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Be careful when prescribing allopurinol 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.1
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.
These ‘findings apply almost exclusively to patients who are starting allopurinol, since nearly all of these severe adverse events occur during the first three to six months of treatment.’ —Dr. Choi
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.
In the U.S., rheumatologists treat more challenging and advanced gout patients, says Dr. Choi. He points out that this information about SJS/TEN risk among Asian and black patients is also “highly relevant” to primary care physicians who manage about 90% of the nation’s gout cases.
Other medical specialists and researchers use allopurinol to treat certain conditions other than gout. It is also prescribed for kidney stones, particularly those composed of uric acid, and tumor lysis syndrome in cancer patients. Some studies are investigating allopurinol’s potential therapeutic impact in cardiovascular-renal patients, even those without gout, such as those with asymptomatic hyperuricemia. Kidney function is closely related to allopurinol hypersensitivity, and epidemiological studies have suggested that gout might lead to cardiovascular and renal conditions, Dr. Choi adds.
Screening to stratify risk in patients taking allopurinol may also be helpful in countries known to have frequency of HLA-B*5801 carriage even higher than the rate among U.S. blacks. In the U.S., the rate of HLA-B*5801 allele frequency is 4% for blacks and 1% for Caucasians, while it is up to 10% in Kenya and 8% in South Africa. The risk of allopurinol hypersensitivity syndrome among patients in these countries “would be higher than what we have observed in the U.S.,” Dr. Choi notes.
Adverse reactions are not a practical concern in patients who have been tolerating allopurinol well for several months, Dr. Choi points out. “It should also be noted that our findings apply almost exclusively to patients who are starting allopurinol, since nearly all of these severe adverse events occur during the first three to six months of treatment,” he explains.
Allopurinol Alternatives
Other drugs that lower urate levels in the blood are available for patients at risk of SJS/TEN and allopurinol hypersensitivity syndrome. An alternative is febuxostat, which was approved by the U.S. Food and Drug Administration (FDA) in 2009. Like allopurinol, febuxostat is an inhibitor of xanthine oxidase, an enzyme involved in purine metabolism.
Recently, the Taiwanese Food and Drug Administration adopted febuxostat as an alternative first-line drug for patients with chronic kidney disease to help reduce allopurinol-associated SJS/TEN. A 2015 JAMA Internal Medicine study that involved a retrospective analysis of Taiwan National Health Insurance Research Database information collected between 2005 and 2011 found that use of allopurinol in patients with asymptomatic hyperuricemia and renal or cardiovascular diseases significantly increased the risk of allopurinol hypersensitivity reactions. That study advised caution when prescribing allopurinol to high-risk populations and urged practitioners to consider the potential risk of fatal adverse reactions.3
However, febuxostat is more expensive than allopurinol because it is a newer drug still under patent in the U.S., says Dr. Choi. According to Dr. Choi, febuxostat costs about $2,385 wholesale per year, and the annual cost of allopurinol is less than $96.
Probenecid, another alternative ULD that increases the excretion of uric acid in the urine, tends to be less effective and is associated with more frequent drug interactions, adds Dr. Choi.
Another xanthine oxidase inhibitor, benzbromarone, has not been approved by the FDA because of reports of acute liver injury and deaths with its use.
In December 2015, the FDA approved lesinurad, which increases the excretion of uric acid in the urine, for use in combination with a xanthine oxidase inhibitor to treat gout. The FDA’s approval is based on data from three Phase 3 studies that included a total of 1,537 gout patients treated with combination urate-lowering therapy.
Because allopurinol remains the drug of choice for the vast majority of gout patients in the U.S., Dr. Choi’s paper points to the value of studying the potential impact of other known risk factors for SJS/TEN. To this end, his team is expanding its focus beyond race and ethnicity to sex, age and other co-morbidities that may increase the risk of severe adverse events. He hopes that results of the ongoing study will comprehensively aid risk stratification of patients taking allopurinol.
In the meantime, Dr. Choi urges rheumatologists and other physicians who care for gout patients or prescribe allopurinol for other purposes to take heed of his findings. “To our knowledge, our study provides the first evidence that U.S. blacks have a higher risk of SJS/TEN as ULD adverse events than U.S. Caucasians,” says Dr. Choi.
Information on racial and ethnic descent “can be used immediately for risk stratification to reduce adverse events,” he emphasizes.
Deborah Levenson is a writer and editor based in College Park, Md.
References
- Lu N, Rai SK, Terkeltaub R, Kim SC, Menendez ME, Choi HK. Racial disparities in the risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the United States. Semin Arthritis Rheum. 2016 Mar 31. pii: S0049-0172(16)30004-X. doi: 10.1016/j.semarthrit.2016.03.014. [Epub ahead of print]
- Khanna D, Fitzgerald JD, Khanna PP, Bae S, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012 Oct;64(10):1431–1446.
- Yang CY, Chen CH, Deng ST, et al. Allopurinol use and risk of fatal hypersensitivity reactions: A nationwide population-based study in Taiwan. JAMA Intern Med. 2015 Sep;175(9):1550–1557.
