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Heart Disease Increases Risk for Severe Skin Reactions to Allopurinol
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Heart disease is associated with an increased risk for severe cutaneous adverse reactions to allopurinol, according to data published in the Canadian Medical Association Journal.
“Allopurinol-associated severe cutaneous adverse reactions are a rare but potentially life-threatening adverse reaction to allopurinol,” Hyon K. Choi, MD, DrPH, of Massachusetts General Hospital, Harvard Medical School, told Healio Rheumatology. “Prior studies have identified several risk factors associated with these reactions, including presence older age, female sex, presence of HLA-B*5801 allele, comorbid [chronic kidney disease] and a higher allopurinol starting dose — generally more than 100 mg daily. A prior study in Taiwan suggested that heart disease could be another risk factor.”
In “the first study to investigate [the association between heart disease and severe allopurinol-related skin reactions] in a non-Asian cohort of patients,” Choi and colleagues studied data from Population Data BC, which contains health and prescription information on nearly all 4.7 million residents in British Columbia, Canada. The researchers used the database to identify 130,325 patients who initiated allopurinol between 1997 and 2015.
The primary endpoint was incidence of hospitalization for severe cutaneous adverse reactions to allopurinol — identified using the hospital’s principal discharge diagnosis — within 3 months after the patient filled their first prescription for the drug, and following treatment discontinuation. The researchers analyzed the link between heart disease — specifically ischemic heart disease and heart failure — and the risk for such adverse events leading to hospitalization, adjusting for known and possible risk factors.
According to the researchers, among the 130,325 patients who initiated allopurinol, where 109 hospitalizations due to severe skin reactions to the drug. The researchers calculated the multivariable relative risk among those with heart disease to be 1.55 (95% CI, 1.01-2.37). In addition, patients with heart disease and chronic kidney disease who began taking allopurinol at a dosage greater than 100 mg per day demonstrated an 11-fold higher risk for severe skin reactions. Lower doses at initiation among patients with heart disease and chronic kidney disease resulted in a fivefold risk reduction.
The researchers also found that older women with heart disease from regions with large Asian populations demonstrated a 23-fold greater risk for severe skin reactions to allopurinol, compared with younger men without heart disease from other regions.
“This study highlights the importance of understanding the commonly accepted risk factors for allopurinol-associated severe cutaneous adverse reactions and implementing strategies to mitigate the risk of this reaction as much as possible,” Choi said. “Possible strategies include screening for HLA-B*5801 in at-risk individuals — primarily East Asians and blacks — and starting allopurinol at a low dose — eg, 50 mg for those with CKD, 100 mg for those with normal renal function — and slowly titrating the dose up.” – by Jason Laday
Disclosure: Choi reports grant funding from the NIH, research support from AstraZeneca and consulting fees from Takeda, Selecta Biosciences and Horizon.
Perspective
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N. Lawrence Edwards, MD
Allopurinol hypersensitivity syndrome (AHS) is a very severe — but fortunately rare — cutaneous reaction seen in the first few months after the initiation of allopurinol. Over the past 50 years, multiple risk factors for developing this life-threatening condition have been identified, including chronic kidney disease, concomitant use of thiazide diuretics, initial dosing of allopurinol at >100 mg/day as well as carrying the allele for HLA-B*58019 which is most often seen in southeast Asians and African-Americans.
This study looked at population data from British Columbia to identify hospital admission for AHS between 1997 and 2015. The investigators found the overall risk for AHS-associated hospital admission was about 1 in 1200 allopurinol initiators. This study supports the previously recognized independent risk of age >70 years, female sex and CKD. It did not, however, support diuretic use as an AHS risk factor.
Although HLA-B*5801 data was not available to these investigators, there was a clear step-wise increase in risk for the 16 different population centers of British Columbia depending on their percentage of Asian ethnicity.
There are two important take-home messages from this study. The first is that — like CKD — heart disease should now be recognized as an independent risk factor for the development of AHS. The second, and statistically more important, finding is the confirmation that regardless of the presence or absence of CKD and heart disease, if your starting dose of allopurinol is >100 mg/day, you are exposing your patient to a three-fold greater risk for this terrible adverse event.
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