Table 1.

Status of Agents Available or in Development for Urate Lowering in Gout

Terkeltaub RA. Gout. N Engl J Med 2003; 349:1647-1655.
Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann RL. Increasing prevalence of gout and hyperuricemia among older adults in a managed care population. J Rheumatol 2004; 31:1582-1587.
Arromdee E, Michet C, Crowson CS, et al. Epidemiology of gout: is the incidence rising? J Rheumatol 2002; 29:2403-2406.
Choi H. Epidemiology of crystal arthropathy. Rheum Dis Clin North Am 2006; 32:255-273.
Roddy E, Zhang W, Doherty M. The changing epidemiology of gout. Nat Clin Pract Rheumatol 2007; 3:443-449.
Kramer HM, Curhan G. The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994. Am J Kidney Dis 2002; 40:37-42.
Perez- Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia: a pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 1998; 57:545-549.
Zhang W, Doherty M, Bardin T, et al. EULAR evidence based recommendations for gout. Part II: management. Report of a task force of the EULAR standing committee for international clinical studies including therapeutics (ESCISIT). Ann Rheum Dis 2006; 65:1312-1324.
Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 2005; 52:916-923.
Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005; 353:2450-2461.
• Schumacher HR, Becker MA, Wortmann RL, 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 Arthritis Care Res 2008; 59:1540-1548. This report documents the urate-lowering superiority of febuxostat (80 and 120 mg) relative to allopurinol (300 mg) and placebo in a 6-month trial. Safety of the agents was compared.
• Jordan KM, Cameron JS, Snaith M, et al. British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology 2007; 46:1372-1374.
• Reinders MK, van Roon EN, Jansen TL, et al. Efficacy and tolerability of urate lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis 2009; 68:51-56.
•• Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose-escalation of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day in patients with gout. Ann Rheum Dis 2008. [Epub ahead of print] This is the sole RCT addressing the safety and efficacy of allopurinol at a dose exceeding 300 mg/day.
Becker M, Chohan S. Can we make gout management more successful now? Curr Opin Rheumatol 2008; 20:167-172.
Lee SJ, Terkeltaub RA, Kavanaugh A. Recent developments in diet and gout. Curr Opin Rheumatol 2006; 18:193-198.
Sarawate CA, Brewer KK, Yang W, et al. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc 2006; 81:925-934.
Hak AE, Choi HK. Lifestyle and gout. Curr Opin Rheumatol 2008; 20:179-186.
Huang H, Appel JL, Choi MJ, et al. The effects of vitamin C supplementation on serum concentrations of uric acid. Arthritis Rheum 2005; 52:1843-1847.
Becker MA, Jolly M. Hyperuricemia and associated diseases. Rheum Dis Clin North Am 2006; 32:275-293.
Enomoto A, Kimura H, Chairoungdu A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417:447-452.
Lee MH, Graham GG, Williams KM, et al. A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interests of patients? Drug Saf 2008; 31:643-665.
Takahashi S, Moriwaki Y, Yamamoto T, et al. Effects of combination treatment using antihyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis 2003; 62:572-575.
Riedel AA, Nelson M, Wallace K, et al. Prevalence of comorbid conditions and prescription medication use among patients with gout and hyperuricemia in a managed care setting. J Clin Rheumatol 2004; 10:308-314.
Sarawate CA, Patel PA, Schumacher HR, et al. Serum urate levels and gout flares: analysis from managed care data. J Clin Rheumatol 2006; 12:61-65.
Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacol 1993; 27:337-343.
Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity: description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984; 76:47-56.
• Dalbeth N, Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. Semin Dial 2007; 20:391-395.
Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004; 31:2429-2432.
Becker MA, Kisicki J, Khosravan R, et al. Febuxostat (TMX-67), a novel, nonpurine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers. Nucleosides Nucleotides Nucleic Acids 2004; 23:1111-1116.
Hoshide S, Nishimura S, Ishii S, et al. Metabolites of TMX-67, a new pharmaceutical entity for the treatment of gout or hyperuricemia, and their pharmacokinetic profiles in humans. Drug Metab Rev 2003; 32(Suppl 2):269.
Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel nonpurine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 2005; 76:1835-1847.
Mayer MD, Khosravan R, Vernillet L, et al. Pharmacokinetics and pharmacodynamics of febuxostat, a new selective nonpurine inhibitor of xanthine oxidase, in subjects with renal impairment. Am J Ther 2005; 12:22-34.
Becker MA, Schumacher HR Jr, Espinosa L, et al. A phase 3 randomized, controlled, multicenter, double-blind trial comparing efficacy and safety of daily febuxostat (FEB) and allopurinol (ALLO) in subjects with gout [abstract]. Arthritis Rheum 2008; 58:4029-4029.
Schumacher HR Jr, Becker MA, Lloyd E, et al. Febuxostat in the treatment of gout: five-year findings of the FOCUS efficacy and safety study. Rheumatology 2009; 48:188-194.
Becker MA, Schumacher HR Jr, MacDonald PA, et al. Clinical efficacy and safety of successful long-term urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol (in press).
Edwards NL. Treatment-failure gout: a moving target. Arthritis Rheum 2008; 58:2587-2590 [editorial].
Ganson NJ, Kelly SJ, Scarlett E, et al. Control of hyperuricemia in refractory gout, and induction of antibody against poly(ethylene) glycol(PEG), in a phase 1 trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther 2006; 8:R12.
Sundy JS, Ganson NJ, Kelly SJ, et al. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum 2007; 56:1021-1028.
•• Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout. Arthritis Rheum 2008; 58:2882-2891.
Sundy JS, Baraf HS, Becker MA, et al. Efficacy and safety of intravenous (IV) pegloticase (PGL) in subjects with treatment failure gout (TFG): results from GOUT 1 and GOUT2 [abstract]. Arthritis Rheum 2008; 58:S400-S401.
Baraf HS, Becker MA, Edwards NL, et al. Tophus response to pegloticase (PGL) therapy: pooled results of GOUT1 and GOUT2 PGL phase 3 randomized, doubleblind, placebo-controlled trials [abstract]. Arthritis Rheum 2008; 58:S176.
Edwards NL, Baraf HS, Becker MA, et al. Improvement in health-related quality of life (HRQL) and disability index in treatment failure gout (TFG) after pegloticase (PGL) therapy: pooled results from GOUT1 and GOUT2, phase 3 randomized, double blind, placebo (PBO)-controlled trials [abstract]. Arthritis Rheum 2008; 58:S178.
Becker MA, Treadwell EL, Baraf HS, et al. Immunoreactivity and clinical response to pegloticase (PGL): pooled data from GOUT1 and GOUT2, PGL phase 3, randomized: double blind, placebo controlled trials [abstract]. Arthritis Rheum 2008; 58:S880.

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Author(s)

Saima Chohan, MD

Rheumatology Section, Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois

Disclosures

Disclosure: Saima Chohan, MD, has disclosed no relevant financial relationships.

Michael A. Becker, MD

Rheumatology Section, Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois

Disclosures

Disclosure: Michael A. Becker, MD, has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD, FAAFP

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosures

Disclosure: Charles P. Vega, MD, FAAFP, has disclosed no relevant financial relationships.

Editor(s)

John Sundy, MD, PhD

Section Editor, Current Opinion in Rheumatology

Disclosures

Disclosure: John Sundy, MD, PhD, has disclosed that he has received grants for clinical research from and has served as an advisor or consultant to Savient Pharmaceuticals, Inc.; Arden Biosciences; and Regeneron Pharmaceuticals, Inc. Dr. Sundy has also disclosed that he has served as an advisor or consultant to Array BioPharma and Takeda Pharmaceuticals North America, Inc. and has received grants for clinical research from Genentech, Inc.

Mary Windle, PharmD, FACCP

Site Editor, Medscape Rheumatology; Pharmacy Editor, eMedicine; Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Omaha, Nebraska

Disclosures

Disclosure: Mary Windle, PharmD, FACCP, has disclosed that she owns stock with Pfizer Inc. and Avanir Pharmaceuticals.

CME

Update on Emerging Urate-Lowering Therapies

Authors: Saima Chohan, MD; Michael A. Becker, MD
CME Released: 8/7/2009
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 8/7/2010

Start Activity

Target Audience and Goal Statement

This activity is intended for primary care physicians, rheumatologists, and other physicians who care for patients with gout.

The goal of this activity is to review the current treatment of and 2 new medications for gout.

Upon completion of this activity, participants will be able to:

Describe patterns in the use of established treatments for gout and the efficacy of these medications
Identify the mechanism of action and efficacy of febuxostat
Specify adverse events more common with febuxostat compared with allopurinol
Describe outcomes of a phase 3 trial of pegloticase in the treatment of gout

Disclosures

Author(s)

Saima Chohan, MD

Rheumatology Section, Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois

Disclosures

Disclosure: Saima Chohan, MD, has disclosed no relevant financial relationships.

Michael A. Becker, MD

Rheumatology Section, Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois

Disclosures

Disclosure: Michael A. Becker, MD, has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD, FAAFP

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosures

Disclosure: Charles P. Vega, MD, FAAFP, has disclosed no relevant financial relationships.

Editor(s)

John Sundy, MD, PhD

Section Editor, Current Opinion in Rheumatology

Disclosures

Disclosure: John Sundy, MD, PhD, has disclosed that he has received grants for clinical research from and has served as an advisor or consultant to Savient Pharmaceuticals, Inc.; Arden Biosciences; and Regeneron Pharmaceuticals, Inc. Dr. Sundy has also disclosed that he has served as an advisor or consultant to Array BioPharma and Takeda Pharmaceuticals North America, Inc. and has received grants for clinical research from Genentech, Inc.

Mary Windle, PharmD, FACCP

Site Editor, Medscape Rheumatology; Pharmacy Editor, eMedicine; Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Omaha, Nebraska

Disclosures

Disclosure: Mary Windle, PharmD, FACCP, has disclosed that she owns stock with Pfizer Inc. and Avanir Pharmaceuticals.

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Abstract and Introduction

Abstract

Purpose of Review: To discuss currently available urate-lowering therapeutic options for gout in the United States and newer therapeutic initiatives in development.
Recent Findings: Currently available urate-lowering drugs include allopurinol and probenecid. These drugs are effective but are often underdosed or underutilized, and caution must be taken in patients with multiple comorbidities. Newer therapeutic agents in development include febuxostat, a nonpurine analogue xanthine oxidase inhibitor, and pegloticase, a pegylated recombinant uricase.
Summary: There have been no new US Food and Drug Administration-approved urate-lowering drugs for gout in the past 40 years. Recent advances in therapeutics promise to provide the opportunity for much needed improvement in patient outcomes in this disorder.

Introduction

Gout is the most common form of inflammatory arthritis in men, affecting 1-2% of adult men in Western countries^[1] and an increasing number of postmenopausal women.^[2] Several recent reports document increases in the incidence^[3-5] and prevalence^[2,4-6] of gout in the last few decades. There is consensus and evidence for the view that achievement and maintenance of serum urate levels (sUAs) below the limit of urate solubility in extracellular fluids (6.8 mg/dl) are necessary for long-term success in treatment of patients with persistent or progressive gouty symptoms. In accord with these aims, goal ranges adopted for sUA maintenance in clinical studies and evidence-based guidelines have included less than 6.0 mg/dl^[7-10,11•] and the more stringent less than 5.0 mg/dl levels.^{[12•,13•,14••]}

Potent urate-lowering agents, effective in many gout patients, have been available for many years, but recent reports of suboptimal clinical outcomes in many current gout patients suggest that contemporary use of urate-lowering therapeutic options has not kept pace.^[15-17] In response to this medical need, multiple urate-lowering initiatives have been launched with the aim of reducing clinical expression and progression of the disease. Here, we review the limitations of current urate-lowering treatment options and two promising new therapeutic agents.

Page 1 of 4

Current Urate-lowering Management

CME Information

References

References

Disclaimer

The material presented here does not necessarily reflect the views of MedscapeCME or companies that support educational programming on www.medscapecme.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

Table 1.

References

Faculty and Disclosures

Author(s)

Saima Chohan, MD

Michael A. Becker, MD

CME Author(s)

Charles P. Vega, MD, FAAFP

Editor(s)

John Sundy, MD, PhD

Mary Windle, PharmD, FACCP

CME

Update on Emerging Urate-Lowering Therapies

Target Audience and Goal Statement

Disclosures

Author(s)

Saima Chohan, MD

Michael A. Becker, MD

CME Author(s)

Charles P. Vega, MD, FAAFP

Editor(s)

John Sundy, MD, PhD

Mary Windle, PharmD, FACCP

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Update on Emerging Urate-Lowering Therapies

Abstract and Introduction

Abstract

Introduction

Table of Contents