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By blocking inhibitory pathways of T-cell activation, immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (IRAEs), including inflammatory arthritis, myositis, vasculitis, and sicca syndrome.
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Treatment of ICI-induced rheumatic IRAE requires different considerations than treatment of classic rheumatic conditions.
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Using ICIs in those with preexisting autoimmunity is possible but with risk of causing a disease flare or a different IRAE.
Immune-Related Adverse Effects of Cancer Immunotherapy— Implications for Rheumatology
Section snippets
Key points
Spectrum and incidence of currently described rheumatic and musculoskeletal immune-related adverse events in clinical trials
Arthralgia and arthritis are the most commonly reported rheumatic and musculoskeletal IRAEs in ICI clinical trials to date. The incidence of arthralgia secondary to nivolumab in phase III trials ranges from 5% to 16%.9 Similar rates have been reported with ipilimumab monotherapy.23, 24 Like other IRAEs, the incidence of arthralgia seems higher in combination ICI therapy, as was seen in a trial for melanoma where the ipilimumab group had a rate of arthralgia of 6.1%, the nivolumab group had an
Inflammatory Arthritis
Two cases of inflammatory arthritis and tenosynovitis after pembrolizumab therapy have been reported.35 Both patients were seronegative (for rheumatoid factor [RF] and anticyclic citrullinated peptide [CCP] antibodies) and had involvement of large joints. One patient also had involvement of the proximal interphalageal joints. MRI of these 2 patients showed synovitis in the ankle and wrist with enhancement in the tendons consistent with tenosynovitis. For 1 patient pembrolizumab was held and
Evaluation of suspected rheumatic immune-related adverse events
For patients with suspected rheumatic IRAE, the authors recommend a full evaluation with a rheumatologist focusing on clinical characteristics, laboratory testing, imaging, and other specific tests as outlined in Table 3. Because the phenotypes of rheumatic IRAE are not fully understood, learning about which ways IRAE are similar to or different from autoimmune diseases not related to ICIs can potentially be helpful in guiding treatment. Because autoantibody formation is a possible mechanism
Treatment considerations
No treatment algorithms currently exist for treatment of rheumatic and musculoskeletal IRAEs. For other IRAEs, like colitis, pneumonitis, dermatologic manifestations, and hepatitis, treatment recommendations have been developed based on clinical experience.15, 45 These treatment algorithms give recommendations based on the grade of adverse event about treating with corticosteroids, TNF inhibitors, and holding or stopping the ICI.
Extrapolating from these algorithms, the authors suggest basing
Other considerations
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Metastatic disease: for patients with inflammatory arthritis, if a single joint is disproportionately affected or not improving with therapy, imaging to evaluate for bony metastasis should be performed. This has been reported in a patient with elbow arthritis.29
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Treatment length: there is uncertainty about how long to continue treatment in patients with rheumatic IRAE. In other nonrheumatic IRAE, some are self-limited or respond quickly to treatment whereas others can be persistent.22
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Immune checkpoint inhibition in patients with known autoimmune disease
The initial trials of ICIs excluded patients with preexisting autoimmune disease, so there are few data on how these drugs affect this group of patients. Now that several therapies are approved, case reports and 1 observational study of patients can provide some guidance on how to manage patients with preexisting autoimmune disease. For inflammatory bowel disease (IBD), pretreatment endoscopy to confirm that the IBD was not active allowed for successful use of ipilimumab for metastatic melanoma
Future directions for clinical practice and research
There are several features of rheumatic IRAEs that merit further study. Pathogenesis of rheumatic IRAE is unclear and will likely differ from classical autoimmune diseases. The optimal timing of treatment (eg, induction, tapering) is unknown as are the true clinical spectrum of illness and risk factors for developing IRAE. Concerns with immunosuppressive agents increasing risk of tumor recurrence must also be evaluated. Addressing these issues will require a concerted effort involving
Summary
ICIs will be increasingly used as they are approved for more tumor types and for use in combination, and as novel therapies targeting other immune checkpoint molecules are also approved. As use increases, there is a great likelihood that patients will be referred to rheumatology for evaluation and longitudinal management. Recognizing these syndromes and rapidly initiating therapy may help improve quality of life for affected patients. With careful evaluation of larger cohorts of patients, the
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The Utility of Laboratory Investigations for the Assessment and Management of Rheumatic Immune-Related Adverse Events
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2023, Joint Bone SpineCitation Excerpt :The blockage of immune-down regulators, responsible for a breakdown in immune homeostasis with an excessively activated immune system lead to the occurrence of immune-related adverse events (irAEs), that may affect any organ system, including the musculoskeletal system [3–5]. Musculoskeletal irAEs are heterogenous, including myalgias, arthralgias, arthritis, rheumatoid arthritis, polymyalgia rheumatica, spondyloarthritis, sicca syndrome, vasculitis, myositis and sarcoidosis [6–10], and their severity is usually assessed as mild to moderate [11]. Musculoskeletal manifestations mimicking chronic inflammatory diseases but they not meet the disease classification criteria, that was it used “-like” as polymyalgia rheumatica-like [12].
A narrative review of the principal glucocorticoids employed in cancer
2022, Seminars in OncologyCheckpoint Inhibitor Immune-Related Adverse Events: A Multimodality Pictorial Review
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Conflicts of Interest: Dr C.O. Bingham has served as a consultant for Bristol-Myers-Squibb.
Funding Sources: Dr L.C. Cappelli is supported by the Jerome L. Greene Foundation Scholar Award (# 90056963). Dr A.A. Shah is supported by National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (# K23-AR061439). Additional support was provided by a Jerome L. Greene Foundation Discovery Award and by RDRCC P30AR053503.