Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.
Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours.
Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.
Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.
- Autoimmune Diseases
- Sjøgren's Syndrome
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Handling editor Tore K Kvien
Correction notice This article has been corrected since it was published Online First. The second author's first name has been corrected.
Contributors LCC and COB planned the manuscript. All authors contributed to the composition and revision of the manuscript. JA obtained the ultrasound images for the manuscript.
Funding This project was supported by Grant Number P30-AR053503 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. AAS is supported by grant K23-AR061439. LCC is supported through a Jerome L. Greene Foundation Scholar Award. Additional support was provided by a Jerome L. Greene Foundation Discovery Award to COB.
Competing interests EJL, ANB and COB have served as consultants for Bristol-Myers Squibb. JRB has served as an unpaid consultant to Bristol-Myers Squibb. EJL also served as a consultant to Amgen and Merck. EJL has received research support from Bristol-Myers Squibb, Merck and AstraZeneca. JN has served as a consultant for Bristol-Myers Squibb and has received honoraria from Bristol-Myers Squibb and AstraZeneca. JRB and DL have received research funding from Bristol-Myers Squibb. Bristol-Myers Squibb provided no financial or writing support for this manuscript, but reviewed the manuscript for accuracy concerning patients who participated in clinical trials.
Provenance and peer review Not commissioned; externally peer reviewed.