By Deborah Levenson
Be careful when prescribing allo¬purinol to black and Asian gout patients, a study newly advises.
Black and Asian patients who take this ubiquitous, more-than-40-year-old medication are at much higher risk of certain serious skin reactions than are Caucasians or Hispanics. Compared with Caucasians, blacks who take allopurinol to lower blood urate levels have an increased risk of the potentially deadly cutaneous disorders Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The risk in blacks is five times higher than in Caucasians who take the drug, according to research published in Seminars in Arthritis Rheumatology.
SJS and TEN cause flu-like symptoms, a widespread rash and blistering and detachment of large portions of the upper layer of skin, including mucus membranes. The disorders leave the body vulnerable to severe infections and are fatal in up to 32% of cases, the study notes. Risk of SJS and TEN in Hispanics taking allopurinol is likely equal to that of Caucasians taking the drug, the study newly reports. It also confirmed a body of research that shows certain patients of Asian descent are at increased risk, relative to Caucasians.
The current study shows that compared with Caucasians, the risk of potentially lethal adverse effects from SJS and TEN is 12 times higher for Asians. These findings are based on an analysis of hospitalizations of patients from various racial and ethnic groups hospitalized for SJS and TEN included in a database representative of U.S. hospitalization between 2009 and 2013, as well as other population data.
Elevated risk in both Asians and blacks correlates with corresponding racial and ethnic incidence of the HLA-B*5801 carriage, a strong determinant of allopurinol hypersensitivity syndrome, the study points out. The syndrome is a collection of symptoms that includes SJS, TEN, eosinophilia, leukocytosis, fever, hepatitis and renal failure.
“[Because] allopurinol is the only ULD [urate-lowering drug] with an established association with SJS/TEN—and in light of its extreme market dominance in the U.S.—our findings support the use of extra caution among Asians and blacks when considering allopurinol,” says Hyon Choi, MD, DrPH, the paper’s senior author. He is professor of medicine in the Division of Rheumatology, Allergy and Immunology at Harvard Medical School and director of the Gout and Crystal Arthropathy Center at Massachusetts General Hospital in Boston.
The Analysis
ACR guidelines already recommend HLA-B*5801 carriage screening for certain Asian populations, including Koreans with severe chronic kidney disease and Han Chinese and Thai patients, even if their renal function is normal.2 “Those who carry the genes are associated with a very high risk of developing severe allopurinol hypersensitivity syndrome,” explains Dr. Choi. However, these guidelines don’t comment on the use of allopurinol in patients of Japanese or other Asian backgrounds, or in blacks or Hispanics. Varying frequencies of HLA-B*5801 carriage across different races and ethnic groups could lead to major disparities in SJS/TEN risk and adverse events among patients who take allopurinol, the researchers warn. The study tested Dr. Choi’s hypothesis that having information on racial and ethnic descent—even before genotyping—could enhance risk stratification to prevent serious adverse events among gout patients. “We wanted to use race and ethnicity as obvious information that could be used to help prevent allopurinol hypersensitivity syndrome,” he explains.
To test their hypothesis, the researchers analyzed data from the Nationwide Inpatient Sample (NIS), a nationally representative, all-payer inpatient care database maintained by the Agency for Healthcare Research and Quality, representing between five and eight million hospital discharges annually. For reference data, researchers included statistics from the U.S. Census population and the National Health and Nutrition Examination Survey (NHANES) for 2009–2012.
Results
The researchers’ analysis of NIS data from between 2009 and 2013 identified 606 hospitalizations of patients with both a principal diagnosis of SJS/TEN and a secondary diagnosis of an adverse event caused by a ULD. Although the database did not identify specific drugs, the researchers assumed that most, if not all, of the adverse reactions involved allopurinol because it is prescribed so frequently.
Meanwhile, the researchers’ NHANES data analysis showed that allopurinol constituted 97% of ULD use.
Asian and black patients hospitalized with SJS/TEN in combination with a secondary diagnosis of an adverse event caused by a ULD were significantly over-represented, compared with Caucasians. The NIS data show that patients with these diagnoses were 27% Asian American, 26% African American and 29% Caucasian. However, Asian Americans, African Americans and Caucasians make up 5%, 12% and 67% of the U.S. population, the researchers note.
Although Hispanics are the largest minority race according to U.S. Census data, the number of SJS/TEN cases among the group was too small to report. The frequency of SJS/TEN cases among Hispanics is unlikely to be higher than any other race, the researchers write.
According to the NHANES data, black patients represented 13% of allopurinol users, and NIS figures show that blacks represented 26% of all hospitalizations for of SJS/TEN in combination with a secondary diagnosis of an adverse event caused by a ULD. Asian patients represented only 2% of U.S. allopurinol users in 2011–12, but 27% of those hospitalized for SJS/TEN related to ULDs. Caucasian patients represented 81% of allopurinol users, but only 29% of hospitalizations. Very few Hispanic patients with these diagnoses were included in the hospitalization database, the researchers note.
Clinical Implications
The paper’s findings support the ACR recommendation to screen for HLA-B*5801 carriage in high-risk Asian groups and suggest doing so for blacks, “particularly when there are co-existing risk factors, such as chronic kidney disease,” says Dr. Choi.