New Studies Validate Guidelines on Allopurinol and Gout

May 08, 2015

New research confirms that taking allopurinol during active gout does not prolong the flare, and genetic studies reveal a new factor in allopurinol sensitivity.

Until recently, physicians did not usually order allopurinol during acute gout attacks, mostly out of concern about triggering or prolonging flares. Updated American College of Rheumatology (ACR) guidelines in 2012 suggested that physicians should do just that: Start urate-lowering therapy during the acute phase.

Another update after recent genome-wide association studies (GWAS) of allopurinol sensitivity calls for genetic screening among certain populations to reduce the risk of serious adverse drug reactions.1

A small study has now validated the former update, and a new review highlights the importance of the latter.

A small placebo-controlled randomized trial by researchers at several US military facilities 2 examined how long it took for gout patients to recover if they took allopurinol during an acute stage. The patients (17 of whom took placebo; 14  took allopurinol) did not show any significant differences in the length of time it took for flares to resolve (13.4 vs 15.4 days, respectively).

There were also no signs of abnormal kidney or liver function among the allopurinol group.

Another study has used GWAS to assess serum uric acid (SUA) response to allopurinol for the first time.3 It finds that patient response is highly variable; only 42%  of patients achieve the recommended SUA target level, said Wen et al in their report.

Wen and colleagues conducted the GWAS among 2,027 non-Hispanic white subjects. They have found that mutations in ABCG2, which codes for an efflux transporter that plays an important role in drug disposition, are associated with individual responses to allopurinol.

The authors also review the association between genes and serious adverse reactions to drugs (ADR), including allopurinol. The common gout drug is known to cause several serious SCARS (drug-induced severe cutaneous adverse reactions):

   Stevens-Johnson syndrome (SJN);
   Toxic epidermal necrolysis (TEN);
   Drug reactions with eosinophilia and systemic symptoms (DRESS) and
   Hypersensitivity syndrome (HSS)

SJS and TEN have a "high potential for severe morbidity and mortality," they note, with TEN having a mortality rate of 30-35%. They review studies that show the HLA-B*58:01 allele strongly linked to allopurinol-induced SCARS among several populations:

  Han Chinese
  Thais and Koreans
  Japanese
  Portuguese

The Clinical Pharmacogenetics Implementation Consortium (CPIC) released a guideline to screen for the HLA-B*58:01 allele when possible, before prescribing allopurinol.4 The ACR’s updated guidelines specifically mention screening for those of Han Chinese or Thai descent, as well as Koreans with stage 3 or worse chronic kidney disease.

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References:

1  Sukasem C, Puangpetch A, Medhasi S, Tassaneeyakul W. Pharmacogenomics of drug-induced hypersensitivity reactions: challenges, opportunities and clinical implementation. Asian Pacific Journal of Allergy and Immunology. 2014; 32:111-123.

2  Hill EM, Sky K, Sit M, et al.Does starting allopurinol prolong acute treated gout? A randomized clinical trial. Journal of Clinical Rheumatology. 2015; 21:120-125. doi: 10.1097/RHU.0000000000000235.

3.  Wen CC, Yee SW, Liang X et al.Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clinical Pharmacology and Therapeutics. 2015;Article first published online 6 Apr 2015. doi: 10.1002/cpt.89

4.  Hershfield MS, Callaghan JT, Tassaneeyakul W et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing.Clin Pharmacol Ther. 2013; Feb;93(2):153-8. doi: 10.1038/clpt.2012.209.
 

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