Allopurinol hypersensitivity: investigating the cause and minimizing the risk

Key Points

  • Allopurinol is a highly effective, cheap and simple therapy for gout if dosing is adequate and patients adhere to the therapy

  • Serious allopurinol-related adverse events (for example, allopurinol hypersensitivity syndrome [AHS]) are rare, but are associated with high morbidity and mortality

  • Risk factors for allopurinol-related serious adverse events include recent introduction of allopurinol, the presence of the HLA-B*58:01 allele, a higher starting dose, renal impairment and the concomitant use of diuretics

  • Allopurinol hypersensitivity is primarily mediated by an oxypurinol-specific T-cell response


Allopurinol is the most commonly prescribed urate-lowering therapy for the management of gout. Serious adverse reactions associated with allopurinol, while rare, are feared owing to the high mortality. Such reactions can manifest as a rash combined with eosinophilia, leukocytosis, fever, hepatitis and progressive kidney failure. Risk factors for allopurinol-related severe adverse reactions include the recent introduction of allopurinol, the presence of the HLA-B*58:01 allele, and factors that influence the drug concentration. The interactions between allopurinol, its metabolite, oxypurinol, and T cells have been studied, and evidence exists that the presence of the HLA-B*58:01 allele and a high concentration of oxypurinol function synergistically to increase the number of potentially immunogenic-peptide–oxypurinol–HLA-B*58:01 complexes on the cell surface, thereby increasing the risk of T-cell sensitization and a subsequent adverse reaction. This Review will discuss the above issues and place this in the clinical context of reducing the risk of serious adverse reactions.

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Figure 1: Allopurinol hypersensitivity includes MPE, AHS and allopurinol-induced SCAR.
Figure 2: Time elapsed (in days) from the start of allopurinol treatment to the occurrence of allopurinol hypersensitivity syndrome in patients with gout.27
Figure 3: Relationship between the levels of plasma oxypurinol and a | serum creatinine and b | the creatinine clearance rate in patients with gout receiving allopurinol.37

Change history

  • 03 March 2016

    In the version of this article initially published online, incorrect information was given regarding the source of Figure 3. This figure was reproduced from Stamp, L. K. et al. Allopurinol and kidney function: an update. Joint Bone Spine 83, 19–24 (2016). The error has been corrected for the HTML and PDF versions of the article.


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All authors researched data for the article and made a substantial contribution to discussions of content, writing and review/editing of the manuscript before submission.

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Correspondence to Lisa K. Stamp.

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L.K.S. declares she has received consulting and speaker fees from Astra Zeneca. The other authors declare no competing interests.

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Stamp, L., Day, R. & Yun, J. Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nat Rev Rheumatol 12, 235–242 (2016).

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