarlo; Atzeni, Fabiola; Ferraccioli, Gianfranco; Gremese, Elisa; Carletto, Antonio; Giollo, Alessandro; Govoni, Marcello; Bergossi, Francesca; Galeazzi, Mauro; Cantarini, Luca; Salaffi, Fausto; Di Carlo, Marco; Bazzani, Chiara; Pellerito, Raffaele; Sebastiani, Marco; Ramonda, Roberta; Lapadula, Giovanni; Caporali, Roberto
abstract

OBJECTIVES: Targeted drugs against key pathogenetic molecules such as TNF-alpha have significantly improved outcomes in rheumatoid arthritis (RA). They are widely used in clinical practice and drug registries give us information to support their use. Adalimumab (ADA) is able to induce a comprehensive disease control in RA by achieving clinical, functional and radiographic control. METHODS: By interrogating 2 Italian registries, LORHEN and GISEA, we analysed the efficacy of ADA in first- or second-line in a total of 2262 RA patients. RESULTS: Patients in 1st line were significantly older, with lower disease activity and HAQ scores compared to 2nd line. In 1st line, rates of DAS28-remission (DAS28rem) at 2 years were 34.4% while 26.5% in 2nd line (p=0.038). A normal HAQ score (HAQ≤0.5) was achieved in 53.5% after 2 years in 1st line versus 30.1% in 2nd (p<0.0001). DAS28rem+HAQ≤0.5, a combined parameter that we defined global clinical disease control, was reached in 20.7% in 1st line versus 13.3% in 2nd (p<0.01). Five-year-survival on therapy was higher for patients in 1st line (45.6% vs. 33.2%, p<0.0001). Discontinuation due to lack of efficacy was lower in 1st line (37.4 vs. 54.4%, p<0.0001). Rates of adverse events were similar. CONCLUSIONS: Responses in 1st line are generally significantly better than after a first anti-TNF-alpha failure but patients in 2nd line have a worse clinical and functional profile. A global disease control with clinical and functional remission is an achievable target in both lines.


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

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


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

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


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

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


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

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


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

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


2017 - Italian consensus Guidelines for the management of hepatitis B virus infections in patients with rheumatoid arthritis [Articolo su rivista]
Sebastiani, Marco; Atzeni, Fabiola; Milazzo, Laura; Quartuccio, Luca; Scirè, Carlo; Gaeta, Giovanni Battista; Lapadula, Giovanni; Armignacco, Orlando; Tavio, Marcello; Olivieri, Ignazio; Meroni, Pierluigi; Bazzichi, Laura; Grassi, Walter; Mathieu, Alessandro; Mastroianni, Claudio; Sagnelli, Evangelista; Santantonio, Teresa; Foppa, Caterina Uberti; Puoti, Massimo; Sarmati, Loredana; Airò, Paolo; Epis, Oscar Massimiliano; Scrivo, Rossana; Gargiulo, Miriam; Riva, Agostino; Manfredi, Andreina Teresa; Ciancio, Giovanni; Zehender, Gianguglielmo; Taliani, Gloria; Meroni, Luca; Sollima, Salvatore; Sarzi Puttini, Piercarlo; Galli, Massimo
abstract

OBJECTIVES: Hepatitis B (HBV) infection, which is prevalent worldwide, is also frequently seen in patients with rheumatoid arthritis (RA). The Italian Society of Rheumatology (SIR) and the Italian Society of Infectious and Tropical Diseases (SIMIT) endorsed a national consensus process to review the available evidence on HBV management in RA patients and to produce practical, hospital-wide recommendations. METHODS: The consensus panel consisted of infectious disease consultants, rheumatologists and epidemiologists and used the criteria of the Oxford Centre for Evidence-based Medicine to assess the quality of the evidence and the strength of their recommendations. RESULTS: A core-set of statements has been developed to help clinicians in the management of patients with RA and HBV infection. Vaccination and prophylaxis of RA patients treated with biological drugs have been also discussed. CONCLUSIONS: HBV Infection isn't rare in clinical practice; a screening for HBV in all patients with early arthritis is not universally accepted, while it is considered mandatory before starting any immunosuppressive or hepato-toxic treatment. In fact, a specific risk, associated with the use of biologic treatments, exists for patients with HBV infection, although longitudinal studies of viral reactivation are generally reassuring. RA patients with HBV infection should be referred to the hepatologist and correctly classified into active or inactive carriers. Patients with active hepatitis B should undergo antiviral treatment before starting immunosuppressive treatments. Occult HBV carriers should be monitored or receive prophylaxis on the basis of the risk of reactivation associated with the administered treatment.


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 - NAILFOLD VIDEOCAPILLAROSCOPY FEATURES OF PATIENTS WITH ANTISYNTHETASE SYNDROME [Abstract in Rivista]
Sebastiani, Marco; Codullo, V.; Manfredi, Andreina Teresa
abstract

Background: Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by the clinical triad arthritis, myositis, and interstitial lung disease (ILD). As in inflammatory myopathies, nailfold videocapillaroscopy (NVC) alterations have been sporadically described also in ASSD patients, but no elucidating data are available. Objectives: To investigate the possible specific NVC features of ASSD patients. Methods: Within the framework of a multicenter study, we retrospectively analyzed NVC images of ASSD patients, after excluding patients with overlap syndrome with systemic sclerosis. Two operators in a blind manner re-evaluated all patients with at least one image per finger. For each patient, we examined number of capillaries (mean number of capillaries per mm in the distal row), enlarged and giant capillaries, micro-hemorrhages, avascular areas, ramified capillaries, and the presence of a scleroderma (SSc)-like pattern, according to manfredi et al. Finally, we correlated NVC features with clinical and serological findings of ASSD patients. Results: The NVC of 54 ASSD patients were analyzed (males/females 1/6.8, mean age 55.79, CI95% 51.9–59.9 years, mean disease duration 59.4, CI95% 27.9–90.9 months). Raynaud's phenomenon (RP) was recorded in 51.9% of patients, arthritis in 79.6%, myositis in 53.7%, and ILD in 92.6%. NVC alterations were observed in 53.7% of AASD patients. Nineteen patients (35.2%) showed a SSc-like pattern; the main features were disarrangement of hairpin and angiogenetic aspects (42.6%), avascular areas (38.9%), giant capillaries (27.6%), and microhemorrhages (20.4%). Finally, the mean number of capillaries was reduced (7.8±2/mm). No significant association was recorded between SSc-like pattern and the presence of arthritis, myositis, and ILD, nor with RP. Among other NVC features, angiogenesis was significantly associated to female gender (p=0.031), while microhemorrhages were inversely associated to the presence of arthritis (0.033). No association was observed between NVC features and autoantibodies profile. Of interest, in 58% of patients with ILD we observed at least a NVC alteration vs no patients without ILD (p=0.04). Finally, in patients with RP NVC alterations were recorded in 15/28 patients (53.6%) and a SSc-like pattern in 11/28 (39.3%), while only 57.9% of patients with SSc-like pattern had a clinically manifest Raynaud's phenomenon. Conclusions: Despite preliminary, the present is the first study concerning NVC in AASD patients. Regardless of the presence of Raynaud's phenomenon, NVC alterations are frequently observed; in particular, a SSc-like pattern is recorded in more than 1/3 of patients. NVC should be performed in all ASSD patients at diagnosis regardless of the presence of RP in the patient history and during follow-up. ASSD should be always considered in the screening of RP. A prospective multicenter study has been planned to identify specific patterns and possible associations between NVC findings and clinical and serological features of ASSD.


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

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


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

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


2017 - Recommendations for the management of pulmonary fungal infections in patients with rheumatoid arthritis [Articolo su rivista]
Galli, Massimo; Antinori, Spinello; Atzeni, Fabiola; Meroni, Luca; Riva, Agostino; Scirè, Carlo; Adorni, Fulvio; Quartuccio, Luca; Sebastiani, Marco; Airò, Paolo; Bazzichi, Laura; Cristini, Francesco; Del Bono, Valerio; Manfredi, Andreina; Viapiana, Ombretta; De Rosa, Francesco; Favalli, Ennio; Petrelli, Enzo; Salvarani, Carlo; Govoni, Marcello; Corcione, Silvia; Scrivo, Rossana; Sarmati, Loredana; Lazzarin, Adriano; Grassi, Walter; Mastroianni, Claudio; Gaeta, Giovanni Battista; Ferraccioli, Gianfranco; Cutolo, Maurizio; De Vita, Salvatore; Lapadula, Giovanni; Matucci-Cerinic, Marco; Armignacco, Orlando; Sarzi-Puttini, Piercarlo
abstract

Often life-threatening pulmonary fungal infections (PFIs) can occur in patients with rheumatoid arthritis (RA) receiving disease-modifying anti-rheumatic drugs (DMARDs). Most of the data concerning PFIs in RA patients come from case reports and retrospective case series. Of the ve most widely described PFIs, Pneumocystis jirovecii pneumonia (PJP) has rarely been seen outside Japan, pulmonary cryptococcosis has been diagnosed in only a small number of patients worldwide, pulmonary coccidioidomycosis has almost only been observed in endemic areas, the limited number of cases of pulmonary histoplasmosis have mainly occurred in the USA, and the rare cases of invasive pulmonary aspergillosis have only been encountered in leukopenic patients. Many aspects of the prophylaxis, diagnosis and treatment of PFIs in RA patients remain to be defined, as does the role of each DMARD in increasing the risk of infection, and the possibility of resuming biological and non-biological DMARD treatment after the infection has been cured. The recommendations for the management of PFIs described in this paper are the product of a consensus procedure promoted by the Italian group for the Study and Management of Infections in Patients with Rheumatic Diseases (the ISMIR group).


2017 - THU0366 Gastrointestinal infections in patients with spondyloarthritis treated with anti-tnf drugs: results of gisea register [Abstract in Rivista]
Atzeni, F.; Panetta, V.; Sebastiani, M.; Salaffi, F.; Carletto, A.; Foti, R.; Iannone, F.; Elisa, G.; Govoni, M.; Marchesoni, A.; Favalli, E. G.; Gorla, R.; Ramonda, R.; Sarzi-Puttini, P.; Ferraccioli, G.; Lapadula, G.
abstract

Background: Tumour necrosis factor (TNF) plays a pivotal role in controlling intracellular of bacterial infection. The BSR Biologics Register (BSRBR) has reported an increase in the occurrence of listeria and salmonella infections in anti-TNF-treated rheumatoid arthritis patients in comparison with those patients treated with non-biological DMARDs. Objectives: The aim of this study was to determine the incidence of gastrointestinal infection in the anti-TNF-treated spondyloarthritis (SpA) patients in the GISEA registry, and identify the factors associated with its development. Methods: The prospective GISEA registry was designed to collect real-world clinical data concerning patients with RA or SpA treated with biological drugs. The baseline information includes demographics, disease duration, HAQ-DI, DAS-28, BASDAI, BASFI and BASMI scores, steroid use, smoking history and comorbidities. Results: Of the 3321 anti-TNF-treated SpA patients in the registry (1731 males, 52.2%; mean age 47±13 years; median disease duration three years, interquartile range [IQR] 0–8), 1065 (32%) were treated with infliximab (IFN), 1052 (32%) with adalimumab (ADA), and 1204 (36%) with etanercept (ETN). Two thousand, one hundred and five patients (63.4%) had a median of one comorbidity (IQR 0–2], the most frequent being hypertension (701), thyroid diseases (281), diabetes mellitus (207), cardiopathy (189), and osteoporosis (145). In combination with the biological drug, 919 patients (27.7%) received steroids and 2451 (79.9%) at least one DMARD. The median follow-up was three months (IQR 1–2 years). Twenty-two patients 0.7% experienced bacterial gastrointestinal infections, the most frequent being due to listeria, klebsilla and salmonella. The crude incidence rate was 2.5 per 1000 patient-years (95% CI 1.6–3.7). Univariate analysis showed that female gender (OR 3.9, 95% CI 1.5–10.0; p=0.004) and comorbidities (OR 3.4, 95% CI 1.0–3.5; p=0.049) were associated with a high risk of gastrointestinal infections, and that the use of IFN rather than ETN and ADA (p=0.712 and p=0.238) was not associated with a higher risk of gastrointestinal infections. Furthermore, univariate models showed that age (p=0.738), disease duration p=0.090, previous DMARDs (p=0.616), and HAQ (p=0.674) and BASFI (scores p=0.850) were not statistically significant predictors of gastrointestinal infections. Conclusions: The incidence rate of gastrointestinal infections in SpA patients treated with anti-TNF drugs is not increased. Being female and having comorbidities are predictive factors of gastrointestinal infections.


2017 - The performance of the GAP model in patients with rheumatoid arthritis associated interstitial lung disease [Articolo su rivista]
Morisset, Julie; Vittinghoff, Eric; Lee, Bo Young; Tonelli, Roberto; Hu, Xiaowen; Elicker, Brett M.; Ryu, Jay H.; Jones, Kirk D.; Cerri, Stefania; Manfredi, Andreina Teresa; Sebastiani, Marco; Gross, Andrew J.; Ley, Brett; Wolters, Paul J.; King, Talmadge E.; Kim, Dong Soon; Collard, Harold R.; Lee, Joyce Sujin
abstract

Background Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Similarities have been observed between patients with idiopathic pulmonary fibrosis (IPF) and the UIP (usual interstitial pneumonia) form of RA-ILD. The GAP (gender, age, physiology) model has been shown to predict mortality in patients with IPF, but its ability to predict mortality in RA-ILD is not known. Methods We identified 309 patients with RA-ILD at 4 academic centers with ongoing longitudinal cohorts of patients with ILD. The primary endpoint was mortality. To handle missing data (n&nbsp;=&nbsp;219 subjects with complete dataset), multiple imputation by iterative chained equations was used. Using the GAP model as a baseline, we assessed improvements in mortality risk prediction achieved by incorporating additional variables. Model discrimination was assessed using the c-index, and calibration was checked by comparing observed and expected incidence of death. Results Patients had a mean age of 65 years and were predominantly female (54%). The mean forced vital capacity (FVC) % predicted was 73 and the mean diffusing capacity for carbon monoxide (DLCO) % predicted was 55. Twenty-four percent of the 236 patients with a high-resolution computed tomography scan available for review had a definite UIP pattern. The original GAP model, including gender, age, FVC%, and DLCO%, had a c-index of 0.746 in our cohort. Calibration of this model was satisfactory at 1, 2 and 3 years. Model discrimination was not meaningfully improved by adding other clinical variables. Conclusion The GAP model that was derived for IPF performs similarly as a mortality risk prediction tool in RA-ILD.


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 - Drug survival of adalimumab in patients with rheumatoid arthritis over 10 years in the real-world settings: high rate remission together with normal function ability [Articolo su rivista]
Iannone, Florenzo; Sinigaglia, Lugi; Favalli, Ennio Giulio; Sarzi Puttini, Piercarlo; Atzeni, Fabiola; Caporali, Roberto; Codullo, Veronica; Ferraccioli, Gianfranco; Gremese, Elisa; Carletto, Antonio; Giollo, Alessandro; Govoni, Marcello; Bergossi, Francesca; Galeazzi, Mauro; Cantarini, Luca; Salaffi, Fausto; Di Carlo, Marco; Bazzani, Chiara; Pellerito, Raffaele; Sebastiani, Marco; Ramonda, Roberta; Lapadula, Giovanni
abstract

The purpose of the study was to estimate the clinical profile of naïve biological patients with rheumatoid arthritis (RA) starting adalimumab through 3-year calendar periods and their clinical outcomes such as drug survival and global clinical disease control (GCDC). RA patients starting adalimumab as first biological drug between 2003 and 2012 were subdivided in 3-year calendar periods. Survival on therapy was estimated using the Kaplan-Meier analysis. One and 2-year clinical response was assessed by calculating percentage of patients attaining GCDC (28-joint Disease Activity Score (DAS28) ≤ 2.6 + Health Assessment Questionnaire (HAQ) ≤ 0.5), low disease activity (DAS28 ≤ 3.2), remission (DAS28 ≤ 2.6) and good European League Against Rheumatism (EULAR) response. Multivariate regression models were used to assess baseline predictors of drug discontinuation or achievement of clinical remission. We recruited 1695 RA patients. Overall drug persistence at 3 years was 40.6 %, while the global rate of nonswitching patients was 54.7 %. Compared to 2003–2005, initiators in more recent years had a significantly lower 3-year crude drug retention rate (log rank, p < 0.0001) and a significantly higher rate of switching to alternative biologics (log rank, p < 0.0001). No difference in adverse events or effectiveness rate among the calendar periods was found. A substantial proportion of patients (up to 27 %) achieved GCDC at 2 years, regardless of the calendar period. In real-life setting, RA patients starting adalimumab in more recent years had a higher rate of drug discontinuation not related to ineffectiveness or side effects but to switching, probably due to a wider availability of biologics. A meaningful proportion of patients attained GCDC without any difference across calendar periods.


2016 - EFFICACIA, SAFETY E TOLLERANZA DI ADALIMUMAB IN PRIMA E SECONDA LINEA IN PAZIENTI CON ARTRITE REUMATOIDE: ESPERIENZA DAI REGISTRI ITALIANI DEI FARMACI BIOLOGICI [Abstract in Rivista]
Sebastiani, Marco
abstract

I farmaci biotecnologici con specifici target patogenetici hanno significativamente migliorato gli outcome dell’artrite reumatoide (AR). Tali farmaci sono ampiamente utilizzati nella pratica clinica e i loro registri permettono di ricavare informazioni uniche circa il loro utilizzo. Adalimumab (ADA) induce un controllo di malattia globale (comprehensive disease control) nell’AR ottenendo risultati clinici, funzionali e radiografici. Scopo. Attraverso l’analisi di due registri italiani, il LORHEN ed il GISEA, sono state analizzate e comparate l’efficacia la sicurezza e la tollerabilità di ADA in prima e seconda linea. I dati sono stati analizzati con STATA software per Windows. Risultati. Sono stati arruolati un totale di 2262 pazienti con AR. ADA rappresentava la prima linea in farmaco biologico in 1780 (78.7%) soggetti e la seconda linea in 482 (21.3%).I pazienti in 1 a linea erano significativamente più anziani (53.3±13.1 vs 51.4±13.2, p=0.010), con attività di malattia e HAQ score meno elevate che in 2a linea (5.3±1.5 vs 5.5±1.3, p=0.002 e 1.2±0.7 vs 1.4±0.7, p=0.001 rispettivamente). In 1 a linea la percentuale di remissione DAS28 a 2 anni era del 34.4% mentre era del 26.5% in 2a linea (p=0.038). Una normalizzazione dell’HAQ (HAQ&lt;0.5) era ottenuto nel 53.5% dopo 2 anni in 1 a linea versus 30.1% in 2 a (p&lt;0.0001). La combinazione dei 2 parametri, DAS28rem+HAQ&lt;0.5, uno score che abbiamo definito “global clinical disease control”, è stato ottenuto nel 20.7% in 1a linea versus 13.3% in 2 a (p&lt;0.01). La sopravvivenza in terapia a 5 anni era più elevata in 1 a linea (45.6% vs 33.2%, p&lt;0.0001). La sospensione della terapia per mancanza di efficacia era inferiore in 1 a linea (37.4 vs 54.4%, p&lt;0.0001). Le percentuali di eventi avversi erano simili tra I due gruppi. Discussione. La risposta clinica e funzionale è in generale migliore in 1 a linea che dopo un primo fallimento di un anti-TNF alfa ma i pazienti in 2 a linea hanno peggiori caratteristiche al basale e le percentuali riscontrate permangono in assoluto elevate. Il global disease control è un target auspicabile e raggiungibile in entrambi i gruppi di trattamento.


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 - IN PATIENTS WITH SPONDYLOARTHRITIS ANTI-TNF THERAPY IS NOT ASSOCIATED WITH AN INCREASE IN NEOPLASIAS: RESULTS OF GISEA REGISTER [Abstract in Rivista]
Atzeni, F; Carletto, A; Foti, R; Sebastiani, Marco; Panetta, V; Salaffi, F; Iannone, F; Gremese, E; Govoni, M; Marchesoni, A; Gorla, R; Ramonda, R; Sarzi Puttini, P; Ferraccioli, Gf; Lapadula, G.
abstract

Data from Italian GISEA register show that anti-TNF therapy is not associated with an increase in neoplasias in patients with spondyloarthritis


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

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


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

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


2016 - Interstitial 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 - Predicting Mortality in Patients with Rheumatoid Arthritis Related Interstitial Lung Disease: Expanding The GAP Model [Abstract in Rivista]
Morisset, Julie; Vittinghoff, Eric; Lee, Bo Young; Tonelli, Tonelli; Hu, Xiaowen; Elicker, Brett M; Ryu, Jay H; Jones, Kirk D; Cerri, Stefania; Manfredi, Andreina Teresa; Sebastiani, Marco; Ley, Brett J; Wolters, Paul J; King, Talmadge E; Kim, Dong Soon; Collard, Harold R; Lee, JOYCE SUJIN
abstract

Rationale: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a disease associated with morbidity and mortality. There is a high prevalence of usual interstitial pneumonia (UIP) pattern in RA-ILD and similarities have been observed between patients with idiopathic pulmonary fibrosis (IPF) and the UIP form of RA-ILD. The GAP (gender, age, physiology) model has been shown to predict mortality in patients with IPF, but its ability to predict mortality in RA-ILD is not known. Methods: We identified 309 patients with RA-ILD at 4 academic centers with ongoing longitudinal cohorts of patients with ILD (Mayo Clinic, University of Ulsan, University of California, San Francisco and University of Modena & Reggio Emilia). The primary endpoint was mortality. To handle the issue of missing data, multiple imputation by iterative chained equations was used, resulting in 20 completed datasets. Linear and logistic imputation models were used for continuous and binary covariates, respectively. Using the GAP model as the baseline mortality prediction model, we determined the additive model performance for mortality risk prediction by incorporating additional variables. Model discrimination was assessed using the c-index. Results: Patients had a mean age of 65 years and were predominantly female (54%). The mean forced vital capacity % predicted was 73 and the mean diffusing capacity for carbon monoxide (DLCO) % predicted was 55. The majority of patients had positive rheumatoid factor (RF) (89%) or positive anti-cyclic citrullinated peptide antibody (71%). Twenty-four percent of patients had a definite UIP pattern on high-resolution computed tomography (HRCT). The original GAP model (Gender, Age, FVC%, DLCO%) had a c-index of 0.69 in our cohort. The performance of this model improved by expanding the GAP model to include 2 additional variables: definite UIP pattern on HRCT and positive RF. The c-index of this expanded model was 0.71. Conclusions: The addition of 2 variables, definite UIP pattern on HRCT and RF, improves the performance of the GAP model to predict mortality in patients with RA-ILD.


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

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


2016 - TIPIZZAZIONE CLINICA DELLA SINDROME ANTISINTETASICA: CONFRONTO TRA PAZIENTI ANTI JO-1 POSITIVI E NEGATIVI [Abstract in Rivista]
V., Codullo; M. A., Gonzalez Gay; R., Neri; S., Barsotti; F., Franceschini; I., Cavazzana; C., Montecucco; R., Caporali; S., Balduzzi; C. F., Selmi; A., Pesci; G., Dei; F., Meloni; A., Batticciotto; G., Emmi; M., Benucci; M. A., Cimmino; A., Doria; A., Ghirardello; L., Quartuccio; G., Paolazzi; N., Pipitone; F., Salaffi; Sebastiani, Marco; Manfredi, Andreina Teresa; M., Govoni; F., Furini; S., Parisi; R., Pellerito; F., Iannone; M., Giannini; E., Bartoloni Bocci; F., Conti; E., Bravi; A., Iuliano; P., Tomietto; C. A., Scirè; S., Castaneda; C., Cosso; A., Selva O’Callaghan; M., Confalonieri; L., Cavagna
abstract

Scopo del lavoro. Valutare se il pattern di presentazione e evoluzione clinica della sindrome antisintetasica (SAS) sia influenzato dal profilo autoanticorpale del paziente (anti Jo-1 versus non anti Jo-1). Materiali e Metodi. Criteri di inclusione: 1) doppia positività per gli anticorpi antisintetasi; 2) presenza di almeno una manifestazione tra artrite, miosite e interstiziopatia polmonare (ILD). Definizioni: a) esordio: prima evidenza di interessamento articolare, muscolare o polmonare; b) esordio concomitante: meno di 3 mesi tra la comparsa di 2 interessamenti d’organo successivi; 3) definizione del pattern di malattia: forma completa, artrite, miosite e ILD; forma incompleta, mancanza di almeno una delle manifestazioni della triade; 4) tipo di studio: retrospettivo. 5) analisi statistica: test Chi quadro, t-test o Mann-Whitney test (in relazione al tipo di variabile e di distribuzione). Stata software (2009, 11; StataCorp, TX, USA). Risultati. Valutati 580 pazienti (431 F, 149 M). Mediane e range interquartili: esordio: 53 anni (43-62), ritardo diagnostico: 6 mesi (2-20.5), follow-up 63.5 mesi (27-122). Pazienti anti Jo-1 positivi: 428; pazienti con altri Ab antisintetasi: 152 (63 anti-12, 59 PL-7, 18 EJ, 8 OJ, 1 EJ e OJ, 2 PL-7 e PL-12, 1 PL-12 e EJ). Nelle tabelle 1 e 2 sono riassunte e confrontate le principali caratteristiche dei pazienti Jo-1 e non Jo-1 inclusi nello studio. Conclusioni. Il pattern di presentazione e di evoluzione della SAS appare influenzato dalla sottostante positività autoanticorpale. Se la forma completa, l’artrite isolata e l’associazione tra miosite e ILD sono più comuni all’esordio nei pazienti anti Jo-1 positivi, l’ILD isolata è più comune nei pazienti non anti Jo-1 positivi. La progressione delle manifestazioni appare più evidente nella SAS anti Jo-1 positiva, anche se questa osservazione potrebbe essere influenzata dalla minor lunghezza del follow-up nei pazienti non anti Jo-1 positivi.


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 - Anti-TNF Therapy Is Not Associated with an Increase in Neoplasias in Patients with Spondyloarthritis (SpA): Results from the GISEA Registry [Abstract in Rivista]
Atzeni, F; Carletto, A; Sebastiani, Marco; Panetta, V; Salaffi, F; Iannone, F; Gremese, E; Govoni, M; Marchesoni, A; Gorla, R; Ramonda, R; Sarzi Puttini, Pc; Ferraccioli, G; Lapadula, G.
abstract

Background/Purpose: The use of TNF inhibitors (TNFIs) has led to efficient control of the signs and symptoms of SpA and rheumatoid arthritis (RA), and significantly improved the patients’ quality of life. However, as most patients need often indeterminately long-term treatment (especially those with SpA), rheumatologists must be aware of treatment side effects such as malignances, even though nine clinical trials of etanercept in SpA patients did not find an increased risk. The aim of this study was to evaluate the risk of malignances in the TNFI-treated SpA patients in the Gruppo Italiano Studio Early Arthritis( GISEA) Registry, and assess predictors of malignancies Methods: The Registry, which is designed to collect real-world clinical data concerning RA and SpA patients receiving biological drugs as part of routine care, was approved by local Ethics Committees, and enrols patients aged ≥18 years who have given their written informed consent. The baseline information includes demographics, disease duration, HAQ, DAS-28, BASDAI, BASFI and BASMI scores, steroid use (defined as actively receiving oral steroids at the time of recruitment), smoking history and comorbidities. Results: The analysis involved 3321 SpA patients (1731 males, 52.2%; mean age 47±13 years; median disease duration three years, interquartile range [IQR] 0, 8 years): 1065 (32%) treated with infliximab (IFN), 1052 (32%) with adalimumab (ADA), and 1204 (36%) with etanercept (ETN). Two thousand, one hundred and five (63.4%) had a median of one comorbity (IQR 0, 2], the most frequent being hypertension (701), thyroid diseases (281), diabetes mellitus (207), cardiopathy (189), and osteoporosis (145). In combination with the biological drug, 919 patients (27.7%) received steroids and 2451 (79.9%) at least one DMARD. The median follow-up time was three months (IQR 12 years). During 12 years of TNFI treatment, 50 patients experienced at least one of 56 neoplasias, 28% of which occurred during the first 12 months. Overall incidence was 6.3/1000 patient-years of follow-up (95% CI 4.7–8.2): 7.3/1000 (95% CI 4.1–11.8) among those treated with ADA; 6.1/1000 (95% CI 3.8–9.4) among those treated with ETN; and 5.8/1000 (95% CI 3.5–9.1) among those treated with IFN. Univariate analysis showed that age at the start of anti-TNF treatment (p=0.001), the number of comorbidities (p<0.001), and HAQ score (p=0.002) were associated with a high risk of malignancy. Multivariate models showed that male gender (hazard ratio [HR] 4.5, 95%CI1.3-16.0; p=0.020), age at the start of anti-TNF treatment (HR 1.1, 95%CI 1.01-1.11; p=0.020), and HAQ score (HR 2.8, 95%CI1.5-5.3; p=0.002) were statistically significant predictors of malignances. Ten of the 50 patients experiencing a neoplasia had had a previous solid cancer (HR 11.2, 95%CI 4.4-28.4; p<0.001). Conclusion: TNFI therapy is not associated with a significant overall risk of malignances in SpA patients, but having had a previous solid cancer is predictive of a new neoplasia.


2015 - Anti-TNF Therapy Is Associated with an Increase in Serious Infections in Patients with Spondyloarthritis (SpA), Especially during the First 12 Monts of Treatment: Results from the GISEA Registry [Abstract in Rivista]
Atzeni, F; Sebastiani, Marco; Panetta, V; Salaffi, F; Marchesoni, A; Ramonda, R; Iannone, F; Gorla, R; Gremese, E; Govoni, M; Sarzi Puttini, Pc; Ferraccioli, G; Lapadula, G.
abstract

Background/Purpose: Infection is by far the most common and most important adverse effect of TNF inhibitors (TNFI) in the treatment of rheumatoid arthritis (RA) and spondyloarthritis (SpA). The aim of this study was to evaluate the risk of SIs in the TNFI-treated SpA patients in the Gruppo Italiano Studio Early Arthritis (GISEA) Registry, and assess the predictors of their occurrence. Methods: The Registry, which is designed to collect real-world clinical data concerning RA and SpA patients receiving biological drugs as part of routine care, was approved by local Ethics Committees, and enrols patients aged ≥18 years who have given their written informed consent. The baseline information includes demographics, disease duration, HAQ, DAS-28, BASDAI, BASFI and BASMI scores, steroid use (defined as actively receiving oral steroids at the time of recruitment), smoking history and comorbidities. Results: The analysis involved 3321 SpA patients (1731 males, 52.2%; mean age 47±13 years; median disease duration three years, interquartile range [IQR] 0, 8 years): 1065 (32%) treated with infliximab (IFN), 1052 (32%) with adalimumab (ADA), and 1204 (36%) with etanercept (ETN). Two thousand, one hundred and five (63.4%) had a median of one comorbity (IQR 0, 2], the most frequent being hypertension (701), thyroid diseases (281), diabetes mellitus (207), cardiopathy (189), and osteoporosis (145). In combination with the biological drug, 919 patients (27.7%) received steroids and 2451 (79.9%) at least one DMARD. The median follow-up was three months (IQR 12 years). During 12 years of TNFI treatment, 259 patients experienced at least one of 391 microbiologically diagnosed SIs, 32% of which were recorded in the first 12 months. Overall incidence was 43.9/1000 patient-years of follow-up (95% CI 39.6–48.4): 29.9/1000 (95% CI 23.1–38.1) among those treated with ADA; 36.1/1000 (95% CI 30.0–43.1) among those treated with ETN; and 61.4/1000 (95% CI 53.3–70.5) among those treated with IFN. The most frequent were lower respiratory tract infections (pneumonia and bronchitis), followed by cutaneous infections. Bacteria were the most frequent micro-organisms (228, 58.3%), followed by fungal infections (40, 10.2%) and viral infections including herpes zoster (22, 5.6%). Univariate analysis showed that female gender (p=0.019) and comorbidities (p<0.001) were associated with a high risk of SI, and that the use of ETN or ADA rather than IFN (p<0.001 and p0.001) was associated with a lower risk of SI. Multivariate models showed that the number of comorbidities (hazard ratio [HR] 1.29, 95%CI 1.2–1.4; p<0.001), age at the start of anti-TNF treatment (HR 0.99, 95%CI 0.97-0.99; p=0.030), steroid use (HR 1.40, 95%CI 1.1–1.8; p=0.012), male gender (HR 0.72, 95%CI 0.5-0.9; p=0.012) were statistically significant predictors of infection. The factors independently associated with a decreased risk of SIs were the use of ETN (HR 0.52, 95%CI 0.4-0.7; p<0.001) or ADA (HR 0.59, 95%CI 0.4-0.8; p=0.002) rather than INF. Conclusion: These data add to currently available evidence suggesting that TNFI therapy is associated with a small but significant overall risk of SI in SpA patients.


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 - Position paper of Italian rheumatologists on the use of biosimilar drugs [Articolo su rivista]
Atzeni, Fabiola; Sebastiani, Marco; Ricci, Cristian; Celano, Antonella; Gremese, Elisa; Iannone, Florenzo; Meroni, Pier Luigi; Minghetti, Paola; Sarzi Puttini, Piercarlo; Ferraccioli, Gianfranco; Lapadula, Giovanni
abstract

The recent availability of biosimilars as a result of the expiry of the patents of first-generation biotechnological drugs may theoretically reduce the direct costs of such treatments, making their use accessible to a larger number of patients. However, the currently available clinical data refer to a relatively small number of patients, and do not provide sufficient information concerning long-term efficacy and safety or the frequency of rare adverse events. Given the importance of the introduction of biosimilar drugs and the limitations of our current knowledge of their efficacy and safety profiles, we believe it is mandatory to draw up a position paper for Italian Rheumatologists. Moreover, in order to guarantee their safety, it is mandatory to indicate behavioural rules for the involved specialists and competent authorities, and perform ad hoc clinical trials and appropriate drug surveillance.


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 - Prevalenza delle epatiti nelle malattie reumatiche [Abstract in Rivista]
Sebastiani, Marco
abstract

I virus dell’epatite B (HBV) e C (HCV) sono ampiamente diffusi in tutto il mondo, anche se con un’elevata variabilità geografica. È stato stimato che 350 milioni di persone al mondo siano portatori cronici del virus B, con un milione di decessi all’anno per patologie HBV correlate. La prevalenza mondiale stimata per l’HCV si aggira invece intorno al 2,2%, corrispondente a circa 130 milioni di individui affetti. Nel complesso il 75-80% dei casi di epatocarcinoma è attribuibile a HBV (50-55%) o HCV (25-30%). Pertanto, in considerazione dell’elevata prevalenza nella popolazione generale delle artropatie infiammatorie croniche (&gt;1%) e delle infezioni croniche da HBV e HCV (circa 3-4%), la loro associazione casuale potrebbe non essere particolarmente rara. Inoltre, anche in virtù del frequente decorso asintomatico delle due infezioni, non si può inoltre escludere una sottostima dei pochi dati epidemiologici al riguardo. Aldilà del noto coinvolgimento epatico, sia l’HCV che l’HBV possono essere responsabili di manifestazioni extraepatiche. Infatti, manifestazioni cliniche come l’artropatia possono essere evidenti nel 40-70% dei pazienti con HCV e nel 20% dei pazienti con infezione da HBV. Proprio per questo motivo e per il suo spiccato linfotropismo, l’HCV è stato messo in relazione allo sviluppo di malattie infiammatorie croniche come l’artrite reumatoide, analogamente a quanto ampiamente dimostrato per la vasculite crioglobulinemica. In un ampio studio prospettico su 1614 pazienti con infezione cronica da HCV il 23% di questi riferiva la presenza di artralgie o artrite, mentre almeno altri 2 studi evidenziavano un’alta prevalenza di HCV fra i malati reumatici, in particolare fra quelli con artrite reumatoide. Analogamente diversi studi hanno ipotizzato un ruolo dell’HBV come trigger per lo sviluppo di malattie autoimmuni sistemiche ed osservavano un alto tasso di fattore reumatoide fra i portatori dell’antigene australe. La variabilità geografica di entrambe le infezioni da HBV e HCV è nota; per quanto riguarda l’HCV la sua prevalenza è estremamente bassa in Nord Europa, Nord America e nei paesi anglosassoni, ad esempio Regno Unito (0,01%), Germania (0,6%), India (0,9%), Francia (1,1%). Valori progressivamente crescenti sono stati evidenziati negli Stati Uniti (1,8%), in Giappone (2,3%), Italia (2,2%), Cina (3,2%) ed Egitto (22%). Come già detto i pochi dati presenti in letteratura sembrerebbero mostrare tassi di infezione da HCV in corso di artropatie infiammatorie croniche come l’artrite reumatoide (AR), la spondilite anchilosante (SA) e l’artrite psoriasica (AP) più alti di quelli attesi, lasciando pertanto ipotizzare un ruolo del virus nella etiopatogenesi di queste malattie. Infatti, diversamente da quanto atteso, un’infezione da HCV in corso di malattia infiammatoria cronica si osserva nel 7,4% dei casi in Italia, nel 2,3% in Francia e nello 0,79% in Spagna. Per quanto riguarda l’epatite B uno studio svolto in Cina mostrava una prevalenza doppia dell’HBsAg nella spondilite anchilosante rispetto alla popolazione generale. Questi dati hanno lasciato ipotizzare per molti anni la possibilità che i virus epatotropi (in particolare B e C) avessero un qualche ruolo nella etiopatogenesi delle artropatie infiammatorie croniche, anche se questo ruolo non è mai stato confermato, al punto che uno studio francese ritiene di scarso beneficio uno screening per HCV in tutti i pazienti con artrite all’esordio, a causa del basso impatto sulla malattia e gli alti costi che ciò comporterebbe. In ogni caso, un così alto dato di prevalenza indica un’elevata possibilità nella pratica clinica di osservare pazienti con infezione da HBV o HCV, determinando una serie di conseguenze nel momento di iniziare terapie immunosoppressive tradizionali o con farmaci biologici, o comunque per tutte quelle terapie potenzialmente epatotossiche come il metotrexat


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

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


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

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


2015 - 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 - Chapter 52 - Cryoglobulins and Cryoglobulins Secondary to Hepatitis C Virus Infection [Capitolo/Saggio]
Ferri, Clodoveo; Sebastiani, Marco; Dilia, Giuggioli; 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 - Efficacy and safety of rituximab with and without methotrexate in the treatment of rheumatoid arthritis patients: results from the GISEA register [Articolo su rivista]
Sebastiani, Marco; Anelli, Maria Grazia; Atzeni, Fabiola; Bazzani, Chiara; Farina, Ilaria; Fedele, Anna Laura; Favalli, Ennio Giulio; Fineschi, Irene; Cino, Nicolò; Dal Forno, Ilaria; Gasparini, Stefania; Cassarà, Emanuele; Giardina, Rita; Bruschi, Eleonora; Addimanda, Olga; Cassone, Giulia; Lopriore, Simona; Sarzi Puttini, Piercarlo; Filippini, Matteo; Pignatti, Federica; Gremese, Elisa; Biggioggero, Martina; Manganelli, Stefania; Amato, Giorgio; Caimmi, Cristian; Salaffi, Fausto; Iannone, Florenzo; Ferri, Clodoveo; Sandri, Gilda; Lapadula, Giovanni; Gorla, Roberto; Govoni, Marcello; Ferraccioli, Gianfranco; Marchesoni, Antonio; Galeazzi, Mauro; Foti, Rosario; Carletto, Antonio; Cantini, Fabrizio; Triolo, Giovanni; Epis, Oscar Massimiliano; Salvarani, Carlo
abstract

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


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

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


2014 - High rate of disease remission in moderate rheumatoid arthritis on etanercept therapy: data from GISEA, the Italian biologics register [Articolo su rivista]
Florenzo, Iannone; Elisa, Gremese; Gaia, Gallo; Piercarlo Sarzi, Puttini; Costantino, Botsios; Francesco, Trotta; Stefania, Gasperini; Mauro, Galeazzi; Silvano, Adami; Fabrizio, Cantini; Sebastiani, Marco; Roberto, Gorla; Antonio, Marchesoni; Annarita, Giardina; Rosario, Foti; Angiola, Mele; Eleonora, Bruschi; Gianluca, Bagnato; Gian Luca, Erre; Giovanni, Lapadula
abstract

The aim of this study was to evaluate the clinical outcomes of etanercept in rheumatoid arthritis (RA) patients with moderate or severe disease activity. We analyzed data from the Italian biologics register Gruppo Italiano Studio Early Arthritides (GISEA) to investigate the rate of disease remission and functional improvement, based on the 28-Joint Disease Activity Score (DAS28) and the (Health Assessment Questionnaire (HAQ) score in RA patients with moderate or severe disease activity beginning etanercept therapy. Disease was defined as severe (H-RA) with DAS28 ≥5.1 and moderate (M-RA) with DAS28 ≥3.2 to 5.1 at baseline. Patients were considered in remission if DAS28 was ≤2.6, and HAQ ≤0.5 defined normal function. We enrolled 953 RA patients, 320 with M-RA and 633 H-RA. Age and disease duration were similar in the two cohorts, but H-RA patients had significantly more comorbidities (p < 0.01) and took significantly more disease-modifying antirheumatic drugs (p < 0.001) than M-RA patients. After 1 year, the percentage of patients achieving disease remission and normal function (DAS28 ≤2.6 plus HAQ ≤0.5) was higher in M-RA (21.4 %) than in H-RA patients (14.8 %, p = 0.007), regardless of the disease duration. Additionally, female gender (p = 0.006) and H-RA class (p = 0.002) negatively predicted disease remission at 1 year. However, the drug survival rate did not differ between the two subsets. This study confirms that etanercept was effective in the treatment of active RA, but best response, in terms of disease remission and normal function ability, was greater and easier to attain in M-RA patients. These findings may aid clinicians to choose the best strategy to treat RA.


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

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


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

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


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; A., Lo Monaco; E., Praino; V., Riccieri; V., Grattagliano; A., Bortoluzzi; K., Stefanantoni; D'Amico, Roberto; D., Giuggioli; 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

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


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

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


2013 - 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; Dilia, Giuggioli; 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 - 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; Dilia, Giuggioli; Mario, Miccoli; Anna Linda, Zignego; Domenico, Sansonno; Santino, Marchi; Ferri, Clodoveo
abstract

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


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

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


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

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


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

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


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

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


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

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


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

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


2012 - D-penicillamine in the treatment of eosinophilic fasciitis: case reports and review of the literature. [Articolo su rivista]
C. U., Manzini; Sebastiani, Marco; D., Giuggioli; Manfredi, Andreina Teresa; Colaci, Michele; A. M., Cesinaro; 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 - La capillaroscopia in reumatologia. Lesioni elementari e metodi di scoring [Monografia/Trattato scientifico]
R., De Angelis; Ferri, Clodoveo; Sebastiani, Marco; Manfredi, Andreina Teresa; W., Grassi
abstract

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


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

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


2012 - Phantom Limb Pain in Patients with Severe Cryoglobulinemic Vasculitis: Usefulness of Long-Term Pregabalin Treatment [Articolo su rivista]
Dilia, Giuggioli; 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 - Polymyositis following Pandemic Influenza A (H1N1) and 2009-10 Seasonal Trivalent Vaccines [Articolo su rivista]
Ferri, Clodoveo; Colaci, Michele; Manzini, Cu; Sebastiani, Marco; Giuggioli, D; Brugioni, L.
abstract

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


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

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


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

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


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; L., Riato; M., Bocci; M., Iudici; G., Vukatana; S., Moscatelli; A., Principato; S., Mazzuca; P., Del Medico; R., De Angelis; D., Giuggioli; Colaci, Michele; Ferri, Clodoveo
abstract

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


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

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


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

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


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

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


2011 - Lung and Breast Cancer in Systemic Sclerosis: Correlations with the Disease's Features [Abstract in Rivista]
Colaci, Michele; D., Giuggioli; Sebastiani, Marco; Manfredi, Andreina Teresa; C., Vacchi; 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 - Prevention of Digital Ulcers in Systemic Sclerosis Patients: A Proposal of Risk Chart. [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; D'Amico, Roberto; V., Carraro; M., Bocci; S., Moscatelli; M., Iudici; Colaci, Michele; D., Giuggioli; 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]
D., Giuggioli; Manfredi, Andreina Teresa; Colaci, Michele; Lumetti, Federica; Sebastiani, Marco; Ferri, Clodoveo
abstract

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


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

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


2010 - Bronchoalveolar lavage and response to cyclophosphamide in scleroderma alveolitis. [Articolo su rivista]
Colaci, Michele; Sebastiani, Marco; D., Giuggioli; 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 - Effects of Rituximab in a large series of patients with HCV-associated mixed cryoglobulinemia syndrome [Abstract in Rivista]
Ferri, Clodoveo; Sebastiani, Marco; P., Cacoub; D., Roccatello; P., Scaini; A., Tavoni; A. L., Zignego; S., De Vita
abstract

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


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

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


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

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


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

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


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

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


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

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


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

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


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; D., Giuggioli; R., La Sala; Ferri, Clodoveo
abstract

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


2008 - Cardiovascular risk and prostanoids in systemic sclerosis [Articolo su rivista]
Colaci, Michele; Sebastiani, Marco; D., Giuggioli; 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; D., Giuggioli; R., La Sala; N., Elkhaldi; A., Antonelli; 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 - High values of CXCL10 serum levels in mixed cryoglobulinemia associated with hepatitis C infection. [Articolo su rivista]
Ferri, Clodoveo; Ferrari, Silvia Martina; Sebastiani, Marco; Ferrari, Daniela; Giunti, Marco; F., Franzoni; F., Galetta; S., Marchi; E., Ferrannini; Antonelli, A; Fallahi, P; Frascerra, S; Tolari, S
abstract

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


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

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


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

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


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

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


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

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


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

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


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

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


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

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


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

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


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

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


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

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


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

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


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


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

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


2005 - Heart involvement and systemic sclerosis [Articolo su rivista]
Ferri, Clodoveo; D., Giuggioli; Sebastiani, Marco; Colaci, Michele; M., Emdin
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 - 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 - Oesophageal involvement is correlated with interstital lung involvement (ILD) in SSc patients [Abstract in Rivista]
Vesprini, E; Della Rossa, A; Sebastiani, Marco; Bazzichi, L; Spisni, R; D'Imporzano, S; Bombardieri, S.
abstract

Evaluation of the relationship between esophageal involvement and interstital lung involvement in scleroderma patients


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

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


2005 - Primary Sjogren's syndrome: clinical and serological feature of a single centre [Articolo su rivista]
Baldini, C; Tavoni, A; Merlini, G; Sebastiani, Marco; Bombardieri, S.
abstract

OBJECTIVE: To describe clinical and serological features of a large series of patients affected by primary Sjogren's syndrome (pSS), assessing the evolution of the disease in a long-term follow-up study. METHODS: Clinical and laboratory data of 250 patients with pSS attending our Unit for a mean follow-up period of 140 months were retrospectively collected and analysed. In all the cases the diagnosis was made according with the recent international criteria. RESULTS: Glandular involvement was almost universally present, typically as the first manifestation of the disease and a slow progression of the salivary and lachrymal dysfunction was seen during the observation period. Extraglandular involvement was mild, quite rare and delayed. The respective percentages for muscle-skeletal disease, urogenital, haematological, skin, pulmonary, gastrointestinal, neurological and renal involvement were 60%, 40%, 24%, 20%, 11%, 7%, 8% and 3%. Only 6 patients developed a lymphoma. The serological pattern of the majority of patients remained constant throughout the follow-up period. CONCLUSIONS: pSS is often a benign condition. Since some patients may develop lymphoid malignancies, clinical follow-up is recommended.


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

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


2005 - Two Takayasu arteritis patients successfully treated with infliximab: a potential disease-modifying agent? [Articolo su rivista]
DELLA ROSSA, A; Tavoni, A; Merlini, G; Baldini, C; Sebastiani, Marco; Lombardi, M; Neglia, D; Bombardieri, S.
abstract

Takayasu arteritis (TA) is a chronic, idiopathic, inflammatorydisease that primarily affects large vessels [1]. The management ofthis disorder is largely unresolved, since a large number of patientsfail to reach stable remission on conventional treatment. anti-TNF treatmentmay prove useful both for disease control and to avoid the risk oflong-term toxicity of corticosteroids and classical immunosuppressivedrugs in Takayasu arteritis.


2004 - Capillaroscopia del letto periungueale in pazienti affetti da artrite psoriasica e spondilite anchilosante. [Abstract in Rivista]
Delle Sedie, A; Riente, L; Bombardieri, S; Sebastiani, Marco
abstract

valutazione delle caratteristiche capillaroscopiche del letto periungueale in pazienti con spondilite anchilosante ed artropatia psoriasica


2004 - Caratteristiche demografiche, clinico-sierologiche e terapeutiche di una casistica di 133 malati italiani affetti da crioglobulinemia mista. [Abstract in Rivista]
Sebastiani, Marco; Merlini, G; Tavoni, Ag; Baldini, C; Della Rossa, A; Bombardieri, S.
abstract

Valutazione delle caratteristiche cliniche e demografiche di una popolazione di pazienti con crioglobulinemmia mista afferenti ad un unico centro


2004 - Clinico-seroligical features and therapeutic approach in a group of Italian patients with HCV-related mixed cryoglobulinemia [Abstract in Rivista]
Merlini, G; Sebastiani, Marco; Tavoni, Ag; Badini, C; Della Rossa, A; Paganucci, P; Longombardo, G; D'Ascanio, A; Bombardieri, S.
abstract

Evaluation of clinico-seroligical features and therapeutic approach in Italian patients with HCV-related mixed cryoglobulinemia


2004 - Fibromyalgia and temporomandibular disorder: Comorbility or the same disease? [Abstract in Rivista]
Bazzichi, L; Sebastiani, Marco; Merlini, G; Tognini, L; Bosco, M; Tonini, S; Romano, O; Bombardieri, S.
abstract

Evaluation of the relationship between fibromyalgia and temporomandibular disorder


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 - Inibitori biologici del TNF alfa nella terapia dell’arterite di Takayasu. [Abstract in Rivista]
Merlini, G; Sebastiani, Marco; Tavoni, Ag; Baldini, C; Bombardieri, S.
abstract

descrizione di casi clinici trattati con inbitori biologici del TNF alfa in corso di arterite di Takayasu


2004 - Minor salivary gland biopsy in patients with suspected primary Sjogren's syndrome: Retrospective evaluation of 100 patients [Abstract in Rivista]
Baldini, C; Tavoni, Ag; Migliorini, R; Sebastiani, Marco; Merlini, G; Tonini, S; Neri, R; Bombardieri, S.
abstract

Retrospective evaluation of the relevance of minor salivary gland biopsy in patients with suspected primary Sjogren's syndrome


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

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


2004 - Parvoviral infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma [Articolo su rivista]
M. C., Magro; G., Nuovo; Ferri, Clodoveo; A. N., Crowson; D., Giuggioli; 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 - Sindrome di Sjogren primitiva: descrizione clinica e sierologica di una casistica monocentrica. [Abstract in Rivista]
Baldini, C; Tavoni, Ag; Merlini, G; Sebastiani, Marco; Bombardieri, S.
abstract

valutazione delle caratteristiche e sierologiche in un'ampia popolazione di pazienti con sindrome di Sjogren afferenti ad un unico centro


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

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


2004 - Valutazione dell’impegno gastroesofageo nella sclerosi sistemica mediante studio combinato con endoscopia, manometria e pH-metria esofagea. [Abstract in Rivista]
Sebastiani, Marco; Bazzichi, L; Ambrosini, Ce; Vesprini, E; Mencaroni, I; Merlini, G; Tonini, S; Della Rossa, A; D’Imporzano, S; Spisni, R; Bombardieri, S.
abstract

valutazione dell'impegno esofageo in corso di sclerosi sistemica mediante un approccio multistrumentale


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.


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. [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.