EULAR Recommendations for the Management of Rheumatic Immune-Related Adverse Events Due to Cancer Immunotherapy

The European League Against Rheumatism (EULAR) task force has issued guidance for assisting rheumatologists to address the increasingly common rheumatic and musculoskeletal immune-related adverse events (irAEs) observed among patients with cancer receiving checkpoint inhibitors. The recommendations were published in the Annals of the Rheumatic Diseases.

For this update, a panel of 19 clinical experts from Europe and North America, including rheumatologists, internists, oncologists, clinical epidemiologists, allied health professionals, and patient representatives, convened to create recommendations that identified the clinical issues to address inflammatory side effects; based on this, they developed consensus of best practice recommendations.

The task force developed and presented the results of research questions for a systematic literature review, and using a consensus-based method, approved a series of recommendations which included 4 overarching principles and 10 points-to-consider.

Overarching Principles

• Rheumatic and musculoskeletal irAEs can occur as manifestations in patients with cancer receiving immunotherapy with checkpoint inhibitors.

• Management of irAEs should be based on a shared decision-making process between patients, oncologists, and rheumatologists.

• Rheumatologists should engage with oncologists to contribute to the interdisciplinary care of patients who present with musculoskeletal signs and symptoms.

• Rheumatologists are recommended to assist oncologists in differential diagnosis and to relieve rheumatic and musculoskeletal symptoms so that patients may maintain effective cancer immunotherapy.

Points-to-Consider for the Diagnosis and Management of Rheumatic irAEs

• Rheumatologists should note the spectrum of clinical presentations of rheumatic irAEs that may not fulfil traditional classification criteria of rheumatic and musculoskeletal diseases.
• Oncologists should be encouraged to promptly consult with rheumatologists when rheumatic symptoms are suspected because of immunotherapy, with rheumatologists providing facilitated access for these patients.
• Metastases, paraneoplastic syndromes, or unrelated rheumatic diseases may be differentially diagnosed as immune-related adverse events. Clinical evidence, laboratory tests, imaging, and if needed, biopsies should be collected to identify target organ inflammation and exclude potential differential diagnoses.
• Local and/or systemic steroids should be considered for immune-related rheumatic or systemic symptoms, and then tapered to the lowest effective dose to control the symptoms once improvement is achieved. Dose regimen and administration route may be decided based on clinical entity and activity.
• Rheumatologists must consider treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with an insufficient response to an acceptable dose of glucocorticoids or those who require glucocorticoid-sparing.
• Biologic DMARDs (bDMARDs) should be considered for patients with severe rheumatic and systemic immune-related adverse events or those with an insufficient response to csDMARDs, with tumor necrosis factor or interleukin-6 inhibitors being the preferred options for inflammatory arthritis.
• There must be shared decision-making between the providers and patient to hold or continue cancer immunotherapy, based on the severity of rheumatic adverse events, required immunosuppressive regimen, the tumor response and duration, and future oncology treatment plan.
• The task force suggested that myositis may be a severe condition and that immunotherapy withdrawal needs to be discussed. If there are life-threatening symptoms (bulbar symptoms [eg, dysphagia, dysarthria, and dysphonia], dyspnea, and myocarditis), a high dose of glucocorticoids plus other treatment options should be used instead; immunotherapy withdrawal is always necessary.
• Patients with pre-existing autoimmune rheumatic and/or systemic disease may receive cancer immunotherapy; however, baseline immunosuppressive regimen should be kept at the lowest dose possible (for glucocorticoids, <10 mg/d prednisone if possible).
• Before beginning cancer immunotherapy, a complete rheumatologic assessment should be performed in case of rheumatic, musculoskeletal, or systemic symptoms because there is no indication to test patients for the presence of autoantibodies.

The EULAR also detailed 3 treatment escalations to consider:

• Local or systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, subsequently tapered to the lowest efficient dose;
• csDMARDs in the event of an inadequate response to glucocorticoids or for steroid-sparing; and
• bDMARDs for severe or refractory adverse events.

Members of the task force also included a warning regarding severe myositis requiring high dose of glucocorticoids and close monitoring. Furthermore, patients with pre-existing rheumatic disease should be kept at the lowest efficient baseline immunosuppressive regimen before beginning immunotherapies.

These statements, being based almost entirely on low levels of evidence and on experts’ opinion, will undoubtedly require updating over the next few years, as new data emerge,” wrote the authors.  “Indeed, we expect that future oncologic data will likely [affect] our irAEs therapeutic strategy. We also anticipate a better understanding of irAEs mechanisms and pathophysiology. Finally, multicenter collaborative efforts, prospective registries and randomized trials will help to define the optimal treatment strategies to relieve patient symptoms without altering oncologic outcomes.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Kostine M, Finckh A, Bingham CO III, Visser K, Leipe J, Schulze-Koops H, et al. EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors [published online April 23, 2020]. Ann Rheum Dis. doi:10.1136/annrheumdis-2020-217139

This article originally appeared on Rheumatology Advisor