番茄社区

Asians and blacks on urate-lowering therapy in the U.S. are at much higher risk than whites or Hispanics are for developing the severe cutaneous reactions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) when on urate-lowering therapy, researchers reported.

The risk of these potentially lethal adverse reactions with allopurinol treatment were 12 times higher for Asians and 5 times higher for blacks, according to , of Harvard Medical School and Massachusetts General Hospital in Boston, and colleagues.

That finding correlates genetically with corresponding frequencies of the HLA-B*5801 allele -- a strong determinant of allopurinol (Zyloprim, Aloprim) hypersensitivity syndrome -- in the U.S. population. Carriage of that allele is estimated to be 7.4% among Asians, 4% among blacks, and 1% among Hispanics and whites, the researchers reported in

"Given its market dominance and established association with SJS/TEN, our findings support the use of vigilance in these minorities when considering allopurinol," the authors wrote.

The study is the first to show a higher risk of allopurinol-related adverse events in U.S. blacks.

"Screening Asian or black gout patients for the HLA-B*5801 variant would help increase treatment safety. If the test is positive, we recommend alternative medications," Choi told 番茄社区.

Asians with chronic kidney disease may be candidates for first-line alternative medications from the outset, Choi added, the exception being those of Japanese ancestry, since they are not frequent carriers of the variant.

Using data from the National Inpatient Sample from 2009 to 2013, the study looked at principal discharge diagnoses of SJS/TEN in combination with secondary discharge diagnoses of adverse effects due to uric acid metabolism therapy, principally allopurinol.

According to the National Health and Nutrition Examination Survey 2009-2012, allopurinol accounted for 96.8% of urate-lowering drug use, followed by probenecid (Benemid, Probalan, 2.1%), which is not known to cause SJS/TEN.

During the study period, 606 hyperuricemia patients (mean age of 68, 44% male) were hospitalized for SJS/TEN. Of these, 57 (9%) died in the hospital.

The average length of stay was 14 days, with 10 days for patients with SJS and 20 days for those with TEN, and the average charge per hospitalization was $157,334 ($60,318 for SJS and $324,259 for TEN).

Among the 606 patients, there was a substantial overrepresentation of Asians (27%) and blacks (26%) compared with whites (29%), in proportion to the racial makeup of the U.S. population, which is 5%, 12%, and 67%, respectively. The corresponding hospitalization rate ratios for SJS/TEN by race were 11.9, 5.0, and 1.0 (referent), among Asians, blacks, and whites, respectively.

In similar findings, found an increased risk of allopurinol hypersensitivity syndrome among users of Chinese descent versus those of European descent. And led the Taiwanese Food and Drug Administration to adopt a new prescription policy recommending febuxostat (Uloric) as a first-line alternative for patients with chronic kidney disease to help reduce allopurinol-associated SJS/TEN.

As a nongeneric, febuxostat, FDA-approved in 2009, is slightly more expensive in the U.S. but is more effective than allopurinol, Choi said. He noted that his study's findings apply almost exclusively to patients starting on allopurinol.

The timing of adverse effects is noteworthy, he said: "Nearly all of these severe adverse events occur during the first 3 to 6 months of treatment, so patients who have been tolerating allopurinol after the initial few months almost certainly do not have to worry about these reactions."

American College of Rheumatology guidelines already recommend screening for the allele in selected Asian populations, said , of North Dakota State University's School of Pharmacy in Fargo, in comments to 番茄社区, noting that Koreans and Han Chinese are at highest risk and Japanese are at lowest risk.

To a large extent this study confirms what we already knew about Asian populations, but the data on blacks are new, Miller added. "Overall, I think the risk of SJS/TEN with allopurinol is somewhat underappreciated, so this study is a good reminder of the need to identify and manage patients at high risk."

Among the study's limitations were the potential for misclassification in the large administrative database and the lack of information on specific medications.

And although the racial/genetic factor cannot be confounded by variables developed after birth such as chronic kidney disease, "it would be valuable to examine the potential impact of other known risk factors at the time of [urate-lowering drug] initiation, as well as the potential role of dose escalation, compliance, and duration of use according to race in future studies," Choi and colleagues wrote.

Comment