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.

Keywords: Allergy; Clinical Trials; Immunology; Immunotherapy.

Figure 1. Preclinical testing of etanercept.

Release of granulysin (A) and TNF-α (B) was measured by ex vivo assay in blister cells from SJS-TEN patients (n = 10). Blister cells were treated with DMSO (Control), 5 μg/ml etanercept, 400 ng/ml cyclosporine, 12 mg/ml IVIG, or 10 μg/ml corticosteroid for 48 hours. All drug concentrations were determined by clinical use. Data are presented as the mean ± SEM and are representative of 3 independent experiments. **P < 0.01 and ***P < 0.001, by Student’s t test; ^†P = 0.003, by Student’s t test.

Figure 2. Flow chart for the selection of study participants.

Ninety-six participants were recruited, among whom 71 completed the study. Thirty-eight patients were treated with etanercept and thirty-three patients with a corticosteroid. ^A–GThe group information can be found in Supplemental Table 3.

Figure 3. Clinical improvement in CTL-mediated SCAR patients after etanercept or corticosteroid treatment.

Kaplan-Meier curves are shown for the time required for skin healing (A and D), beginning of reepithelialization (B and E), and oral mucosa healing (C and F) in CTL-mediated SCAR patients in the 2 treatment groups. The numbers in red and green represent the median number of days for the etanercept and corticosteroid groups, respectively. P values were calculated by the Kaplan-Meier product-limit estimates method. ^#P = 0.010, by Kaplan-Meier product-limit estimates method. (G) Shown are representative clinical photographs of patients with TEN who received etanercept or corticosteroids.

Figure 4. Immunological effects in SJS-TEN patients with 10% or greater BSA detachment after etanercept or corticosteroid treatment.

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⁺CD25^hiFOXP3⁺ 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.