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 programmed cell death protein 1 (PD‐1) and cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4), and the development of immune checkpoint inhibitors (ICIs), which have revolutionized cancer therapy. However, ICI cancer treatment is commonly associated with autoimmune side effects, including inflammatory arthritis (IA). ICI‐IA occurs in approximately 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 hi CD127 ‐ CD8 + T cells and expansion of interleukin‐1β hi macrophages, communicating along CXCL10‐CXCR3 and CCR1‐CCL3/5 axes. Activation of naive CD4 + T cells and impaired Treg cells 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 IA. In this review, we summarize our current understanding of ICI‐IA and propose promising avenues for future research. image