Randomized, controlled trial of TNF-[alpha] antagonist in CTL-mediated severe cutaneous adverse reactions

BACKGROUND. Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-[alpha] and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-[alpha] antagonist in CTL-mediated SCARs. METHODS. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-[alpha] antagonist etanercept versus traditional corticosteroids. RESULTS. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-[alpha] and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS. The anti-TNF-[alpha] biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01276314. FUNDING. Ministry of Science and Technology of Taiwan.
Introduction Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are severe cutaneous adverse reactions (SCARs) involving keratinocyte apoptosis and detachment of the epidermis. Allopurinol and carbamazepine are [...]