Abstract and Introduction
Introduction: Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced cancer. Rheumatoid arthritis (RA) is associated with an increased risk of malignancies; however, patients with RA have been excluded from ICI trials. In this study, we evaluated risk of toxicity after initiation of ICI treatment in RA patients.
Methods: We conducted a single-institution, medical records review analysis to assess the incidence of immune-related adverse events (irAEs) and autoimmune disease (AID) flares among patients with AIDs treated with ICIs from 2011 to 2018. A subgroup analysis for RA patients was performed with frequencies of irAEs and AID flares reported.
Results: Twenty-two patients with RA who were treated with ICI for malignancy were identified. At the time of ICI initiation, 86% had inactive RA disease activity. Immune-related adverse events occurred in 7 (32%) of patients, with 2 (9%) developing grade 3 (i.e., severe) irAEs. Immune checkpoint inhibitors were temporarily discontinued because of irAEs in 5 patients (23%), and permanently in 1 patient. Rheumatoid arthritis flares occurred in 12 patients (55%). Of those, 10 (83%) received oral corticosteroids with an adequate treatment response.
Conclusions: Our analysis suggests that irAEs following ICI treatment are not increased among RA patients compared with other cancer patients. Heightened RA disease activity during ICI treatment is common, but most adverse events are manageable with oral corticosteroids, and few require permanent ICI discontinuation. A close collaboration between the oncologist and rheumatologist is advisable when considering ICIs in patients with RA.
Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of oncology. Immune checkpoint inhibitors have been developed for 3 unique molecular targets—cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1)—involved in the maintenance of immune tolerance. These agents have shown efficacy and been approved for use in a wide range of cancers, including non–small cell lung cancer (NSCLC), metastatic melanoma,[2–4] and renal cell carcinoma, among others.
By blocking immunoregulatory pathways, ICIs also have the unintended but not unexpected adverse effect of autoimmune-like phenomena known as immune-related adverse events (irAEs). The biology of irAEs has raised the concern that patients with preexisting autoimmune diseases (AIDs) may experience more severe and potentially treatment-limiting irAEs than patients without AID or exacerbations of their underlying autoimmune illnesses. On this basis, patients with preexisting AIDs have been largely excluded from clinical trials evaluating efficacy of ICI therapy for treating malignancy.[2,6–9] While some clinicians nonetheless choose to administer ICIs in AID patients, the risks of irAE development and/or disease flare remain unclear.
Rheumatoid arthritis (RA) affects approximately 1% of the general population in the developed world. Importantly, RA is associated with more than double the risk of malignant lymphoma, and 60% increased risk of lung cancer, when compared with the general population. The CTLA-4 and PD-1/PD-L1 pathways have been implicated in the pathophysiology of RA,[12–14] with several groups reporting that genetic polymorphisms in the PD-1 gene and CTLA-4 genes are associated with RA risk.[15–17] Additionally, PD-1 expression levels have been shown to be increased on the surface of T lymphocytes from the blood and synovial fluid in RA patients with cells producing increased levels of IL-21. It is unclear, however, if increased PD-1 expression in RA is a compensatory mechanism to modulate disease via B-cell–T-cell interactions. A recent study comparing the PD-1 pathway during different phases of RA progression also identified increased PD-1 transcription. Additionally, Matsuda et al. showed increased PD-L1 transcription in T lymphocytes infiltrating synovium in RA patients with high disease activity, both suggesting a role for PD-1 and PD-L1 in RA pathogenesis.[12,13] Furthermore, the CTLA-4 fusion protein abatacept is used to treat RA by promoting T-cell inhibition, suggesting that native CTLA-4 on T cells may play an important role in down-modulating RA disease.
The implied role of PD-1 and CTLA-4 in modulating RA raises concerns that administration of ICIs might have particularly adverse implications for RA patients. For this reason, ICI treatment has not been formally studied in RA patients, and ICI therapy is often either not offered or delayed due to concern for heightened toxicity. Available data have therefore been limited to case reports, small case series, or reviews of case series.[20–22] Here, we report the incidence of irAEs and RA flares after ICI treatment in a cohort of 22 patients with preexisting RA. To our knowledge, this constitutes the largest retrospective analysis of ICI administration in RA patients.
J Clin Rheumatol. 2021;27(7):267-271. © 2021 Lippincott Williams & Wilkins