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Range of Paradoxical Adverse Events Tied to Biologics
A number of paradoxical adverse events have been described with the use of biologic agents in clinical practice, including psoriasis, Crohn's disease, and hidradenitis suppurativa, according to a review by French researchers.
Among the paradoxical adverse events with biologics, the most frequently described one is psoriasis, which is seen most often in patients with rheumatoid arthritis (RA) with good disease control on an a TNF-α inhibitor, noted Éric Toussirot, MD, PhD, and François Aubin, MD, PhD, of the University Hospital of Besançon. The areas affected most frequently are the scalp and flexures and palmoplantar areas.
Paradoxical adverse events were defined as the occurrence of a pathologic condition that usually responds to a particular class of agents, they wrote in RMD Open.
"This is well illustrated by the onset of (de novo) psoriasis during anti-tumor necrosis factor (TNF)-α therapy," they wrote. "In parallel, the biological agent may worsen a pre-existing condition (for instance, psoriasis may worsen when an anti-TNF-α agent is started for psoriasis or psoriatic arthritis)."
Anti-TNF-α agents are "the leading class of drugs associated with these unexpected reactions," they added.
Data from U.K. and Spanish registers estimated the incidence rate of psoriasis in an RA population treated with biologics as 1.04 to 2.31/1,000 patient-years. Confidence intervals were large, however. Most patients affected were able to continue their treatment "with full or partial resolution of their lesions." Psoriasis has been reported with other biologic agents, but at a lower frequency.
A recent nationwide retrospective study in France identified 25 new-onset cases of hidradenitis suppurativa among patients treated with biologics, mostly TNF-α inhibitors. Lesions resolved completely after discontinuation or switch to a different biologic agent.
Crohn's disease and other inflammatory bowel disease have occurred after initiation of anti-TNF-α agents for the treatment of inflammatory rheumatic disease. An incidence rate of Crohn's disease as high as 362/100,000 patient-years was reported for etanercept (Enbrel) in patients with juvenile idiopathic arthritis, about 43 times higher than in the general population. Favorable intestinal outcome resulted after discontinuing the anti-TNF-α agent or switching to an agent that was not a monoclonal antibody.
Anecdotal reports of uveitis have surfaced with the use of anti-TNF-α agents, even though a reduction in the frequency of uveitis flares has also been reported with the use of anti-TNF-α agents in patients with spondyloarthropathy. No new onset or flare of uveitis has been associated with the use of rituximab (Rituxan), tocilizumab (Actemra), or abatacept (Orencia), the authors reported.
Cases of sarcoidosis and granulomatosis-like diseases occurring with anti-TNF-α therapy have been described in the literature. "Taking these data together, etanercept was found to be the main anti-TNF-α agent associated with the development of such cases (57%), but sarcoidosis may also occur during treatment with an anti-TNF-α monoclonal antibody (infliximab [Remicade] or adalimumab [Humira])," the authors wrote. Eleven cases of pulmonary nodulosis or granulomatous lung disease under anti-TNF-α therapy have been documented; six while on etanercept and five on either infliximab or adalimumab.
More than 200 cases of vasculitis, mainly cutaneous small vessel vasculitis, have been described worldwide with the use of anti-TNF-α therapy, including eight in a retrospective analysis from the Mayo Clinic. Cessation of therapy generally leads to favorable outcomes.
Anti-TNF-α therapy has had mixed success in the treatment of vitiligo, but case reports documenting the development of vitiligo can be found in the literature, along with 18 patients who developed new-onset vitiligo while being treated with a biologic agent as part of a nationwide retrospective study.
Alopecia areata developed in equal proportions in 29 patients on infliximab, etanercept, and adalimumab in a multicenter prospective study, but 76% of the cases had a favorable outcome with or without interruption of their anti-TNF-α agent.
The mechanism behind the development of psoriasis and other paradoxical adverse events may involve disequilibrium in cytokine balance with TNF-α inhibition, the authors suggested. Theories advanced include differential immunologic properties between the monoclonal antibodies and TNF-α soluble receptor, activation of type I interferon pathways, and a shift towards a Th1/Th2 profile.
Treatment interruption, cessation, or a switch to an alternate biologic agent can result in resolution of paradoxical adverse events in many instances, according to the authors.
For patients with Crohn's disease who develop psoriasis, "Ustekinumab (Stelara; still not approved for Crohn's disease), certolizumab [Cimzia] or vedolizumab [Entyvio] are valuable biological alternatives," they suggested. In selected cases of vasculitis with mild symptoms such as skin involvement, "the biological agent may be maintained but with close dermatological monitoring," they advised.
Toussirot and Aubin disclosed no relevant relationships with industry.
Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco