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 CD38hi CD127- CD8+ T cells and expansion of interleukin-1βhi 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.