Rheumatic Immune-Related Adverse Events from Checkpoint Inhibitor Therapy: Update

irAEs are a formidable challenge


By Cassandra Calabrese, DO, and Leonard H Calabrese, DO


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While the mainstream use of checkpoint inhibitors and other immunotherapy strategies is now considered a major pillar of cancer treatment, the related adverse events — namely a wide spectrum of autoimmune diseases including a variety of rheumatic diseases — have been referred to as its possible Achilles’ heel. It is now evident that we, as a general medical community and rheumatologists in particular, will have a growing role in the management of such patients, which will only increase in the years to come.

Since 2011 the field of cancer immunotherapy has grown growing rapidly, with many new drugs and strategies being approved for many different malignancies, including the first-ever FDA approval for treatment agnostic of tumor type and instead based on a common biomarker for the PD-1 inhibitor pembrolizumab. It is now estimated that 43.5% of cancer patients are eligible for checkpoint inhibitor therapy.

For rheumatologists, the emergence of immune-related adverse events (irAEs) represents a formidable challenge both in terms of patient care and the need for continuing medical education. In patient care, we are seeing a rapid rise in new onset inflammatory rheumatic diseases in patients who cannot wait a long time for appointments. Educationally, we need to keep up with the rapid pace of new knowledge regarding clinical and immunologic issues. We have been committed to meeting these challenges since 2016, when we developed a specialized interprofessional clinic to evaluate such patients and created new formats for interprofessional education and research.

In September 2017, a monthly conference was developed at our institution dedicated to the presentation and management of irAEs. This tumor board consists of clinicians from numerous departments with known interest and experience in irAEs. The goal is to discuss new and/or challenging cases of irAEs, review the extant literature and receive input on interprofessional management. On average, we discuss six cases at each conference. Approximately six months after the tumor board began, we surveyed participants to assess its educational value and appraise its impact on their confidence in managing irAEs. Our survey results indicated that 66.7% of physicians felt attending the tumor board significantly increased their awareness of the scope and presentation of irAEs, and 41.7% reported significantly increased confidence in diagnosing and managing certain irAEs. Most (75%) felt that the conference format/content was superior to other conferences in terms of interest and practical content. When queried about what aspects they valued most, the most common response was the multidisciplinary nature of the conference. Now, two years later, we suspect these results would be even more impressive, as the tumor board has grown in size to standing-room only.

Also, we are involved in a national tumor board started at MD Anderson with rheumatologists from institutions all over the country including Mayo Clinic, Johns Hopkins, NYU, Standford and others. We meet monthly on a web-based platform to discuss complex rheumatic irAE cases, and brainstorm on opportunities to collaborate through research. Dr. Len Calabrese is also a member of European League Against Rheumatism (EULAR) Task Force, which is developing the first rheumatology specific guidelines for management of irAEs.

Rheumatologists play an important role in management of irAEs

The diagnosis and management of patients who develop irAEs from checkpoint inhibitor therapy requires multidisciplinary care and rheumatologists play an important role in their management. Patients who develop irAEs from checkpoint inhibitor therapy need to be triaged and seen by the appropriate subspecialist immediately. With the ever-present patient access issue in our current healthcare system, this can be a problem. At Cleveland Clinic, a multidisciplinary referral system was created to help efficiently triage this patients. Dr. Cassandra Calabrese works directly with the immune-oncology teams to get these patients seen in real time. She sees an average of 10 new immunotherapy patients per month, and this number is expected to grow as rheumatologists will be increasingly called upon to participate in the care of these patients.

irAEs are a new area of medicine that require multidisciplinary collaboration for investigation and optimal management. The multisystem involvement and autoimmune, inflammatory mechanisms of these complications makes rheumatologists valued — if not central — partners in both patient management and research. Novel venues for educational interchange are needed to further this evolving field.


Educational opportunities for a rapidly changing field

In Cleveland Clinic’s Rheumatology department, a morning lecture series has been a great venue for learning about irAEs and immunotherapy. Dr. Cassandra Calabrese presented an introduction to irAEs for the fellows in August, followed by a deeper dive into underlying basic and clinical immunology by Dr. Len Calabrese. In September, we were fortunate to host visiting professor Esfahani Khashayer, MD, from McGill University, who spoke to both the Rheumatology department and at Taussig Cancer Center. He is co-leader of one of Canada’s largest biobanking/research platforms on irAEs. The focus of his visit was to explore the experience and underlying biology for the use of targeted therapies to treat irAEs over and above glucocorticoids and TNF inhibitors.

Along with Pauline Funchain, MD, and Laura Wood, RN, from Taussig Cancer Center, Dr. Cassandra Calabrese is planning Cleveland Clinic’s first live CME event exclusively dedicated to irAEs. The course will be held on March 6, 2020 at Cleveland Clinic’s Intercontinental Hotel and Convention Center. This will be an interdisciplinary conference, geared toward oncologists and non-oncologists, with representation from oncology, rheumatology, dermatology, endocrinology, ophthalmology, pulmonary, gastroenterology and cardiology.

To refer patients, visit https://my.clevelandclinic.org/departments/orthopaedics-rheumatology/medical-professionals/refer-a-patient.

A sample of the publications produced from the department on this topic

Calabrese C, Cappelli LC, Kostine M, Kirchner E, Braaten T, Calabrese LH. Polymyalgia rheumatica-like syndrome from checkpoint inhibitor therapy: case series and systematic review of the literature. RMD Open. 2019;5(1):e000906.

Calabrese C, Kirchner E, Kontzias A, Velcehti V, Calabrese LH. Rheumatic immune related adverse events of checkpoint inhibitor therapy for cancer: case series of a new nosological entity. RMP Open. 2018;3(1):e000412

Calabrese LH. Sorting out the complexities of autoimmunity and checkpoint inhibitors: not so easy. Ann Intern Med. 2018;168(2):149-150.

Calabrese LH, Calabrese C, Cappelli LC. Rheumatic immune related adverse events from cancer immunotherapy. Nat Rev Rheumatol. 2018;14(10):569-579.


Calabrese, LH, Marriette,X, The evolving role of the rheumatologist in the management of immune related adverse events from cancer immunotherapy. Ann Rheum Dis. 2017 Sep 19. pii: annrheumdis-2017-212061

Calabrese LC and Velcheti V. Checkpoint immunotherapy: good for cancer therapy, bad for rheumatic diseases. Ann Rheum Dis. 2017;76(1):1-3.

Khunger M, Calabrese C, Kontzias A, Velcheti V. To treat or not to treat: role of immunotherapy in patients with concomitant diagnosis of advanced stage non-small cell lung cancer and psoriasis. J Thorac Oncol. 2017;12(9):e417-e419.

Ornstein MC, Calabrese C, Wood LS, Kirchner E, Profusek P, Allman KD, Martin A, Kontzias A, Grivas P, Garcia JA, Calabrese LH, Rini BI. Myalgia and arthralgia immune related adverse events (irAEs) in patients with genitourinary malignancies treated with immune checkpoint inhibitors. Clin Genitourin Cancer. 2019;17(3):177-182.

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