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Ann Rheum Dis doi:10.1136/annrheumdis-2014-205577
  • Clinical and epidemiological research
  • Extended report

Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin

  1. Shuen-Iu Hung4
  1. 1Department of Dermatology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
  2. 2Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
  3. 3College of Medicine, Chang Gung University, Taoyuan, Taiwan
  4. 4Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
  5. 5Department of Clinical Pharmacology & Toxicology, St. Vincent's Hospital, Sydney, New South Wales, Australia
  6. 6St Vincent's Hospital Clinical School and School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
  7. 7Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
  8. 8Department of Nephrology, Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
  9. 9Division of Allergy, Immunology and Rheumatology, Department of Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
  10. 10Graduate Institute of Clinical Medical Science, Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan
  11. 11Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan
  1. Correspondence to Dr Shuen-Iu Hung, Institute of Pharmacology, National Yang-Ming University, 155, Linong Street, Section 2, Beitou, Taipei 11221, Taiwan; sihung@ym.edu.tw Dr Richard O Day, Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, New South Wales, Australia; r.day@unsw.edu.au
  • Received 17 March 2014
  • Revised 29 June 2014
  • Accepted 26 July 2014
  • Published Online First 12 August 2014

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.

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