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  • Review Article
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Rheumatic immune-related adverse events from cancer immunotherapy

Nature Reviews Rheumatology volume 14, pages 569–579 (2018)Cite this article

Subjects

Abstract

Immunotherapy has revolutionized the treatment of cancer, but a rapid rise in the use of the family of therapeutic agents known as checkpoint inhibitors (CPIs) is associated with a new group of immune-related adverse events (irAEs) in almost any organ system. Among these irAEs, rheumatic complications are common and seem to have features that are distinct from irAEs in other organ systems, including a highly variable time of clinical onset and the capacity to persist, possibly indefinitely, even after cessation of CPI therapy. In this Review, mechanisms of action of CPIs and how they might cause rheumatic irAEs are described. Also covered are epidemiology and clinical descriptions of rheumatic irAEs, plus guiding principles for managing irAEs. Finally, we outline future directions that must be taken in response to a series of unanswered questions and unmet needs that now confront rheumatologists who are, or will be, engaged in this new area of rheumatology.

Key points

  • Cancer immunotherapy with checkpoint inhibitors (CPIs) has revolutionized the treatment of cancer but presents the risk of developing autoimmune or autoinflammatory complications know as immune-related adverse events (irAEs).

  • irAEs are clinically common and can occur in almost any organ system during and/or after treatment with a CPI.

  • Treatment of irAEs often requires immunosuppression with glucocorticoids, which are sometimes administered with conventional synthetic or biologic disease-modifying drugs.

  • Rheumatic irAEs are not as common as some other irAEs but are underdiagnosed and less well recognized.

  • Rheumatic irAEs seem to be nosologically distinct, occurring both early and late in response to CPI therapy, and a substantial proportion of them are chronic, persisting even after cessation of CPI therapy.

  • Rheumatologists must be prepared for irAEs and contribute to inter-professional teams in managing immunotherapy for patients with cancer.

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Fig. 1: irAEs can affect most organ systems.
Fig. 2: Immunopathogenic mechanisms of irAEs: four broad mechanisms that might account for the immunopathogenesis of CPI-induced irAEs.

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  1. Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Foundation, Cleveland, OH, USA

    Leonard H. Calabrese & Cassandra Calabrese

  2. Division of Rheumatology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Laura C. Cappelli

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Glossary

Immune-related adverse events

(irAEs). A term now used commonly to describe the range of toxic effects in one or more organs after exposure to checkpoint inhibitors.

Antimetabolites

Chemicals that inhibit the function of a metabolite, for example, the DMARDs methotrexate or azathioprine.

Amaurosis fugax

A temporary loss of vision in one eye or both eyes owing to lack of blood flow to the retina.

Parotitis

Inflammation of the parotid salivary glands.

Eosinophilic fasciitis

A rare scleroderma-like disorder that involves inflammation, thickening and tethering of the skin and underlying fascia.

Hypophysitis

A general term used to describe inflammation of the pituitary gland. Before checkpoint inhibitor therapy, hypophysitis was exceedingly rare in medical practice, but it is now one of the most well described and common immune-related adverse events, especially with anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) therapy.

Cross presentation

In immunology, this term refers to the capacity of professional antigen-presenting cells to take up antigens of extracellular origin and present these in the context of MHC class I molecules to cytotoxic CD8+ T cells. This phenomenon is believed to occur in the tumour microenvironment when tumour cells and nearby host cells of non-cancerous origin are destroyed, and might be important in the pathogenesis of off-target autoimmune responses mediated by T cells.

Sialagogues

Drugs that cause salivation

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Calabrese, L.H., Calabrese, C. & Cappelli, L.C. Rheumatic immune-related adverse events from cancer immunotherapy. Nat Rev Rheumatol 14, 569–579 (2018). https://doi.org/10.1038/s41584-018-0074-9

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