Current and Potential New Targets in Systemic Sclerosis Therapy: a New Hope

Current Rheumatology Reports (2020) 22: 42 https://doi.org/10.1007/s11926-020-00918-3 SCLERODERMA (J VARGA, SECTION EDITOR) Current and Potential New Targets in Systemic Sclerosis Therapy: a New Hope Monique Hinchcliff 1 & Steven O’Reilly 2 Published online: 19 June 2020 # The Author(s) 2020 Abstract Purpose of Review Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is an activation of fibroblast to a myofibroblast that secretes huge amounts of extracellular matrix. Currently, no treatment exists that modifies the fibrosis elements and new therapeutic targets are badly needed. This review examines the current state of treatments and emerging therapeutics. Recent Findings Nintedanib was found to significantly reduce the rate of decline in SSc associated FVC, although it has no benefit on skin fibrosis. New cannabinoid receptor2 agonist has shown superb effects in phase II and results in phase III are anticipated. Other targets are currently being tested in clinical trials and new targets that are yet to be tested are increasing in the SSc literature. Summary Nintedanib is now licenced for SSc interstitial lung disease but this does not modify the skin fibrosis. Current ongoing trials will determine the role of various targets. New targets are emerging as we gain a deeper understanding of disease pathogenesis. Keywords Systemic sclerosis . Pathogenesis . Cytokines . Janus kinases . STAT3 Introduction Systemic sclerosis (SSc) is an autoimmune idiopathic disease which is characterised by a specific triad of features; these are vasculopathy, inflammation and fibrosis [1–3] with a high casespecific mortality (Table 1). Fibrosis is a key component of the disease and is increasingly recognised as a key cause of morbidity and mortality in many diseases with organ-specific targets. Although tremendous strides have been made in understanding the biology of fibrosis, still no targeted therapies have been approved for fibrotic diseases and none especially in SSc. Fibrosis is defined as the excessive deposition of fibrous tissue and extracellular matrix in an organ often in response to injury. This is chiefly mediated by a specific cell type termed the myofibroblast that becomes ‘activated’ in response to a multitude of factors that then endows the cell with resistance to apoptosis [4], increased contractility and exuberant expression of extracellular matrix (ECM) molecules including collagen and fibronectin [5]. This is conserved among whichever organ system is affected and is mainly the dermal and lung fibroblasts that are activated in SSc. The precise molecular mechanisms that govern activation of the myofibroblast are still not fully resolved but huge strides in our understanding have occurred in recent years [2, 6]. The aim of this review is to give an overview of current perspectives on pathogenesis and new possible therapeutic targets in a disease that currently has an unmet need. This article is part of the Topical Collection on Scleroderma * Steven O’Reilly steven.o' 1 Section of Rheumatology and allergy, Yale School of medicine, Yale University, New Haven, CT, USA 2 Department of Biosciences, Durham University, Stockton Road, Durham, UK Fibrosis as a Concept Accumulation of fibrosis tissue and ECM in an organ defines fibrosis. It is often in response to injury as a normal reparative response to restore homeostasis. The failure to terminate this wound healing response may underlie all fibrotic diseases. Damage to the tissue can come from a variety of diverse 42 Page 2 of 7 Table 1 Clinical features of systemic sclerosis Curr Rheumatol Rep (2020) 22: 42 Vasculopathy/Raynaud’s phenomenon Inflammation fibrosis sources including infections, autoimmune reactions and physical damage. The normal wound healing response is normally initiated by damage to endothelial epithelial cells that induces the release of inflammatory mediators and begins clotting. This is followed by the release of platelet factors and chemokines that result in the recruitment of leukocytes that then release pro-resolving factors (such as IL-13) that facilitate repair and thus restore homeostasis [7]. Local fibroblasts are differentiated into myofibroblasts that express the marker αsmooth muscle actin and the increased deposition of ECM. This all results in the resolution of the wound, but if the rate of synthesis of ECM outweighs the rate of degradation, fibrosis ensues, which culminates in organ failure. It is suggested that around 45% of deaths in the Western world are attributed to a fibrosis component [8]. This means that fibrosis is currently a significant unmet need. SSc in particular has no therapies that target the fibrosis but recent discoveries are shedding light on the mechanisms that underlie the disease process. endogenous cannabinoids produced endogenously in the body, phytocannabinoids that are plant-derived and synthetic cannabinoids that are generated in the laboratory [17]. This system employs two types of cannabinoid receptors CB1 and CB2. It has been shown that both CB1 and CB2 are upregulated in SSc dermal fibroblasts in culture and that incubation with the synthetic cannabinoid Win55,212–2 in vitro reduced collagen 1 production. This was also associated with a downregulation of TGF-β1 levels and the pro-fibrotic cytokine Interleukin-6 [18]. Win55,212–2 also abrogated dermal fibrosis in the bleomycin model of fibrosis [19] suggesting that this works in vivo. Indeed, stimulation of CB2 receptor with the agonist JWH133 reduced lung fibrosis in the bleomycin lung fibrosis model [20]. Ajulemic acid, a synthetic cannabinoid, is also anti-fibrotic in animal models of lung fibrosis [21]. It appears that the CB2 receptor is important for the therapeutic anti-fibrotic effects of cannabinoid agonists in SSc, and in keeping with this lenabasum, synthetic CB2Rspecific agonists developed by Corbus Pharmaceuticals recently revealed in a phase II study that patients receiving lenabasum had a mean reduction of 9.2 points on the modified Rodnan skin score with no severe or serious adverse events recorded. The phase 3 trial is now underway with enrolment complete. These are eagerly anticipated as this appears a promising therapeutic. WNT Signalling as a Target in SSc Serotonin/5HT Wnt is a highly conserved signalling pathway that is involved in organ development [9]. Since Wnt was discovered over 35 years ago [10], there has been a major interest in this pathway in regard to development, cancer and most recently fibrosis [11, 12]. Enhanced Wnt signalling has been found in SSc with higher levels of the Wnt agonists both in the blood and tissues from patients [13–15]. Indeed, forced stabilisation of β-catenin, a main hub of Wnt signalling, in dermal fibroblasts, results in spontaneous fibrosis and increased collagen fibres in the mouse [14]. A recent clinical trial in SSc patients using C-82 to block Wnt signalling was well tolerated and showed reduction in (...truncated)