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: Wen-Hung Chung, Wan-Chun Chang, Sophie L Stocker, Chiun-Gung Juo, Garry G Graham, Ming-Han H Lee, Kenneth M Williams, Ya-Chung Tian, Kuo-Chang Juan, Yeong-Jian Jan Wu, Chih-Hsun Yang, Chee-Jen Chang, Yu-Jr Lin, Richard O Day, Shuen-Iu Hung
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 74 Issue 12 Pg. 2157-64 (Dec 2015) ISSN: 1468-2060 [Electronic] England
• PMID: 25115449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 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/

Chemical References

• Antigens, Differentiation, T-Lymphocyte
• GNLY protein, human
• HLA-B Antigens
• Allopurinol
• Oxypurinol

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Allopurinol (adverse effects)
• Antigens, Differentiation, T-Lymphocyte (blood)
• Drug Eruptions (blood, etiology, mortality)
• Female
• Follow-Up Studies
• HLA-B Antigens (immunology)
• Humans
• Male
• Middle Aged
• Oxypurinol (blood)
• Prognosis
• Prospective Studies
• Renal Insufficiency (blood, etiology, mortality)
• Survival Rate (trends)
• Taiwan (epidemiology)
• Young Adult