Upcoming treatments for morphea

Abstract

Morphea (localized scleroderma) is a rare autoimmune connective tissue disease with variable clinical presentations, with an annual incidence of 0.4-2.7 cases per 100,000. Morphea occurs most frequently in children aged 2-14 years, and the disease exhibits a female predominance. Insights into morphea pathogenesis are often extrapolated from studies of systemic sclerosis due to their similar skin histopathologic features; however, clinically they are two distinct diseases as evidenced by different demographics, clinical features, disease course and prognosis. An interplay between genetic factors, epigenetic modifications, immune and vascular dysfunction, along with environmental hits are considered as the main contributors to morphea pathogenesis. In this review, we describe potential new therapies for morphea based on both preclinical evidence and ongoing clinical trials. We focus on different classes of therapeutics, including antifibrotic, anti-inflammatory, cellular and gene therapy, and antisenolytic approaches, and how these target different aspects of disease pathogenesis.

Keywords: clinical trial; localized scleroderma; morphea; treatment.

Figure 1

Potential drug targets for the treatment of morphea (created with Biorender.com). An unknown stimulus leading to tissue damage causes secretion of chemokines to recruit leukocytes to the dermis. Recruited leukocytes release cytokines including TGFβ and IL‐1, and IL‐6, in addition to IL‐4, 8, 13 (not shown), leading to differentiation of progenitor cells (fibroblasts, pericytes, and endothelial cells) into myofibroblasts. Abnormally activated myofibroblasts lead to excess production of collagen, fibronectin, and tenascin‐C, which act as DAMP and can activate undifferentiated fibroblasts into myofibroblasts. This self‐fibrotic process leads to uncontrolled proliferation of myofibroblasts. Here we have highlighted potential treatments for both morphea and scleroderma in yellow, and treatments used previously for scleroderma in pink. Antifibrotic targets for treatments include: TGFβ, tyrosine‐protein kinase, ABL‐1 inhibitor, anti‐CTGF, CB2 receptor agonist, PPAR‐γ and pan‐PPAR agonists, direct thrombin inhibitors. No current clinical trials for vascular targets exist for Morphea, but the 2017 EULAR treatment guidelines and current clinical trials for vascular agents targeting cutaneous manifestations of SSc are indicated. Anti‐inflammatory targets for treatments include: MMF, cyclophosphamide, CB2 receptor agonist, anti‐BAFF/BLyS (belimumab), anti‐CD20, thalidomide, IL‐6R blockade, abatacept, TGFβ inhibitor, PPAR agonist, UVA1 and UVB. CB2, cannabinoid‐2; CTGF, connective tissue growth factor; DAMP, damage associated molecular patterns; EULAR, European League Against Rheumatism; IL, interleukin; PPAR‐γ, peroxisome proliferator‐activated receptor γ; SSc, systemic sclerosis; TGFβ, transforming growth factor‐β

Figure 2

Targeting the JAK/STAT pathway for morphea (created with Biorender.com). Binding of cytokine to type‐1 interferon receptor activates downstream signaling pathways. Specifically, receptor dimerization causes subsequent phosphorylation of JAK and STAT proteins. STAT proteins (transcription factors) dimerize, translocate into the cell nucleus and regulate transcription of inflammatory genes such as IL‐2, IL‐4, IL‐6, IL‐12, IL‐21, IL‐22, IL‐23, IFN‐α, IFN‐β, and IFN‐γ, and oncostatin M. JAK inhibitors prevent JAK phosphorylation, STAT activation, and transcription of genes. GSK2330811, a novel oncostatin M inhibitor, has recently been tested in a double‐blinded, placebo controlled clinical trial in male and female participants with diffuse cutaneous SSc (dcSSc)