Elsevier

The Lancet

Volume 352, Issue 9140, 14 November 1998, Pages 1586-1589
The Lancet

Early Report
Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis

https://doi.org/10.1016/S0140-6736(98)02197-7Get rights and content

Summary

Background

Toxic epidermal necrolysis (TEN) is associated with a 30% death rate. Tumour necrosis factor a (TNF-α) has been implicated in the pathogenesis of TEN. Thalidomide is a potent inhibitor of TNF-α action. We did a double-blind, randomised, placebo-controlled study of thalidomide in TEN.

Methods

The patients received a 5-day course of thalidomide 400 mg daily or placebo. The main endpoint was the progression of skin detachment after day 7. Secondary endpoints were the severity of the disease, evaluated with the simplified acute physiology score (SAPS), and the mortality. TNF-α and interleukin 6 were measured.

Findings

The study was stopped because there was excess mortality in the thalidomide group—ten of 12 patients died compared with three of ten in the placebo group (Fisher's exact test with Katz's approximation, relative risk=2·78, p=0·03). After adjustment for SAPS, mortality remained significantly higher in the thalidomide group than in the placebo group (exact logistic regression mid-p=0·007; 95% CI for odds ratio 2·7 to infinity). Plasma TNF-α concentration was higher in the thalidomide group than the placebo group on day 2, though the difference was not significant (Wilcoxon rank-sum test p=0·07).

Interpretation

Even though few patients were included, our data suggest that thalidomide is detrimental in TEN, possibly because of a paradoxical enhancement of TNF-α production.

Introduction

Toxic epidermal necrolysis (TEN) is a rare, acute, and life-threatening condition. The incidence is one case per million inhabitants per year.1 Apoptosis of cells causes erosions of the mucous membranes, extensive detachment of the epidermis, and severe constitutional symptoms. Cases with the most extensive skin detachment are associated with the poorer prognosis, and a 30–40% death rate. Milder forms are known as Stevens-Johnson syndrome (SJS) or SJS/TEN overlap.2 TEN is usually drug-related.3

At present there is no specific treatment for TEN. Some retrospective studies claimed a benefit of corticosteroids in milder forms,4 whereas several showed no benefit or even increased morbidity and mortality.5, 6, 7 Plasmapheresis, cyclosporin, cyclophosphamide, and N-acetylcysteine have been used in isolated cases and short uncontrolled series,8, 9, 10, 11 allowing no conclusion on the efficacy. Nevertheless, because the extent of final epidermal detachment is the main prognostic factor,12 therapies with the potential to stop the process of epithelial necrosis would be valuable during the initial phase of the disease.

Apoptosis is the mechanism of keratinocyte death in TEN, and tumour necrosis factor α (TNF-α) is the likely cause for this and for constitutional symptoms during TEN.10, 13 Thus, TNF-α production is believed to be an early pathogenetic event in TEN.

Thalidomide is a potent inhibitor of TNF-α in vitro and in vivo,14, 15 and appeared beneficial in several acute disorders thought to involve TNF-α.16, 17 We undertook a randomised placebo-controlled study of thalidomide in patients with TEN with the aim of testing the efficacy and safety of thalidomide in stopping the necrolysis process and reducing systemic symptoms during the initial phase of extension in TEN.

Section snippets

Patients

Patients were enrolled from nine centres representing recruitment of about half the cases of TEN in France. Patients over 18 years old were eligible if they had detachment of epidermis of more than 10% of body surface area,2 if the disease was still in the initial phase of extension and so had evolved for less than 4 days after the first mucocutaneous symptoms, and if they were expected to survive longer than 48 h. Diagnosis of TEN had to be confirmed with photographs and skin biopsy samples

Study population and clinical data

22 patients were enrolled in the study (figure 1) from May, 1995, to September, 1996. Of 15 patients at a single centre (Créteil), nine (60%) had died. This unusually high mortality rate alerted the local investigators. The trial coordinator was informed and decided to convene a safety board of three experts. The safety board first looked at the overall data without breaking the code—13 of 22 patients enrolled had died (overall mortality 59%). Because this rate was higher than expected from

Discussion

This study is the first double-blind, randomised, placebo-controlled trial of any therapy in TEN. Thalidomide was not effective in halting the necrolysis process during the initial phase of extension. On the contrary, thalidomide treatment was associated with increased mortality. This difference was not the result of an unexpectedly low rate of death in the placebo group, because the mortality rate in that group was of the same order in previous series.12, 20 The mortality remained

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