Glucocorticoids (GC) play a critical role in managing inflammatory conditions and have gained attention in cancer immunotherapy due to their immunosuppressive properties. This review explores the relationship between GC and immune checkpoint inhibitors (ICI) in cancer progression and therapy, and most importantly, synthesizes updated evidence linking GC-induced upregulation of inhibitory checkpoint molecules leading to ICI therapy failure in some cases. This review examines the role of co-inhibitory molecules (CIMs) like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) in modulating immune responses and enabling tumor evasion. It also considers immune-related adverse events (irAEs) associated with ICI therapy, which are often mitigated using GCs. While GCs manage irAEs effectively, their influence on therapeutic outcomes remains controversial. Preclinical and clinical evidence shows that GCs may activate CIMs, potentially undermining the efficacy of immunotherapy. Preclinical studies indicate that both synthetic and endogenous GC upregulate CIMs like PD-1 and LAG-3 on immune cells, impairing immune activation and anti-tumor responses. Pharmacologic inhibition of GCs signaling, such as 11β-HSD1 inhibitors, has shown promise in enhancing ICI efficacy. GCs timing and dosage are critical; early GC use often correlates with poorer treatment responses, while later use may improve clinical outcomes. This review highlights the dual role of GCs as potential immunomodulators of immune responses in cancer immunotherapy. A deeper understanding of GC-ICI interactions is vital to optimize treatment strategies. Future studies are needed to refine therapeutic approaches and individualized patient outcomes.

Full Papers; Authors: S. Gertel, A. Polachek, V. Furer, D. Levartovsky, H. Sidis, S. Pel, D. Paran, O. Elkayam

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4, anti-programmed cell death 1, and anti-programmed cell death ligand 1 (PD-L1) antibodies, are currently widely used in oncology clinical practice, achieving considerable success in improving disease outcomes. New checkpoint targets are being discovered and investigated through basic science research and clinical trials. ICI remove negative regulatory immune signals on T cells, leading to immune activation and induction of antitumor immunity. Patients who receive ICI, however, are at risk for developing immune-related adverse events (irAEs), which are attributed to increased T cell activity against antigens in both tumors and in healthy tissues, to increased inflammatory cytokine levels, to increased levels of preexisting autoantibodies, and to enhanced complement-mediated inflammation. Arthritis is one of the most common irAEs. ICI-induced rheumatic irAEs are categorized by levels of severity which guide the choice of treatment options. Management of ICI-induced rheumatic irAEs includes the use of glucocorticoids, disease-modifying antirheumatic drugs (mainly methotrexate), and biological agents (e.g., tumor necrosis factor, interleukin-6 receptor, and CD20 inhibitors). This review aims to summarize the current ICI subtypes, their role in rheumatic irAEs development, and therapies current used in clinical practice to manage irAEs. In addition, we propose to use an ex vivo personalized diagnostic assay for the selection of the most effective ICI with antirheumatic drugs combinations that will inhibit the advancement of ICI-induced adverse events. Cite this article as: Rose N, Furer V, Polachek A, Elkayam O, Gertel S. Immune checkpoint inhibitor-induced inflammatory arthritis: Overview of therapies and a personalized approach to optimized combined therapy. Eur J Rheumatol. 2024;11(1):27-32.