An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years

Abstract

New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.

New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

“…Different molecular mechanisms and signaling pathways that underlie fibroblast-to-myofibroblast transition have been found to regulate also EndoMT, and are supposed to be involved in pericyte-to-myofibroblast transition and pathologic activation of VSMCs, as well [ 8 , 43 , 109 , 110 , 111 , 112 ]. Accordingly, several compounds have been tested or are currently under investigation in order to unravel their possible therapeutic efficacy in targeting the mechanisms underlying the differentiation of profibrotic myofibroblasts inside the vessel wall, likely ameliorating both the “fibroproliferative vasculopathy” and the “destructive vasculopathy” contributing to tissue fibrosis in SSc [ 113 , 114 , 115 ].…”

“…Peroxisome proliferator-activated receptor (PPAR)-γ is a molecule with antifibrotic properties that is downregulated in SSc skin and whose pharmacological activation with its agonist rosiglitazone has been demonstrated to ameliorate fibrosis in mice [ 118 ]. Moreover, the pan-PPAR agonist IVA337 was reported to be effective in mitigating fibrosis in preclinical models of SSc [ 205 , 206 ], even if in a phase IIb clinical trial performed on diffuse cutaneous SSc patients it failed to improve mRSS [ 114 ].…”

Management of Connective Tissue Disease–related Interstitial Lung Disease

“…Various therapies have been tried in the context of phase 1/2 trials for SSc including inebilizumab (anti-CD19), dabigatran, Wnt signaling blocker C-82, pomalidomide (anti-angiogenic and immunomodulator of lymphocytes and myelocytes), rilonacept (IL-1 receptor analog), romilkimab (bispecific antibody against IL-4 and IL-13), lenabasum (type 2 cannabinoid receptor agonist), abatacept (co-stimulation blocker), belimumab (anti-BAFF, B cell–activating factor), riociguat (soluble guanylate cyclase stimulator), and lanifibranor (PPAR agonist) [ 94 ]. A phase II study of abituzumab in SSc-ILD was terminated due to very low recruitment [ 95 ].…”

Cardiovascular Imaging for Systemic Sclerosis Monitoring and Management

“…There are many novel therapeutics under investigation for use in scleroderma. While none appear specifically targeted toward myocardial involvement, they may impact cardiac disease through anti-inflammatory, anti-fibrotic, vascular/endothelial pathways ( 93 , 94 ). Cardiovascular imaging has the potential to play an important role in the evaluation of these agents.…”