Abstract
Gout management involves two broad aspects: treatment of gout flares to provide rapid symptomatic relief and long-term urate-lowering therapy to lower serum urate sufficiently to prevent gout flares from occurring. All of the major rheumatology societies recommend a target serum urate of <5 mg/dl (<0.30 mmol/l) or <6 mg/dl (<0.36 mmol/l), both of which are below the point of saturation for urate and therefore lead to monosodium urate crystal dissolution. In this Review, we describe the rationale for treat-to-target urate approach in the long-term management of gout and the current evidence and controversy around the appropriate serum urate targets.
Key points
-
The major rheumatology societies all recommend a treat-to target serum urate approach with the targets being <5 mg/dl (0.30 mmol/l) or <6 mg/dl (<0.36 mmol/l).
-
The treat-to target serum urate strategy for the management of gout has been questioned with the American College of Physicians, which states that insufficient evidence exists for such an approach.
-
Sustained reduction in serum urate to levels <6 mg/dl (<0.36 mmol/l) is associated with a reduction in the dissolution of gout flares and tophi but these clinical benefits take time to occur.
-
More than one target might be appropriate during gout management, with a lower target (<5 mg/dl (0.30 mmol/l)) in the initial phase of urate-lowering treatment and a higher target (<6 mg/dl (< 0.36 mmol/l)) once the flares and tophi have resolved.
-
Which serum urate target results in the best clinical outcomes for people with gout remains to be determined.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dehlin, M., Jacobsson, L. & Roddy, E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat. Rev. Rheumatol. 16, 380–390 (2020).
FitzGerald, J. et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res. 72, 744–760 (2020).
Richette, P. et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann. Rheum. Dis. 76, 29–42 (2017).
Hui, M. et al. The British Society for Rheumatology guideline for the management of gout. Manag. Gout. Rheumatol. 56, e1–e20 (2017).
Ford, J. A. & Solomon, D. H. Challenges in implementing treat-to-target strategies in rheumatology. Rheum. Dis. Clin. North. Am. 45, 101–112 (2019).
Qaseem, A. et al. Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians. Ann. Int. Med. 166, 58–68 (2017).
Dalbeth, N. et al. Discordant American College of Physicians and international rheumatology guidelines for gout management: consensus statement of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN). Nat. Rev. Rheumatol. 13, 561–568 (2017).
Garrod, A. B. Observations on certain pathological conditions of the blood and urine, in gout, rheumatism, and Bright’s disease. Med. Chir. Trans. 31, 83–97 (1848).
Narang, R. K. & Dalbeth, N. Pathophysiology of gout. Semin. Nephrol. 40, 550–563 (2020).
Loeb, J. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum. 15, 189–192 (1972).
Campion, E., Glynn, R. & DeLabry, L. Asymptomatic hyperuricaemia: risks and consequence in the normative aging study. Am. J. Med. 82, 421–426 (1987).
Dalbeth, N. et al. Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis. Ann. Rheum. Dis. 77, 1048–1052 (2018).
Faires, J. & McCarty, D. J. Acute arthritis in man and dog after intra-synovial injection of sodium urate crystals. Lancet 280, 682–685 (1962).
Schumacher, H. Pathology of the synovial membrane in gout. Light and electron microscopic studies. Interpretation of crystals in electron micrographs. Arthritis Rheum. 18, 771–782 (1975).
So, A. K. & Martinon, F. Inflammation in gout: mechanisms and therapeutic targets. Nat. Rev. Rheumatol. 13, 639–647 (2017).
Trost, J. R. & Konstantinov, K. N. The consequences of untreated gout: is this a tophus? Am. J. Med. 132, e805–e806 (2019).
Towiwat, P. et al. Urate crystal deposition and bone erosion in gout: ‘inside-out’ or ‘outside-in’? A dual-energy computed tomography study. Arthritis Res. Ther. 18, 208 (2016).
Khanna, P. et al. Tophi and frequent gout flares are associated with impairments to quality of life, productivity, and increased healthcare resource use: results from a cross-sectional survey. Health Qual. Life Outcomes 10, 117 (2012).
Abhishek, A., Valdes., A. M., Zhang, W. & Doherty, M. Association of serum uric acid and disease duration with frequent gout attacks: a case–control study. Arthritis Care Res. 68, 1573–1577 (2016).
Shiozawa, A., Buysman, E. K. & Korrer, S. Serum uric acid levels and the risk of flares among gout patients in a US managed care setting. Curr. Med. Res. Opin. 33, 117–124 (2017).
Shiozawa, A., Szabo, S. M., Bolzani, A., Cheung, A. & Choi, H. K. Serum uric acid and the risk of incident and recurrent gout: a systematic review. J. Rheumatol. 44, 388–396 (2017).
Lu, B. et al. Risk factors of ultrasound-detected tophi in patients with gout. Clin. Rheumatol. 39, 1953–1960 (2020).
Lam-Erwin, C. & Nancollas, G. H. The crystallization and dissolution of sodium urate. J. Cryst. Growth 53, 215–223 (1981).
Perez-Ruiz, F., Calabozo, M., Pijoan, J., Herrero-Beites, A. & Ruibal, A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Care Res. 47, 356–360 (2002).
Sivera, F. et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann. Rheum. Dis. 73, 328–335 (2014).
Khanna, D. et al. 2012 American College of Rheumatology guidelines for the management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricaemia. Arthritis Care Res. 64, 1431–1446 (2012).
Becker, M. et al. Febuxostat compared with allopurinol in patients with hyperuricaemia and gout. N. Engl. J. Med. 353, 2450–2461 (2005).
Sundy, J. et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA 306, 711–720 (2011).
Pui, K., Gow, P. & Dalbeth, N. Efficacy and tolerability of probenecid as urate-lowering therapy in gout; clinical experience in high-prevalence population. J. Rheumatol. 40, 872–876 (2013).
Stamp, L. et al. A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout. Ann. Rheum. Dis. 76, 1522–1528 (2017).
Stamp, L. et al. Allopurinol dose escalation to achieve serum urate below 6mg/dl: an open label extension study. Ann. Rheum. Dis. 76, 2065–2070 (2017).
Doherty, M. et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial. Lancet 392, 1403–1412 (2018).
Schumacher, H. et al. Outcome domains for studies of acute and chronic gout. J. Rheumatol. 36, 2342–2345 (2009).
Stamp, L. et al. Serum urate as surrogate endpoint for flares in people with gout: a systematic review and meta-regression analysis. Semin. Arthritis Rheum. 48, 293–301 (2018).
Morillon, M. et al. Serum urate as a surrogate outcome in gout: results from the OMERACT 2020 Virtual Gout Special Interest Group. Semin Arthritis Rheum. 51, 1378–1385 (2021).
Chhana, A., Lee, G. & Dalbeth, N. Factors influencing the crystallization of monosodium urate: a systematic literature review. BMC Musculoskelet. Disord. 16, 296 (2015).
Li-Yu, J. et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J. Rheumatol. 28, 577–580 (2001).
Pascual, E. & Sivera, F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann. Rheum. Dis. 66, 1056–1058 (2007).
Gutierrez, M. et al. International consensus for ultrasound lesions in gout: results of Delphi process and web-reliability exercise. Rheumatology 54, 1797–1805 (2015).
Choi, H. K. et al. Dual energy computed tomography in tophaceous gout. Ann. Rheum. Dis. 68, 1609–1612 (2009).
Ebstein, E. et al. Ultrasound evaluation in follow-up of urate-lowering therapy in gout: the USEFUL study. Rheumatology 58, 410–417 (2019).
Hammer, H. B. et al. Ultrasound shows rapid reduction of crystal depositions during a treat-to-target approach in gout patients: 12-month results from the NOR-Gout study. Ann. Rheum. Dis. 79, 1500–1505 (2020).
Uhlig, T. et al. Two-year reduction of dual-energy CT urate depositions during a treat-to-target strategy in gout in the NOR-Gout longitudinal study. Rheumatology 61, Si81–si85 (2022).
Dalbeth, N. et al. Effects of allopurinol dose escalation on bone erosion and urate volume in gout: a dual-energy computed tomography imaging study within a randomized, controlled trial. Arthritis Rheumatol. 71, 1739–1746 (2019).
Stamp, L. et al. Association between serum urate and flares in people with gout and evidence for surrogate status: a secondary analysis of two randomised controlled trials. Lancet Rheumatol. 4, e53–60 (2022).
Uhlig, T. et al. One- and 2-year flare rates after treat-to-target and tight-control therapy of gout: results from the NOR-Gout study. Arthritis Res. Ther. 24, 88 (2022).
Baraf, H. et al. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res. Ther. 15, R137 (2013).
Eason, A. et al. Factors associated with change in radiographic damage scores in gout: a prospective observational study. Ann. Rheum. Dis. 75, 2075–2079 (2016).
Dalbeth, N., Doyle, A. J., McQueen, F. M., Sundy, J. & Baraf, H. S. Exploratory study of radiographic change in patients with tophaceous gout treated with intensive urate-lowering therapy. Arthritis Care Res. 66, 82–85 (2014).
Dalbeth, N., Becce, F., Botson, J. K., Zhao, L. & Kumar, A. Dual-energy CT assessment of rapid monosodium urate depletion and bone erosion remodelling during pegloticase plus methotrexate co-therapy. Rheumatology https://doi.org/10.1093/rheumatology/keac173 (2022).
Perez-Ruiz, F., Martin, I. & Canteli, B. Ultrasonographic measurement of tophi as an outcome measure for chronic gout. J. Rheumatol. 34, 1888–1893 (2007).
Araujo, E. G. et al. Tophus resolution with pegloticase: a prospective dual-energy CT study. RMD Open 1, e000075 (2015).
Dalbeth, N. et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout. Arthritis Rheum. 69, 1903–1913 (2017).
Dalbeth, N. et al. Intensive serum urate lowering with oral urate-lowering therapy for erosive gout: a randomized double-blind controlled trial. Arthritis Rheumatol. https://doi.org/10.1002/art.42055 (2021).
Chen, H., Mosley, T. H., Alonso, A. & Huang, X. Plasma urate and Parkinson’s disease in the atherosclerosis risk in communities (ARIC) study. Am. J. Epidemiol. 169, 1064–1069 (2009).
Kim, T. S. et al. Decreased plasma antioxidants in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry 21, 344–348 (2006).
Loebl, W. Y. & Scott, J. T. Withdrawal of allopurinol in patients with gout. Ann. Rheum. Dis. 33, 304–307 (1974).
Gast, L. Withdrawal of longterm antihyperuricemic therapy in tophaceous gout. Clin. Rheumatol. 6, 70–73 (1987).
Perez-Ruiz, F., Atxotegi, J., Hernando, I., Calabozo, M. & Nolla, J. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Care Res. 55, 786–790 (2006).
Graham, G. et al. Understanding the dose-response relationship of allopurinol: predicting the optimal dosage. Br. J. Clin. Pharmacol. 76, 932–938 (2013).
Perez-Ruiz, F., Herrero-Beites, A. M. & Carmona, L. A two-stage approach to the treatment of hyperuricemia in gout: the “dirty dish” hypothesis. Arthritis Rheum. 63, 4002–4006 (2011).
Saag, K. G. et al. Evaluation of serum urate levels and the clinical manifestation of gout with cardiovascular mortality from the CARES trial. Arthritis Rheumatol. https://doi.org/10.1002/art.42160 (2022).
Solomon, D. H. et al. Designing a strategy trial for the management of gout: the use of a modified Delphi panel. ACR Open Rheumatol. 3, 341–348 (2021).
Shmerling, R. H. Editorial: the ethics of recent gout trials. Arthritis Rheumatol. 68, 2057–2060 (2016).
O’Dell James, R. et al. Comparative effectiveness of allopurinol and febuxostat in gout management. NEJM Evid. 1, EVIDoa2100028 (2022).
Scirè, C. A. et al. Development and first validation of a disease activity score for gout. Arthritis Care Res. 68, 1530–1537 (2016).
de Lautour, H. et al. Development of preliminary remission criteria for gout using Delphi and 1000Minds consensus exercises. Arthritis Care Res. 68, 667–672 (2016).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
L.K.S. reports research funding from the New Zealand Health Research Council and consulting fees from Pharmac. N.D. reports research funding from the New Zealand Health Research Council, grants and personal fees from AstraZeneca, grants from Amgen, personal fees from Horizon, Dyve Biosciences, PK Med, JW Pharmaceuticals, Selecta, Arthrosi, Janssen, AbbVie and Cello Health outside the submitted work.
Peer review
Peer review information
Nature Reviews Rheumatology thanks the anonymous reviewers for their contribution to the peer review of this work.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Stamp, L.K., Dalbeth, N. Critical appraisal of serum urate targets in the management of gout. Nat Rev Rheumatol 18, 603–609 (2022). https://doi.org/10.1038/s41584-022-00816-1
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41584-022-00816-1
This article is cited by
-
Cardiovascular safety of using non-steroidal anti-inflammatory drugs for gout: a Danish nationwide case-crossover study
Rheumatology International (2024)
-
Urate-lowering therapy following a treat-to-target continuation strategy compared to a treat-to-avoid-symptoms discontinuation strategy in gout patients in remission (GO TEST Finale): study protocol of a multicentre pragmatic randomized superiority trial
Trials (2023)