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

Lisa K. Stamp*, Christopher Frampton, Melanie B. Morillon, William J. Taylor, Nicola Dalbeth, Jasvinder A. Singh, Michael Doherty, Weiya Zhang, Helen Richardson, Aliya Sarmanova, Robin Christensen


Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


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 (0·36 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, 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] 0·29 [95% CI 0·17 to 0·51], p<0·0001). 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 –0·41 [95% CI –1·77 to –1·04], p<0·0001). 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. Funding: None.

TidsskriftThe Lancet Rheumatology
Udgave nummer1
Sider (fra-til)e53-e60
StatusUdgivet - jan. 2022

Bibliografisk note

Funding Information:
LKS is grateful to the New Zealand Health Research Council for funding and the Health Research Council Independent Data Monitoring Core Committee for monitoring the study. MD acknowledges support from Arthritis Research UK (grant number 19703). We thank members of the Nottingham Rheumatology Patient and Public Involvement group for advice during development of the study, and the participating centres. RC acknowledges that The Parker Institute at Bispebjerg and Frederiksberg Hospital is supported by a core grant from the Oak Foundation (OCAY-18–774-OFIL).

Funding Information:
LKS reports research funding from the New Zealand Health Research Council and consulting fees from Pharmac. ND reports grants and personal fees from AstraZeneca, grants from Amgen, and personal fees from Horizon, Dyve Biosciences, PK Med, JW Pharmaceuticals, Selecta, Arthrosi, Janssen, AbbVie, and Cello Health, outside the submitted work. ND is president of the New Zealand Rheumatology Association and a board member of Auckland Medical Research Foundation and the Gout and Crystal Arthritis Network. She is an international advisory council member of the Gout Education Society, a member of the core oversight team for the American College of Rheumatology Gout Management Guidelines, and on the advisory committee for the Asia-Pacific Gout Consortium. AbbVie has provided an ultrasound machine to the Auckland Rheumatology Department to which ND has access. JAS has received consulting fees from Crealta (Horizon), Medisys, Fidia, UBM, Trio Health, Medscape, WebMD, Two Labs, Adept Field Solutions, Clinical Care Options, ClearView Healthcare Partners, Putnam Associates, FocusForward, Navigant Consulting, Spherix, MedIQ, Practice Point Communications, the National Institutes of Health, and the American College of Rheumatology. JAS owns stock options in TPT Global Tech, Vaxart, and Charlotte's Web Holdings. JAS previously owned stock options in Amarin, Viking, and Moderna, and is on the speaker's bureau of Simply Speaking. JAS is a member of the executive committee of Outcome Measures in Rheumatology, an organisation that develops outcome measures in rheumatology and receives arm's length funding from eight companies. MD has received honoraria for attending ad-hoc advisory boards on gout and osteoarthritis for Grunenthal, Mallinckrodt, and Pfizer, and author royalties from UpToDate, and was an investigator in an AstraZeneca-funded, investigator-led study (the Sons of Gout Study), unrelated to this work. WZ has received honoraria from Regeneron and Eli Lilly for advice on the treatment of osteoarthritis, and funding from Versus Arthritis. All other authors declare no competing interests.

Publisher Copyright:
© 2022 Elsevier Ltd


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