Wen-Hung Chung1, Wan-Chun Chang2, Sophie L Stocker3, Chiun-Gung Juo4, Garry G Graham3, Ming-Han H Lee3, Kenneth M Williams3, Ya-Chung Tian5, Kuo-Chang Juan5, Yeong-Jian Jan Wu6, Chih-Hsun Yang7, Chee-Jen Chang8, Yu-Jr Lin8, Richard O Day3, Shuen-Iu Hung2. 1. Department of Dermatology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan College of Medicine, Chang Gung University, Taoyuan, Taiwan. 2. Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 3. Department of Clinical Pharmacology & Toxicology, St. Vincent's Hospital, Sydney, New South Wales, Australia St Vincent's Hospital Clinical School and School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia. 4. Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan. 5. College of Medicine, Chang Gung University, Taoyuan, Taiwan Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. 6. College of Medicine, Chang Gung University, Taoyuan, Taiwan Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan. 7. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan College of Medicine, Chang Gung University, Taoyuan, Taiwan. 8. Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Abstract
OBJECTIVE: Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR. METHODS: We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined. RESULTS: In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05). CONCLUSIONS: Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVE:Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR. METHODS: We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The humanleucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined. RESULTS: In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05). CONCLUSIONS: Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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