Another AE Identified With Checkpoint Inhibitors

Nick Mulcahy

February 28, 2017

For the first time, an analysis of cancer patients treated with immune checkpoint inhibitors has found cases of new-onset connective tissue diseases, according to a letter published online February 27 in the Annals of the Rheumatic Diseases.

The phenomenon is "uncommon" but "underlines the need for close collaboration" between oncologists and other specialist physicians with these patients, write the authors, led by Sébastien Le Burel, MD, from the Bicêtre Hospital in Le Kremlin-Bicêtre, France.

The authors estimate a prevalence of 0.7% for connective tissue diseases in cancer patients being treated with immune checkpoint inhibitors. The estimate comes from a prospective registry of patients sponsored by the Gustave Roussy Institute in Villejuif, France.

The team reports four cases that developed among the 447 registry patients. Specifically, there are two cases of Sjögren’s syndrome associated with a programmed cell death 1 (PD1) inhibitor and one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren's syndrome seen in a patient taking a PD ligand 1 (PDL1) inhibitor. Additionally, there is a case of antinuclear antibody (ANA)–positive myositis in a patient taking a PD-L1 inhibitor. Positivity for ANA often indicates an autoimmune reaction.

Connective tissue diseases have not previously been reported in patients treated with anti-PD1/PDL1 agents, say the authors.

The new data are part of an ongoing effort at Gustave Roussy Institute to detect, document, and manage immune-related adverse events that are induced by checkpoint inhibitors.

Immune checkpoint inhibitors are making a huge impact in the treatment of cancer and are now approved for use in several cancer types, including melanoma, lung cancer, head and neck cancer, and lymphoma.

Along with slowing the advance of cancer in many patients, these agents can also cause a range of immune-related side effects, including pneumonitis, colitis, hypothyroidism, and hepatitis, as well as inflammatory conditions of the pituitary, skin, eye, kidney, pancreas, and neurologic system. Recently, inflammatory arthritis was added to the list, as reported by Medscape Medical News. Experts say that many of these side effects are treatable.

The authors of the new report make a clinical call to action. "Our findings raise the question of screening for asymptomatic patients at risk of IrAEs [immune-related adverse events]," they say. The screening should include recording a full medical history and testing for ANAs. At-risk patients should be closely monitored during their immunotherapy.

The authors support this proposal by pointing out that flare-ups of preexisting active rheumatic diseases in patients treated with anti-PD1 agents have been reported recently (Ann Oncol. 2016 Sep 29).

In the new analysis, among the four patients with connective tissue diseases, none had apparent symptoms before the initiation of the immune checkpoint inhibitors.

The mean patient age was 62 years, and all patients had metastatic disease. Three of the patients were female. Two had received anti-PD1 agents and two, anti-PDL1 agents.

The mean time interval between the first checkpoint inhibitor infusion and the first symptom of the connective tissue disease was 60 days (range, 24 to 72 days). The mean time interval between the first symptom and diagnosis of the connective tissue disease was 40 days (range, 10 to 74 days). The immune checkpoint drug was discontinued in three patients, and two patients were subsequently treated with steroids, report the authors.

The team looked for ANAs in serum samples that had been collected before initiation of the immune checkpoint inhibition. All three tested patients (who were patients at Gustave Roussy Institute; the fourth was from another center) were positive for ANAs, and two patients had antibodies indicating Sjögren's syndrome (despite the lack of any clinical symptoms suggestive thereof).

Thus, the prevalence of connective tissue disease might be higher in patients treated with checkpoint inhibitors, the authors suggest, because "some patients with milder symptoms might not have been investigated by their oncologist."

On the other hand, the prevalence may also be lower, they say. That's because one patient in the analysis received nivolumab plus ipilimumab, a combination of checkpoint inhibitors that is known to increase the risk for immune-related adverse events, they say.

Some study authors have financial ties with industry, including Bristol-Myers Squibb, Novartis, Merck, Roche, Janssen, and Sanofi.

Ann Rheum Dis. Published online February 27, 2017. Abstract

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