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

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.

Competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MEH reports a relationship with AbbVie Inc that includes: consulting or advisory. MEH reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. MEH reports a relationship with Eli Lilly and Company that includes: consulting or advisory. MEH reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. MEH reports a relationship with Novartis as consulting or advisory. MEH reports a relationship with UCB Inc that includes: consulting or advisory. MEH reports a relationship with National Psoriasis Foundation that includes: board membership. MEH reports a relationship with Rheumatology Research Foundation that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.