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Recent progress and missing gaps to achieve goal in the care of systemic sclerosis–associated interstitial lung disease

Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysregulation, microvascular damage, and excessive fibrosis.1 SSc affects many critical organ systems, including lung, heart, kidney, and gastrointestinal tract. Of these, interstitial lung disease (ILD) is a common manifestation of SSc and the leading cause of morbidity and mortality in patients with SSc.2,3 Currently, the mainstay of treatment for SSc-ILD is non-selective immunosuppression based primarily on evidence from two randomized double-blind trials (Scleroderma Lung Studies I and II).4,5 In fact, the consensus of experts recommends mycophenolate mofetil and cyclophosphamide as treatment options for SSc-ILD.6 Recently, nintedanib, an intracellular inhibitor of multiple tyrosine kinases involved in fundamental process of excessive fibrosis, immunomodulation, and vasculopathy,7 has been approved for the treatment of SSc-ILD,8 based on the result of a phase III randomized, double-blind, placebo-controlled, parallel group SENSCIS trial.9 Consequently, nintedanib was included in the evidence-based recommendations as a treatment option for SSc-ILD either as monotherapy or in combination with mycophenolate mofetil.10 We now have at least two options of treatment modality for SSc-ILD, that is, immunosuppressants and anti-fibrotic, immunomodulatory agents, but there are many missing gaps between current knowledge on SSc-ILD and how to implement anti-fibrotic agents in our clinical practice, that is, in what cases, at what timing, how to use them properly, or in combination with which kind of immunosuppressants. Anti-fibrotic, immunomodulatory agents were first approved for idiopathic pulmonary fibrosis (IPF). SScILD is considered to share to some extent an overlapping pathophysiology with IPF in terms of the underlying fibrotic cascade, and IPF and SSc-ILD are categorized as a disease entity of chronic fibrosing ILD with a progressive phenotype. However, there are apparent differences in the clinical course, pathogenic process, and treatment response between IPF and SSc-ILD.11 The most common histological and imaging pattern of SSc-ILD is nonspecific interstitial pneumonia, rather than usual interstitial pneumonia. In addition, the fibrogenic process of SSc-ILD is obviously amplified through inflammation and immune activation that promote activation of myofibroblasts. Therefore, evidence and experience of antifibrotic/immunomodulatory agents in the treatment of IPF are not necessarily applied to SSc-ILD. Vice versa, some immunosuppressive agents have been shown to be harmful in IPF, while there is evidence for efficacy of immunosuppressants in SSc-ILD.12 The clinical course of SSc-ILD is highly variable, in contrast to IPF, in which almost all patients experience an accelerated decline in lung function over time. Findings from observational cohort studies show that less than one-third of patients with SSc-ILD at diagnosis progress to end-stage lung disease, with the remaining patients exhibiting stable or slowly progressing lung function throughout the disease course.13,14 With new options available for treating patients with SSc-ILD, it is more important than ever to accurately identify patients who have a progressive fibrosing phenotype and derive the most benefit from aggressive treatment regimen. In clinical practice, therapy of SSc-ILD has been reserved for patients exhibiting dyspnea with restrictive ventilatory impairment. Since lung function decline is prominent at Recent progress and missing gaps to achieve goal in the care of systemic sclerosis–associated interstitial lung disease