Tumor necrosis factor-alpha (TNF-α) inhibitors may increase the risk of dermatologic conditions including skin infections, eczema, and drug-related skin eruptions in rheumatoid arthritis (RA) patients, according to a new study in the April issue of Arthritis Research & Therapy.¹

In the prospective cohort study of 289 RA patients taking biologics, 72 (25%) consulted a dermatologist about skin problems during an average follow-up period of 2 years. By comparison, 37 (13%) patients who had never used TNF-α inhibitors were referred to a dermatologist, and the odds ratio for dermatologic referral associated with biologic use was 2.26. The patients' baseline characteristics indicate that those in the control group tended to have less severe RA.

The TNF-α-inhibiting agents approved for use in RA, which include adalimumab (HumiraR), infliximab (RemicadeR), and etanercept (EnbrelR), have also been linked to an increased risk of lymphoma and tuberculosis. "The encountered dermatological conditions are a clinically significant problem due to the frequent occurrence, but are less severe than the tuberculosis issue and lymphoma [issue]," lead researcher Marcel Flendrie, MD, rheumatologist at Radboud University Nijmegen Medical Centre in The Netherlands, tells CIAOMed.

There were a total of 128 dermatologic events recorded among the 72 patients taking biologic agents, occurring at a rate of 0.14 per patient-year. The most common events were skin infections (27 patients), eczema (19 patients) and drug-related skin eruptions (15 cases). None required hospitalization, but 19 patients decided to stop taking the drugs because of skin problems. Other conditions recorded in the study included psoriasis, drug-induced systemic lupus erythematosus, dermatomyositis, and a lymphomatoid-papulosis-like eruption. Most of the dermatologic conditions occurred in the first 5 months of treatment with biologics and were caused by all drugs studied.

When asked if certain patients are at higher risk of developing skin conditions with TNF-α inhibition, Dr. Flendrie responds, "we could not identify a specific subset at risk, although concomitant disease-modifying antirheumatic drugs (DMARDs) and prednisolone were more often recorded in the group experiencing skin infections."

 

Referral encouraged

"In cases of generalized eruptions or skin malignancies, we advise dermatological consultancy-including histology-as different histological patterns were described [in the study] and much is to be learned about the pathogenesis [of these cases]," Dr. Flendrie says. Five skin malignancies were reported in four patients.

Dr. Flendrie points out that most events were not serious, and treatment using topical steroids was effectively applied in appropriate situations. "Most encountered skin conditions responded well to mostly local dermatological therapy, and TNF-blocking agents could be continued, sometimes after a temporary withdrawal."

"Despite treatment, the encountered conditions can be severe and persistent," Dr. Flendrie cautions. "In these cases, permanent discontinuation of anti-TNF therapy should be considered." These cases included mostly generalized exanthema and erythematosquamous eruptions, as well as some bacterial skin infections such as folliculitis, erysipelas, and impetiginization of eczema.

 

Causation not established

RA is known to be associated with dermatologic conditions including vasculitis, nodulosis, palmar erythema and bullous pemphigoid. It has also been suggested that host defense impairment may play a role in the susceptibility of RA patients to skin infections, and TNF-α inhibition may exacerbate this problem.

For these reasons, the causative factor of dermatologic problems in RA patients using biologics is often unclear. "We cannot give a definite answer to the chicken/egg question, although an interesting finding was the difference in skin conditions during and after cessation of therapy within the same patients, suggesting a role for TNF-blocking agents," Dr. Flendrie says. "Future studies are needed to investigate [questions of] incidence and pathogenesis, and to confirm the possible relationship which is suggested by the results of this study."

 

Results should not affect use of TNF-α inhibitors

The new study "puts us on alert for a less than major complication of this treatment," according to H. Michael Belmont, MD, chief medical officer at the New York University (NYU) Hospital for Joint Disease and assistant director of the department of rheumatology at the NYU School of Medicine, both in New York City.

"On balance, these drugs do remain some of the most effective ways to manage RA, and I don't feel that [the new findings] should reduce our current utilization of TNF blockers for rheumatoid patients," he tells CIAOMed.

"I do not see [skin reactions] as worrisome," because they are caught "early on, due to the ease with which skin conditions are detected," Dr. Belmont says, adding that other adverse events provide greater cause for concern. By comparison, liver, kidney, and heart problems are often more serious because they can be missed, he points out.

Reference:

Flendrie M, Vissers WHPM, Creemers MCW, et al. Dermatological conditions during TNF-α-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2005;7:666-676.