Immune-Related Adverse Events Rise with Immune Checkpoint Inhibitors

Rheumatologists are likely to encounter a wide variety of immune-related adverse events as use of immune checkpoint inhibitors expands, a scientific review shows.

Immune checkpoint inhibitors (ICIs) have improved the prognosis of some patients with cancer, but this treatment can lead to immune-related adverse events, and for patients with an autoimmune disease being treated with ICIs, it can sometimes make pre-existing conditions worse, shows a review by Johns Hopkins Medicine researchers.

The authors of the review, published in a December issue of Arthritis Care & Research, describe ICIs as a “paradigm shift in the treatment of advanced malignancies,” which is true, but ICIs are associated with some notable i­­­mmune-related adverse events often requiring a rheumatology referral.

Researchers, led by Laura C. Cappelli, M.D, of Johns Hopkins University, Baltimore, reviewed 231 studies about immune-related adverse events that occur after treatment with immune checkpoint inhibitors. Musculoskeletal or rheumatic immune-related adverse events (IRAEs) were described in 52 studies. These studies included a mix of clinical trials (33), observational studies (3) and case reports (16).

There was also one observational study and three case reports that described outcomes for patients with pre-existing autoimmune disease who were treated with immune checkpoint inhibitors. These patients were described as developing inflammatory arthritis, vasculitis, myositis and lupus nephritis.

Cappelli et al., state that immune checkpoint inhibitor-induced inflammatory arthritis, arthralgia, myositis, and sicca syndrome, are increasingly being appreciated. Also, in some among those with pre-existing autoimmune disease, use of ICIs may precipitate autoimmune disease flares. While arthralgia and myalgia have commonly been reported in trials of ICIs, musculoskeletal and rheumatic immune-related adverse events (IRAEs), however, have not been well characterized in current literature, and no estimates for prevalence or incidence are extant.

“To put our findings in context, the incidence and clinical characteristics of IRAEs with other phenotypes range widely. Colitis and hepatitis, associated with potential mortality, have been reported in up to two percent of patients treated with ICIs. Other IRAEs are more common but less severe,” the authors wrote.

Among the 33 based on clinical trials, arthralgia (joint pain) was reported most often (in 24 trials) with a prevalence among patients treated with ICIs ranging widely from 1-43 percent. Myalgia was the second most commonly reported (in 12 trials), and occurred in 2-21 percent of trial subjects. Dry eyes and dry mouth were noted in 3 and 4 trials, respectively, with incidence from 3-24 percent. Two trials reported vasculitis and one reported giant cell arteritis. Sarcoidosis, autoimmune disease, back pain, bone pain and musculoskeletal pain were reported in a limited number of trials. Overall, arthritis was noted in 15 percent of trials.

Immune checkpoint inhibitors included in this review

The literature search encompassed abstracts on use of ipilimumab, nivolumab, pembrolizumab, atezolizumab, agents targeting PD-1, PD-L1 and CTLA-4. After wide screening, 231 abstracts with ICI-related data were narrowed down to 52 reporting rheumatic and musculoskeletal IRAES secondary to ICI treatment.

Immune checkpoint inhibitors are currently approved for multiple indications including metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck cancer and Hodgkin’s lymphoma.

• Ipilimumab, targeting CTLA-4, was the first ICI approved for metastatic melanoma.

• Nivolumab, targeting PD-1, is approved for melanoma, non-small cell lung cancer, renal cell carcinoma and Hodgkin’s lymphoma.

• Pembrolizumab, targeting PD-1, is approved for metastatic melanoma, lung cancer and metastatic head and neck cancer.

• Atezolizumab, a PD-L1 inhibitor, is approved for urothelial carcinoma and non-small cell lung cancer.

Although these therapies are effective, activating the immune system can lead to tissue damage or immune-related adverse events that affect organs, such as hepatitis or colitis.

Rheumatic and musculoskeletal phenotypes - such as inflammatory arthritis, arthralgia, myositis, sicca syndrome, Sjogren’s syndrome, systemic lupus erythematosus, vasculitis, among others - are not as well documented, but they do occur.

The case reports highlighted in this review illustrate the wide variety of rheumatic IRAE that rheumatologists are likely to encounter as ICI use expands.

How immune checkpoint inhibitors work

Immune checkpoint inhibitors work by blocking negative co-stimulation of T-cells leading to an enhanced anti-tumor immune response, wrote the authors of the review. These therapies target cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed deathligand-1 (PD-L1) and eventually leading to a downregulated T-cell response, which are generally blocked by ICIs.

But in treating rheumatic disease, immune checkpoints work by promoting a negative co-stimulation. For example, abatacept, “a fusion protein of the extracellular domain of CTLA-4 and the Fc portion of IgG1,” is approved to treat rheumatoid arthritis in adults. It works by “blocking binding of the positive costimulatory molecule CD28 to its receptor, CD80/86.”

Pembrolizumab

Case studies included in the review showed that pembrolizumab was associated with polyarthritis and tenosynovitis in two cases (both patients were negative for rheumatoid arthritis and anti-CCP antibodies).

Ipilimumab

A third ipilimumab treatment study of 30 patients with pre-existing autoimmune disease found exacerbations in 8 patients and development of other IRAEs after treatment in 10. In a second observation study of 198 ipilimumab-treated patients for melanoma or renal cell carcinoma patients, 2 percent developed grade 3 or 4 arthritis. A third A third ipilimumab treatment study of 30 patients with pre-existing autoimmune disease found exacerbations in eight patients and development of other IRAEs after treatment in 10. 

Nivolumab

Ipilimumab treatment was associated with one case of dermatomyositis, one of polymyositis, one case of lupus nephritis, and two cases of giant cell arteritis and polymyalgia rheumatica. Nivolumab treatment was associated with polymyositis in at least one case. These patients improved with corticosteroid treatment. In patients with pre-existing autoimmune disease, three patients being treated with ipilimumab for metastatic melanoma developed inflammatory bowel disease (Crohn’s disease or ulcerative colitis).

Conclusion

Cappelli et al. caution also that they have observed, albeit in limited experience, rheumatic IRAEs persisting beyond the discontinuation of ICI therapy. If confirmed in future research, the implications for long-term management of these patients may be significant.

The analysis, Cappelli et al. conclude, highlights the wide variety of IRAE that rheumatologists will encounter as ICI use continues to grow. They urge research focused on knowledge deficits in epidemiology, evaluation and treatment of rheumatic and musculoskeletal IRAE.

“To put our findings in context, the incidence and clinical characteristics of IRAEs with other phenotypes range widely. Colitis and hepatitis, associated with potential mortality, have been reported in up to two percent of patients treated with ICIs. Other IRAEs are more common but less severe,” the authors wrote. “Better understanding of why these musculoskeletal IRAE develop and how to treat them will benefit patients and could give insight in to pathogenesis of traditional rheumatic diseases.”

References:

Laura C. Cappelli MD MHS, Anna Kristina Gutierrez MD, et al. “Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: A systematic review of the literature,” Arthritis Care & Research. Dec. 20, 2016. DOI: 10.1002/acr.23177.