Association between serum urate and flares in people with gout and evidence for surrogate status: a secondary analysis of two randomised controlled trials

Background Use of serum urate as a treatment target and outcome measure has become controversial in view of the 2017 American College of Physicians guidelines, which advocated a treat-to-symptom rather than a treat-to-target serum urate approach to gout management. The relevance of serum urate as a treatment target measure implies that achievement of target serum urate is causally associated with improvement in patient-important outcomes such as reduction in the number of gout flares. The aim of this study was to assess the causal relationship between achieving target serum urate and the occurrence of gout flares. Methods We analysed individual patient-level data from two randomised trials on urate-lowering therapies in people with gout conducted in Nottingham, UK, and New Zealand. We included participants randomly assigned to immediate dose escalation in the New Zealand study and all participants in the Nottingham study (a nurse-led gout care group and a general practitioner-led usual care group). Individuals who on average achieved a serum urate concentration less than 6 mg/dL (0middot36 mmol/L) based on data at 6, 9, and 12 months post-baseline were defined as serum urate responders. The primary outcome was the proportion of participants having at least one gout flare, and the secondary outcome was the mean number of flares per participant per month, from 12 to 24 months after baseline, compared between serum urate responders and non-responders. In adjusted logistic regression models, serum urate at baseline, previous flare history (in the year preceding study entry), presence of tophi at baseline, and, for the Nottingham dataset, the original randomisation group, were included as covariates. The Nottingham study was registered with ClinicalTrials.gov, NCT01477346. The New Zealand study was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000845932. Findings From the combined individual data from both trials, we identified 343 serum urate responders and 245 serum urate non-responders. Significantly fewer serum urate responders had a gout flare than did serum urate non-responders between 12 and 24 months (91 [27%] of 343 vs 156 [64%] of 245; adjusted odds ratio [OR] 0middot29 [95% CI 0middot17 to 0middot51], p<0middot0001). The mean number of flares per participant per month between 12 and 24 months was significantly lower in serum urate responders than in serum urate non-responders (adjusted mean difference -0middot41 [95% CI -1middot77 to -1middot04], p<0middot0001). This association was independent of the original randomised treatment allocation. Interpretation Achieving an average serum urate concentration less than 6 mg/dL is associated with an absence of gout flares and a reduction in the number of flares in the subsequent 12 months in people with gout. These results support a treat-to-target serum urate approach in the management of gout.