Immunosuppressants reduced modified Rodnan skin scores in patients with early diffuse cutaneous systemic sclerosis (dcSSc) compared with patients who were not using immunosuppressants, according to recent research from the European Scleroderma Observational Study (ESOS) published in the Annals of the Rheumatic Diseases.
“[T]here were no significant differences in outcome between the four treatment protocols (methotrexate, MMF [mycophenolate mofetil], cyclophosphamide, no immunosuppression), although there may be a signal in favour of immunosuppression for early dcSSc,” Ariane L. Herrick, MD, professor of rheumatology at the University of Manchester in the United Kingdom, and colleagues wrote in their study. “Although skin score improved in all treatment groups, this was least in the no immunosuppressant category, who also had the highest mortality,” they added.
Dr Herrick and colleagues said the design of ESOS differed from a typical observational study. “[I]ts standardised protocols emulated the conditions of a clinical trial, and although not randomised, patients were enrolled into four homogenous treatment arms with well-defined interventions and a systematic record of protocol changes and exits,” they wrote.
High-Yield Data Summary
- Immunosuppressants were effective for treating early diffuse cutaneous systemic sclerosis, but better treatments after 12 months are needed, where there were modest benefits.
The researchers performed a prospective, observational study of 326 patients with early dcSSc from 50 centers who received methotrexate (oral or subcutaneous, 20-25 mg per week), cyclophosphamide (intravenous 500 mg/m2 for 6-12 months or oral 1-2 kg/day for 12 months), MMF twice daily (500 mg), or no immunosuppressant. Patients were included if they experienced skin thickening within 3 years of beginning the study. Of the patients included, 65 patients received methotrexate, 87 patients received cyclophosphamide, 118 patients received MMF, and 56 patients received no immunosuppressant.
The researchers noted that the group not using immunosuppressants was not a control group. “Patients in this group had a longer disease duration than the other three groups and were more likely to have renal involvement,” Dr Herrick and colleagues observed.
A total of 84.7% of patients completed 12-month follow-up (n = 276), and 71.7% of patients completed 24-month follow-up (n = 234). At 12 months, all patients showed statistically significant reductions in modified Rodnan skin scores in the methotrexate (−4.0 units; 95% CI, −5.2 to −2.7), MMF (−4.1; 95% CI, −5.3 to −2.9), cyclophosphamide (−3.3; 95% CI, −4.9 to −1.7), and no immunosuppressant (−2.2; 95% CI, −4.0 to −0.3) groups (between-group differences, P =.0346).
Although Dr Herrick and colleagues found no statistically significant differences in survival among the groups, the group not using immunosuppressants had an 84.0% survival rate at 24 months.
Summary and Clinical Applicability
The researchers noted that immunosuppressants were indicated for early dcSSc, but more research is needed about better treatments after 12 months, where there was a modest benefit of using immunosuppressants.
“The message for clinicians is that there is a weak signal to support using immunosuppressants for early dcSSc (and in particular cyclophosphamide for patients with pulmonary fibrosis),” Dr Herrick and colleagues concluded. “However, it is clear that there remains a pressing need for the development of more effective and targeted treatments.”
- Researchers noted that the observational nature of the study limited their ability to completely separate patients’ initial characteristics with the outcome for their treatment group.
Dr Herrick has been a consultant for Actelion, served on a Data Safety Monitoring Board for Apricus, and received research funding and speaker’s fees from Actelion and speaker’s fees from GSK. Jörg H. W. Distler has consultancy relationships and/or has received research funding from Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma, Active Biotech, Galapagos, Inventiva, Medac, Pfizer, Anamar, and RuiYi and is stock owner of 4D Science GmbH. Oliver Distler has been a consultant for 4D Science, Actelion, Active Biotech, Bayer, Biogenidec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare Foundation, Genentech/Roche, GSK, Inventiva, Lilly, Medac, Medimmune, Pharmacyclics, Pfizer, Serodapharm, and Sinoxa and received research grants from Actelion, Bayer, Boehringer Ingelheim, Ergonex, Pfizer, and Sanofi, and has a patent mir-29 for the treatment of systemic sclerosis licensed. William J. Gregory has received teaching fees from Pfizer. Frances C. Hall has received research funding from Actelion. Marina E. Anderson performed advisory board work and received honoraria from Actelion, and received speaker’s fees from Bristol-Myers Squibb. Lorinda Chung performed advisory board work for Gilead and served Data Safety Monitoring Boards for Cytori and Reata. Harsha Gunawardena performed advisory board work and received honoraria from Acetelion. Ulf Müller-Ladner is partly funded by EUSTAR/EULAR. Jacob M. van Lar has received honoraria from Eli Lilly, Pfizer, Roche, MSD, and BMS. Anna Rudin receives funding from AstraZeneca. Christopher P. Denton has been a consultant for GSK, Actelion, Bayer, Inventiva, and Merck-Serono; received research grant funding from GSK, Actelion, CSL Behring and Inventiva; received speaker’s fees from Bayer; and given trial advice to Merck-Serono.
Herrick AL, Pan Xiaoyan P, Peytrignet S, et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS) [published online February 10, 2017]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2016-210503