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Publications

Journal Article Preprint Epublish 4 citations

PubMed: 40502578 DOI: 10.1101/2025.06.06.25328991

Inflammatory arthritis immune related adverse events represent a unique autoimmune disease entity primarily driven by T cells, but likely not autoantibodies.

medRxiv

Authors: Xingxing Zhu, Yue Yu, Yanfeng Li, Panwen Wang, Ying Li, Chantal McCabe, Shiju Chen, Hannah E Langenfeld, Andrew C Hanson, Brenna E Sharp, Amber Woltzen, Cynthia S Crowson, Svetomir N Markovic, John M Davis, Haidong Dong, Uma Thanarajasingam, Hu Zeng

Affiliations

  • Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
  • Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.
  • Department of Quantitative Health Sciences, Mayo Clinic, Arizona, Florida.
  • Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida.
  • Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota. Department of Immunology and Rheumatology, The First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China.
  • Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota. Department of Immunology, Mayo Clinic, Rochester, Minnesota.
  • Department of Urology, Mayo Clinic, Rochester, Minnesota. Department of Immunology, Mayo Clinic, Rochester, Minnesota.
  • Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota. Department of Immunology, Mayo Clinic, Rochester, Minnesota.

Abstract

Immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA) is an increasingly recognized immune-related adverse event (irAE), yet its underlying immunopathogenesis remains poorly understood. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA irAE is unclear. Here, we performed in-depth immunophenotyping of peripheral blood from patients with IA irAE, and compared them with seronegative RA patients, ICI-treated patients without irAE, and healthy controls. IA irAE was marked by a distinct T cell-dominated profile, with CD4 + T cells exhibiting reduced CXCR3 and CCR6 expression, and both CD4 + and CD8 + T cells showing increased cytotoxic molecule expression and metabolic activation. In contrast to seronegative RA, IA irAE patients displayed no significant elevation in autoantibody levels or atypical CD11c +CD21 - B cells. IA irAE was further characterized by a proinflammatory cytokine milieu, with elevated levels of IL-6, IL-12, and type I IFN, which correlated with the observed T cell activation phenotypes. Altogether, our findings define IA irAE as an immunologically distinct entity from RA, representing a naturally occurring model of antibody-independent systemic autoimmunity in humans. These results suggest that pathogenic T cell responses, potentiated by specific inflammatory cytokines, may be sufficient to drive arthritis in the absence of humoral autoimmunity, offering new insights into immune tolerance breakdown and therapeutic targeting in irAEs.

MeSH

Cells, Autoantibodies, Arthritis, Drug-Related Side Effects And Adverse Reactions, Autoimmune Diseases