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Cancer treatments create immune-related adverse events


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Checkpoint inhibitors, used as cancer immunotherapy, can trigger immune-related adverse events in 30 to 40 percent of patients, so rheumatologists are treating a new class of immune-related diseases.

“Up to 25 and 30 percent of rheumatologists have seen at least one of these cases,” said Clifton O. Bingham III, MD, Professor of Medicine, Director of the Johns Hopkins Arthritis Center and Co-Director of the Rheumatic Diseases Research Core Center at the Johns Hopkins University. “And these cases do not present in isolation. Patients present not just with inflammatory arthritis but with a spectrum of systemic immune-mediated processes.”

Dr. Bingham will explore the growing issue of immunotherapy-related adverse events during a basic science symposium on Checkpoint Inhibitors & Immune-Related Adverse Events on Sunday from 2:30 – 4:00 pm. Immune-related events stemming from cancer immunotherapy are typically associated with antibodies to programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) receptors. Similar events could become more common as other immunotherapies move into clinical use.

These PD-1 and PD-L1 immunomodulatory antibodies enhance the immune system in cancer treatment and have significantly improved the prognosis in a growing variety of tumors.

The list currently includes melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck cancers, urothelial carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, and microsatellite instability-high or mismatch repair-deficient solid tumors. Other indications are likely to appear with more clinical experience and research.

Checkpoint inhibitors can be highly effective in treating tumors, but they can also produce a new spectrum of inflammatory events that affect the skin, GI tract, liver, endocrine system, joints, and other systems. These events are thought to arise from the heightened immunologic responses induced by checkpoint inhibition.

Inflammatory arthritis is the most common immune-related side effect, Dr. Bingham said. In general terms, temporary use of immunomodulatory or anti-inflammatory agents such as methotrexate is usually the appropriate treatment. Medications such as mycophenolate and TNF antagonists have been used to deal with immune-mediated hepatitis and a variety of immune-mediated dermatoses.

Cancer is the complicating factor in treating all of these immune-mediated adverse events.

“Administering immunosuppressive drugs that in a normal population you would be loath to use over concerns that it would lead to a reactivation or worsening of their cancer is just one of the difficult decisions,” he said.

“You no longer have the luxury of being cautious because you absolutely have to control the immune-related consequences of their treatment. In fact, the consequential nature of the therapy, these immune-related adverse events, may be linked in some ways to a better prognosis for the outcomes of cancer treatment. Our usual risk-benefit evaluations change considerably in these patients. It is a conceptual issue that rheumatologists are going to have to get over.”

Familiar treatment recommendations for autoimmune diseases do not apply to patients with these immune-mediated inflammatory events. Inflammation must be quelled within days to weeks, not weeks to months. Agents such as rituximab that can take months to show any noticeable effects are simply not practical.

A second challenge is that patients with immunotherapy-related inflammatory events usually present with multiple problems. The patient does not just have an inflammatory arthritis that needs immediate treatment but likely has colitis or a dermatological complication — sometimes all three and more.

The good news, Dr. Bingham said, is that oncologists are increasingly recognizing rheumatologists as the appropriate specialists to bring into the treatment equation.

“In patients who have multiple immune-related adverse events taking place at the same time as their obvious rheumatologic manifestations, oncologists are calling on us to coordinate care and come up with ways to manage inflammatory adverse events,” he said.

Managing immune-related adverse events is a role that more rheumatologists are likely to fill as the use of checkpoint inhibition and other cancer immunotherapies expands.

“Immunotherapy is one of the most important reasons our role as rheumatologists will be increasing in coming years,” Dr. Bingham said. “We will increasingly be called upon as the multi-organ specialist to evaluate and manage treatment.”