Americans of Asian and African descent have much higher risk than white and Hispanic Americans of developing rare but severe, sometimes life-threatening skin reactions to the gout drug allopurinol (Zyloprim), according to a new study published recently in Seminars in Arthritis & Rheumatism.
These two skin reactions, called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), cause flu-like symptoms, a widespread rash, and large portions of the upper layer of skin (including mucus membranes) to blister and detach. They can also damage other major organs. SJS and TENS, which are believed to be different manifestations of the same disorder, are usually caused by a reaction to a drug (including acetaminophen [Tylenol] and certain antibiotics).
Allopurinol, which reduces the production of uric acid in the body, is the most commonly-used first-line treatment for gout and hyperuricemia; it has been around for 50 years.
The risk of developing SJS/TENS for Asian Americans who take allopurinol is 12 times greater than for white and Hispanic Americans; for African Americans, it’s 5 times greater.
Still, these reactions are uncommon even among higher-risk groups, emphasizes study author Hyon Choi, MD, PhD, professor of medicine at Harvard Medical School and director of the Gout and Crystal Arthropathy Center at Massachusetts General Hospital in Boston, .
Regardless of a patient’s ethnicity, Dr. Choi says, SJS/TEN, if it is going to occur, almost always does so within the first three to six months of treatment with allopurinol, the most commonly used gout drug for lowering urate levels, so people who have been taking it for a while needn’t worry about these reactions.
Race and Risk
Dr. Choi and his colleagues looked at U.S. hospitalization records from 2009 to 2013, with 5 million to 8 million admissions per year, and found only 606 cases of SJS/TEN. But when they looked more closely, they found many more cases of the serious reactions among Americans of Asian and African descent than one would expect, given the racial makeup of the general U.S. population. Of the SJS/TEN patients, for example, 27% were Asian American, 26% were African American and 29% were white. Asian Americans, African Americans and whites, however, make up 5%, 12%, and 67%, respectively, of the U.S. population.
To put it another way, says Dr. Choi, approximately 1 in 4,000 whites, 1 in 740 African Americans, and 1 in 340 Asian Americans taking allopurinol will develop a severe reaction. (The number of SJS/TENs cases linked to allopurinol use among Hispanics during the study period was too low to report, meaning they are unlikely to have a higher risk than Asian, African, or white Americans.)
It’s almost certainly the presence of an allele (a variant form of a gene) called HLA-B*5801 causing these race-related increases in risk, says Dr. Choi. Experts have known for some time that Asians are more likely to carry the allele; about 7.4% of Asian Americans do, compared with 4% of African Americans and 1% of both white and Hispanic Americans.
The American College of Rheumatology (ACR) in 2012 updated its gout management guidelines to recommend screening for the allele in patients of Asian descent before starting allopurinol, which accounts for 96% of all urate-lowering drug use in the Unites States. Dr. Choi, who was a co-author of the ACR guidelines, expects the findings of the recent study to prompt rheumatologists to expand screening for the allele, a simple blood test that costs about $150. He now screens all of his Asian-American and African-American patients before beginning allopurinol therapy. If they test positive for the allele, Dr. Choi begins therapy with one of the handful of alternative urate-lowering drugs, such as probenecid or febuxostat (Uloric).
People with gout typically take allopurinol long-term. Taking it regularly is the key to lowering uric acid levels, which can reduce frequency and severity of gout attacks. “This information will allow us to use allopurinol in a safer way and, if patients perceive better safety, they may be more likely to use it and therefore be better treated,” says Dr. Choi. Even though SJS/TEN is uncommon, some patients can be understandably reluctant to take a drug that can cause frightening and potentially fatal side effects, he says. About 30% of patients die from these reactions, and those who survive can have long-term kidney and eye damage.
“The presence of this allele is a major risk factor for SJS/TEN. I would hope that, if we can predict the risk of this reaction more precisely by screening for this allele and identifying other known risk factors, such as poor kidney function, we can bring the probability of developing this to almost zero,” Dr. Choi says.
The current study “confirms what we know about risk for allopurinol-related SJS/TEN in Asians and gives us new information about risk in African Americans, which will help doctors choose the best drugs for specific patients and avoid doing harm,” says Puja Khanna, MD, assistant professor of medicine at the University of Michigan in Ann Arbor. Dr. Khanna was also a co-author of the 2012 ACR gout guidelines, but wasn’t involved in this study.
“One important message I see for patients who are newly diagnosed with gout is that it could be wise to have a discussion with your doctor about your ethnic background,” she says. “Sometimes doctors aren’t comfortable asking, and it may not always be obvious that someone is one-eighth Han Chinese, for example, and therefore might have a higher risk of having this allele than their appearance suggests.”
People who test positive for the allele do have some alternate treatment options, but there is definitely a need for more oral urate-lowering drugs, says Dr. Khanna. “There are several [new treatments] in development, but, because allopurinol works for most and these reactions are rare, the pipeline for new drugs is slow.”
Author: Emily Delzell for the Arthritis Foundation