Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort.

Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference -1.0, 95% CI -3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (-6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.

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Competing interests: SK, SJ, ME, FC, ES, SR, VC, YB-M, MS, AMG, KR-P, FJL-L; PIN, AG, YS, LB, VS, TS, AG: none. CB reports consulting fees from Boehringer Ingelheim, Eli-Lilly. Research Grants from Gruppo Italiano Lotta alla Sclerodermia (GILS), Foundation for Research in Rheumatology (FOREUM), European Scleroderma Trial and Research (EUSTAR), New Horizon Fellowship. AMG has received research funding and/or consulting fees from Abbvie, GenevaRompharm, Novartis and Boehringer Ingelheim. SV received consultancy for BI Global and BI Italy spa. PA reports personal fees (consultancies) from Bristol Myers Squibb, Boehringer Ingelheim, non-financial support from CSL Behring, SOBI, Janssen, Roche, Sanofi, Pfizer. NH has received lecture fees from Boehringer Ingelheim, Pfizer, Sanofi, Roche. VR has/had personal fees or received research funding from Bayer, Boehringer Ingelheim, MSD, Corbus, Inventiva, Roche. JJAS reports personal fees and/or research funding from Janssen, Boehringer Ingelheim, Eli Lilly, Pfizer, Roche, MSD, Corbus, Inventiva, and GSK, outside of the submitted work. IC reports personal fees or research funding from Boehringer Ingelheim, Janssen, Roche, Kern, BMS, Sanofi-Aventis, Roche, UCB and BioCAT. MET has had consultancy relationships and/or has received research funding from Boehringer Ingelheim, Genentech/Roche and Sanofi in the area of potential treatments of scleroderma and its complications. EZ reports speaker honoraria and consultancy fees from Boehringer Ingelheim, Janssen, GlaxoSmithKline. CD reports personal fees or research funding from Janssen, GlaxoSmithKline, Bayer, Sanofi-Aventis, Galapagos, Boehringer Ingelheim, Roche, CSL Behring, Corbus, Acceleron, Horizon, ARXX Therapeutics. RMI had received consultancy and speaker fee from Abbvie, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Pfizer, Roche. JHWD has consultancy relationships with Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Janssen, Novartis, Pfizer and UCB. JHWD has received research funding from Anamar, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Sanofi-Aventis, RedX, UCB. JHWD is stock owner of 4D Science. AMHV has received research funding and/or consulting fees and/or other remuneration from Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly, Janssen and Medscape. MK has received grants or personal fees from AbbVie, Asahi Kasei Pharma, Astellas, Bayer, Boehringer Ingelheim, Chugai, Corbus, Eisai, Galapagos, Janssen, Kissei, MBL, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer and Tanabe-Mitsubishi Pharma. YA has had consultancy relationships and/or has received research funding from Alpine, Boehringer Ingelheim, Genentech/Roche, Medsenic, Menarini and Sanofi in the area of potential treatments of scleroderma and its complications. OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143).