Medline ® Abstracts for References 84-86

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.

BACKGROUND: Immune checkpoint inhibitors (ICI) are improving prognosis in advanced stage cancers, but also lead to immune-related adverse events (IRAE). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAE have not been well characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAE to better understand prevalence and clinical characteristics.

METHODS: Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence and treatment data were extracted and summarized.

RESULTS: 1725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in pre-existing autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged from 1-43%, and myalgia was reported in 2-20%. Arthritis was reported in 5/33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with pre-existing autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis.

CONCLUSIONS: Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs like inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with pre-existing autoimmune disease. This article is protected by copyright. All rights reserved.