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Gout, tophi and kidney disease

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It's challenging to treat patients with gout who also have chronic kidney disease. Here's a review of literature on how to proceed. This happens to be my second PRA convention presentation.

It's challenging to treat patients with gout who also have chronic kidney disease. Here's a review of literature on how to proceed. This happens to be my second PRA convention presentation.


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  • 1. ISSUES IN THE ARTHRITIDESGout, Tophi andKidney DiseaseSIDNEY ERWIN T. MANAHAN, MD, FPCP Rheumatologist 18th PRA Annual Meeting February 5, 2011
  • 2. Session Objectives• Define Complicated Gouty Arthritis• Discuss the Management of Gout in the Background of Chronic Kidney Disease• Enumerate Novel Therapies for Gout
  • 3. Prevalence of Gout in the PH1.8 FACTORS1.6 • Obesity1.4 • Aging Population1.2 • Kidney Failure and Hypertension • Thiazides and Aspirin 1 • Beer Consumption0.80.60.4 Manahan L, et al Rheum Int 1985 Dans LF, et al J Rheum 19970.2 Dans LF, et al. PJIM 2006 Edwards NL Arth Rheum 2008 0 COPCORD 1985 COPCORD 1997 NNHeS 2003
  • 4. Relationship between Gout & CKD Frequency Annual Time Period Male Female FlaresRenal Function >2 years 15.4% 4.1% 2.0 + 4.2 pre-HDInflammatory Cytokines <2 years 7.7% 0.6% 1.9 + 6.6 pre-HD <2 years 3.4% None 0.2 + 0.7 Acute Gout post HD >2 years 1.2% None 0.1 + 0.6 post HD Iwao O, et al. Int Med. 2005 Schreider O, et al. Nephro Dial Trans. 2000
  • 5. Complicated GoutRisk Factors for Complications SUA 11 + 2 mg/dl  Upper extremity involvement Early Onset Gout  Polyarticular flares Flares >4/ year  Prolonged steroid use Long periods of untreated gout Nakayama A, et al. 1984; Raso AA, et al. 2009 Vazques Mellado J, J Rheum 1999
  • 6. Complicated GoutTreatment Failure Gout (TFG)Symptomatic Gout• Intolerance to urate lowering therapies (ULT)• Refractory to maximal doses of ULTFeatures• Presence of complications• Impaired QOL and chronic disability• Significant co-morbid conditions• Polypharmacy and drug interactions Edwards HL, Arth Rheum 2008 Terkeltaub R. Arth Res Ther 2009.
  • 7. Gout in Renal DiseaseTerminate attacks• Steroids• ACTH• Colchicine• NSAIDs / COXIBsPrevent flares• Colchicine• NSAIDPrevent/ Reverse complications• Urate Lowering Therapies El-Zawawy H, Mandell BF, Cleveland Clin J Med. 2010
  • 8. Steroids in GoutIndications• Acute Gout• Not for ProphylaxisRecommended Doses• Prednisone 20-50 mg over mean of 10 days• Prednisone 30 mg single dose on Day 1, taper dose by 5 mg daily and discontinue by Day 7 Li-Yu J, et al. Phil J Int Med 2008• ACTH 25 IU IM for monoarthritis• ACTH 40 IU IM for polyarthritis El-Zawawy H, Mandell B. Cleveland Clin J Med 2010
  • 9. Colchicine in GoutIndications• 6 months from achieving target SUA• Attacks continue• Persistent tophiRecommended DosesCrea Cl > 50 ml/min 0.6 – 1.8 mg/day 35-49 ml/min 0.6 mg/day 10-34 ml/min 0.6 mg q 2-3 days < 10 ml/min CAUTIONMonitor CK-MM, LFTs if CrCl < 50 ml/min Wallace S, et al. J Rheumatol 1991 El-Zawawy H, Mandell B. Cleveland Clin J Med 2010
  • 10. Colchicine in GoutContraindications• Creatinine Clearance < 10 ml/min• Patients undergoing hemodialysis• Significant hepatic disease• Combined hepatic and renal diseaseDrug Interactions• Macrolides (i.e. Clarithromycin)• Statins (i.e Pravastatin)• Ketoconazole• Cyclosporin El-Zawawy H, Mandell B. Cleveland Clin J Med 2010
  • 11. Preventing Complications Target Serum uric acid <6 mg/dl Li Yu J, Salido E, et al. PJIM. 2008; Zhang W, Doherty M, et al. Ann Rheum Dis. 2006Benefits of Achieving Target SUA• Reduction in flares• Reduction in tophus size• Retarded decline in GFR Li Yu J, Salido E, et al. PJIM. 2008; Zhang W, Doherty M, et al. Ann Rheum Dis. 2006; Li Yu J, et al. J Rheum 2001; Shoji A, et al. Arth Rheum 2004; Gibson T, et al. Ann Rheum Dis 1982
  • 12. Reversing ComplicationsP – 63 CTG patients treated with ULTI – Allopurinol, Benzbromarone or bothM – Observational study Average SUA Levels Rate of Tophus Reduction 6.1 – 7.0 mg/dl 0.53 + 0.59 mm/mo 5.1 – 6.0 mg/dl 0.77 + 0.41 mm/mo 4.1 – 5.0 mg/dl 0.99 + 0.50 mm/mo <4.0 mg/dl 1.52 + 0.67 mm/mo Perez Ruiz F, et al. Arthritis Rheum 2002
  • 13. Reversing ComplicationsTarget SUA 3-5mg/dl in those with massive or numerous tophi Schumacher HR, Am J Med. 1996 Perez Ruiz F, et al. Arth Rheum. 2002 Jordan K, et al. Rheumatol 2007 Herschfield M. Curr Opin Rheum 2009 Diseases Associated with Increased Uric Acid Reduced Uric Acid Gout Multiple Sclerosis Kidney Disease Parkinson’s Disease Hypertension Alzheimer’s Disease Cardiovascular Dse Optic Neuritis Kutzing M, et al. J Pharma Exp Therap 2008
  • 14. Urate Lowering Therapies Uricosurics • Probenecid • Sulfinpyrazone • BenzbromaroneULT Indications • RDEA594• At least 2 Gout Flares• Tophaceous Deposits XO Inhibitors• Arthropathy • Allopurinol• Nephrolithiases • Febuxostat• Difficult to treat attacks Urate Oxidase • Rasburicase • Pegloticase
  • 15. Allopurinol in Renal Disease Maximum Recommended AllopurinolDecline in Renal Function Dose Based on Crea Clearance Crea Cl (ml/min) Dose 0 100 mg q 3 days Inc Allopurinol Half-life 10 100 mg q 2 days 20 100 mg/day 40 150 mg/dayDec Oxypurinol Clearance 60 200 mg/day 80 250 mg/day 100 300 mg/day 120 350 mg/dayIncrease in Adverse Events Hande KR, et al. Am J Med, 1984
  • 16. Allopurinol in Renal DiseaseP – 120 Gout patients receiving AllopurinolI – Allopurinol in prescribed renally-adjusted doses vs Allopurinol in higher than usual dosesO – Incidence of Adverse EventsM – Retrospective CONCLUSION Frequency of adverse events were SIMILAR between groups Vasquez-Mellado J, et al.Ann Rheum Dis 2002
  • 17. Allopurinol in Renal DiseaseP – 250 Gout patients with Crea Cl 12-130 ml/minI – (A) Allopurinol in prescribed renally-adjusted doses vs. (B) Allopurinol in higher than usual dosesO – Incidence of Adverse Events No. of pateints achieving SUA <6mg/dlM – RetrospectiveRESULTS/ CONCLUSIONS• 4 had hypersensitivity reactions• 19% of Group A achieved target SUA• 38.1% of Group B achieved target SUA Dalbeth N, et al. J Rheum 2006 Perez Ruiz F, et al. J Clin Rheum 1999
  • 18. Allopurinol in Renal Disease Patients achieving SUA <6mg/dl Study Normal Renal FailureFACT 2005 53/251 (21%) -----APEX 2008 60/268 (22%) 0/10CONFIRMS 2010 106/254 (42%) 212/501 (42%)CONCLUSION• Adherence to renal-dosing guidelines lead to SUB-OPTIMAL treatment of hyperuricemia
  • 19. Allopurinol in Renal Disease Treat to Max Allopurinol based on Renal Function TREAT TO TARGETRECOMMENDATION• Initial dose of Allopurinol based on Crea Clearance• Titrate up by 50-100 mg/day every 2-4 weeks• Target SUA 3-5 mg/dl
  • 20. GOUT, TOPHI AND KIDNEY DISEASENEW DRUGS IN GOUT
  • 21. Febuxostat: A Novel XOI• Non-purine Xanthine Oxidase Inhibitor• Commercial availability – 2008 Europe – 2009 United States• Clinical Trials – Febuxostat against Allopurinol Controlled Trial (FACT), 2005 – Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX), 2008 – Comparing Efficacy And Safety of Daily Febuxostat and Allopurinol in Patients with Gout (CONFIRMS), 2010 – Febuxostat Open Label Clinical Trial of Urate Lowering Efficacy and Safety (FOCUS), 2009
  • 22. Febuxostat Patients achieving SUA < 6mg/dl for 3 consecutive months Study FEBUXOSTAT ALLOP 40mg 80mg 120mg 240mgFACT 2005 53% 62% 21%APEX 2008 76% 87% 94% 41%CONFIRMS 2010 45.2% 67.1% 42.1%CONFIRMS RD 49.7% 71.6% 42.3%FOCUS 2009 100% 82% 81%OBSERVATION: Patients receiving Febuxostat were able to achieveSUA <4 mg/dl and 5 mg/dl. Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008 Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009
  • 23. Febuxostat Patients suffering a gout flare Study FEBUXOSTAT ALLOP 40mg 80mg 120mg 240mgFACT 2005 64% 70% 64%APEX 2008 10-15%CONFIRMS 2010 <5% <5% <5%CAVEAT: Similar proportions of patients between groupsexperienced gout flares during treatment. Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008 Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009
  • 24. REDUCTION IN TOPHUS SIZE• FACT and APEX – no statistically significant difference in mean reduction of tophus size in between groups Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008 Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009
  • 25. Febuxostat ADVERSE EVENTS Study FEBUXOSTAT ALLOP 40mg 80mg 120mg 240mgFACT 2005 25% 24% 23% (4%) (8%) (8%)APEX 2008 68% 68% 73% 75% (4%) (3%) (4%) (3%)CONFIRMS 2010 56.7% 54.2% 57.3% (2.5%) (3.7%) (4.1%)ADVERSE EVENTS – abnormal LFT, diarrhea and rashesSERIOUS AE – abnormal LFT, cardiovascular events Becker M, et al. NEJM 2005; Schumacher HR, et al. Arth Rheum 2008 Becker M, et al. Arth Res Ther 2010; Schumacher HR, et al. Rheum 2009
  • 26. Uricase• Concept of using urate oxidase (uricase) since 1981• Concerns regarding uricase development – Short half-life – Risk of immunologic reactions – G6 PD Deficiency
  • 27. PegloticaseRESPONSE TO ADMINISTRATION• DOSE: 8 mg infused over 2 hours q 2-4 weeks• All patients achieve SUA<2mg/dl after 1st infusion• Persistent Responders – Sustained reduction in SUA <6mg/dl• Transient Responders – Initial SUA <6mg/dl but later increased to >6mg/dl – Infusion reactions – Development of Anti-pegloticase IgM and IgG – Coincided with 3rd or 4th infusion Reinders M, et al. Ther Clin Risk Mngt. 2010
  • 28. PegloticaseGout Outcome and Urate Therapy (GOUT)TREATMENT FAILURE GOUT• >3 flares in previous 18 months• >1 tophus• Documented arthropathy• SUA >8 mg/dl• Contra-indications to Allopurinol• Failure to achieve target SUA with maximum medically appropriate doses of Allopurinol
  • 29. Pegloticase Reduction in SUA <6mg/dlTreatment GOUT 1 GOUT 2 Combined8mg q 2 weeks 46.5% 38.1% 42.3%8 mg q 4 weeks 19.5% 48.8% 34.5%Placebo 0 0 0Treatment Flares Tophus8mg q 2 weeks 77% 40.4%8 mg q 4 weeks 81% 21.2%Placebo 54% 0
  • 30. Pegloticase Adverse EventsTreatment SAE IR Abs8mg q 2 weeks 24% 26% 88%8 mg q 4 weeks 23% 41% 89%Placebo 12%Most Common Adverse Events• Flares• Infusion ReactionsOther Concerns• Higher rate of serious adverse events• Infusion reactions• Immunogenicity
  • 31. RDEA594• Uricosuric drug• Selectively inhibits URAT1• Maintains efficacy even in moderate renal insufficiency• Enhances urate lowering effects of Febuxostat and Allopurinol• No identified adverse events in Phase II and case series
  • 32. COMBINATION THERAPYALLOPURINOL Combination of Allopurinol and SulfinpyrazoneSerum Urate Production • Diminution of SUAUrine Urate Excretion • Rapid softening & dissolution of tophi • Cessation of renal stone formation Kuzell W, et al. Ann Rheum Dis 1966URICOSURICS Combination of Allopurinol and BenzbromaroneUrine Urate Excretion • Lowered SUA in patients with renal dysfunction • Lower doses of both drugs were used • Reduced serum Oxypurinol levelsUrine Urate Excretion Ohno I, et al. Nippon Jinzo Gakkai. 2008Serum Urate Production
  • 33. Biologics in Gout• P – 10 Patients with Treatment Failure Gout• I – Rilonacept 320 mg SC initially then 160 mg SC q weekly• M – Proof of Concept Study Terkeltaub R, et al. Ann Rheum Dis 2009
  • 34. PROPOSED APPROACH TO Gout Patients with Indication for ULT URATE LOWERING THERAPY IN GOUT Start ALLOPURINOL TREATEMENT FAILURE (TF) to Allopurinol and Titrate up Intolerance/ ADR Shift to to Allopurinol FEBUXOSTAT ??Consider Combination TxStart Sulfinpyrazone and Titrate up INTOLERANCE or Consider Tophi-Debulking Therapy TF to Sulfinpyrazone with Pegloticase Adapted from Terkeltaub R. Nat Rev Rheum 2010
  • 35. Summary• Defined Complicated Gouty Arthritis as – Presence of Complications – Treatment Failure Gout• Managing Gout in Patients with Chronic Kidney Disease – Reviewed Treatment Goals – Discussed Differences in Medications used• Enumerated Novel Therapies for Gout• Proposed an Algorithm to Treat Gout/ Hyperuricemia
  • 36. Thank You! Philrheumajr.blogspot.com