Varied Response to TNF Inhibitors in Psoriatic Arthritis

By M. Elaine Husni, MD, MPH, Unnikrishnan M. Chandrasekharan, PhD, and Chris Sun, BS

Tumor necrosis factor alpha (TNF-α) inhibitors (TNFi) represent a cornerstone of therapy for psoriatic arthritis (PsA). Yet up to 40% of patients either fail to respond, achieve only partial benefit or lose therapeutic efficacy over time. The biological basis for this variability in treatment response remains poorly understood, and currently no biomarker exists to guide clinicians in predicting who will benefit from TNFi therapy.

Addressing this gap is a major focus of the Elaine Husni laboratory. TNF-α signals through two receptors, TNFR1 and TNFR2. Interestingly, a single nucleotide polymorphism in the TNFR2 gene (rs1061622) has been implicated in TNFi responsiveness across multiple immune-mediated diseases. This polymorphism results in either a methionine (TNFR2-M, the major allele present in ~80%-95% of the population) or an arginine (TNFR2-R, the minor allele present in ~5%-20%) at amino acid position 196. Patients carrying the TNFR2-R variant have been reported to respond less favorably to TNFi therapy. Despite this important association, the mechanistic underpinnings of the reduced responsiveness remain unknown.

To explore this question, we examined whether the TNFR2-M and TNFR2-R variants differ in cellular localization, a factor that could alter receptor availability for TNF-α binding and downstream signaling. Using cultured human endothelial cells, we expressed GFP-tagged TNFR2-M or TNFR2-R and visualized their distribution with fluorescence microscopy. Strikingly, TNFR2-M localized predominantly at the cell membrane, whereas TNFR2-R was largely retained intracellularly.

This difference in receptor trafficking may reduce surface accessibility of TNFR2-R to TNF-α, thereby altering signaling dynamics and ultimately contributing to diminished TNFi responsiveness.

These findings provide a novel mechanistic link between TNFR2 genetic variation and treatment response in PsA. By illuminating how a single amino acid change can influence receptor localization and function, this work highlights a potential pathway for precision medicine approaches in PsA and opens the door to new therapeutic strategies for patients who do not respond to current TNF blockade.

M. Elaine Husni, MD, MPH, is Vice Chair of Rheumatology and Director, Arthritis and Musculoskeletal Center. Lab members Raminderjit Kaur, PhD; Vincent Del Signore, BS; Jean Lin, MD; and Shashank Cheemalavagu, MD, contributed to this research.

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