Placing patients who have early diffuse cutaneous systemic sclerosis (dcSSc ) on an immunosuppressant regimen can have a beneficial, but not necessarily sustainable, impact, according to findings from the European Scleroderma Observational Study.

“At present, there is no drug known to favorably influence disease course [because] randomized controlled trials have historically been confounded by disease rarity [and] strict entry criteria,” wrote the study investigators – led by Ariane L. Herrick, MD, of the University of Manchester (England). They sought to get around the lack of randomized, controlled trial data by comparing observational data on “the effectiveness of standard treatment approaches [in] the early management of patients with dcSSc.”

The European Scleroderma Observational Study (ESOS) prospectively observed and followed 326 patients with dcSSc who were recruited from 50 health care centers spread across 19 countries. The patients were sorted into one of four groups based on the treatment they received: methotrexate (20%), mycophenolate mofetil (MMF; 36%), cyclophosphamide (27%), and no immunosuppressant (17%).

The patients receiving methotrexate had a target dose of 20-25 mg/week, either orally or subcutaneously. Patients on MMF were given two 500-mg doses a day for 2 weeks, then two 1-g doses daily. Cyclophosphamide regimens varied based on the centers, with some patients receiving one IV 500-mg/m2 dose monthly for 6-12 months and others receiving a daily dose of 1-2 mg/kg/day orally for 12 months, with most being transferred later to maintenance with methotrexate, MMF, or azathioprine. All patients underwent assessment at baseline and then every 3 months for the trial duration of 24 months; however, because the study occurred during 2010-2014 and some patients were recruited in 2013, those who joined after September 2013 were followed for only 12-24 months. Of the 326 subjects enrolled, 276 completed 12 months of follow-up and 234 completed 24 months (Ann Rheum Dis. 2017 Feb 10. doi: 10.1136/annrheumdis-2016-210503 ).

After weighting the 12-month outcomes between the groups by equalizing the distribution of confounding variables, all groups experienced a significant reduction in the study’s primary outcome measure, the modified Rodnan skin score (mRSS), which can range from 0 to 51. From a median baseline mRSS of 21 (interquartile range of 16-27), the mRSS for the methotrexate group fell 4.0 (IQR −5.2 to −2.7), for those on MMF it dropped 4.1 (IQR −5.3 to −2.9), for the cyclophosphamide group it decreased 3.3 (IQR −4.9 to −1.7), and for those on no immunosuppressants it dropped 2.2 (IQR −4.0 to −0.3). There were no significant differences between the groups.

Although none of the treatments had a significant effect on improving forced vital capacity (FVC) or carbon monoxide–diffusing capacity in the groups overall, the subgroup of patients with confirmed or suspected pulmonary fibrosis showed a significant difference in the rate of change over time for FVC in patients who were initially prescribed cyclophosphamide (7.4% absolute increase), but not for MMF (3.2% increase), methotrexate (2.0% decrease), or no immunosuppressant (4.0% increase). The investigators noted that this finding “confirms the relative effectiveness of cyclophosphamide in patients with pulmonary fibrosis.”

At 24 months, there were no significant differences in mortality between the four groups. After weighting, the predicted survival rates were 94% for methotrexate, 89% for MMF, 90% for cyclophosphamide, and 84% for those with no immunosuppressants. All three immunosuppressants also showed no significant difference in terms of tolerability. At this point in time, the rate of adherence to the initial protocol was comparable between the groups: 76% for methotrexate, 80% for MMF, 79% for cyclophosphamide, and 73% for those not taking an immunosuppressant, although 10 who started without an immunosuppressant later started one.

“An important point when interpreting our findings (and therefore a note of caution) is that the ‘no immunosuppressant’ group was not a control group,” Dr. Herrick and her coauthors wrote. “Patients in this group had a longer disease duration than the other three groups and were more likely to have renal involvement.”

Nevertheless, the authors contend that these findings carry a strong take-home message for clinicians: “There is a weak signal to support using immunosuppressants for early dcSSc (and in particular cyclophosphamide for patients with pulmonary fibrosis). However, it is clear that there remains a pressing need for the development of more effective and targeted treatments.”

The study was funded by a grant from the European League Against Rheumatism’s Orphan Disease Program, and additional support from Scleroderma and Raynaud’s UK. Dr. Herrick disclosed relationships with Actelion, Apricus, and GlaxoSmithKline; her coauthors disclosed numerous financial relationships of their own.