Mycophenolate mofetil for scleroderma-related interstitial lung disease

On Aug 11, 2016, our Twitter-based University of Toronto Respirology and Sleep Journal Club (@respandsleepjc, #rsjc) discussed Donald P Tashkin and colleagues' scleroderma lung study II1Tashkin DP Roth MD Clements PJ et al.Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial.Lancet Respir Med. 2016; 4: 708-719Summary Full Text Full Text PDF PubMed Scopus (585) Google Scholar (SLS II). This randomised, controlled, double-blind trial compared the use of mycophenolate mofetil (MMF) with cyclophosphamide in the management of scleroderma-related interstitial lung disease. The study is a follow-up to SLS I, which showed modest but unsustained improvements in several health outcomes for patients with scleroderma-induced lung disease who received 1 year of cyclophosphamide.2Tashkin DP Elashoff R Clements PJ et al.Cyclophosphamide versus placebo in scleroderma lung disease.N Engl J Med. 2006; 354: 2655-2666Crossref PubMed Scopus (1276) Google Scholar, 3Tashkin DP Elashoff R Clements PJ et al.Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease.Am J Respir Crit Care Med. 2007; 176: 1026-1034Crossref PubMed Scopus (375) Google Scholar Our discussions highlighted the challenges of studying this population and the associated difficulty with management of this rare illness (for relevant Tweets, see appendix). SLS II was predicated on the hypothesis that a prolonged course of MMF would provide improved outcomes when compared with cyclophosphamide. Although this result was not shown for the primary endpoint (change in percent predicted forced vital capacity), Tashkin and colleagues showed that MMF appeared to have modest effects on respiratory and rheumatological outcomes—similar to what was seen with cyclophosphamide in SLS I. However, participants in our online discussion emphasised that SLS II was not designed or powered to demonstrate MMF equivalency to cyclophosphamide in this regard—as a superiority study, inference of non-inferiority from its results would not be valid. The strength of this study was in its reaffirmation of the tolerability of MMF in its treatment of the study population, with significantly reduced reports of adverse drug events and lower instances of treatment withdrawal compared with cyclophosphamide. Notably, 11 deaths occurred in the cyclophosphamide arm compared with only five in the MMF arm—a potentially important finding probably related to treatment withdrawal and disease progression, but difficult to interpret as the study was not powered to evaluate mortality. Significant treatment withdrawal was identified by our participants as a potential confounding factor, particularly in the cyclophosphamide arm with approximately half of patients withdrawing. Furthermore, some of these patients in the cyclophosphamide arm were subsequently placed on other potent disease-modifying agents such as rituximab, tocilizumab, intravenous immunoglobulin, azathioprine, and even open-label MMF or intravenous cyclophosphamide. As noted by the authors, these factors potentially complicate analysis of the effect seen at 24 months in patients randomised to the cyclophosphamide arm, and could explain why SLS II participants did not experience the regression to the mean seen in SLS I. Furthermore, these factors underscore the problems involved in study of a rare disease that has the recalcitrant and progressive properties seen in scleroderma-related lung disease. SLS II highlights the importance of treatment tolerability in a chronic illness that mandates prolonged therapy. Despite being limited by the issues with treatment withdrawal, our participants found the study to be robust in its design, although they highlighted that a multiple imputation model for missing data might have made the analysis stronger. Ultimately, the opinion shared by most was that the study had failed to yield a clear answer to the question it had been designed to address. Although the study provides hope for MMF in the treatment of scleroderma-related interstitial lung disease, more studies will be needed to confirm this. However, some of our participating rheumatologists expressed that although this study does not provide evidence for equivalency to cyclophosphamide, its clear benefit in patient tolerability made MMF the preferred initial treatment in an arena with limited options. One participant also noted that adverse events from MMF in the study appeared greater than what is seen in the “real world.” In summary, most of our online participants did not feel that the results of SLS II alone would be practice changing, leaving the treatment of scleroderma-associated interstitial lung disease reliant upon expert clinical judgement, patient preference, and further study into the potential use of novel disease-modifying agents. We declare no competing interests. Download .pdf (.29 MB) Help with pdf files Supplementary appendix Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trialTreatment of scleroderma-related interstitial lung disease with mycophenolate mofetil for 2 years or cyclophosphamide for 1 year both resulted in significant improvements in prespecified measures of lung function over the 2 year course of the study. Although mycophenolate mofetil was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than cyclophosphamide was not confirmed. These findings support the potential clinical effectiveness of both cyclophosphamide and mycophenolate mofetil for progressive scleroderma-related interstitial lung disease, and the present preference for mycophenolate mofetil because of its better tolerability and toxicity profile. Full-Text PDF