Background/Purpose: Despite of unprecedented clinical success in cancer therapeutics, immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Arthritis-irAE can not only cause bone erosions but also warrant early termination of ICI treatment. Further, treatment for the arthritis-irAE can mitigate anti-tumor immunity revived by the ICI treatment. To overcome such clinical challenges, understanding the pathophysiology of arthritis-irAE is critical; however, these mechanisms remain unknown.

Methods: We collected and performed immunoprofiling of synovial fluid from seven patients with active arthritis-irAE and three control patients with osteoarthritis. In parallel, we examined the impact of ICIs on collagen induced arthritis (CIA).

Results: Four patients developed arthritis after PD-1 inhibitor monotherapy and three after combination therapy with CTLA-4 and PD-1 inhibitors. Two patients in the combination therapy group required interleukin (IL)-6 receptor inhibitor therapy in addition to steroids, compared with one patient in the monotherapy group (sulfasalazine). IL-17-producing CD4⁺ T cells (Th17) were enriched in the combination therapy group compared to monotherapy group (1.01±0.73% in live CD4⁺ T cells in the monotherapy group compared with 3.19±0.31% in the combination therapy group; P=0.005). Synovial fluid levels of IL-6 and IL-17A, key cytokines for Th17 cell differentiation and function, were higher in the combination ICI therapy group than in the monotherapy group, suggesting the role of Th17-related cytokines in disease pathogenesis. Like humans, ICIs, especially in combinations, facilitate the development and progression of CIA. Importantly, although not reached statistical significance, like humans, collagen-specific Th17 cells were enriched in CIA mice receiving combined ICI treatment.

Conclusion: Our data suggests that Th17 cells, especially in post combination ICI therapy, play a critical role in the disease pathogenesis. Comprehensive studies with more patients/controls along with recapitulating mouse models will unmask underlying mechanisms of arthritis-irAE. Further, understanding of altered immunity in the arthritis-irAE will provide insights of inflammatory arthritis secondary to the classical autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-t-cell-responses-in-inflammatory-arthritis-associated-with-combined-ctla-4-and-pd-1-inhibitor-therapy/