Thalidomide in toxic epidermal necrolysis.

Sir—The report of unexplained deaths associated with thalidomide therapy for toxic epidermal necrolysis by Pierre Wolkenstein and colleagues (Nov 14, p 1586), points to the need for a more complete understanding of the putative mechanism(s) of action of this drug. This issue is lent further urgency by the recent licensure of thalidomide by the US Food and Drug Administration for the treatment of erythema nodosum leprosum (ENL). This decision is likely to lead to the increased use of thalidomide in various disorders. The dramatic efficacy of thalidomide among patients with ENL in association with inhibition of tumour necrosis factor (TNF)-α provided compelling evidence for a mechanism of action of this drug. The rationale for its use in toxic epidermal necrolysis was the potential of thalidomide to inhibit TNF-α. However, thalidomide has other, unexpected effects on the immune response. The drug acts as a costimulator of primary human T cells in vitro, synergising with stimulation via the T-cell receptor complex, which leads to increased interleukin-2mediated T-cell proliferation and production of interferon gamma. Data from clinical studies suggest that thalidomide may also have T-cell stimulatory properties in vivo. Thalidomide therapy in HIV-infected patients was associated with increases in plasma concentrations of soluble interleukin-2 receptor and CD8+ T lymphocytes. These responses occurred within the first 2 weeks of thalidomide therapy, a time when cutaneous and febrile reactions to the drug are most likely to occur in HIVinfected patients. Taken together these findings suggest that thalidomide has both antiinflammatory and immune-stimulatory activities, and may thus produce different clinical results in different diseases. In conditions characterised by monocyte/macrophage activation and high circulating concentrations of TNF-α, such as ENL, the use of thalidomide to inhibit production of TNF-α may be beneficial to the patient. However, in diseases where T-cell activation contributes to the pathogenic process, further T-cell stimulation by thalidomide may be detrimental and result in clinical deterioration. The latter situation may explain the findings of Wolkenstein and colleagues, as well as the finding that thalidomide caused a paradoxical increase in mortality when used prophylactically for chronic graftversus-host disease. Another possibility is that the T-cell costimulatory effects of thalidomide may mediate its beneficial effects in diseases where T-cell function is defective. The use of a placebo group by Wolkenstein and colleagues led to a rapid and definitive conclusion that thalidomide was harmful in this clinical setting, underscoring yet again the importance of carefully controlled trials for the evaluation of new therapies, or old therapies for a new indication.