Allopurinol: Extra Caution Urged in High-Risk Groups

Janis C. Kelly

April 17, 2018

Allopurinol-associated cutaneous adverse reactions severe enough to require hospitalization occurred three to six times as often in Asians, blacks, and Native Hawaiians/Pacific Islanders than in whites or Hispanics, and up to 12 times as often in members of the high-risk groups who were also female and older than 60 years, researchers report in an article published online April 13 in the Annals of the Rheumatic Diseases.

The elevated risk paralleled the frequency of the HLA-B*5801 allele in each ethnic/racial group, and higher risk was also associated with initial allopurinol dosing of more than 100 mg/day. Neither gout nor prior diuretic use was associated with increased risk.

These findings support current recommendations that allopurinol be initiated at a dose of 100 mg/day or lower. The authors also recommend screening of Asian, black, and native Hawaiian/Pacific Islander patients for the presence of HLA-B*5801 before initiating allopurinol, particularly those who also have additional risk factors (female, age >60 years, or chronic kidney disease [CKD]). The risk for allopurinol-associated severe cutaneous reactions (AASCARs) was more than six times higher among Native Hawaiians/Pacific Islanders compared with whites, the first time this racial/ethnic group has been identified as at high risk.

Sarah F. Keller, MD, from the Division of Rheumatology, Allergy, and Immunology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, and colleagues write, "These findings support the use of extra caution among Native Hawaiians/Pacific Islanders, Asians and blacks when considering allopurinol (including screening for HLA-B*5801), particularly among elderly women with CKD. Importantly, a low initial allopurinol dose (eg, <100 mg/day) was the only modifiable risk factor, which is readily implementable and is also recommended by the latest rheumatology guidelines."

Researchers Analyzed More Than 400,000 Allopurinol Users

Keller and colleagues used US Medicaid data to identify patients who began using allopurinol between 1999 and 2012. Among these 400,401 allopurinol initiators, they found 203 hospitalized AASCAR cases, with an average 9.6 days of hospitalization. There were also 43 (21%) deaths. They note the analysis included only hospitalized AASCAR cases and likely underestimates the AASCAR risk associated with allopurinol.

The study population was 62% white, 53% male, 52% younger than age 60 years, 5% with CKD, and 61% prescribed allopurinol at an initial dose higher than 100 mg/day.

The primary study objective was to identify high-risk patients, with the goal of finding ways to prevent severe cutaneous adverse events associated with allopurinol. These severe reactions can involve major organs, result in corneal damage and renal insufficiency, and be fatal in up to 32% of cases, the authors write. The researchers defined cutaneous adverse effects using International Classification of Diseases, Ninth Revision, Clinical Modification, codes for dermatitis resulting from drugs and medicines, erythema multiforme, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, unspecified erythematous conditions, and other unspecified erythematous conditions.

The incident AASCAR cases requiring hospitalization began to appear within 10 days of allopurinol initiation, peaked at about 30 days, and subsided by 90 days. Hospitalization risk was 1 in 3883 whites and Hispanics, 1 in 1227 blacks, 1 in 1429 Asians, and 1 in 571 Native Hawaiians/Pacific Islanders.

AASCAR Risk for Ethnic/racial Groups Linked to HLA-B*5801

Multivariable-adjusted relative risks (RR) for AASCARs compared with those among whites and Hispanics were 3.00 among blacks, 3.03 among Asians, and 6.68 among Native Hawaiians/Pacific Islanders. AASCAR risk roughly paralleled the estimated allele frequency of HLA-B*5801 in these groups in the United States: 1% in whites and Hispanics, 4% in blacks, and 7.4% in Asians. A prior meta-analysis reported the risk of developing AASCARs was up to 97 times higher in patients with the allele than in those without it.

The authors further warn that allele frequency is higher in other Pacific Island countries such as Malaysia, where it is 11% to 22%, so the risk for patients from those areas would be expected to be at least as high as that observed in the current study. The authors explain that the 20% prevalence of HLA-B*5801 in Taiwan is why the Taiwanese Food and Drug Administration adopted an alternate first-line urate-lowering drug for patients with CKD.

Furthermore, allele frequencies are 7% to 10% among blacks in Kenya and 8% in black South Africans, suggesting a higher AASCAR risk in those populations as well.

The authors write, "The recommendation to screen for HLA-B*5801 or to consider the use of an alternative [urate-lowering drug] would be applicable to Native Hawaiians/Pacific Islanders prior to initiating allopurinol therapy, particularly when additional AASCAR risk factors are present (eg, in the case of being an elderly woman with CKD)."

Furthermore, the various independent risk factors combine to produce even greater risk. Female sex (RR, 1.96) and age 60 years or older (RR, 2.79) were significant independent risk factors for AASCAR. But women older than 60 years from high-risk race/ethnicity groups had a 12-fold higher risk for hospitalized AASCARs than younger men from a low-risk subgroup. Men older than 60 years from one of the high-risk race/ethnicity groups had a more than six-fold higher risk for hospitalized AASCAR than younger men from the same subgroup.

CKD was associated with a multivariable-adjusted RR of 2.33, and initial allopurinol dose more than 100 mg/day was associated with a multivariable-adjusted RR of 1.85. Combining these two independent risk factors in a patient from a high-risk race/ethnicity group produced a relative risk nine times higher than for a patient without CKD with an initial allopurinol dose 100 mg or lower who was from a low-risk race/ethnicity group.

More Cautious Approach to Allopurinol Recommended

The researchers conclude, "[T]hese findings from a large, racially diverse cohort indicate that Native Hawaiians/Pacific Islanders, Asians and blacks all have a substantially higher risk for hospitalized AASCARs compared with whites and Hispanics, calling for heightened vigilance when initiating allopurinol in these racial/ethnic groups. Furthermore, female sex, older age, CKD and an initial allopurinol dose >100 mg/day are all independent risk factors for hospitalised AASCARs and should also be considered when initiating allopurinol to help prevent this severe and potentially fatal adverse reaction."

The study was supported in part by a grant from the National Institutes of Health. One coauthor reported research grants from Pfizer and AstraZeneca to Massachusetts General Hospital for unrelated studies, and consulting fees from Takeda Pharmaceuticals, Selecta, Horizon and Ironwood. Another coauthor reported research grants to the Brigham and Women's Hospital from Pfizer, AstraZeneca, Bristol-Myers Squibb, and Roche for unrelated studies. The remaining authors have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online April 13, 2018. Abstract

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