TNF inhibitor tactics
Paradoxical reactions require quick action
With a lengthy history in dermatology and rheumatology, tumor necrosis factor alpha (TNFa) inhibitors have earned new indications while accumulating reassuring safety data, says an expert at the American Academy of Dermatology 75th Annual Meeting. Keeping patients on these drugs when they are working sometimes requires aggressively managing TNF-induced psoriasiform reactions, he added.
Dermatologists are somewhat spoiled with the plethora of biologic choices for treating moderate to severe psoriasis, says Anthony P. Fernandez, M.D., Ph.D. He is director of medical dermatology in the departments of dermatology and pathology at Cleveland Clinic.
All about experience
"What makes the TNF inhibitors stand out from those other options? Because they have been out longer, we have more experience (with them)," with commensurate efficacy and safety data gleaned from real-world patients, he says. Etanercept, adalimumab and infliximab began earning U.S. Food and Drug Administration (FDA) approval for psoriatic arthritis in 2002, followed by approvals for psoriasis in 2004 through 2008 (See the latest safety and efficacy information).
Clinically, Dr. Fernandez says, dermatologists may be underutilizing the strategy of combining a TNF inhibitor with methotrexate.
"There seems to be good evidence that combining etanercept with methotrexate is more effective than etanercept or methotrexate alone.1 Combining infliximab or adalimumab with methotrexate also may result in better efficacy in the appropriate patient population, but we probably need better data to support that.,” says Dr. Fernandez. One issue is that research has not yet established the optimum methotrexate dose to boost biologic results -- "How low can we go to prevent anti-drug antibodies and maximize efficacy and safety?"
Regarding psoriasis comorbidities, Dr. Fernandez says, Psoriasis Longitudinal Assessment and Registry (PSOLAR) data reveal that major adverse cardiovascular events in patients with psoriasis remain extremely low with TNF alpha inhibitors.2
"Perhaps more importantly," he says, "we are accumulating a large body of evidence to suggest that TNF inhibitors can improve a number of parameters associated with cardiovascular event risk." These parameters include insulin resistance, several pro-inflammatory cytokines and vascular measures including carotid intima media thickness and aortic stiffness. Whether TNF inhibitors can decrease cardiovascular events has not yet been confirmed, says Dr. Fernandez, although trials of this type are underway.
In 2015, adalimumab became the only FDA-approved treatment for hidradenitis suppurativa (HS), based on results from the Efficacy and Safety Study of Adalimumab in Treatment of Hidradenitis Suppurativa (PIONEER I and II) trials.3 In PIONEER II, "Patients were allowed to continue antibiotics if they were on them." Among such patients, 58.9% reached the clinical endpoint of 50% reductions in abscesses and inflammatory lesion counts at week 12, versus 41.8% among adalimumab-treated patients in PIONEER I who were not using antibiotics. Because treating HS with adalimumab requires weekly dosing, he adds, it's reassuring that both groups experienced similar rates of serious adverse events. Furthermore, says Dr. Fernandez, emerging long-term data for the weekly dose show consistent safety and sustained efficacy.4
"In my experience, adalimumab is less effective in HS than in psoriasis." Accordingly, Dr. Fernandez says it's critical to set appropriate patient expectations. "Adalimumab will not wipe away their scarring or other disfiguring aspects of the disease. We're really looking to calm down the inflammatory component and associated pain." By the same token, he advised against discontinuing previous treatments that provided partial efficacy, with the caveat that it is always particularly important to consider the risk-benefit ratio of long-term antibiotic use.
Regarding etanercept in children, a 5-year safety study requested by the FDA has shown that the drug maintained efficacy, and that adverse events were uncommon, with only one considered to be related to etanercept.5 In September 2016, etanercept became the only systemic therapy approved for moderate-to-severe psoriasis in children and adolescents.
"Whether or not TNF inhibitors will continue to attain new indications is unclear. But clearly, they play a very important off-label role in treating several challenging conditions," Dr. Fernandez says.
Dr. Fernandez also reports that one of his patients with pityriasis rubra pilaris who had failed a combination of cyclosporine, prednisone and acitretin cleared with adalimumab. A patient with Crohn's disease and pyoderma gangrenosum completely cleared with infliximab, he added, without needing long-term prednisone.