New promising drugs for the treatment of systemic sclerosis: pathogenic considerations, enhanced classifications, and personalized medicine

Abstract

Introduction: Systemic sclerosis (SSc), also known as scleroderma, is a complex orphan disease characterized by early inflammatory features, vascular hyper-reactivity, and fibrosis of the skin and internal organs. Although substantial progress has been made in the understanding of the pathogenesis of SSc, there is still no disease-modifying drug that could significantly impact the natural history of the disease.Areas covered: This review discusses the rationale, preclinical evidence, first clinical eevidence,and pending issues concerning new promising therapeutic options that are under investigation in SSc. The search strategy was based on PubMed database and clinical trial.gov, highlighting recent key pathogenic aspects and phase I or II trials of investigational drugs in SSc.Expert opinion: The identification of new molecular entities that potentially impact inflammation and fibrosis may constitute promising options for a disease modifying-agent in SSc. The early combinations of antifibrotic drugs (such as pirfenidone) with immunomodulatory agents (such as mycophenolate mofetil) may also participate to achieve such a goal. A more refined stratification of patients, based on clinical features, molecular signatures, and identification of subpopulations with distinct clinical trajectories, may also improve management strategies in the future.

Keywords: Autoimmunity; fibrosis; investigational drugs; macrophages; myofibroblasts; scleroderma; systemic sclerosis; vasculopathy.

Figure 1:. Main cellular types, pathogenic mechanisms and hypotheses in systemic sclerosis.

The pathogenesis of SSc involves 3 main mechanisms: occlusive microangiopathy, early inflammatory processes and uncontrolled extra-cellular matrix (ECM) production with resultant fibrosis. Recent studies highlight the role of oligoclonal cytotoxic T-CD4+, driving the apoptosis of endothelial cell (EC) (175,176). Innate immunity, and notably monocytes and macrophages, play a key role in the pathogenesis of SSc (177). Macrophages can adopt various activation profiles depending on their surrounding micro-environment. Interferon (IFN) type II signaling, involving JAK1/TYK2/STAT-1 or TLR-4 agonists induce a classical M1 pro-inflammatory polarization. Th2 cytokines such as IL-4 or IL-13 can induce an alternative profibrotic M2 activation through a STAT3/6 dependent signaling (181): IL-6 also potentiates M2 polarization, notably through the up-regulation of the IL-4 receptor (182). A concomitant excess of CD163^highM2 and M1 macrophages has been identified in skin tissues of SSc patients (183) (9). SSc-macrophages show impaired capacities efferocytosis apoptotic cells (phagocytosis of apoptotic cells) with the potential release of internuclear components from these un-eliminated cell debris. The impact of immune complexes composed by autoantibodies and intra-nuclear proteins (topoisomerase, centromere proteins) may also participate to macrophage and fibroblast activation. Myofibroblasts are the major effectors of fibrosis. Myofibroblasts in SSc originate from a variety of tissue-resident mesenchymal progenitor cell types, including fibroblasts, pericytes, microvascular endothelial cells and vascular pre-adipocytes (12). The trans-differentiation of resting fibroblasts and other progenitor cells into pro-fibrotic and inflammatory myofibroblasts is driven by canonical smad-dependent (smad2/3 and 4) and non-canonical smad-independent tumoral growth factor (TGF)-β signaling. Activated myofibroblasts also produce profibrotic mediators such as IL-6 or connective tissue growth factor (CTGF)/CCN2, leading to an autocrine profibrotic pathogenic loop maintaining sustained cellular activation. IL-6 mediates its effects through JAK1/2/TYK2 with subsequent phosphorylation of STAT3 (predominantly) and STAT 1. STAT3 notably promotes the production of key ECM components such as col1a1, col1a2, and profibrotic markers such as CTGF/CCN2 (10). CTGF/CCN2 exerts profibrotic properties notably as a co-factor of TGF-β signaling. CTGF/CCN2 can interact with specific receptors (such as integrins or lipoprotein receptor-related proteins), ECM proteins (such as fibronectin or perlecan) and growth-factors (such as VEGF and TGF-β), with subsequent activation of fibroblast proliferation and myofibroblasts activation (184,185). Uncontrolled production of extra-cellular ECM components such as collagens, tenascin C or fibronectin can in turn activate myofibroblasts either through a direct process involving innate immune sensors such as TLR-4, or through an indirect activation notably depending on mechano-sensing of increased matrix stiffness by integrins (23,24). IFN= interferon, endoMT=endothelial to mesenchymal transition, Autoab=autoantibodies, PDGF-R-Ab= autoantibodies with agonist effects on PDGF-Receptor, AEC-ab=anti-endothelial cell antibodies, notably including anti endothelin-receptor antibodies with agonists properties, ROS=reactive oxygen species

Figure 2:. Non approved pharmacological targets and interaction of selected profibrotic pathways in SSc myofibroblasts that are currently being evaluated in clinical trials.

Latent TGF-β can notably be activated by integrins (notably from the αV class) or thrombospondins. In its active form, TGF-β can interact with a specific heterodimeric receptor (TGF-β-R-I and -II). Two TGF-β-dependent signalization pathways are described: a canonical pathway involving the interaction of TGF-β-R-I with smad 2/3 and 4; and a non-canonical pathway, Smad independent, that notably involves (but is not limited to) c-Abl, TAK1, p38, JNK, SRC, RhoA/ROCK and JAK2-STAT-3. TGF-β1 also increases SSc-related oxidative stress notably through the up-regulation of NADPH oxidase (NOX) 4. This upregulation of NOX4 by TGF-β1 is smad3 dependent and results in increased collagen type I, alpha-SMA and fibronectin 1 gene expression in dermal fibroblasts. These effects are suppressed by pan-NOX inhibitors such as diphenyleneidonium (not represented) or specific NOX1/4 inhibitor such as GKT-137831 (not represented), highlighting that NOX4 may constitute a relevant therapeutic target (152,186). IL-6 mediates its effects through its receptor (composed of IL-6Ra or the soluble form of IL-6R in association with a 130kDA signaling transducer (gp130)) that activates JAK1/2/TYK2 with subsequent phosphorylation of STAT3 (predominantly) and STAT 1. STAT-3 acts as a key integrator of profibrotic signals. STAT3 notably promotes the production of key extra-cellular matrix components such as col1a1, col1a2, and profibrotic markers such as CTGF/CCN2 (10). CTGF/CCN2 exerts profibrotic properties notably as a co-factor of TGF-β signaling and as a target of YAP. CTGF/CCN2 can interact with specific receptors (such as integrins or lipoprotein receptor-related proteins), extra-cellular matrix proteins (such as fibronectin or perlecan) and growth-factors (such as VEGF and TGF-β), with subsequent activation of fibroblast proliferation and myofibroblasts activation, although the specific mechanisms involved are still to be determined (184,185). Rho serves as another integrator of profibrotic pathways and can be activated by TGF-β, LPA agonists or integrin signaling in a FAK dependent manner. Rho subsequently activates ROCK that participates in a cascade sustaining fibrotic response and induces cytoskeleton remodeling. In return, increased extra-cellular matrix stiffness participates in the activation of latent TGF-β perpetuating a pro-fibrotic pathogenic loop. IL-4 and IL-13 participate in fibrosis by inducing the proliferation of fibroblasts and by increasing their production of TGF-β and CTGF/CCN2 in a STAT6 dependent manner (103). On the contrary, α-MSH and MC1-R agonists may exert anti-fibrotic properties by suppressing TGF-β signaling although the precise sub-cellular mechanisms are still to be determined. FAK=focal adhesion kinase, LPA= lysophosphatidic acid; LPA-R=LPA-Receptor; IL-6R=IL-6 receptor; TGF-βRI & II= TGF-β receptor I & II; PAI-1=plasminogen activator inhibitor 1; ROS=Reactive Oxygen Species; YAP=Yes Associated Protein; α-MSH =α-Melanocyte-stimulating hormone; IL-4Rα=IL-4 receptor α; IL-13Rα1= IL-13 receptor α1; ECM=Extra-cellular matrix