Immune checkpoints, regulators of the immune system, consist of inhibitory and stimulatory pathways. Although there are several immune checkpoint interactions, those most studied in cancer are the inhibitory pathways consisting of cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1).1 Binding of CTLA-4 and PD-1/PD-L1 to a cancer cell or tumor microenvironmental ligands leads to T-cell attenuation, which enables the tumor cells to avoid immune-mediated destruction. Inhibition of this interaction is an approach that has been exploited for cancer therapy.1

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Several ICIs have been approved by the US Food and Drug Administration, including ipilimumab (targeting CTLA-4), nivolumab and pembrolizumab (targeting PD-1), and atezolizumab (a PD-L1 inhibitor).2 These agents are approved for use as monotherapy, some in combination, and for multiple indications including metastatic melanoma, nonsmall cell lung cancer, renal cell carcinoma, bladder cancer, head and neck cancer, and Hodgkin lymphoma.2 Immune checkpoint inhibitors work by targeting CTLA-4, PD-1, and PD-L1 and by blocking negative interactions among T cells, antigen-presenting cells, and tumors, allowing positive costimulation to occur and T cells to become activated, leading to an enhanced antitumor immune response.1 However, the therapeutic strategy of blocking negative interactions between T cells for cancer treatment can also increase the activity of the immune system and induce a variety of immune-related adverse events (irAEs), including inflammatory adverse effects.2

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The irAEs associated with ICIs can affect any organ system, although the most commonly affected organs include the gastrointestinal tract, endocrine glands, skin, and liver. Less often, the central nervous system and cardiovascular, pulmonary, musculoskeletal, and hematologic systems are involved.3 However, irAEs that resemble a wide spectrum of rheumatic manifestations are increasingly being recognized, with the most common being arthralgia or arthritis, myalgia or myositis, polymyalgia rheumatica, systemic lupus erythematosus, rheumatoid arthritis, and Sjogren syndrome. Immune checkpoint inhibitors have also been known to exacerbate existing rheumatologic diseases.4-6

As more ICIs are approved, used earlier in the cancer treatment cycle, and approved for an increasing number of indications, irAEs resembling rheumatic musculoskeletal phenotypes are likely to increase in the coming years.4,5 Rheumatologists play a critical role in the effective management of inflammatory rheumatic diseases, and are therefore expected to play an increasing role in the diagnosis and management of patients with cancer with ICI-related rheumatic diseases. Rheumatologists should be prepared to take on this role, especially when accommodating new expectations for collaboration with oncologists for the successful management of patients with ICI-induced rheumatic diseases.

The immediate challenge rheumatologists will face in the diagnosis and management of ICI-induced rheumatic disease is that irAEs associated with rheumatic phenotype do not appear to behave identically to the corresponding classic rheumatic disease.4 For example, autoantibodies associated with rheumatoid arthritis and Sjogren syndrome in traditional diseases appear to be lacking4; as a consequence, traditional diagnostic evaluation may present some challenges. Challenges are also associated with treatment, in that patients with irAE-associated rheumatic phenotype are likely to be immunosuppressed as a result of their advanced disease and potentially other treatments they are receiving, and as a consequence, treatment options used in patients without cancer will need to be carefully evaluated in patients with cancer.

Collaboration between oncology and rheumatology practices for these disease entities becomes critical. “I think the collaboration between rheumatologists and oncologists is key for the best treatment of patients who either have a preexisting autoimmune disease or need immune checkpoint inhibitor therapy or who develop rheumatic immune-related adverse events,” said Laura Cappelli, MD, assistant professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr Cappelli added, “The rheumatologist knows how to diagnose, monitor, and treat autoimmune disease and rheumatic irAEs, but all decisions regarding immune checkpoint inhibitor therapy must be made by the oncologist and patient. Without knowing the plan for continuing or holding further immune checkpoint inhibitor therapy, the rheumatologist cannot know what medications will be acceptable.”

Although the underlying mechanisms involved in rheumatic irAEs are not fully understood, it is important that rheumatologists are able to promptly recognize irAEs in their patients with cancer who are receiving treatment with ICIs. A survey of practicing rheumatologists explored their knowledge of ICI and irAEs and their clinical experience managing patients who present with ICI-associated rheumatic disease. The survey, which included a total of 502 rheumatologists (153 from the United States and 349 from France), was distributed at 2 times: in 2016 to US-based rheumatologists and in 2018 to rheumatologists based in France.7 Despite the 2-year time interval and the different countries in which the survey was conducted, the overall findings were strikingly the same. Specifically, the survey found that familiarity with ICIs and irAEs was low: fewer than 30% of participants indicated familiarity, and fewer than 10% declared being “very confident” in treating patients receiving ICI who present with rheumatic diseases. Clearly, this survey exposes gaps in knowledge and clinical practice among rheumatologists, who will be increasingly charged with managing patients with cancer presenting with rheumatic phenotype as the use of ICI increases among patients with cancer.7

Although the authors highlighted efforts to help rheumatologists and other specialists become more confident with ICI-related irAEs, including attending local multidisciplinary meetings and national and international conferences, there is also a need for education and support to prepare rheumatologists for the emerging new normal for their practice. “Online CME courses on this topic are one option,” said Dr Cappelli, when asked about resources available to rheumatologists, adding that, “Reviews written for the rheumatologist on this topic have also been published over the last few years. Additionally, there are several cancer societies that issue guidelines for managing immune-related adverse events: the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and the Society for Immunotherapy of Cancer (SITC).” The recognition of irEAs relevant to rheumatologists and the development of treatment algorithms are essential, and were identified as the greatest educational need among the rheumatologists surveyed.

References

1. Marin-Acevedo JA, Dholaria B, Soyano AE, Knutson KL, Chumsri S, Lou Y. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Hematol Oncol. 2018;11(1):39.

2. Cappelli LC, Gutierrez AK, Bingham CO 3rd, Shah AA. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature. Arthritis Care Res (Hoboken). 2017;69(11):1751-1763.

3. Brahmer JR, Lacchetti C, Thompson JA. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline summary. J Oncol Pract. 2018;14(4):247-249.

4. Cappelli LC, Shah AA, Bingham CO 3rd. Cancer immunotherapy-induced rheumatic diseases emerge as new clinical entities. RMD Open. 2016;2(2):e000321.

5. Cappelli LC, Shah AA, Bingham CO 3rd. Immune-related adverse effects of cancer immunotherapy- implications for rheumatology. Rheum Dis Clin North Am. 2017;43(1):65-78.

6. Gediz F, Kobak S. Immune checkpoint inhibitors-related rheumatic diseases: what rheumatologist should know? [published online January 18, 2019]. Curr Rheumatol Rev. doi: 10.2174/1573397115666190119094736

7. Kostine M, Cappelli LC, Calabrese C, et al. Addressing immune-related adverse events of cancer immunotherapy: how prepared are rheumatologists? [published online January 18, 2019]. Ann Rheum Dis. doi:10.1136/annrheumdis-2018-214748