Abstract
Systemic sclerosis (SSc) is a complex rare autoimmune disease with heterogeneous clinical manifestations. Currently, interstitial lung disease (ILD) and cardiac involvement (including pulmonary arterial hypertension) are recognized as the leading causes of SSc-associated mortality. New molecular targets have been discovered and phase II and phase III clinical trials published in the last 5 years on SSc-ILD will be discussed in this review. Details on the study design; the drug tested and its dose; the inclusion and exclusion criteria of the study; the concomitant immunosuppression; the outcomes and the duration of the study were reviewed. The two most common drugs used for the treatment of SSc-ILD are cyclophosphamide and mycophenolate mofetil, both supported by randomized controlled trials. Additional drugs, such as nintedanib and tocilizumab, have been approved to slow pulmonary function decline in SSc-ILD. In this review, we discuss the therapeutic alternatives for SSc management, offering the option to customize the design of future studies to stratify SSc patients and provide a patient-specific treatment according to the new emerging pathogenic features of SSc-ILD.
Highlights
forced vital capacity (FVC) was used as a lung performance measure and was associated with numerical improvement from baseline in the lenabasum group compared to the placebo group starting at week 8, with a maximal but non-significant mean ± SEM treatment difference of 1.7 ± 1.6% observed at week 12
Based on growing evidence suggesting a key role for T cells in the development of both skin and internal organ damage in systemic sclerosis [46,47], a phase II investigator-initiated, multi-center, double-blind randomized placebo-controlled trial was designed to assess the safety and efficacy of abatacept in 88 early diffuse Systemic sclerosis (SSc) [48]. modified Rodnan skin score (mRSS) change at 12 months, which was the primary endpoint of the study, was not statistically significant; neither was
III trials, nintedanib and tocilizumab achieved this goal with different endpoints, while the results of the lenabasum study are not available [22,61]
Summary
Nintedanib, a multi-target tyrosine kinase inhibitor, is a small molecule designed as an ATP-competitive inhibitor of platelet-derived growth factor receptor (PDFGR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR), recently approved for the treatment of idiopathic pulmonary fibrosis (IPF) [13]. The phase III, multi-center, randomized, double-blind, placebo-controlled SENSCIS (Safety and Efficacy of Nintedanib in Systemic SClerosIS) trial evaluated nintedanib safety and efficacy in patients affected by SSc-ILD (NCT02597933). In the primary end-point analysis, the adjusted annual rate FVC change was −52.4 mL/year in the treated group and −93.3 mL/year in the placebo group (difference, 41.0 mL per year; 95% confidence interval (CI), 2.9 to 79.0;. The adjusted mean annual rate of FVC change as a percentage of the predicted value at week 52 was −1.4% in the nintedanib arm and −2.6% in the placebo arm (difference, 1.2 percentage points: 95% CI, 0.1 to 2.2). Additional studies are necessary to explore the combined use of MMF and nintedanib in SSc-ILD patients.
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