Etanercept Therapy for Toxic Epidermal Necrolysis
28/01/2015 00:40
Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug reaction characterized by widespread epidermal necrosis and detachment. It results in severe morbidity, with mortality rates of up to 35%.Standard treatment includes supportive care in a burn unit with management of complications of widespread blistering, including infections and electrolyte imbalances.
Corticosteroids, although often administered, show no proven benefit and may even increase morbidity. Intravenous immunoglobulin has been shown in some studies to reduce mortality and in others to yield no measurable benefit.
The proinflammatory cytokine tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of TEN, and may induce widespread Fas-mediated keratinocyte apoptosis via activation of inducible nitric oxide synthase. Over the past decade, TNF-alpha antagonists, such as infliximab and etanercept, have been used to treat TEN, with anecdotal success.
Building on these sporadic reports, Paradisi and colleagues sought compassionate use of etanercept to treat a series of 10 consecutive patients who met clinical criteria for TEN (acute epithelial denudation with blisters and erosions covering > 30% of body surface area). In addition to supportive care (intravenous fluids, aseptic handling, nutritional support), all patients received a single subcutaneous dose of etanercept (50 mg), administered within 6 hours of hospitalization (within 72 hours of symptom onset in most cases).
At admission, the severity of each patient's TEN was graded using the SCORTEN (SCORe of Toxic Epidermal Necrolysis) scale, which ranges from 0 to 7 and factors in prognostic variables, such as body surface area involvement, presence of underlying cancer, age, electrolyte imbalances, and cardiac function. Investigators then compared the expected probabilities of death based on SCORTEN scores with observed mortality rates.
Intriguingly, all 10 patients with TEN who received etanercept experienced complete epidermal healing without complications. Healing, defined as complete re-epithelialization, occurred after a median of 8.5 days. The observed number of deaths in this small trial was significantly below the expected number based on SCORTEN data. Of note, three patients had SCORTEN scores above 5 (high risk, poor prognosis), whereas no patients were in the low-risk category (SCORTEN score 0-1).
Viewpoint
TEN is fortunately rare, with an estimated incidence of fewer than 1.2 cases per million persons per year.The most common culprit drugs are anticonvulsants, allopurinol, antibiotics (especially sulfonamides), and nonsteroidal anti-inflammatory drugs.
Given the rare and sporadic nature of TEN, it may never be possible to conduct a placebo-controlled trial to test the safety and efficacy of the TNF-alpha blocker etanercept. Nevertheless, Paradisi and colleagues have given us compelling evidence that etanercept yielded better clinical outcomes than expected in their group of 10 patients with this condition.
Because TEN is both rare and potentially fatal, it may be hard to justify withholding anti–TNF-alpha treatment in the future, unless a more promising option comes along. Statistical analysis of whether or not etanercept truly yields a survival benefit over standard burn unit care may require meta-analysis of several case series such as this one.
