Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.
Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.
Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).
Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
- systemic sclerosis
- lung fibrosis
- skin fibrosis
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Handling editor Josef S Smolen
Collaborators EUSTAR coworkers, Serena Guiducci; Ulrich A. Walker; Diego Kyburz; Giovanni Lapadula; Britta Maurer; Suzana Jordan; Rucsandra Dobrota; Radim Becvar; Stanislaw Sierakowsky; Otylia Kowal Bielecka; Alberto Sulli; Maurizio Cutolo; Giovanna Cuomo; Ileana Nicoara; André Kahan; Panayiotis G. Vlachoyiannopoulos; Carlo Maurizio Montecucco; Roberto Caporali; Jiri Stork; Murat Inanc; Patricia E. Carreira; Srdan Novak; László Czirják; Cecilia Varju; Eugene J. Kucharz; Anna Kotulska; Magdalena Kopec-Medrek; Malgorzata Widuchowska; Franco Cozzi; Blaz Rozman; Carmel Mallia; Bernard Coleiro; Armando Gabrielli; Dominique Farge; Chen Wu; Zora Marjanovic; Helene Faivre: Darin Hij; Roza Dhamadi; Frank Wollheim; Agneta Scheja; Dirk M Wuttge; Kristofer Andréasson; Duska Martinovic; Alexandra Balbir-Gurman; F. Trotta; Andrea Lo Monaco; Raffaele Pellerito; Ospedale Mauriziano; Paola Caramaschi ; Jadranka Morovic-Vergles; Carol Black; Christopher Denton; Nemanja Damjanov; Jörg Henes; Vera Ortiz Santamaria; Stefan Heitmann; Dorota Krasowska; Matthias; Paul Hasler; Harald Burkhardt; Andrea Himsel; Gianluigi Bajocchi; José Antonio Pereira Da Silva; Maria João Salvador; Bojana Stamenkovic; Aleksandra Stankovic; Carlo Francesco Selmi; Maria De Santis; Mohammed Tikly; Lev N. Denisov; Ariane Herrick,Ulf Müller-Ladner; Marc Frerix; Ingo Tarner; Raffaella Scorza; Francesco Puppo; Merete Engelhart; Gitte Strauss; Henrik Nielsen; Kirsten Damgaard; Gabriela Szücs; Antonio Zea Mendoza; Carlos de la Puente; Sifuentes Giraldo WA; Øyvind Midtvedt; Silje Reiseter; Torhild Garen; David Launay; Guido Valesini; Ruxandra Maria Ionescu; Laura Groseanu; Daniela Opris; Roxana Sfrent Cornateanu; Razvan Ionitescu; Ana Maria Gherghe; Alina Soare; Marilena Gorga; Mihai Bojinca; Mihaela Milicescu; Cord Sunderkötter; Annegret Kuhn; Nora Sandorfi; Georg Schett; Christian Beyer; Pierluigi Meroni; Francesca Ingegnoli; Luc Mouthon; Filip De Keyser; Karin Melsens; Francesco P. Cantatore; Ada Corrado; Line Iversen; Carlos Alberto von Mühlen; Jussara Marilu Bohn; Lilian Scussel Lonzetti; Kilian Eyerich; Rüdiger Hein; Elisabeth Knott; Piotr Wiland; Magdalena Szmyrka-Kaczmarek; Renata Sokolik; Ewa Morgiel; Marta Madej; Frédéric A. Houssiau; Brigitte Krummel-Lorenz; Petra Saar; Martin Aringer; Claudia Günther; Rene Westhovens; Jan Lenaerts; Branimir Anic; Marko Baresic; Miroslav Mayer; Maria Üprus; Kati Otsa; Brigitte Granel; Carolina de Souza Müller; Sebastião C. Radominski; Valderílio F. Azevedo; Sergio Jimenez; Joanna Busquets; Svetlana Agachi; Liliana Groppa; Lealea Chiaburu; Eugen Russu; Sergei Popa; Thierry Zenone; Margarita Pileckyte; Alessandro Mathieu; Alessandra Vacca; Percival D. Sampaio-Barros; Natalino H. Yoshinari; Roberta G. Marangoni; Patrícia Martin; Luiza Fuocco; Simon Stebbings; John Highton; Peter Chapman; John O’Donnell; Lisa Stamp; Alan Doube; Kamal Solanki; Douglas Veale; Marie O’Rourke; Esthela Loyo; Mengtao Li; Walid Ahmed Abdel Atty Mohamed; Antonio Amoroso; Antonietta Gigante; Fahrettin Oksel; Figen Yargucu; Cristina-Mihaela Tanaseanu; Monica Popescu; Alina Dumitrascu; Isabela Tiglea; Rosario Foti; Rodica Chirieac; Daniel Furst; Peter Villiger; Sabine Adler; Jacob van Laar; Cristiane Kayser; Nihal Fathi; Manal Hassanien; Paloma García de la Peña Lefebvre; Silvia Rodriguez Rubio; Marta Valero Exposito; Emmanuel Chatelus; Jean Sibilia; Jacques Eric Gottenberg; Hélène Chifflot; Ira Litinsky; Paul Emery; Maya Buch; Francesco Del Galdo; Algirdas Venalis; Irena Butrimiene; Paulius Venalis; Rita Rugiene; Diana Karpec; Joseph A. Lasky; Vanesa Cosentino; Eduardo Kerzberg; Fabiana Montoya; Washington Bianchi; Sueli Carneiro; Giselle Baptista Maretti; Dante Valdetaro Bianchi; Massimiliano Limonta; Antonio Luca Brucato; Elide Lupi; Itzhak Rosner; Michael Rozenbaum; Gleb Slobodin; Nina Boulman; Doron Rimar; Maura Couto; Sarah Kahl; Fei Chen; Deborah McCloskey; Halina Malveaux; François Spertini; Camillo Ribi; Guillaume Buss; Thierry Martin; Aurélien Guffroy; Vincent Poindron; Fatima Chotchaeva; Nikolay A. Mukhin; Sergey Moiseev.
Contributors ME, MB and YA formulated the study hypotheses and contributed to its design, literature search, composition of the tables and figures and redaction of the first draft and subsequent iterations of the manuscript. ME, MB, CB-Q and YA: analysis and interpretation of data. ME and MB performed the statistical analyses. OD, VS, MM-C, JJAS, M-ET, YB-M, FI, PIN, AL, ES, IC, PA, SV, EDL, EH, AE, LA, MK, FJL-L, JHWD, NH, A-MH-V, VR, VMH, MRP, CA, ER, CM, MK, LAS, CC, RH, SU, SY, SR, CC and YA conceived and launched the EUSTAR database, collected data in their respective countries and offered critical comments regarding the manuscript. All authors have finally approved the submitted version to be published.
Funding EUSTAR database is supported by the World Scleroderma Foundation.
Competing interests OD has consultancy relationship with Actelion, Bayer, BiogenIdec, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Sinoxa and UCB in the area of potential treatments of scleroderma and its complications. OD has received research funding from Actelion, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe Pharma and Roche in the area of potential treatments of scleroderma and its complications. In addition, OD has a patent mir-29 for the treatment of systemic sclerosis licensed. M-ET has received consulting fees, speaking fees or honoraria from Abbvie, BMS, Lilly, Medac, MSD, Pfizer, Roche and UCB. PA has received travel expenses from Roche (<2500€). SV received speaking fees by Pfizer, Abbvie, Bristol-Myers Squibb, consultant fee from Thermofischer and Boehringer-Ingelheim Italia and Educational support from Pfizer, Roche, BMS. EH has received speaker fees and/or honoraria for consultations from Roche, less than 10 000€. NH received lecture fees from Actelion Pharmaceuticals, Pfizer, Roche and grant support from Actelion and Bayer Pharmaceuticals. CM has/had consultancy relationship and/or has received honoraria from Actelion, Abbvie, Roche and Geneva Romfarm in the area of systemic sclerosis and its complications. CC has received travel grants from Roche. YA has/had consultancy relationship and/or has received grants from Actelion, Bayer, BMS, Boehringer-Ingelheim, Inventiva, Roche, Sanofi-Aventis in the area of systemic sclerosis.
Patient consent for publication Obtained.
Ethics approval Each participating centre obtained approval of the local ethics committee and all registered patients granted their informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional unpublished data from the study are available.
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