Although interstitial lung disease accounts for the majority of deaths of 
patients with systemic sclerosis, treatment options for this manifestation of 
the disease are limited. Few high-quality, randomized, controlled trials exist 
for systemic sclerosis-related interstitial lung disease, and historically, 
studies have favored the use of cyclophosphamide. However, the benefit of 
cyclophosphamide for this disease is tempered by its complex adverse event 
profile. More recent studies have demonstrated the effectiveness of 
mycophenolate for systemic sclerosis-related interstitial lung disease, 
including Scleroderma Lung Study II. This review highlights the findings of this 
study, which was the first randomized controlled trial to compare 
cyclophosphamide with mycophenolate for the treatment of systemic 
sclerosis-related interstitial lung disease. The results reported in this trial 
suggest that there is no difference in treatment efficacy between mycophenolate 
and cyclophosphamide; however, mycophenolate appears to be safer and more 
tolerable than cyclophosphamide. In light of the ongoing advances in our 
understanding of the pathogenic mechanisms underlying interstitial lung disease 
in systemic sclerosis, this review also summarizes novel treatment approaches, 
presenting clinical and preclinical evidence for rituximab, tocilizumab, 
pirfenidone, and nintedanib, as well as hematopoietic stem cell transplantation 
and lung transplantation. This review further explores how reaching a consensus 
on appropriate study end points, as well as trial enrichment criteria, is 
central to improving our ability to judiciously evaluate the safety and efficacy 
of emerging experimental therapies for systemic sclerosis-related interstitial 
lung disease.