Rheumatic immune-related adverse events associated with immune checkpoint inhibitors compared with placebo in oncologic patients: a systemic review and meta-analysis

Objective: We aim to characterize the incidence and relative risk of rheumatic and systemic immune-related adverse effects (irAEs) among immune checkpoint inhibitor (ICI) therapy compared with those after placebo treatment.Methods: Randomized clinical trial studies with placebo control with the following keywords were searched from Embase, PubMed, Cochrane databases: immune checkpoint inhibitors, neoplasms, randomized controlled trials, and adverse effects.Results: Among the 5444 published and 316 registration records, nine placebo-controlled randomized clinical trials met our selection criteria, and included data from 5560 patients. Compared with placebo use, using ICIs increases the risk of overall-rheumatic irAEs. The incidence and relative risk of all-grade rheumatic irAEs were 18.40% [95% confidence interval (CI) 12.16–25.59%, p < 0.01] and 2.30 (95% CI 1.32–4.02), respectively, while musculoskeletal irAEs were 11.30% (95% CI 9.76–12.85%) and 1.01 (95% CI 0.84–1.22). The incidence and relative risk of severe rheumatic irAEs were 5.72% (95% CI 3.92–7.82%), and 8.29 (95% CI 3.75–18.35), respectively. Arthralgia was the most common rheumatic irAE (incidence 11.00%, 95% CI 9.55–12.64%; relative risk 0.99, 95% CI 0.82–1.19), although usually not severe. Colitis (incidence 3.23%, 95% CI 1.27–7.98%; relative risk 6.53, 95% CI 2.66–16.04) and pneumonitis (incidence 3.11%, 95% CI 1.56–6.21; relative risk 4.04, 95% CI 1.65–9.89) were commonly observed and tended to be severe. Hepatitis, hypophysitis, thyroiditis, and myositis were rare and less recorded, yet can be severe and life threatening. Other extremely rare severe rheumatic irAEs included sarcoidosis ( n = 11), autoimmune arthritis ( n = 8), autoimmune uveitis ( n = 3), autoimmune pericarditis, bursitis, osteochondrosis, psoriasis, polymyalgia rheumatica, systemic inflammatory response syndrome, and Sjögren syndrome ( n = 1, each).Conclusion: ICI therapy increased the incidence and relative risk of all-grade and severe rheumatic irAEs. Arthralgia was the most commonly observed non-severe irAE, while colitis and pneumonitis were commonly observed severe irAEs. Rare rheumatic irAEs like hepatitis, hypophysitis, thyroiditis, and myositis warrant special attention.