Immune checkpoint inhibitor‐associated inflammatory arthritis

Understanding the cellular and molecular mechanisms of T cell activation has enabled the identification of immune checkpoints, such as PD-1 and CTLA-4, and the development immune checkpoint inhibitors (ICI) which have revolutionized cancer therapy. However, ICI cancer treatment is commonly associated with autoimmune side effects, including inflammatory arthritis (ICI-IA). ICI-IA occurs in ~6% of ICI-treated patients and often resembles rheumatoid arthritis phenotypically, although it is generally seronegative. Imaging often demonstrates joint inflammation in patients with ICI-associated joint pain, even in the absence of joint swelling. The ICI-IA synovium is characterized by clonal expansion of actively proliferating CD38^hiCD127^-CD8⁺ T cells and expansion of IL-1β^hi macrophages, communicating along CXCL10-CXCR3 and CCR1-CCL3/5 axes. Activation of naïve CD4⁺ T cells and impaired Tregs play a synergistic and amplifying role especially in the setting of combination ICI (anti-CTLA-4 plus anti-PD-1). ICI-IA has the potential to teach us about mechanisms underlying the biology and evolution of other forms of inflammatory arthritis. In this review, we summarize our current understanding of ICI-IA and propose promising avenues for future research.