Abstract and Introduction
Abstract
Objectives: With the increased use of immune checkpoint inhibitors (ICIs) in cancer patients, arthralgia has been the most commonly reported musculoskeletal immune-related adverse event (irAE). We aimed to characterize arthralgia and its association with overall survival (OS).
Material and Methods: Randomized controlled trials (RCTs) reporting on data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (ORs) with 95% CIs were calculated for arthralgia using a random-effects model meta-analysis. Individual patient data were reconstructed from RCTs assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry.
Results: We analysed 14 377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20, 1.56). Of the 369 patients in the YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs, which was noticeably more frequent than in those without arthralgia (OR 1.92, 95% CI 1.04, 3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80, 8.39). In the YCU registry, patients with (vs without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17, 0.65, P < 0.001).
Conclusions: If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS, and the condition of patients with irAEs must be carefully evaluated to determine optimal management.
Introduction
Immune checkpoint inhibitors (ICIs) are antibodies designed to block molecules that inhibit the host's immune cells, thereby reactivating suppressed T cell functions and achieving anticancer immunity. Since the US Food and Drug Administration's approval of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody in 2011, its therapeutic efficacy and the associated prolonged survival, compared with conventional chemotherapy, have been confirmed in various cancer types.[1] Anti-programmed cell death protein-1 (PD-1) and anti-programmed death ligand-1 (PD-L1) antibodies have also been approved, and their indications are expanding rapidly.
Treatment with ICIs triggers a pronounced immune response, which can damage non-cancerous cells. This phenomenon, called immune-related adverse events (irAEs), can sometimes be severe enough to require discontinuation of treatment. The major irAEs are thyroiditis, skin rash, and interstitial pneumonia, but musculoskeletal irAEs can occur less frequently. Of these, arthralgia is reported most frequently, with an incidence of nearly 10%.[2] Musculoskeletal irAEs are now classified as a 'new spectrum of rheumatic and musculoskeletal diseases' that may be seen by rheumatologists, and which often persist chronically.[3] However, the effect on the survival of cancer patients with arthralgia from ICIs has not been described. Interestingly, some important differences are also noted between musculoskeletal irAEs and existing rheumatic diseases, and the pathobiology of these syndromes may provide clues about the role of antitumour effects.
Here, we performed a meta-analysis to determine the incidence of arthralgia in patients treated with ICIs, by collecting data on the frequency of arthralgia and the associated treatment protocols. We also summarized the characteristics of ICI-induced arthralgia in patients attending our hospital and evaluated the association between ICI-induced arthralgia and prognosis. We pooled individual participant–level data from selected randomized controlled trials (RCTs) to validate our findings regarding the patients' prognoses.
Rheumatology. 2023;62(4):1451-1459. © 2023 Oxford University Press
