Checkpoint Inhibitors Linked to Inflammatory Arthritis

Veronica Hackenthal, MD

June 29, 2016

Some cancer patients treated with the immune checkpoint inhibitors (ICIs) ipilimumab (Yervoy, Bristol-Myers Squibb Company) and/or nivolumab (Opdivo, Bristol-Myers Squibb Company) may be at risk of developing inflammatory arthritis and sicca syndrome, warn US researchers.

The warning comes from a small case series (13 patients) published online June 15 in the Annals of Rheumatic Diseases.

This represents the largest case series to date of ICI-induced inflammatory arthritis, and it is the first case series of sicca syndrome related to ICI use, say the researchers.

"We wanted to put out our experience with taking care of patients who developed inflammatory arthritis so that providers in both oncology and rheumatology could be on the lookout and treat these patients," commented first author Laura C. Cappelli, MD, a rheumatologist at the Johns Hopkins University School of Medicine, in Baltimore, Maryland. She noted that the inflammatory arthritis seen in these cancer patients was unlike what is usually seen in rheumatology.

Approached for comment, Jeffrey Weber, MD, PhD, professor of medicine at NYU Langone Medical Center, New York City, told Medscape Medical News that this case series is a "worthwhile addition to the armamentarium of cautionary material on the toxicities of these excellent drugs."

It reveals a "dirty little secret" among clinicians in the field, which is that ICIs may be linked to chronic arthritis, Dr Weber added.

Although poorly understood, a range of immune-related side effects have been described for ICIs, which target the patient's own immune system to treat cancer. These include pneumonitis, colitis, hypothyroidism, and hepatitis, as well as inflammatory conditions of the pituitary, skin, eye, kidney, pancreas, and neurologic system.

Severe Form of Inflammatory Arthritis

The case series included 13 adult cancer patients who were evaluated for symptoms of inflammatory arthritis or sicca syndrome that developed after starting ipilimumab and/or nivolumab. These patients were seen at Johns Hopkins rheumatology outpatient clinics between 2012 and 2016.

These patients were being treated with ipilimumab monotherapy (five patients) or a combination of ipilimumab and nivolumab (eight patients) for a variety of solid tumors, including melanoma, non–small cell lung cancer, small cell lung cancer, and renal cell carcinoma. The average age of the patients was 58.7 years, and were 83% men.

Four patients developed sicca syndrome, with abrupt, severe salivary hypofunction and less severe dry eye symptoms.

Nine patients developed inflammatory arthritis, characterized by a wide range of presentations involving large and small joints. Some had joint involvement consistent with rheumatoid arthritis, whereas others showed a reactive pattern or spondyloarthritis.

The common thread, Dr Cappelli pointed out, is that the arthritis was very inflammatory. Six patients eventually developed a rheumatoid arthritis–like pattern of disease. Five of these patients were treated with systemic prednisone at a dosage of up to 120 mg daily, a much higher dosage than is usually needed to control inflammatory arthritis.

The period between the initiation of treatment and symptom onset varied widely for these patients. Some patients developed symptoms within a few weeks after starting therapy, Dr Cappelli said, though the median time was 3 months. For two patients, symptoms persisted after ICI therapy was discontinued; in one of these patients, symptoms persisted for 15 months. These patients required tumor necrosis factor inhibitors to achieve disease control.

The severity and early symptom onset are surprising, Dr Weber said.

"I've never seen arthritis that bad that it required infliximab. That's pretty extreme," he said.

One reason for the differences in severity and onset between ICI-induced inflammatory arthritis and classic forms of inflammatory arthritis is that they may have different mechanisms, according to Dr Cappelli. Antibodies that are typically seen with rheumatoid arthritis were absent in these patients, suggesting a different mechanism.

No patients with inflammatory arthritis tested positive for rheumatoid factor or anti–cyclic citrullinated peptide antibodies. Three tested positive for antinuclear antibodies (ANA), but only one had a high titre. Three patients with sicca syndrome tested positive for ANA, but none had Ro/SSA antibodies. One patient had La antibodies.

It really is a different disease than what we normally see in rheumatology. Dr Laura Cappelli

"It really is a different disease than what we normally see in rheumatology," Dr Cappelli said.

Dr Weber suspects that some of these patients may have had preexisting arthritis.

However, the case series excluded anyone with a diagnosis of inflammatory arthritis or related autoimmune disease before treatment, Dr Cappelli pointed out. It is still possible, though, that patients might have forgotten to report subclinical or minor symptoms. Some patients with preexisting arthritis (not included in the case series) have experienced exacerbations while receiving ICIs, she explained.

"I think this will be a really important area to research now that these drugs are standard of care," Dr Cappelli told Medscape Medical News. "More patients with known autoimmune disease are going to be treated with those drugs, and managing their autoimmune disease will be important while they're on therapy."

Both Dr Cappelli and Dr Weber agreed that clinicians should be alerted about the need to evaluate symptoms of arthritis and sicca syndrome among patients receiving ICIs.

Any symptoms lasting more than 4 to 6 weeks should be referred to a rheumatologist for evaluation. Dr Laura Cappelli

"We have seen patients develop erosive disease from this type of arthritis, so earlier evaluation and treatment is key to preventing joint damage and controlling symptoms," Dr Cappelli emphasized. "We want to work together with oncology to evaluate these patients as soon as we can. Any symptoms lasting more than 4 to 6 weeks should be referred to a rheumatologist for evaluation."

The study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr Cappelli has disclosed no relevant financial relationships. Several coauthors have consulted for or received research support, honoraria, or research funding from one or more of the following companies: Bristol-Myers Squibb, Amgen, and AstraZeneca. Dr Weber has consulted for BMS, Merck, and Genentech.

Ann Rheum Dis. Published online June 15, 2016. Abstract

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