Altering the local cytokine balance
Dupilumab is a monoclonal antibody that binds to the alpha subunit of the interleukin-4 receptor. This results in blocking the function of not only IL-4 but also IL-13.
Dr. Kirkham and colleagues think this might not only alter the balance of cytokines in the skin but also in the joints and entheses with IL-17, IL-23, or even tumor necrosis factor playing a possible role. Another thought is that many circulating T-cells in the skin move to the joints and entheses to trigger symptoms.
IL-13 inhibition does seem to be important, as another British research team, from the Centre for Epidemiology Versus Arthritis at the University of Manchester (England), has found.
At the recent annual meeting of the British Society for Rheumatology, Sizheng Steven Zhao, MBChB, PhD, and colleagues reported that among people who carried a genetic variant predisposing them to having low IL-13 function, there was a higher risk for inflammatory diseases such as psoriatic arthritis and other spondyloarthropathy-related diseases.
Sara Freeman/Frontline Medical News
Dr. Steven Sizheng Zhao
Indeed, when the single nucleotide polymorphism rs20541 was present, the odds for having psoriatic arthritis and psoriasis were higher than when it was not.
The findings are consistent with the idea that IL-4 and IL-13 may be acting as a restraint towards MSK diseases in some patients, Dr. Zhao and co-authors suggest.
“The genetic data supports what [Dr. Kirkham and team] have said from a mechanistic point of view,” Dr. Zhao said in an interview. “What you’re observing has a genetic basis.”
Dermatology perspective
Approved by the U.S. Food and Drug Administration in 2017, dupilumab has since been hailed as a “breakthrough” in atopic dermatitis treatment. Given as a subcutaneous injection every 2 weeks, it provides a much-needed option for people who have moderate-to-severe disease and have tried other available treatments, including corticosteroids.
Dupilumab has since also been approved for asthma, chronic sinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis and is used off-label for other skin conditions such as contact dermatitis, chronic spontaneous urticaria, and alopecia areata.
“Dupilumab, like a lot of medications for atopic dermatitis, is a relatively new drug, and we are still learning about its safety,” Joel M. Gelfand, MD, MSCE, of the University of Pennsylvania Perelman School of Medicine, Philadelphia, told this news organization.
“Inflammatory arthritis has been reported in patients treated with dupilumab, and this new study provides some useful estimates,” added Dr. Gelfand, who is a professor of dermatology and epidemiology and directs the Psoriasis and Phototherapy Treatment Center, Philadelphia.
“There was no control group,” Dr. Gelfand said, so “a causal relationship cannot be well established based on these data alone. The mechanism is not known but may result from a shifting of the immune system.”
Dr. Zhao observed: “We don’t know what the natural history of these adverse events is. We don’t know if stopping the drug early will prevent long-term adverse events. So, we don’t know if people will ultimately develop permanent psoriatic arthritis if we don’t intervene quick enough when we observe an adverse event.”
Being aware of the possibility of rheumatic side effects occurring with dupilumab and similar agents is key, Dr. Gelfand and Dr. Kirkham both said independently.
“I have personally seen this entity in my practice,” Dr. Gelfand said. “It is important to clinicians prescribing dupilumab to alert patients about this potential side effect and ask about joint symptoms in follow-up.”
Dr. Kirkham said: “Prescribers need to be aware of it, because up until now it’s been just very vaguely discussed as sort of aches and pains, arthralgias, and it’s a much more specific of a kind of syndrome of enthesitis, arthritis, tenosynovitis – a little like psoriatic arthritis.”
Not everyone has come across these side effects, however, as Steven Daveluy, MD, associate professor and dermatology program director at Wayne State University, Detroit, said in an interview.
“This article and the other case series both noted the musculoskeletal symptoms occurred in about 5% of patients, which surprised me since I haven’t seen it in my practice and have enough patients being treated with dupilumab that I would expect to see a case at that rate,” Dr. Daveluy said.
“The majority of cases are mild and respond to treatment with anti-inflammatories like naproxen, which is available over the counter. It’s likely that patients with a mild case could simply treat their pain with naproxen that’s already in their medicine cabinet until it resolves, never bringing it to the doctor’s attention,” he suggested.
“Dupilumab is still a safe and effective medication that can change the lives of patients suffering from atopic dermatitis,” he said.
“Awareness of this potential side effect can help dermatologists recognize it early and work together with patients to determine the best course of action.”
All research mentioned in this article was independently supported. Dr. Kirkham, Mr. Nathan, Dr. Zhao, and Dr. Daveluy report no relevant financial relationships. Dr. Gelfand has served as a consultant for numerous pharmaceutical companies and receives research grants from Amgen, Boehringer Ingelheim, and Pfizer. He is a co-patent holder of resiquimod for treatment of cutaneous T-cell lymphoma.