1791: Exploring the Mechanism of Anti-TNFα Therapy Non-response in Psoriatic Arthritis: The Role of TNF Receptor 2 Polymorphisms rs1061622

James Sullivan¹, Vandana Rai², Jennifer Harvey², Vincent Del Signore², Unnikrishnan Chandrasekharan² and M. Elaine Husni³, ¹Cleveland Clinic Lerner College of Medicine, Cleveland, OH, ²Cleveland Clinic, Cleveland, OH, ³Cleveland Clinic / Department of Rheumatic and Immunologic Diseases, Cleveland, OH

Background/Purpose: Despite the widespread use of anti-TNFα therapy in psoriatic arthritis (PsA), a significant proportion of patients fail to achieve a complete treatment response. There are no predictive markers for response to TNFα blockade. Rs1061622 polymorphisms (T/T, T/G, or G/G genotypes) corresponds to a methionine with T allele or arginine with G allele at amino acid position 196 of TNFα receptor 2 (TNFR2). These polymorphisms in TNFR2 have been associated with treatment response in rheumatoid arthritis and PsA, with the G/G genotype being less likely to respond to anti-TNFα therapy compared to the T/T genotype. However, the underlying molecular mechanism explaining this association remains unknown. This study aimed to investigate the signaling differences between TNFR2 variants associated with rs1061622 polymorphisms carrying the T allele (TNFR2-196M) and G allele (TNFR2-196R), which could potentially elucidate the differential responsiveness to anti-TNFα therapy in PsA patients.

Methods: Gene expression studies were conducted in Jurkat T cells and primary human endothelial cells. Recombinant TNFR2-196M or TNFR2-196R were expressed in both cell types using a lentiviral approach. Cells were treated with TNFα alone (2 ng/mL) or TNFα in the presence of a TNFα neutralizing antibody. The expression of, ICAM-1, a TNFR2-dependent proinflammatory gene, was assessed using quantitative RT-PCR. These findings were further validated using human umbilical vein endothelial cells (HUVEC) with rs1061622 polymorphisms. The polymorphisms were determined by genotyping (T/T, T/G, and G/G) discarded umbilical cord tissues prior to isolating and culturing the endothelial cells. Signaling pathways through TNFR2 were assessed using RTqPCR and Western blot analysis.

Results: In Jurkat T cells, successful expression of TNFR2-196M and TNFR2-196R was achieved (Figure 1A). Cells expressing TNFR2-196R exhibited increased basal expression of ICAM-1 compared to TNFR2-196M (Figure 1B). Importantly, treatment with a TNFα neutralizing antibody did not affect basal ICAM-1. Similarly, HUVEC cells over TNFR2-196R expressing (by lentiviral approach) showed increased ICAM-1 and IL-1β mRNA levels, while TNFR2-196M did not exhibit this effect (Figure 2). Furthermore, HUVEC isolated from subjects with G allele demonstrated higher basal expression of proinflammatory genes (IL-1β, IL-6, ICAM-1, GM-CSF2, CXCL2, E-selectin, Il-8) in the absence of TNFα (Figure 3). Notably, the TNFR2-independent gene P-selectin, did not show an increase in basal activity in cells expressing TNFR2-196R.

Conclusion: Our findings suggest that at least one G allele for the TNFR2 rs1061622 polymorphisms (TNFR-196R) confers a TNFα independent proinflammatory activity. These results may provide insights into a potential underlying mechanism for the association between rs1061622 polymorphisms and likelihood of response to anti-TNFα treatment in PsA. Further understanding of these signaling differences may contribute to the development of personalized treatment strategies for PsA patients based on their genetic profiles.








J. Sullivan: None; V. Rai: None; J. Harvey: None; V. Del Signore: None; U. Chandrasekharan: None; M. Husni: AbbVie, 1, 2, Amgen, 1, 2, Bristol-Myers Squibb, 1, 2, Eli Lilly, 1, 2, Janssen, 1, 2, Novartis, 1, 2, Pfizer, 1, 2, UCB, 1, 2.