Current advances in the treatment of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a rare, systemic autoimmune disease of unknown etiology. Among the systemic rheumatic diseases, SSc carries the highest mortality, in part due to the historical lack of disease modifying therapies. Recently, landmark randomized controlled trials (RCTs) have been conducted that have illustrated the heterogeneous nature of SSc and furthered our understanding of the key inflammatory and fibrotic pathways involved in SSc pathogenesis. Although SSc affects various organ systems, RCTs have focused on investigating treatments for diffuse cutaneous sclerosis (dcSSc) and interstitial lung disease (ILD). While recent RCTs for dcSSc have failed to demonstrate a treatment benefit, the outcomes of two RCTs led to the approval of two novel therapies for SSc-ILD: nintedanib and tocilizumab. This review summarizes the salient outcome data from recent SSc trials within a practical clinical framework and points out gaps in knowledge that may help inform the design of future SSc studies.

Keywords: Cutaneous sclerosis; Interstitial lung disease; Nintedanib; Systemic sclerosis; Therapeutics; Tocilizumab.

Figure 1.. Key pathways involved in SSc pathogenesis and therapeutic targets of current and emerging therapies.

Vascular injury occurs early in the SSc disease course, resulting in endothelial cell activation, expression of adhesion molecules, chemokine production, release of ET1, and platelet activation with subsequent coagulation. Chemokines recruit macrophages from the circulation into the tissue. DAMPs activate dendritic cells via toll-like receptor 4. Activated T cells undergo differentiation to T_h2 cells, releasing IL-6, IL-4, and IL-13. B cells are subsequently activated via IL-4 and undergo transformation into plasma cells with subsequent production of autoantibodies. Resident fibroblasts are activated by TGF-B, IL-13, and IL-6, generating ROS and differentiating into myofibroblasts. Myofibroblasts secrete profibrotic growth factors and produce extracellular matrix molecules, forming a fibrotic matrix. Abbreviations: CYC: cyclophosphamide; MMF: mycophenolate mofetil; IL-6: interleukin-6; IL-4 ; interleukin-4; IL-13: interleukin-13; ET1: Endothelin-1; PDGF: Platelet-derived growth factor; LPA: lysophosphatidic acid; CXCL4: chemokine ligand 4; 5-HT: serotonin receptor; BAFF: B-cell activating factor; TGFß: Transforming growth factor beta; FGFR: fibroblast growth factor receptor; PDGFR: Platelet-derived growth factor receptor; VEGF: Vascular endothelial growth factor; CB2: cannabinoid receptor type 2; ROS: reactive oxygen species; sGC: soluble guanylate cyclase; DAMP: Damage-associated molecular patterns; ECM: extracellular matrix.

Figure 2.. Approach to pre-treatment evaluation in patients with SSc.

(A) Disease subsets are defined by the extent of skin thickening and include diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc) and systemic sclerosis sine scleroderma. (B) Recommended baseline evaluation in SSc. (C) Autoantibodies and their associated subsets and disease-specific associations. Abbreviations: Scl-70: topoisomerase 1; RNA: ribonucleic acid; RNP: ribonuclear protein; DU: digital ulceration; PAH: pulmonary arterial hypertension; SRC: scleroderma renal crisis; GIT: gastrointestinal tract disease; MCTD: mixed connective tissue disease.