Background/Purpose: Systemic 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, a Th2 cell derived cytokine, is implicated in causing pruritus in conditions including atopic dermatitis and T cell lymphoma. T-lymphocyte-derived factors provide a possible mechanistic link between autoimmune inflammation and the 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. In addition, recombinant IL-31 was investigated for its capacity to influence fibroblast and mesenchymal stem cell (MSC) activity.

Methods:  Dermal blister fluid (BF) was obtained by a suction blister method from the involved skin of SSc patients or matched site of healthy controls synchronous to plasma sampling (SSc n=28, controls n=15) and IL-31 measured by ELISA. SSc and control fibroblasts lysates, MSC lysates, and tissue biopsied from involved skin lesions or control samples were analysed by qPCR for IL-31 receptor expression. Normal skin fibroblasts as well as MSCs were cultured and treated with IL-31 and phenotypic changes were assayed by protein assays, and next generation sequencing. Dermal fibroblast and MSC migration was assessed through scratch wound assay.

Results:  IL-31 levels were higher in dermal blister fluid from SSc patients compared to controls (99.4pg/ml in SSc vs 2.3pg/ml in controls, p<0.0003) as well as in plasma samples (1370 vs 196pg/ml, p<0.01). Dermal BF IL-31 levels correlated strongly with itch severity (R=0.72, p<0.0038) and elevated BF IL-31 was characteristic of a subgroup of mainly diffuse cutaneous SSc patients with severe pruritus. SSc fibroblasts showed a higher IL-31 receptor mRNA expression compared to healthy controls (relative copy number 6.4 and 1.4 respectively, p<0.01), whereas the epidermal tissue extracts showed a non-significant increase in SSc (18.4 vs 8.2 respectively, p=ns). Treating fibroblasts with IL-31 led to induction of type I collagen but not CTGF, and promoted fibroblast and MSC migration dependent on the PI3kinase pathway. Furthermore, recombinant IL-31 induced major changes in gene expression profile of both fibroblasts and MSCs.

Conclusion:  We have shown that an increased expression of IL-31 correlates with severe itch in SSc patients. IL-31 receptor was expressed in SSc fibroblasts and epidermal tissues at increased levels, and recombinant IL-31 protein induced major phenotypic changes in fibroblasts and MSCs. IL-31 may link T-cell autoimmune responses to fibroblast and fibroblast precursor activation in SSc. Blocking IL-31 therapeutically may provide effective treatment in a subgroup of SSc patients identified clinically by severe pruritus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-31-is-an-inflammatory-pro-fibrotic-factor-elevated-in-a-subset-of-scleroderma-patients-with-severe-pruritus/