Comparative effectiveness of mycophenolate mofetil versus cyclophosphamide in systemic sclerosis-related interstitial lung disease

Abstract

On the manuscript by Ma and associates [1], a comparative effectiveness systematic review (SR) and meta-analysis (MA) is presented, regarding mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) in systemic sclerosisrelated interstitial lung disease (SSc-ILD). Such studies are valuable in assessing the best possible treatment in terms of efficacy and safety for a specific patient population, comparing two available options [2]. Although 15 years ago the lack of comparative effectiveness studies was apparent according to the Institute of Medicine [3], today, the number of such studies has increased substantially and their importance is acknowledged. In the field of SSc and that of disease-related well ILD in particular, the authors promptly noted the limited available placebo-comparator randomized controlled trials (RCTs) [1], as the ethics of placebo interventions consist of a grey area in medical research. It has become apparent that, when effective therapies exist, placebo RCTs would violate the Hippokratian oath [4] regarding the therapeutic obligation of all physicians to their patients that the optimal medical care would be provided, while, in parallel, a placebo arm also lacks scientific and clinical merit in this case [5]. Moreover, this is the first SR and MA examining the comparative effectiveness of these two therapies, using six primary studies in total, one RCT and the remaining five being observational studies. In their analysis, Ma and colleagues underline the relative superiority of MMF compared to the CYC in improving the diffusing capacity for carbon monoxide (DLCO) and in being associated with fewer adverse events [1]. With regard to the forced vital capacity (FVC), no difference was observed between the two therapies. DLCO and FVC were the two primary outcomes of the MA [1], also used for the diagnosis of SSc-ILD, assessment of its clinical course, and prognosis. All primary studies used by the meta-analysts exceeded 6 months of follow-up and included a relatively small number of patients, ranging between 10 and 73 patients, mostly women as this disease predominantly affects females. These findings could be further improved if a random-effects model was employed, which consists of the preferred tactic when observational studies are pooled [6]. This has been a likely drawback of the study. Nevertheless, Ma [1] provides evidence to support the use of MMF against CYC, which has been shown to induce toxicity in the long run [7]. Moreover, despite the fact that the analysis of the Scleroderma Lung Studies I and II was not included in the MA as a non-randomized interventional study, albeit being published in the year 2017 [8], both Ma et al. [1] and Volkmann et al. [8] collectively agree in the relative superiority of the MMF against CYC as the introductory treatment of SSc-ILD. Researchers interested in This comment refers to the article available online at https:// doi. org/ 10. 1007/ s1006702105794-5.