乌鸦传媒

ORLANDO -- The spectacular success and rapidly widening use of the immune checkpoint inhibitors in the treatment of cancer has been accompanied by a notable increase in rheumatic immune-related adverse events, according to Andrew Oster, MD, of Cabrini Medical Center in Melbourne, Australia.

"It's likely that the rheumatic complications of these drugs will be more common than rheumatoid arthritis itself," Oster said at the Florida Society of Rheumatology annual meeting.

In fact, these adverse events are being seen in more than 20% of patients, he said, "and if you haven't seen patients with these problems already you will be seeing them."

"In 2016, there were no abstracts on this topic at all at the American College of Rheumatology [ACR] meeting, and now it's the hottest topic at ACR and the European League Against Rheumatism meetings," he said.

"What the immune checkpoint inhibitors do -- ramping up the immune system through enhancing T cell activity -- is the exact opposite of what we do, which is to suppress the immune system to treat our diseases," he explained.

Multiple rheumatic phenotypes for these adverse events have now been reported and virtually every organ has been affected, with cases of skin rash, colitis, hepatotoxicity, pneumonitis, ocular and renal involvement and even hypophysitis, which was almost unheard of in the past.

What will be required is understanding the balance required between the immune activation needed to control the cancer and the immune suppression that manages the rheumatic disease, he said.

These rheumatic immune-related adverse events have been greatly underrecognized and underreported in the oncology literature and during clinical trials. "The oncologists are aware of the fulminant colitis that could kill the patient, but not about the rheumatic problems that may be very troubling for the patient. So we need a lot more collaboration with our colleagues in oncology, basic science, and industry," he stated.

One common presentation is a rheumatoid arthritis-like phenotype, although affected patients do not typically have autoantibodies. Another prevalent manifestation is the reactivation of pre-existing autoimmune disease, which may occur in up to half of patients.

Additional presentations have included reactive arthritis, myalgias, and vasculitis, including subclinical disease. "It appears that checkpoints are important to maintain homeostasis in blood vessels, and by blocking checkpoints you can cause vasculitis," he noted.

Other rheumatic adverse events have included sicca symptoms, lupus nephritis, myocarditis, and lymphocytic fasciitis. These are not the same as the other autoimmune events such as colitis, which generally occur early in treatment and respond rapidly to therapy.

"The colitis that occurs is very similar to florid ulcerative colitis, and can develop after the first few doses. These patients are treated with steroids and then one dose of infliximab [Remicade] and it switches the whole thing off." In contrast, the rheumatic problems tend to occur later, after months of therapy, and can persist even after the checkpoint therapy has finished.

Guidelines for the treatment of these adverse events are being developed. Currently the initial treatment is steroids and then disease-modifying drugs such as methotrexate, but some patients will also require biologics and in severe cases, stopping the cancer treatment. "These guidelines thus far are not particularly evidence-based, but are being refined as we gain more experience," he said.