Mycophenolate Mofetil Versus Placebo for Systemic Sclerosis–Related Interstitial Lung Disease: An Analysis of Scleroderma Lung Studies I and II

Abstract

Objective To compare mycophenolate (MMF) with placebo for the treatment of systemic sclerosis-related interstitial lung disease (SSc-ILD). Methods Participants enrolled in the placebo arm of Scleroderma Lung Study (SLS) I and the MMF arm of SLS II were included. SLS I randomized participants to oral cyclophosphamide (CYC) versus placebo for 1 year, while SLS II randomized participants to MMF for 2 years versus oral CYC for 1 year followed by 1 year of placebo. Eligibility criteria for SLS I and II were nearly identical. The primary outcome was FVC%-predicted and key secondary outcomes included the DLCO%-predicted, skin score, and dyspnea. Joint models were created to evaluate the treatment effect on the course of these outcomes over 2 years. Results SLS II-MMF (N=61) and SLS I-placebo (N=61) participants had similar baseline characteristics for gender, disease duration, SSc subtype, extent of skin disease and FVC%-predicted. SLS II-MMF patients were slightly older (mean[SD] years: 52.6[9.7] vs. 48.1[12.4]; P=0.015) and had a higher DLCO%-predicted (mean[SD]: 54.0[11.1] vs. 46.2[13.3]; P=0.0002) than SLS I-placebo participants. After adjusting for baseline disease severity, treatment with MMF in comparison with placebo was associated with an improved course of FVC%-predicted (P<0.0001), DLCO%-predicted (P<0.001), skin score (P<0.0001), and dyspnea (P=0.0112) over 2 years. Conclusions Although there are inherent limitations in comparing participants from different trials, treatment with MMF was associated with improvements in physiologic outcomes and dyspnea compared with placebo, even after accounting for baseline disease severity. These results further substantiate the use of MMF for the treatment of SSc-ILD.

Treatment Algorithms for Systemic Sclerosis According to Experts

“…The use of GCs among experts was not high in our study; however, they have been used more frequently in some trials . Experts incorporated MMF (as first‐line treatment) and IV CYC (as third‐line treatment) to treat SSc patients with high MRSS scores.…”

“…Management of ILD induction therapy has changed considerably. After the Scleroderma Lung Studies (SLS 1 and SLS 2) , experts have changed their first‐line preference from CYC to MMF. Oral CYC was used in the SLS studies, but the majority of experts said that if they used CYC, it would be mostly IV.…”

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

“…1,2 Conventional therapy has limited benefit on disease control and modest impact on mortality. [3][4][5][6] Three randomized studies have shown that autologous hematopoietic stem cell transplantation (AHSCT) has superior efficacy when compared with conventional therapy for SSc. [7][8][9][10] Nevertheless, clinical guidelines and immune monitoring studies after AHSCT aim to further improve patient care and transplant outcomes.…”

Major lung complications of systemic sclerosis

“…After 12 months, the benefits of this treatment were no different from placebo, although FVC showed a trend towards improvement in the treatment group compared with the placebo group that did not reach statistical significance [120]. In the Scleroderma Lung Study II (SLS II), mycophenolate mofetil (MMF) was as efficacious as oral cyclophosphamide in improving cough-specific measurements [121], which was also observed when the data from both SLS studies were combined, to include the placebo control from SLS I [122] However, the tolerability of MMF was superior to cyclophosphamide and MMF is now used as a first line treatment in most centers [123]. The optimal dose of MMF for the treatment of SSc-associated ILD is probably 3g/day, which was the target dose in the SLS II trial, although for patients who struggle to tolerate 3/g day, 2g/day might be considered.…”