Inadequate response to anti-TNFα therapy is associated with a gain-of-function TNFR2-R polymorphic variant in patients with psoriatic arthritis.

Abstract

Front-line treatment for psoriatic arthritis (PsA) often involves the use of tumour necrosis factor alpha (TNFα) blocking medications (tumour necrosis factor alpha inhibition [TNFi]). However, more than 40% of patients exhibit inadequate responses, and there is no predictive clinical test available. Our goal is to investigate whether the response to TNFi treatment is associated with TNFα receptor 2 (TNFR2) rs1061622 polymorphic variants, TNFR2-M or TNFR2-R, in PsA. Furthermore, to elucidate the underlying mechanisms, differences in cell signalling and gene expression conferred by TNFR2-M vs TNFR2-R were examined. TNFR2 rs1061622 polymorphism status of 164 patients was assessed using restriction fragment length polymorphisms analysis. Discontinuation of the TNFi agents <12 months due to inadequate efficacy determined by chart review was the primary outcome. Human endothelial cells expressing endogenous or recombinant TNFR2-M or TNFR2-R and Jurkat T cells expressing recombinant TNFR2-M or TNFR2-R were utilised to investigate differences in cell signalling and gene expression. Patients with PsA with TNFR2-R variant had a ∼5-fold increased likelihood of discontinuing TNFi therapy <12 months, vs TNFR2-M carriers (95% CI 1.98-12.78). The cells with TNFR2-R alleles showed higher levels of proinflammatory gene expression in the absence of TNFa stimulation (P < .01). This activity of TNFR2-R was unaffected by a TNFα-neutralising antibody, whereas blocked by a Rho kinase (ROCK)-specific inhibitor. TNFR2 rs1061622 polymorphism significantly influences TNFi therapy responsiveness in PsA. The TNFα-independent, but ROCK activity-dependent gain-of-function activity conferred by TNFR2-R variant potentially serves as a mechanism underlying inadequate responses to TNFi in a subset of patients with PsA.