Treatment of Systemic Sclerosis–related Interstitial Lung Disease: A Review of Existing and Emerging Therapies

Abstract

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.

The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype

“…SSc is a chronic autoimmune CTD of unknown aetiology, associated with considerable morbidity and increased mortality [55]. Reported percentages of patients with SSc who develop ILD range 35-90%; SSc-ILD often manifests as NSIP and is a major cause of morbidity and mortality [56][57][58][59]. Although SSc can occur at any age, patients are usually 30-60 years of age, and women are more likely to develop SSc than men [55,60,61].…”

“…The cause of SSc is unknown, but its onset is associated with the interaction of environmental factors (including occupational, dietary, medical and lifestyle exposures and possibly infectious agents) in genetically predisposed individuals (e.g. African-American race) [55,58].…”

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

“…[3, 4] Given concerns regarding the potential long-term toxicity associated with CYC use, mycophenolate mofetil (MMF) has emerged as an alternative treatment agent for SSc-ILD. [5] Uncontrolled studies have demonstrated that MMF may prevent progression of SSc-ILD. [6–12]…”

“…emerged as an alternative treatment for SSc-related ILD (5). Uncontrolled studies have demonstrated that MMF may prevent progression of SSc-related ILD (6)(7)(8)(9)(10)(11)(12).…”

Current and future perspectives on management of systemic sclerosis-associated interstitial lung disease

“…There is no established algorithm for the management of SSc-ILD, but patients with advanced ILD on HRCT, or ILD plus a decline in lung function or symptoms, generally undergo treatment with immunosuppression [29][30][31][32][33]. The treatment recommendations for SSc issued by the European League Against Rheumatism (EULAR) use a stringent selection of randomized controlled trials as supportive evidence.…”