OP0048 IL-31 Is An Inflammatory Pro-Fibrotic Factor Elevated in A Subset of Scleroderma Patients with Severe Pruritus

Abstract

BackgroundSystemic sclerosis (SSc) is an autoimmune rheumatic disease associated with fibroblast activation in the skin and visceral organs. In SSc, refractory pruritus is a common symptom in a subgroup of patients. IL-31 is a Th2 cell derived cytokine implicated in severe itch in other conditions including atopic dermatitis and T cell lymphoma. T-lymphocyte-derived factors provide a possible link between autoimmune inflammation and fibrosis reported in SSc. In this study we measured IL-31 levels in SSc tissue fluid and plasma, and sought correlation with itch severity and clinical parameters. Recombinant IL-31 was found to influence fibroblast and fibroblast precursor activity.MethodsIL-31 was measured by ELISA of dermal tissue fluid samples obtained by a suction blister analysis method from the involved skin of SSc patients or matched site of healthy controls (SSc n=28, controls n=15), and matched plasma samples. IL-31 receptor mRNA expression was assayed by qPCR of SSc and control fibroblast lysates, as well as epithelial tissue biopsy samples. Normal skin fibroblasts as well as fat derived mesenchymal stem cells (MSCs) were treated with IL-31 (50 ng/ml) and migratory and fibrotic responses were assayed.ResultsIL-31 levels were increased in dermal interstitial fluid in SSc patients compared to controls (mean of 99.4 pg/ml vs 2.3 pg/ml in controls, P<0.0003) and in plasma samples (mean plasma IL-31 1370 vs 196 pg/ml, P<0.01). Dermal fluid IL-31 levels correlated strongly with itch severity in these patients R=0.72, P<0.0038). Raised blister fluid IL-31 was characteristic of a subgroup of SSc patients with severe pruritus, which included individuals from both limited and diffuse SSc clinical subsets. Both normal and disease fibroblast extracts contained IL-31 receptor mRNA (qPCR relative copy number 6.4 SSc vs 1.4 controls, p<0.01) which was also seen in epidermal tissue extracts (qPCR 18.4 SSc vs 8.2 in control, p NS). Treatment of normal dermal fibroblasts with IL-31 led to induction of type I collagen but not CTGF, and promoted fibroblast and MSC migration dependent on ERK and PI3kinase pathways.ConclusionsThis is the first analysis of IL-31 in systemic sclerosis and we have shown increased expression in the skin and plasma of a subgroup of SSc patients, correlating with severe itch. IL-31 protein induced fibroblasts and MSCs and may link T-cell autoimmune responses to fibroblast and precursor cell activation in SSc. Blocking IL-31 therapeutically may provide effective treatment in a subgroup of SSc patients identified clinically by severe pruritus.Disclosure of InterestNone declared

The pruritogenic role of the type 2 immune response in diseases associated with chronic itch

“…Moreover, increased levels of IL-31 within the raised blister fluid of active lesions were characteristic of a subgroup of SSc patients with severe pruritus compared to SSc patients without pruritus. 44 Altogether, IL-4 and IL-13 likely drive SSc-associated pruritus in an indirect manner by activating fibroblasts and M2 macrophages, while the significant association of IL-31 with the severity of pruritus may point to a more direct role in SSc-associated pruritus.…”

Oncostatin M and its role in fibrosis

“…IL-31 shares some biological activities with OSM, including regulation of cell proliferation and tissue remodeling [28–30]. Similarly to OSM, IL-31 is elevated in chronic inflammatory diseases including atopic dermatitis, liver fibrosis and Scleroderma [31–33].…”

CCN proteins as potential actionable targets in scleroderma

“…Another aspect is abnormal terminal differentiation, with an altered expression of key proteins of the barrier, such as involucrin, loricrin and filaggrin . The skin barrier function could be altered through the increase of IL‐31, which has been shown in vivo to be responsible for transepidermal water loss (TEWL) . However, TEWL seems not altered in SSc skin …”