title: Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin.
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.
authors.affiliation: 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.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Sophie L
authors.initials: SL
authors.lastname: Stocker
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chiun-Gung
authors.initials: CG
authors.lastname: Juo
authors.affiliation: 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.
authors.forename: Garry G
authors.initials: GG
authors.lastname: Graham
authors.affiliation: 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.
authors.forename: Ming-Han H
authors.initials: MH
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Williams
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ya-Chung
authors.initials: YC
authors.lastname: Tian
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Kuo-Chang
authors.initials: KC
authors.lastname: Juan
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Yeong-Jian
authors.initials: YJ
authors.lastname: Jan Wu
authors.affiliation: Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Hsun
authors.initials: CH
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Chee-Jen
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Yu-Jr
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Day
authors.affiliation: Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol / Q000009:adverse effects*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000097:blood*; D003875:Drug Eruptions / Q000097:blood / Q000209:etiology* / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D015235:HLA-B Antigens / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010117:Oxypurinol / Q000097:blood*; D011379:Prognosis; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000097:blood / Q000209:etiology* / Q000401:mortality; D015996:Survival Rate / Q000639:trends; D013624:Taiwan / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human; D015235:HLA-B Antigens; D000493:Allopurinol; D010117:Oxypurinol
keywords: Disease Activity; Gout; Treatment