Effects of Febuxostat in Early Gout: A Randomized, Double-Blind, Placebo-Controlled Study

Nicola Dalbeth, Kenneth G Saag, William E Palmer, Hyon K Choi, Barbara Hunt, Patricia A MacDonald, Ulrich Thienel, Lhanoo Gunawardhana, Nicola Dalbeth, Kenneth G Saag, William E Palmer, Hyon K Choi, Barbara Hunt, Patricia A MacDonald, Ulrich Thienel, Lhanoo Gunawardhana

Abstract

Objective: To assess the effect of treatment with febuxostat versus placebo on joint damage in hyperuricemic subjects with early gout (1 or 2 gout flares).

Methods: In this double-blind, placebo-controlled study, 314 subjects with hyperuricemia (serum uric acid [UA] level of ≥7.0 mg/dl) and early gout were randomized 1:1 to receive once-daily febuxostat 40 mg (increased to 80 mg if the serum UA level was ≥6.0 mg/dl on day 14) or placebo. The primary efficacy end point was the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint. Additional efficacy end points included change from baseline to month 24 in the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) scores for synovitis, erosion, and edema in the single affected joint, the incidence of gout flares, and serum UA levels. Safety was assessed throughout the study.

Results: Treatment with febuxostat did not lead to any notable changes in joint erosion over 2 years. In both treatment groups, the mean change from baseline to month 24 in the modified Sharp/van der Heijde erosion score for the single affected joint was minimal, with no between-group differences. However, treatment with febuxostat significantly improved the RAMRIS synovitis score at month 24 compared with placebo treatment (change from baseline -0.43 versus -0.07; P <0.001), decreased the overall incidence of gout flares (29.3% versus 41.4%; P < 0.05), and improved serum UA control (62.8% versus 5.7%; P < 0.001). No major safety concerns were reported.

Conclusion: Urate-lowering therapy with febuxostat improved magnetic resonance imaging-determined synovitis and reduced the incidence of gout flares in subjects with early gout.

Trial registration: ClinicalTrials.gov NCT01078389.

© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1
Figure 1
Study design and subject disposition. * = Of the 157 subjects randomized to receive febuxostat 40 mg once daily, 60 required a dosage increase to 80 mg once daily at month 1.
Figure 2
Figure 2
Change from baseline in the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring synovitis score. Values are the mean ± SD. * = P = 0.025; † = P < 0.001.
Figure 3
Figure 3
Percentage of subjects with at least 1 gout flare. * = P < 0.05; † = P < 0.01 versus placebo, by Fisher's exact test.

References

    1. Pascual E, Batlle‐Gualda E, Martinez A, Rosas J, Vela P. Synovial fluid analysis for diagnosis of intercritical gout. Ann Intern Med 1999;131:756–9.
    1. Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al. 2015 gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol 2015;67:2557–68.
    1. 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;64:1431–46.
    1. Qaseem A, Harris RP, Forciea MA, for the Clinical Guidelines Committee of the American College of Physicians . Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2017;166:58–68.
    1. Barthelemy CR, Nakayama DA, Carrera GF, Lightfoot RW Jr, Wortmann RL. Gouty arthritis: a prospective radiographic evaluation of sixty patients. Skeletal Radiol 1984;11:1–8.
    1. Dalbeth N, Clark B, Gregory K, Gamble G, Sheehan T, Doyle A, et al. Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography. Ann Rheum Dis 2009;68:1290–5.
    1. Popovich I, Dalbeth N, Doyle A, Reeves Q, McQueen FM. Exploring cartilage damage in gout using 3‐T MRI: distribution and associations with joint inflammation and tophus deposition. Skeletal Radiol 2014;43:917–24.
    1. Eason A, House ME, Vincent Z, Knight J, Tan P, Horne A, et al. Factors associated with change in radiographic damage scores in gout: a prospective observational study. Ann Rheum Dis 2016;75:2075–9.
    1. Chowalloor PV, Siew TK, Keen HI. Imaging in gout: a review of the recent developments. Ther Adv Musculoskelet Dis 2014;6:131–43.
    1. Carter JD, Kedar RP, Anderson SR, Osorio AH, Albritton NL, Gnanashanmugam S, et al. An analysis of MRI and ultrasound imaging in patients with gout who have normal plain radiographs. Rheumatology (Oxford) 2009;48:1442–6.
    1. Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yü TF. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977;20:895–900.
    1. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247–54.
    1. Dalbeth N, Clark B, McQueen F, Doyle A, Taylor W. Validation of a radiographic damage index in chronic gout. Arthritis Rheum 2007;57:1067–73.
    1. Ostergaard M, Peterfy C, Conaghan P, McQueen F, Bird P, Ejbjerg B, et al. OMERACT rheumatoid arthritis magnetic resonance imaging studies: core set of MRI acquisitions, joint pathology definitions, and the OMERACT RA‐MRI scoring system. J Rheumatol 2003;30:1385–6.
    1. HUMIRA™ (adalimumab) prescribing information . North Chicago: Abbott Laboratories; 2002. URL: .
    1. Hench PS. Diagnosis and treatment of gout and gouty arthritis. JAMA 1941;116:453–9.
    1. Breedveld FC, Emery P, Keystone E, Patel K, Furst DE, Kalden JR, et al. Infliximab in active early rheumatoid arthritis. Ann Rheum Dis 2004;63:149–55.
    1. Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two‐year radiographic and clinical outcomes. Arthritis Rheum 2002;46:1443–50.
    1. Carter JD, Patelli M, Anderson SR, Prakash N, Rodriquez EJ, Bateman H, et al. An MRI assessment of chronic synovial‐based inflammation in gout and its correlation with serum urate levels. Clin Rheumatol 2015;34:345–51.
    1. McQueen FM, Doyle A, Reeves Q, Gao A, Tsai A, Gamble GD, et al. Bone erosions in patients with chronic gouty arthropathy are associated with tophi but not bone oedema or synovitis: new insights from a 3 T MRI study. Rheumatology (Oxford) 2014;53:95–103.
    1. Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease‐modifying antirheumatic drug–induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006;54:3761–73.
    1. 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:R63.
    1. 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;353:2450–61.
    1. Schumacher HR Jr, 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;59:1540–8.
    1. 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;27:585–91.
    1. 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;166:58–68.
    1. 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;36:1273–82.
    1. Schumacher HR Jr, 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;48:188–94.
    1. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castañeda‐Sanabria J, et al. 2016 updated EULAR evidence‐based recommendations for the management of gout. Ann Rheum Dis 2017;76:29–42.

Source: PubMed

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