• Immune Checkpoint Inhibitor-Related Post-Immunotherapy Arthritis: Mechanisms, Manifestations, and Management Strategies
  • Mohammad-Salar Hosseini,1,*
    1. Hematology and Oncology Research Center, Tabriz University of Medical Sciences


  • Introduction: Immune checkpoint inhibitors (ICIs) are cutting-edge therapeutic approaches in clinical oncology that have transformed the cancer treatment landscape by unleashing the immune system's potential to attack tumoral cells. Nonetheless, this enhanced immune activation can also lead to various immune-related adverse events (irAEs). Post-immunotherapy arthritis (PIA), primarily associated with ICIs, presents a clinical challenge, demanding a multidisciplinary approach to diagnosis and management. This review delves into the mechanisms, clinical manifestations, and management strategies for post-immunotherapy and ICI-related arthritis.
  • Methods: A comprehensive literature review was performed using Medline (via PubMed) and Scopus databases, Google Scholar search engine, and ClinicalTrials.gov registry of clinical trials in August 2023. Relevant studies, discussing the mechanisms, manifestations, and management of post-immunotherapy and ICI-related arthritis were reviewed critically, regardless of the cancer type and population.
  • Results: PIA is seen in both PD-1/PD-L1 and CTLA-4-targeting monotherapy and ICI combination therapy strategies. The precise mechanisms of PIA are not fully elucidated. However, several hypotheses have been proposed so far, including dysregulated immune response by disrupting the balance of pro-inflammatory and regulatory immune responses, molecular mimicry as activated T cells potentially cross-react with the autoantigens expressed in joint tissues, and alterations in regulatory T cells (Tregs), which ultimately affects the immune tolerance and could lead to unchecked activation of autoreactive T cells. ICI-related PIA is presented with a variety of manifestations, ranging from mild arthralgias to severe polyarthritis, typically from weeks to months after the initiation of treatment. The most commonly affected joints are the knees, wrists, and small hand joints. Morning stiffness, joint swelling, and pain are hallmark features. Meanwhile, metastasis and infection could also present with the same initial symptoms. Laboratory evaluation often reveals elevated inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Rheumatoid factor (RF) may be positive in a subset of patients, resembling seropositive rheumatoid arthritis. However, seronegative cases have been commonly observed in the studies. Management of PIA requires a collaborative effort to maintain the efficacy of the cancer treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) can provide symptomatic relief for mild cases but should be used with caution, as they are associated with many gastrointestinal and renal adverse events. Systemic corticosteroids, such as prednisone, are often required to control moderate to severe PIA. Still, long-term use of systemic corticosteroids is not generally recommended and requires further studies. Disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, could be considered for refractory cases. DMARD-resistant cases might benefit from cytokine-targeting biological agents, which are still under investigation in the context of cancer treatment irAEs. Finally, similar to other irAEs, temporary discontinuation of ICIs may be necessary in cases of severe arthritis.
  • Conclusion: PIA is an emerging challenge in cancer immunotherapy. Understanding the underlying mechanisms, presenting manifestations, and clinical management strategies could direct a collaborative approach to effective management of this cancer treatment complication. Future studies should provide in-depth insight into potential prognostic and early-diagnostic biomarkers for ICI-related PIA. Additionally, the development of novel therapies with a more favorable safety profile is a priority approaching the irAEs.
  • Keywords: Adverse events, Arthritis, Cancer immunotherapy, Immune checkpoint inhibitor, Inflammation