Background/Purpose: The two most common causes of inadequate serum urate (SU) lowering with allopurinol are low adherence and under-dosing. Those who are adherent, but do not reach target SU despite allopurinol dose escalation, could be considered to have “inadequate response” to allopurinol. The aim of this study was to investigate the reasons for not reaching target SU and to identify factors that predict response and inadequate response in a randomised controlled trial of allopurinol dose escalation in gout.

Methods: We analysed data from participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial. Participants undergoing allopurinol dose escalation were classified as having: complete response (CR) – reached target SU at month 9 and 12 of the dose escalation phase OR if still dose escalating at month 9 reached target SU by month 12; partial response (PR) – reached target at some stage but not fulfilling criteria for CR; or inadequate response (IR) – did not reach target SU at any time. The analysis was designed to minimise the effects of two common causes of inadequate response; low adherence and under-dosing.

Results: Inadequate response was uncommon, occurring in 13/150 (8.7%), compared to 82 (54.7%) CR, and 55 (36.6%) PR. Mean (SEM) SU was higher at the end of the 12-month dose escalation in the IR group compared with both CR and PR groups; 7.6 (0.31) vs. 5.01 (0.06) and 5.97 (0.17) mg/dl respectively (p<0.001). There was a relatively linear relationship between increasing allopurinol dose and increasing plasma oxypurinol and between increasing plasma oxypurinol and decreasing SU in the CR group (Figure A and B) over the 12-month dose escalation period. Those with partial response had more static dose and SU levels that were close to the target SU while those with inadequate response had no obvious relationship between allopurinol dose, plasma oxypurinol and SU (Figure C-E). Using ROC curve analysis, baseline SU≥8mg/dl had a sensitivity of 69.2% and specificity of 85.1% in predicting inadequate response. The OR for an inadequate response if baseline SU was ≥8mg/dl was 11.7 (95%CI 3.3-41.2). For those with baseline SU ≥8mg/dl and baseline allopurinol dose >200mg/d, 7/15 (47%) had an inadequate response.

Conclusion: A minority of people with gout never reach target SU when allopurinol dose is increased in a treat-to-target manner. Approximately half of those with SU≥8mg/dl despite allopurinol >200mg/d have an inadequate response to dose escalation. 

Figure: Relationship between mean allopurinol dose and mean (SEM) plasma oxypurinol and mean serum urate and mean (SEM) plasma oxypurinol in the complete response, partial response, and inadequate response groups at months 0 (●), 3 (□), 6(Δ), 9(▼) and 12 (ο) of the dose escalation period.