MADRID – Rheumatologists all over the world are beginning to find that the new class of anticancer immune checkpoint inhibitor therapies have the potential to elicit symptoms of rheumatoid arthritis (RA) and other rheumatic diseases in patients with no previous history of them, and two reports from the European Congress of Rheumatology provide typical examples.
These immune checkpoint inhibitor (ICI) agents, which include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), target regulatory pathways in T cells to boost antitumor immune responses, leading to improved survival for many cancer patients, but the induction of rheumatic disease can sometimes lead to the suspension of the agents, according to investigators.
Dr. Cassandra Calabrese
“This phenomenon was unknown to me and my group before [February 2016], when we started noting referrals of patients from oncology,” Dr. Calabrese said. “We were seeing symptoms of everything from Sjögren’s syndrome to inflammatory arthritis and myositis in patients being treated with these drugs for their cancer.” The same year, Dr. Calabrese and her team began coordinating an ongoing study to assess these patients.
Dr. Calabrese said that the cohort has shown so far that patients who develop autoimmune disease after immune checkpoint inhibitors “require much higher doses – of steroids in particular – to treat their symptoms,” and this can all too often result in being taken out of a clinical trial or having to stop cancer treatment.
Most of the patients in the cohort were treated with steroids only, while three patients received biologic agents, and four received methotrexate or antimalarials.
Dr. Calabrese said that the serology results were available for all the patients in the cohort and “were largely unremarkable.”
She noted that the rheumatic symptoms did not always resolve after pausing or stopping the cancer treatment. “We have some patients that have been off their checkpoint inhibitors for over a year and still have symptoms, so it’s looking like it might be a more long-term effect,” she said.
Dr. Rakiba Belkhir
“In my unit, we also manage patients with myeloma, and I developed a weekly consultation with a cancer center,” Dr. Belkhir said. In 2015, she saw her first patient with RA and no previous history who had been treated with checkpoint inhibitors. That patient’s symptoms resolved after treatment with nonsteroidal anti-inflammatory drugs alone.
Dr. Belkhir is sharing results from this and five other patients presenting with symptoms of RA after their cancer treatment with immune checkpoint inhibitors, taken from a larger cohort of patients (n = 13) with a spectrum of rheumatic disease–like adverse effects. None of the six patients in this study had a previous clinical history of RA. They manifested their RA symptoms after a median of 1 month on cancer immunotherapy.
Some were able to continue their checkpoint inhibitors and be treated simultaneously for RA with steroids, antimalarials, methotrexate, and NSAIDs, Dr. Belkhir said. None received biologic agents, and each medication strategy, she said, was arrived at in consultation with the treating oncologist.
Dr. Belkhir’s team also looked closely at serology and found all six patients to be at least weakly, and mostly strongly, seropositive for RA. Three patients underwent testing for anticyclic citrullinated protein antibodies prior to starting cancer immunotherapy and two of these three were anti-CCP positive. Now, she said, the oncologists she’s working with are testing for anticyclic citrullinated peptides and rheumatoid factor prior to initiating cancer immunotherapy, so that this relationship is better understood.
“It is possible that antibodies were already present and that the anti-PD1 immunotherapy,” one type of immune checkpoint inhibitor, “acted as a trigger for the disease.” Animal studies have suggested a role for PD1 in the development of autoimmune disease, “but it’s not well investigated,” Dr. Belkhir said.
Dr. Belkhir and Dr. Calabrese both acknowledged that the understanding of checkpoint inhibitor–induced autoimmune disease is in its infancy. Clinical trials largely missed the phenomenon, the researchers said, because the trials were not designed to capture musculoskeletal adverse effects with the same granularity as other serious adverse events.
“This will be a long discussion in the months and the years ahead with oncologists,” Dr. Belkhir said.
Neither Dr. Calabrese nor Dr. Belkhir reported having any relevant conflicts of interest.