Chuang-Wei Wang1,2, Lan-Yan Yang3, Chun-Bing Chen1, Hsin-Chun Ho1,4, Shuen-Iu Hung5, Chih-Hsun Yang1,4, Chee-Jen Chang6,7, Shih-Chi Su1,8, Rosaline Chung-Yee Hui1,4, See-Wen Chin1, Li-Fang Huang3, Yang Yu-Wei Lin1, Wei-Yang Chang3, Wen-Lang Fan8, Chin-Yi Yang1, Ji-Chen Ho4,9, Ya-Ching Chang1,4, Chun-Wei Lu1,4, Wen-Hung Chung1,2,4,8. 1. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital (CGMH), Linkou, Taipei and Keelung, Taiwan. 2. Chang Gung Immunology Consortium, CGMH and Chang Gung University, Taiwan. 3. Clinical Trial Center, CGMH, Linkou, Taiwan. 4. College of Medicine, Chang Gung University, Taoyuan, Taiwan. 5. Department and Institute of Pharmacology, School of Medicine, Infection and Immunity Research Center, National Yang-Ming University, Taipei, Taiwan. 6. Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan. 7. Biostatistical Center for Clinical Research, CGMH, Linkou, Taiwan. 8. Whole-Genome Research Core Laboratory of Human Diseases, CGMH, Keelung, Taiwan. 9. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, CGMH, Chiayi, Taiwan.
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.
RCT Entities:
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: P Wolkenstein; J Latarjet; J C Roujeau; C Duguet; S Boudeau; L Vaillant; M Maignan; M H Schuhmacher; B Milpied; A Pilorget; H Bocquet; C Brun-Buisson; J Revuz Journal: Lancet Date: 1998-11-14 Impact factor: 79.321
Authors: Diana Chessman; Lyudmila Kostenko; Tessa Lethborg; Anthony W Purcell; Nicholas A Williamson; Zhenjun Chen; Lars Kjer-Nielsen; Nicole A Mifsud; Brian D Tait; Rhonda Holdsworth; Coral Ann Almeida; David Nolan; Whitney A Macdonald; Julia K Archbold; Anthony D Kellerher; Debbie Marriott; Simon Mallal; Mandvi Bharadwaj; Jamie Rossjohn; James McCluskey Journal: Immunity Date: 2008-06 Impact factor: 31.745
Authors: Wan-Chun Chang; Riichiro Abe; Paul Anderson; Wanpen Anderson; Michael R Ardern-Jones; Thomas M Beachkofsky; Teresa Bellón; Agnieszka K Biala; Charles Bouchard; Gianpiero L Cavalleri; Nicole Chapman; James Chodosh; Hyon K Choi; Ricardo R Cibotti; Sherrie J Divito; Karen Dewar; Ulrike Dehaeck; Mahyar Etminan; Diane Forbes; Esther Fuchs; Jennifer L Goldman; James H Holmes; Elyse A Hope; Shuen-Iu Hung; Chia-Ling Hsieh; Alfonso Iovieno; Julienne Jagdeo; Mee Kum Kim; David M Koelle; Mario E Lacouture; Sophie Le Pallec; Rannakoe J Lehloenya; Robyn Lim; Angie Lowe; Jean McCawley; Julie McCawley; Robert G Micheletti; Maja Mockenhaupt; Katie Niemeyer; Michael A Norcross; Douglas Oboh; Cristina Olteanu; Helena B Pasieka; Jonathan Peter; Munir Pirmohamed; Michael Rieder; Hajirah N Saeed; Neil H Shear; Christine Shieh; Sabine Straus; Chonlaphat Sukasem; Cynthia Sung; Jason A Trubiano; Sheng-Ying Tsou; Mayumi Ueta; Simona Volpi; Chen Wan; Hongsheng Wang; Zhao-Qing Wang; Jessica Weintraub; Cindy Whale; Lisa M Wheatley; Sonia Whyte-Croasdaile; Kristina B Williams; Galen Wright; Sonia N Yeung; Li Zhou; Wen-Hung Chung; Elizabeth J Phillips; Bruce C Carleton Journal: J Dermatol Sci Date: 2020-03-07 Impact factor: 4.563
Authors: Dario de Perosanz-Lobo; D Fernández-Nieto; P Burgos-Blasco; M Aroca-Ruiz; M Fernández-Guarino Journal: Indian J Dermatol Venereol Leprol Date: 2021 [SEASON] Impact factor: 2.545
Authors: Joseph R Stoll; Toral S Vaidya; Shoko Mori; Stephen W Dusza; Mario E Lacouture; Alina Markova Journal: J Am Acad Dermatol Date: 2020-03-12 Impact factor: 11.527
Authors: Jason H Karnes; Matthew A Miller; Katie D White; Katherine C Konvinse; Rebecca K Pavlos; Alec J Redwood; Jonathan G Peter; Rannakoe Lehloenya; Simon A Mallal; Elizabeth J Phillips Journal: Annu Rev Pharmacol Toxicol Date: 2018-08-22 Impact factor: 13.820