Immune Checkpoint Inhibitor-Associated Inflammatory Arthritis

Area of Science:

• Immunology
• Oncology
• Rheumatology

Background:

• Immune checkpoint inhibitors (ICIs) like PD-1 and CTLA-4 blockers revolutionized cancer therapy.
• However, ICIs can cause autoimmune side effects, notably immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA) in ~6% of patients.
• ICI-IA often mimics rheumatoid arthritis but is typically seronegative, with imaging revealing joint inflammation even without swelling.

Purpose of the Study:

• To review the current understanding of the cellular and molecular mechanisms of ICI-IA.
• To explore the role of specific immune cells and signaling pathways in ICI-IA pathogenesis.
• To identify potential research avenues for ICI-IA and other inflammatory arthritides.

Main Methods:

• Review of existing literature on ICI-IA.
• Analysis of cellular and molecular characteristics of ICI-IA synovium.
• Examination of immune cell populations (T cells, macrophages, Tregs) and signaling axes (CXCL10-CXCR3, CCR1-CCL3/5).

Main Results:

• ICI-IA synovium shows clonal expansion of CD38^hiCD127^-CD8⁺ T cells and IL-1β^hi macrophages.
• Communication occurs along CXCL10-CXCR3 and CCR1-CCL3/5 pathways.
• Naïve CD4⁺ T cell activation and impaired regulatory T cells (Tregs) synergistically amplify inflammation, particularly with combination ICI therapy.

Conclusions:

• ICI-IA pathogenesis involves specific T cell and macrophage activation patterns and signaling pathways.
• Understanding ICI-IA provides valuable insights into the broader mechanisms of inflammatory arthritis.
• Further research into ICI-IA could inform the development of targeted therapies for both ICI-induced autoimmunity and other forms of arthritis.