Background/Purpose: Immune checkpoint inhibitors (ICI) are effective treatments for advanced solid tumors that act by blocking negative costimulation of T-cells leading to an anti-tumor response. ICIs also cause non-specific immunologic activation leading to immune-related adverse events (IRAE), including colitis, pneumonitis, and hepatitis. Rheumatic and musculoskeletal events have been described in clinical trials, case reports, and observational studies, but have not been summarized or reviewed. This topic will become important to rheumatologists as the number of ICIs and indications for their use increase.

Methods: We conducted a systematic review of published literature (Medline, CENTRAL databases) reporting rheumatic and musculoskeletal IRAE secondary to inhibition of PD-1, CTLA-4, or PD-L1.

Results were screened for relevance and inclusion of original data. Studies were grouped by type: case series or reports, observational studies, and clinical trials. Data extraction was performed in duplicate. Results: Searches yielded 1725 unique results; 233 abstracts contained original data, which went on to full text screening. Of these, 51 mentioned a musculoskeletal or rheumatic IRAE and were included. Among 33 clinical trials, the incidence of arthralgia ranged from 1-43 %, while myalgia was reported in 2-20%. True rheumatic IRAE were reported less often in trials with rates of arthritis reported in 5/33 (incidence 1-7%) and vasculitis in 2/33 (incidence 2-3%). In 1 of 3 observational studies, the incidence of arthritis was 2% in patients receiving ipilimumab for renal cell carcinoma or melanoma. In case series and reports, inflammatory arthritis, inflammatory myopathy, eosinophilic fasciitis, vasculitis, and lupus nephritis secondary to ICIs were described (Table 1). No evidence-based information about treatment of rheumatic IRAE or studies evaluating specific pathogenesis was found.

Conclusion: Arthralgia and myalgia are common in patients treated with ICIs. The incidence of true rheumatic IRAEs, like inflammatory arthritis, is less clear from trials, partly due to lack of consensus on event coding and reporting of adverse events only of grade 3 or higher severity. There have been no prospective cohort studies to date that evaluate rheumatic IRAE, but more comprehensive data concerning pathogenesis, evaluation, and management are critical to inform rheumatologists, who will increasingly be referred patients for these complications of cancer therapy.