Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions
Chuang-Wei Wang, … , Wen-Hung Chung, and the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium
Chuang-Wei Wang, … , Wen-Hung Chung, and the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium
Published February 5, 2018
Citation Information: J Clin Invest. 2018;128(3):985-996. https://doi.org/10.1172/JCI93349.
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Clinical Medicine Clinical trials Immunology

Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions

Abstract

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-α 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-α antagonist in CTL-mediated SCARs. METHODS. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α 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-α 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-α 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.

Authors

Chuang-Wei Wang, Lan-Yan Yang, Chun-Bing Chen, Hsin-Chun Ho, Shuen-Iu Hung, Chih-Hsun Yang, Chee-Jen Chang, Shih-Chi Su, Rosaline Chung-Yee Hui, See-Wen Chin, Li-Fang Huang, Yang Yu-Wei Lin, Wei-Yang Chang, Wen-Lang Fan, Chin-Yi Yang, Ji-Chen Ho, Ya-Ching Chang, Chun-Wei Lu, Wen-Hung Chung, and the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium

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Figure 4

Immunological effects in SJS-TEN patients with 10% or greater BSA detachment after etanercept or corticosteroid treatment.

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Immunological effects in SJS-TEN patients with 10% or greater BSA detach...
Release of granulysin (A) and TNF-α (B) was measured in blister fluids from SJS-TEN patients with 10% or greater BSA detachment in the etanercept (n = 11) and corticosteroid (n = 11) treatment groups. The blister fluids were continually collected on day 0 (before treatment) and each day afterward (days 1, 2, 3, and 4 after treatment) until blister production stopped. Expression levels of granulysin (C) and TNF-α (D) in plasma were also detected. The acute stage was defined as occurring within 6 days from the onset of illness; the maximum stage was defined as the time from illness onset to maximal skin detachment; the late stage was defined as the point at which complete skin healing occurred. Subsets (E) and population (F) of CD4+CD25hiFOXP3+ Tregs detected in the patients’ blood. Data are presented as the mean ± SEM based on 3 (A–D) or 2 (F) independent experiments; all P value was calculated by Student’s t test. ***P < 0.001, †P = 0.014, ††P = 0.005, †††P = 0.002, ##P = 0.011, §P = 0.004, §§P = 0.003, P = 0.037, ¶¶P = 0.028.