Immune Checkpoint Inhibition—Does It Cause Rheumatic Diseases? Mechanisms of Cancer-Associated Loss of Tolerance and Pathogenesis of Autoimmunity

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Key points

  • Immune checkpoints transmit inhibitory signals, preventing excessive cellular responses and helping to maintain self-tolerance and limit tissue damage during immune responses.

  • Immune checkpoint inhibitors (ICIs) are cancer treatment strategies directed at improving the host response to cancer and are associated with the development of immune-related adverse events (irAEs).

  • Rheumatic irAEs (Rh-irAEs) arise from ICI therapy and have a broad clinical spectrum that mirrors many classic rheumatic

Immune-related adverse events

The hallmarks of cancer immunotherapy are durable clinical responses that presumably are mediated by persistent activation of the immune system. Such responses could result, however, in off-target inflammatory responses and irAEs that can be severe and occasionally fatal. The phenotype of irAEs varies widely; many patients develop toxicity involving multiple organs, others develop toxicity limited to 1 organ, and some patients may not develop toxicity despite continued ICI therapy.

Rheumatic immune-related adverse events

Rh-irAEs have been reported in 5% to 10% of cancer patients treated with ICIs,35 yet the true incidence rates remain imprecise because most of these adverse events are not typically perceived as severe or life threatening and, therefore, are underreported in oncology trials.36 A broad spectrum of Rh-irAEs has been reported so far; arthritis, sicca, myositis, and polymyalgia rheumatica are most frequent. Other rheumatic syndromes also have been reported, however, including de novo onset of

Arthritis

Two systematic reviews of ICI trials and few additional observational studies have provided data primarily on Rh-irAEs; arthralgia was the most frequent, ranging from 1% to 43%, and arthritis occurred in 1% to 7%.38,42, 43, 44, 45, 46 Most of the reported cases occurred after the administration of anti–PD-1 agents or combination ICIs, and duration between ICI initiation and onset of arthritis was variable (0.1–24 months). Different patterns of inflammatory arthritis have been reported so far.

Myositis

Three systematic reviews of ICI trials have reported myalgia as the second most common Rh-irAEs, with a prevalence ranging from 2% to 21%, whereas myositis was diagnosed less frequently (0.4% to 6%).43,57,73 Several observational studies37,44,74, 75, 76, 77, 78, 79 as well as case reports and small series35,58, 59, 60,70,75,76,78,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 have documented de novo onset of myositis as an adverse event in patients receiving ICIs. Most of the

Immune checkpoints—mechanism of action

CTLA-4 is a coinhibitory molecule expressed on both activated T cells and regulatory T cells (T-reg). CTLA-4 is up-regulated on T cells that have received signal 1 through engagement of the T-cell receptor (TCR) with the cognate antigen–major histocompatabiltiy complex presented by an antigen-presenting cell (APC). CTLA-4 competes with the costimulatory molecule, CD28, for their shared ligands CD80 and CD86, whereas CD28 binding to these ligands results in an activating signal, which amplifies

Cytotoxic T-lymphocyte–associated protein 4 and programmed death 1 and autoimmunity

CTLA-4 has been implicated in several rheumatic diseases, including RA, systemic lupus erythematosus, and Sjögren syndrome. In RA, CTLA-4-Ig, or abatacept, is a useful treatment strategy attributable to a variety of mechanisms, including decreased Treg cell death, increased T-cell susceptibility to Treg functions, and down-regulation of proinflammatory cytokine production.117

The PD-1/PD-L1 pathway has been investigated in autoimmunity, primarily in experimental animal models, with limited study

Summary

Immune checkpoints are critical for the immunomodulation of immune responses, and their absence or blockade has been associated with various manifestations of autoimmunity. ICI has proved an effective, largely tumor-agnostic cancer therapy but is associated with irAEs, including Rh-irAEs, which share variable clinical and pathologic similarities with classic rheumatic diseases. The mechanisms underlying ICI effectiveness and irAE occurrence, however, are far from fully understood. Disruption of

Disclosure

Dr. Thanarajasingam is supported by the “Catalyst” award for Advancing in Academics Program, funded by the Department of Medicine, Mayo Clinic, Rochester, MN.

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