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20-03-2018 | Gout | Review | Article

What Is the Evidence for Treat-to-Target Serum Urate in Gout?

Journal: Current Rheumatology Reports

Authors: David Bursill, Nicola Dalbeth

Abstract

Purpose of Review

Most current clinical guidelines for gout management advocate a treat-to-target serum urate approach, although notable differences exist. Serum urate is a rational target for gout treatment given the central role of urate in disease causality, its association with key outcomes and its practicality of use in clinical practice. This review analyses the evidence for this strategy in gout.

Recent Findings

Recent studies have confirmed the efficacy of urate-lowering therapy in achieving serum urate targets, both in trials using fixed doses and those applying a treat-to-target strategy. In a limited number of long-term studies (> 12-month duration), interventions that incorporate a treat-to-target serum urate approach have been shown to promote regression of tophi, reduce the frequency of gout flares and improve MRI-detected synovitis.

Summary

A strong case can be made for a treat-to-target serum urate strategy in gout, supported by existing knowledge of disease pathophysiology, outcomes from urate-lowering therapy studies and emerging results of randomised strategy trials of sufficient duration.

Gutman AB, Yü T. Uric acid metabolism in normal man and in primary gout. N Engl J Med. 1965;273(6):313–21. https://doi.org/10.1056/NEJM196508052730607.CrossRefPubMed

Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet. 2016;388(10055):2039–52. https://doi.org/10.1016/S0140-6736(16)00346-9.CrossRefPubMed

De Vera MA, Marcotte G, Rai S, Galo JS, Bhole V. Medication adherence in gout: a systematic review. Arthritis Care Res (Hoboken). 2014;66(10):1551–9. https://doi.org/10.1002/acr.22336.CrossRef

Vaccher S, Kannangara DRW, Baysari MT, Reath J, Zwar N, Williams KM, et al. Barriers to care in gout: from prescriber to patient. J Rheumatol. 2016;43(1):144–9. https://doi.org/10.3899/jrheum.150607.CrossRefPubMed

Robinson PC, Taylor WJ, Dalbeth N. An observational study of gout prevalence and quality of care in a national Australian general practice population. J Rheumatol. 2015;42(9):1702–7. https://doi.org/10.3899/jrheum.150310.CrossRefPubMed

Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431–46. https://doi.org/10.1002/acr.21772.CrossRef

Sivera F, Andrés M, Carmona L, Kydd ASR, Moi J, Seth R, 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. 2014;73(2):328–35. https://doi.org/10.1136/annrheumdis-2013-203325.CrossRefPubMed

• Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda-Sanabria J, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29–42. https://doi.org/10.1136/annrheumdis-2016-209707. An update of the 2006 European League Against Rheumatism gout management guidelines based on a systematic review of the literature and consensus reached through a Delphi exercise. CrossRefPubMed

• Hui M, Carr A, Cameron S, Davenport G, Doherty M, Forrester H, et al. The British Society for Rheumatology guideline for the management of gout. Rheumatology (Oxford). 2017;56(7):e1–e20. https://doi.org/10.1093/rheumatology/kex156. An update of BSR guidelines for the management of gout in the UK based on a systematic literature review and Delphi consensus exercise. Notable for its recommendation of a two-phase approach to treat-to-target management consisting of an initial target < 5.0 mg/dL, followed by < 6.0 mg/dL once clinical remission achieved. CrossRef

10.

• Kiltz U, Smolen J, Bardin T, Cohen Solal A, Dalbeth N, Doherty M, et al. Treat-to-target (T2T) recommendations for gout. Ann Rheum Dis. 2017;76(4):632–8. https://doi.org/10.1136/annrheumdis-2016-209467. Treat-to-target recommendations for the management of gout and a future research agenda developed by a task force of international experts based on the results of a systematic literature review. CrossRefPubMed

11.

Solomon DH, Bitton A, Katz JN, Radner H, Brown EM, Fraenkel L. Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis? Arthritis Rheumatol. 2014;66(4):775–82. https://doi.org/10.1002/art.38323.CrossRefPubMedPubMedCentral

12.

Hoerslev-Petersen K, Hetland ML, Oernbjerg LM, Junker P, Poedenphant J, Ellingsen T, et al. Clinical and radiographic outcome of a treat-to-target strategy using methotrexate and intra-articular glucocorticoids with or without adalimumab induction: a 2-year investigator-initiated, double-blinded, randomised, controlled trial (OPERA). Ann Rheum Dis. 2016;75(9):1645–53. https://doi.org/10.1136/annrheumdis-2015-208166.CrossRef

13.

Vermeer M, Kuper HH, Moens HJ, Drossaers-Bakker KW, van der Bijl AE, van Riel PL, et al. Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort. Arthritis Care Res (Hoboken). 2013;65(8):1219–26. https://doi.org/10.1002/acr.21984.CrossRef

14.

Smolen JS, Emery P, Fleischmann R, van Vollenhoven RF, Pavelka K, Durez P, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet. 2014;383(9914):321–32. https://doi.org/10.1016/S0140-6736(13)61751-1.CrossRefPubMed

15.

Coates LC, Moverley AR, McParland L, Brown S, Navarro-Coy N, O’Dwyer JL, et al. Effect of tight control of inflammation in early psoriatic arthritis (TICOPA): a UK multicentre, open-label, randomised controlled trial. Lancet. 2015;386(10012):2489–98. https://doi.org/10.1016/S0140-6736(15)00347-5.CrossRefPubMedPubMedCentral

16.

van Vollenhoven RF, Mosca M, Bertsias G, Isenberg D, Kuhn A, Lerstrom K, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. 2014;73(6):958–67. https://doi.org/10.1136/annrheumdis-2013-205139.CrossRefPubMed

17.

Smolen JS, Braun J, Dougados M, Emery P, Fitzgerald O, Helliwell P, et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis. 2017;77(1):3–17. https://doi.org/10.1136/annrheumdis-2017-211734.CrossRefPubMedPubMedCentral

18.

Manara M, Bortoluzzi A, Favero M, Prevete I, Scirè CA, Bianchi G, et al. Italian Society of Rheumatology recommendations for the management of gout. Reumatismo. 2013;65(1):4–21. https://doi.org/10.4081/reumatismo.2013.4. CrossRefPubMed

19.

• Qaseem A, Harris RP, Forciea MA. Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166(1):58–68. https://doi.org/10.7326/M16-0570. Gout management guidelines released by the American College of Physicians based on grading of evidence from randomised controlled trials, large observational studies and systematic reviews. Found insufficient evidence to support a treat-to-target approach and serum urate monitoring. CrossRefPubMed

20.

Kiltz U, Alten R, Fleck M, Krüger K, Manger B, Müller-Ladner U, et al. Full version of the S2e guidelines on gouty arthritis: evidence-based guidelines of the German Society of Rheumatology (DGRh). Z Rheumatol. 2016;75(S2):11–60. https://doi.org/10.1007/s00393-016-0147-6.CrossRefPubMed

21.

Sakuta H, Suzuki K, Miyamoto T, Miyamoto M, Numao A, Fujita H, et al. Serum uric acid levels in Parkinson’s disease and related disorders. Brain Behav. 2017;7(1):e00598. https://doi.org/10.1002/brb3.598.CrossRefPubMed

22.

Lu N, Dubreuil M, Zhang Y, Neogi T, Rai SK, Ascherio A, et al. Gout and the risk of Alzheimer’s disease: a population-based, BMI-matched cohort study. Ann Rheum Dis. 2016;75(3):547–51. https://doi.org/10.1136/annrheumdis-2014-206917.CrossRefPubMed

23.

Chhana A, Lee G, Dalbeth N. Factors influencing the crystallization of monosodium urate: a systematic literature review. BMC Musculoskelet Disord. 2015;16(1):296. https://doi.org/10.1186/s12891-015-0762-4.CrossRefPubMedPubMedCentral

24.

Allen DJ, Milosovich G, Mattocks AM. Inhibition of monosodium urate needle crystal growth. Arthritis Rheum. 1965;8(6):1123–33. https://doi.org/10.1002/art.1780080611.CrossRefPubMed

25.

Loeb JN. The influence of temperature on the solubility of monosodium urate. Arthritis Rheum. 1972;15(2):189–92. https://doi.org/10.1002/art.1780150209.CrossRefPubMed

26.

Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the normative aging study. Am J Med. 1987;82(3):421–6. https://doi.org/10.1016/0002-9343(87)90441-4.CrossRefPubMed

27.

Bhole V, de Vera M, Rahman MM, Krishnan E, Choi H. Epidemiology of gout in women: fifty-two-year followup of a prospective cohort. Arthritis Rheum. 2010;62(4):1069–76. https://doi.org/10.1002/art.27338.CrossRefPubMed

28.

Shiozawa A, Szabo SM, Bolzani A, Cheung A, Choi HK. Serum uric acid and the risk of incident and recurrent gout: a systematic review. J Rheumatol. 2017;44(3):388–96. https://doi.org/10.3899/jrheum.160452.CrossRefPubMed

29.

Abhishek A, Valdes AM, Zhang W, Doherty M. Association of serum uric acid and disease duration with frequent gout attacks: a case-control study. Arthritis Care Res (Hoboken). 2016;68(10):1573–7. https://doi.org/10.1002/acr.22855.CrossRef

30.

Rashid N, Levy G, Wu Y, Zheng C, Koblick R, Cheetham T. Patient and clinical characteristics associated with gout flares in an integrated healthcare system. Rheumatol Int. 2015;35(11):1799–807. https://doi.org/10.1007/s00296-015-3284-3.CrossRefPubMedPubMedCentral

31.

Shiozawa A, Buysman EK, Korrer S. Serum uric acid levels and the risk of flares among gout patients in a US managed care setting. Curr Med Res Opin. 2017;33(1):117–24. https://doi.org/10.1080/03007995.2016.1239193.CrossRefPubMed

32.

Halpern R, Fuldeore M, Mody R, Patel P, Mikuls T. The effect of serum urate on gout flares and their associated costs: an administrative claims analysis. J Clin Rheumatol. 2009;15(1):3–7. https://doi.org/10.1097/RHU.0b013e3181945d2c.CrossRefPubMed

33.

• Schumacher HR, Becker MA, Lloyd E, MacDonald PA, Lademacher C. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford). 2009;48(2):188–94. https://doi.org/10.1093/rheumatology/ken457. An open-label extension of a 28-day safety and efficacy trial involving febuxostat 80 mg. Dose titrations were subsequently allowed (resulting in doses 40–120 mg) between 1 and 6 months of the study to a target a serum urate < 6.0 mg/dL; achievement of this target occurred in 93% and was associated with a reduced rate of gout flares and increased tophus resolution. CrossRef

34.

• Becker MA, Schumacher HR, Macdonald PA, Lloyd E, Lademacher C. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009;36(6):1273–82. https://doi.org/10.3899/jrheum.080814. An open-label extension study involving 1086 subjects followed up to 40 months after initial randomisation to febuxostat (80 or 120 mg) or allopurinol (300 mg). Over 80% of the febuxostat group achieved a serum urate target < 6.0 mg/dL, which was associated with a reduced rate of gout flares and increased tophus resolution. CrossRefPubMed

35.

Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Bhakta N, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol. 2017;69(9):1903–13. https://doi.org/10.1002/art.40159.CrossRefPubMedPubMedCentral

36.

Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711–20. https://doi.org/10.1001/jama.2011.1169.CrossRefPubMed

37.

Baraf HS, Becker MA, Gutierrez-Urena SR, Treadwell EL, Vazquez-Mellado J, Rehrig CD, 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. 2013;15(5):R137. https://doi.org/10.1186/ar4318.CrossRefPubMedPubMedCentral

38.

Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002;47(4):356–60. https://doi.org/10.1002/art.10511.CrossRefPubMed

39.

Perez-Ruiz F, Martin I, Canteli B. Ultrasonographic measurement of tophi as an outcome measure for chronic gout. J Rheumatol. 2007;34(9):1888–93.PubMed

40.

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. 2007;66(8):1056–8. https://doi.org/10.1136/ard.2006.060368.CrossRefPubMedPubMedCentral

41.

Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450–61. https://doi.org/10.1056/NEJMoa050373.CrossRefPubMed

42.

Schumacher HR, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540–8. https://doi.org/10.1002/art.24209.CrossRefPubMed

43.

Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12(2):R63. https://doi.org/10.1186/ar2978.CrossRefPubMedPubMedCentral

44.

Becker MA, MacDonald PA, Hunt BJ, Lademacher C, Joseph-Ridge N. Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy. Nucleosides Nucleotides Nucleic Acids. 2008;27(6):585–91. https://doi.org/10.1080/15257770802136032.CrossRefPubMed

45.

Saag KG, Fitz-Patrick D, Kopicko J, Fung M, Bhakta N, Adler S, et al. Lesinurad combined with allopurinol: a randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol (a US-based study). Arthritis Rheumatol. 2017;69(1):203–12. https://doi.org/10.1002/art.39840.CrossRefPubMed

46.

Bardin T, Keenan RT, Khanna PP, Kopicko J, Fung M, Bhakta N, et al. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). Ann Rheum Dis. 2017;76(5):811–20. https://doi.org/10.1136/annrheumdis-2016-209213.CrossRefPubMed

47.

Becker MA, Baraf HS, Yood RA, Dillon A, Vázquez-Mellado J, Ottery FD, et al. Long-term safety of pegloticase in chronic gout refractory to conventional treatment. Ann Rheum Dis. 2013;72(9):1469–74. https://doi.org/10.1136/annrheumdis-2012-201795.CrossRefPubMed

48.

Strand V, Khanna D, Singh JA, Forsythe A, Edwards NL. Improved health-related quality of life and physical function in patients with refractory chronic gout following treatment with pegloticase: evidence from phase III randomized controlled trials. J Rheumatol. 2012;39(7):1450–7. https://doi.org/10.3899/jrheum.111375.CrossRefPubMed

49.

Araujo EG, Bayat S, Petsch C, Englbrecht M, Faustini F, Kleyer A, et al. Tophus resolution with pegloticase: a prospective dual-energy CT study. RMD Open. 2015;1(1):e000075. https://doi.org/10.1136/rmdopen-2015-000075.CrossRefPubMedPubMedCentral

50.

•• Stamp LK, Chapman PT, Barclay ML, Horne A, Frampton C, Tan P, 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. 2017;76(9):1522–8. https://doi.org/10.1136/annrheumdis-2016-210872. Participants with gout were randomised to either a treat-to-target serum urate strategy or a fixed dose of allopurinol. Significantly more patients in the treatment group reached the target of < 6.0 gm/dL (69%) compared to controls (32%); this was not associated with improved gout flare rates or tophus reduction at the end of 12 months. CrossRefPubMed

51.

• Stamp LK, Chapman PT, Barclay M, et al. Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study. Ann Rheum Dis 2017:pii:annrheumdis-2017-211873. Doi:https://doi.org/10.1136/annrheumdis-2017-211873. An open-label extension study of a randomised controlled trial involving a treat-to-target serum urate strategy for allopurinol dose escalation. In the initial control group, cross-over to a treat-to-target approach resulted in similar high levels of target serum urate achievement as seen in the original treatment group. Gout flares were significantly reduced over the second 12 months for both treatment groups.

52.

•• Dalbeth N, Saag KG, Palmer WE, Choi HK, Hunt B, MacDonald PA, et al. Effects of febuxostat in early gout: a randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. Accepted Author Manuscript. Doi:https://doi.org/10.1002/art.40233. A randomised controlled trial assessing the efficacy of febuxostat in reducing radiologic damage in early gout. Febuxostat doses were titrated from 40 to 80 mg to target a serum urate of < 6.0 mg/dl (achieved by 62.8%). Febuxostat therapy resulted in a significant reduction in MRI-detected synovitis at 24 months and decreased the overall incidence of gout flares.

53.

•• Doherty M, Jenkins W, Abhishek A, Ashton D, Barclay C, Duley L, et al. Nurse-led care versus general practitioner care of people with gout: a UK community-based randomised controlled trial. Abstract: EULAR 2017, Madrid. 517 patients randomised in a 1:1 ratio to either general practitioner-led care or nurse-led care, the latter involving a treat-to-target serum urate protocol based on the EULAR and BSR guidelines. Results included significantly improved target serum urate achievement, reduction of tophi and gout flare rates in the nurse-led group.

54.

• Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study. Ann Rheum Dis. 2013;72(6):826–30. https://doi.org/10.1136/annrheumdis-2012-201676. A proof-of-concept study demonstrating high rates of adherence and serum urate target achievement after 1 year through a structured approach to urate-lowering therapy escalation, principally under the guidance of nurse specialists. CrossRefPubMed

55.

• Abhishek A, Jenkins W, La-Crette J, Fernandes G, Doherty M. Long-term persistence and adherence on urate-lowering treatment can be maintained in primary care—5-year follow-up of a proof-of-concept study. Rheumatology (Oxford). 2017;56(4):529–33. https://doi.org/10.1093/rheumatology/kew395. A follow-up study to Rees et al (2013). Patients returned to GP care after 1 year and still maintained high rates of adherence and attainment of target serum urate concentrations.

56.

•• Goldfien R, Pressman A, Jacobson A, Ng M, Avins A. A pharmacist-staffed, virtual gout management clinic for achieving target serum uric acid levels: a randomized clinical trial. Perm J. 2016;20(3):18–23. https://doi.org/10.7812/TPP/15-234. A study involving randomization to pharmacist-guided escalation of urate lowering therapy in a treat-to-target serum urate strategy compared to usual care. Significantly higher rates of target serum urate achievement in the treatment group. PubMedPubMedCentral

57.

Perez-Ruiz F, Herrero-Beites AM, Carmona L. A two-stage approach to the treatment of hyperuricemia in gout: the “dirty dish” hypothesis. Arthritis Rheum. 2011;63(12):4002–6. https://doi.org/10.1002/art.30649.CrossRefPubMed

58.

de Lautour H, Taylor WJ, Adebajo A, Alten R, Burgos-Vargas R, Chapman P, et al. Development of preliminary remission criteria for gout using Delphi and 1000Minds consensus exercises. Arthritis Care Res (Hoboken). 2016;68(5):667–72. https://doi.org/10.1002/acr.22741.CrossRef

59.

Scirè CA, Carrara G, Viroli C, Cimmino MA, Taylor WJ, Manara M, et al. Development and first validation of a disease activity score for gout. Arthritis Care Res (Hoboken). 2016;68(10):1530–7. https://doi.org/10.1002/acr.22844.CrossRef

Medicine Matters Rheumatology

Abstract

Purpose of Review

Recent Findings

Summary