COMMENTARY

Starting Dose of Allopurinol in Gout

Kevin Deane, MD

Disclosures

September 17, 2012

Starting Dose Is a Risk Factor for  Allopurinol Hypersensitivity Syndrome: A Proposed Safe Starting Dose of Allopurinol

Stamp LK, Taylor WJ, Jones PB, et al
Arthritis Rheum. 2012;64:2529-2536

Allopurinol Hypersensitivity Syndrome

Allopurinol hypersensitivity syndrome (AHS) is characterized by severe rash, fever, eosinophilia, hepatitis, and renal failure.[1] It is a feared, albeit rare, complication of therapy and is sometimes fatal.

Reported risk factors for AHS include renal impairment and diuretic use. Furthermore, although controversial, some data suggest that a higher dose of allopurinol in patients with renal impairment raises the risk for hypersensitivity.[2,3] The effect of a creatinine clearance–based initial dosing regimen on risk for hypersensitivity is not well understood.

Stamp and colleagues performed a case-control study in New Zealand to evaluate factors that were associated with the development of AHS.

Study Summary

Fifty-four patients treated for gout with allopurinol and who developed AHS were identified. These patients were compared with 157 patients with gout treated with allopurinol therapy but who did not develop AHS.

The median onset of AHS was 30 days after starting allopurinol, and 90% of cases occurred within the first 6 months; 43 cases required hospitalization, and 3 patients (6%) died from AHS.

Patients with AHS were more likely than control patients to start allopurinol at a higher dose as corrected for glomerular filtration rate (GFR), calculated using the Modification of Diet in Renal Disease study formula.[4] In receiver operating characteristic (ROC) curve analyses, the investigators found that a starting dose of allopurinol of 1.5 mg per unit of estimated GFR minimized risk for AHS. They also found that increasing the allopurinol dose after an initial lower dose did not appear to increase the risk for AHS.

Stamp and colleagues concluded that starting allopurinol at a dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk for AHS, and that gradually increasing the dose to achieve a target uric acid level may not substantially increase risk over time in patients who initially tolerate allopurinol.

Viewpoint

Although guidelines have long recommended that allopurinol be dosed according to creatinine clearance, a dearth of scientific evidence supports such an approach.[2]

These findings by Stamp and colleagues provide data that suggest that initial dosing of allopurinol affects the risk for AHS.

Of importance, the finding that increasing the allopurinol dose in patients who tolerate it does not necessarily increase later risk for AHS allows for a "treat to target" approach for gout management, rather than healthcare providers getting "stuck" with an initial low dose of allopurinol and poorly controlled gout.

The impact of these findings is somewhat lessened by the fact that this was a case-control -- rather than a randomized controlled -- study, and ideally the effect of specific dosing regimens on risk for AHS should be evaluated in randomized controlled trials. However, given the rarity of AHS, such studies are not likely to be undertaken. As Stamp and colleagues suggest, perhaps the most feasible way to validate these findings would be to evaluate them in existing cohorts of gout patients.

Abstract

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