Background/Purpose: A recent US Medicaid study found that in addition to certain races (Asians and Blacks), older age, female sex, chronic kidney disease (CKD), and initial allopurinol dose >100 mg/day are associated with a higher risk of hospitalized allopurinol-associated severe cutaneous adverse reactions (AASCARs) (Ann Rheum Dis 2018).  We aimed to replicate these findings in a general population database from another country (Canada) and expand our investigation for an independent role of cardiovascular disease (CVD) on the risk of AASCARs.   

Methods: We used PopulationData BC, a population-based administrative database that covers the entire general population of British Columbia, Canada, to identify incident allopurinol users between 1999 and 2012. We examined the risk of hospitalized AASCARs according to purported key risk factors and used Poisson regression models to calculate relative risks (RR), adjusting for purported risk factors for AASCARs (Table).

Results: Among 451,897 allopurinol initiators, we documented 110 hospitalized AASCAR cases (mean age, 62 years; 71% male) during a mean follow-up of 3 months.  The risk of hospitalized AASCARs was apparent within 10 days of allopurinol initiation, peaked around one month after initiation, and declined progressively thereafter, reaching its nadir at the end of the third month (Figure).  Of the 110 cases, 10 (9%) died during hospitalization. The overall risk of hospitalized AASCARs was 1 out of 1185 allopurinol initiators (Table).  Female sex, older age (>60 years), CKD, and initial allopurinol dose (>100 mg/day) were independently associated with a 2.6-, 1.5-, 1.7-, and 2.8-fold higher risk of AASCARs, respectively (Table).  CVD was associated with a 2.5 higher risk of AASCARs after adjusting for other risk factors (RR, 2.45; 95% CI, 1.59 to 3.77), whereas diuretic use, a previously suspected risk factor, was not (RR, 1.05; 95% CI, 0.69 to 1.60) (Table).

Conclusion:  This general population-based cohort study confirms the independent role of older age, female sex, CKD, and initial allopurinol dose (>100 mg/day) in predicting a higher risk of AASCARs.  Furthermore, having CVD is also strongly associated with an increased risk of AASCARs, independent of these risk factors. These factors should be considered when initiating allopurinol to help prevent this extremely severe and potentially fatal adverse reaction.