11/9/2011. DISCLOSURES: Robert Terkeltaub MD ACR Gout Guidelines Task Force Preliminary Recommendations: GRANT SUPPORT: VA, NIH

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1 2011 R Gout Guidelines Task Force Preliminary Recommendations: MNGEMENT OF GOUT: URTE-LOWERING THERPY (ULT) HRONI TOPHEOUS GOUTY RTHROPTHY Robert Terkeltaub, MD VM/University of alifornia San Diego DISLOSURES: Robert Terkeltaub MD GRNT SUPPT: V, NIH ONSULTNT: Takeda, Savient, RDE, Bioryst, URL, Regeneron, Novartis, Pfizer, Metabolex, Nuon, hugai, janta, Prescription Solutions SPEKER: None GOUT SE SENRIOS: To replicate mild, moderate, severe in-office presentations of gout (# s 1-6: intermittent symptoms without and with tophi; # s 7-9: chronic tophaceous gouty arthropathy) NOT DISESE LSSIFITION SHEME Symptoms Intermittent symptoms Intermittent symptoms Tophus or Tophi detected on Physical Exam Frequency SE SENRIO NO Infrequent Symptoms (< 1 attack/yr) 1 NO Frequent Symptoms (2-6 attacks/yr) 2 NO Very Frequent Symptoms (> 7 attacks/yr) 3 YES Infrequent Symptoms (< 1 attack/yr) 4 YES Frequent Symptoms (2-6 attacks/yr) 5 YES Very Frequent Symptoms (> 7 attacks/yr) 6 hronic Tophaceous Gouty rthropathy: SE SENRIOS Disease Severity Mild Moderate Severe Stable disease haracteristics Simple chronic tophaceous gouty arthropathy ffecting 1 joint Stable disease Simple chronic tophaceous gouty arthropathy ffecting 2-4 joints hronic tophaceous gouty arthropathy of >4 joints 1 unstable, complicated, severe articular tophus or tophi SE SENRIO

2 SE SENRIOS: MILD hronic Tophaceous Gouty rthropathy Stable, simple tophus limited to one joint (Scenario #7) Lack of drainage Lack of aggressive connective tissue mass or destructive effects Lack of high risk of infection Stable in size, or slow growth Lack of severe chronic, tophaceous joint inflammation MODERTE hronic Tophaceous Gouty rthropathy Stable, simple tophi affecting 2-4 joints (Scenario #8) SE SENRIOS: SEVERE hronic Tophaceous Gouty rthropathy: Numerous, omplicated, or Unstable Tophi (Scenario #9) Tophi affecting more than 4 joints One or more Tophi demonstrating Drainage ggressive mass or connective tissue destructive effects High risk of infection Very rapid growth Severe, chronic tophaceous joint inflammation Summary of Gout Management Options and Objectives in Varying Disease Severity ase Scenarios 1-9 Measure Diet, alcohol, weight management, and co-morbidity and medication review No tophi on exam SE SENRIOS Intermittent Symptoms >1Tophi detected on exam TG Target serum urate should be lowered sufficiently to improve signs and symptoms of gout PHRMOLOGI ULT First line: SINGLE GENT XOI titrated to maximum appropriate dose (lternative: Probenecid) serum urate target not achieved ombination L XOI+URIOSURI ULT at maximum appropriate doses serum urate target not achieved PEGLOTISE Finding of a tophus or tophi on imaging study, or KD Stage 2-5, or ESRD, are appropriate indications for first line pharmacologic ULT in Scenario 1. Failure of combination XOI and uricosuric therapy at maximum appropriate doses is an acceptable indication for consideration of Pegloticase therapy in Scenario 5. Outline of preliminary gout management recommendations: Diagnostic, Imaging, o-morbidity onsiderations General Management Principles for all Patients ULT Domain Principles of Non-pharmacologic and Pharmacologic ULT pproach to Refractory Disease hronic Tophaceous Gouty rthropathy Domain 2

3 Summary Preliminary Recommendations in Diagnosis of Gout that Impact on Therapy The diagnosis of gout should be definitive before initiation of ULT in all case scenarios High Resolution Ultrasound: Preliminary Recommendation as Imaging pproach in Gout DOUBLE ONTOUR SIGN : ccepted by TFP as evidence for urate crystal deposition Recommended measures for diagnosis of gout extend beyond clinical classification criteria, synovial fluid aspiration/crystal analysis PROXIML DISTL Particular focus of the panel: High Resolution Ultrasound Image of a big toe with a double contour sign attached (dorsal long axis view) Image provided by Dr. Ralf Thiele, University of Rochester Preliminary Recommendations on Imaging Measures in Supporting Diagnosis of Gout and with the Potential to Impact on Therapy High resolution ultrasound finding of Double ontour Sign is a valid and useful measure to detect urate crystal deposition High resolution ultrasound findings suggestive of tophus or tophi Plain radiography findings such as erosion dvanced imaging (eg, T, dual energy T [DET]): High resolution ultrasound finding of Double ontour Sign by itself NOT an appropriate indication for pharmacologic ULT Preliminary General Recommendations for MNGEMENT OF LL PTIENTS with Gout Primary Principle: ommunicate and educate patients on treatment objectives and adherence ssess gout symptom severity and tophus burden onsider cause(s) of hyperuricemia Diagnose and treat co-morbidities ommunicate and initiate diet, lifestyle recommendations Eliminate non-essential prescription of specific serum urateelevating medications Thiazide and loop diuretics Niacin alcineurin inhibitors 3

4 Specific Recommendations: O-MBIDITY HEKLIST for Gout patients ppropriate to consider, and, if indicated, evaluate: Serum urate-elevating medications Hypertension Metabolic syndrome, Type 2 Diabetes Mellitus KD, renal disease Excessive lcohol Use Obesity, Dietary Factors Hyperlipidemia, Modifiable risk factors for D or stroke History of urolithiasis In selected cases, potential genetic and acquired causes of uric acid overproduction Lead toxicity Preliminary Specific Recommendations: GENERL HELTH, DIET, LIFESTYLE MESURES IN GOUT PTIENTS: for all grades chieve optimal BMI Healthy overall diet Exercise Smoking cessation Stay well hydrated void Limit Encourage Organ meats high in purine content High fructose corn syrupsweetened drinks or foods *Serving Sizes of: Beef, Lamb, Pork Lean meat Seafood with high purine content (eg sardines) Shellfish Naturally sweet fruit juices Table sugar, and sweetened beverages and desserts Table salt, including in sauces and gravies lcohol including beer oncentrated binges of caffeinated beverages including coffee Low fat or non fat dairy products Vegetables offee (caffeinated or decaffeinated) *Specifically advise: Total limit of 6 ounces per day of meat or high purine seafood (combined total no more than 6 ounces per day) LK OF ONSENSUS: scorbate, cherries, nuts, legumes Preliminary: Indications for Pharmacologic ULT ny patient with established diagnosis of gouty arthritis and Tophus or tophi by clinical exam or imaging study Frequent attacks of gouty arthritis ( 2 per year) KD Stage 2-5, ESRD Uric acid urolithiasis Yes Define SU target Initiate 1 st line ULT ND Treat to SU target Xanthine Oxidase Inhibitor Uricosuric agent llopurinol Febuxostat Probenecid Monitor for Side Effects SU (q6-12 mo) Yes SU target achieved? Evaluate ongoing gout symptoms and signs No symptoms No Ongoing symptoms Initiate Pharmacologic nti-inflammatory Prophylaxis Refractory Hyperuricemia Refractory Gouty rthritis ontinue Gout ttack Prophlyaxis Start pharmacologic ULT + Start Pharmacologic Gout ttack Prophylaxis Ultimately Discontinue Prophylaxis Maintain serum urate <6.0 mg/dl indefinitely (by non-pharmacologic measures, and any necessary pharmacologic ULT) 4

5 Summary Preliminary Recommendations for MNGEMENT OF HYPERURIEMI in Gout Xanthine Oxidase Inhibition (XOI) endorsed as primary first line pharmacologic ULT Probenecid endorsed as alternative first line therapy Preliminary Recommendations for SU TRGET WITH ULT in Gout Goal of ULT is SU target, at a minimum, of < 6mg/dL in all case scenarios Pharmacologic ULT can be started during an acute gout attack, providing that effective anti-inflammatory management has been achieved B (to be defined in talk by D Khanna) Monitor serum urate regularly Target Serum Urate should be lowered sufficiently to improve signs and symptoms of gout, which may involve lowering to below 5 mg/dl B Velocity of Tophus Reduction ccelerates as Serum Urate drops Below 5 mg/dl Perez-Ruiz F et al. rthritis Rheum 47:356-60, 2002 Summary Preliminary Recommendations for LLOPURINOL IN ULT for Gout Prior to initiation, consider HL-B*5801 in selected high risk patients for severe hypersensitivity (eg, Han hinese; sians with KD stage 3-5) Starting dose <100 mg/d, and lower than 100 mg/d in stage 4 or worse KD Gradually titrate maintenance dose upwards every 2-5 weeks to appropriate maximum dose, in order to treat to chosen SU target Dose can be raised >300 mg/d with monitoring for drug toxicity (eg, pruritis, rash, elevated hepatic transaminases) 5

6 Meta-nalysis: HL-B*5801 Linkage to Severe llopurinol Hypersensitivity Reactions (HS/DRESS, SJS, TEN) Somkrua R, et al. BM Med Genet Sep 9;12(1):118. ssociation of HL-B*5801 llele and llopurinol-induced SJS and TEN: Systematic Review and Meta-analysis. Matched-control studies: 96.60, 95%I , p<0.001 Population-control studies: 79.28, 95%I , p< : 21 Summary Preliminary Recommendations for URIOSURI ULT in Gout History of urolithiasis contra-indicates primary uricosuric ULT Urinary uric acid should be measured before uricosuric ULT Elevated 24hr urine uric acid or high urine uric acid on spot urine collection contra-indicates uricosuric ULT ontinue to monitor urinary uric acid during uricosuric ULT onsider urine alkalinization (eg, K+ ITRTE), with monitoring of urine ph LK OF ONSENSUS: UNDISSOITED URINE URI ID SSY Specific Preliminary Recommendations for HOIE OF URIOSURI ULT in Gout PROBENEID FIRST HOIE MONG URIOSURIS USE PROBENEID ONLY FTER FILURE OF >1 OTHER ULT Initiate 1 st line ULT ND Treat to SU target Xanthine Oxidase Inhibitor Uricosuric agent llopurinol Febuxostat Probenecid Initiate Pharmacologic nti-inflammatory Prophylaxis If rl <50, other ULTs favored over probenecid onsider other agents with uricosuric effects (eg, FENOFIBRTE, LOSRTN, SBTE) where appropriate B ddition of uricosuric to XOI drug is an effective therapeutic approach Monitor for Side Effects SU (q6-12 mo) Yes SU target achieved? No Refractory Hyperuricemia 6

7 Summary Preliminary Recommendations for REFRTY or DIFFIULT TO TRET Gout patients ttempt upwards dose titration of a Xanthine Oxidase inhibitor (XOI) when serum urate target has not been met If upward titration of initial ULT agent does not meet target onsider DDING URIOSURI (if on XOI) onsider HNGING XOI onsider DDING XOI (if on Uricosuric) B Pegloticase: Preliminary Summary Recommendations for REFRTY or DIFFIULT TO TRET Gout patients Pegloticase appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, conventional and appropriately dosed ULT LK OF ONSENSUS: ppropriate duration of pegloticase therapy relative to intended and achieved decrease in symptoms and signs of gout, including decrease in tophus size Pegloticase therapy not recommended as first line ULT agent for any case scenarios Preliminary: dditional gout management options and objectives in HRONI KIDNEY DISESE(KD) and END STGE RENL DISESE (ESRD) KD STGE 2-5 ESRD patient with gout: Sufficient indication for first line pharmacologic ULT in any gout patient For specific scenario of a DILYSIS patient with gout: Serum urate should not be measured during dialysis session Hemodialysis is often associated with reduction of symptomatic arthritis in those with pre-existing gout For dialysis patients with hyperphosphatemia, sevelamer should be considered in ULT HIGHLIGHTS OF PRELIMINRY SYSTEMTI GOUT/HYPERURIEMI MNGEMENT REOMMENDTIONS: Ultrasound: Useful Imaging Modality in Symptomatic Gout Specific o-morbidity and Diet dvice hecklists Established Pharmacologic ULT lgorithm Developed onsensus: SU Target to Improve Gout Symptoms and Signs llopurinol: Starting Dose, Selective Pharmacogenomics ombination Oral ULT Endorsed for Broad ase Scenarios Pegloticase Recommendations in Distinct ase Scenarios Specific Recommendations for Management of Refractory Disease Developed in: hronic Tophaceous Gouty rthropathy Gout KD Stage 3 or Worse 7

8 Limitations in ssessing Evidence for these Gout Domains dd-on vs. Substitution vs. ll omers 1 gent Rx Real World Patients (eg. selection due to prior failure of allopurinol therapy) vs. Industry-Sponsored linical Trials Non-titrated llopurinol vs. Titrated Febuxostat Placebo omparator, Low Numbers/Duration: Pegloticase ross-sectional, Prospective, or Retrospective Designs Epidemiology, and Internet-Based ase rossover Studies vs. Prospective, ontrolled linical Trials: eg, Diet, lcohol, SU, Disease ctivity Issues and Limitations in ssessing Outcomes Evidence in these Domains in Gout Outcomes, linical ctivity, Response riteria Uneven, Poorly Defined, or Surrogate: eg, linical ctivity (Gout ttack Frequency, Severity, Duration) Serum Urate (eg, <6, <5), Joint Damage, QOL QOL Instruments: Variable, Evolving Index Tophus: Visible Resolution or Size Reduction Velocity: riteria, Differing Tophus Sites,? Role of Imaging Imaging: Not Yet Utilized in Outcomes nalyses Extra slides Serum Urate Reduction Using llopurinol Dose Escalation bove Previous Renal Dose djustment in Gout, Including Those With Renal Impairment Stamp L, et al. RTHRITIS & RHEUMTISM Vol. 63, No. 2, February 2011, pp

9 Evidence Reviewed: High Risk Populations re HL-B*5801 Linkage to Severe llopurinol Hypersensitivity Reactions Examples: (HS/DRESS, SJS, TEN) HL-B*5801 Prevalence Odds Ratio of Severe Reaction Han hinese: 9% ~580:1 Koreans: 12.2% ~380:1 with KD stage 3-5 Thai: >6% >100:1 Specific Recommendations: URINE URI ID SREENING F SELETED GOUT PTIENTS Gout onset before age 25 History of urolithiasis omparison to aucasians: aucasians: 1-3% in most Up to ~80:1 (lower negative predictive value) HL-B*5801 screening endorsed for high risk groups: PR screening (followed by sequencing for inconclusive results (in ~10% of PR tests)) Evidence for Urinary Uric cid Monitoring Before and During Uricosuric Therapy Velocity of Tophus Reduction ccelerates as Serum Urate drops Below 5 mg/dl Perez-Ruiz and colleagues, rthritis & Rheum, 2003 Perez-Ruiz F et al. rthritis & Rheum 47:356-60,

10 Initiate 1 st line ULT therapy Xanthine Oxidase Inhibitor Uricosuric agent llopurinol Febuxostat Probenecid Initiate Pharmacologic nti-inflammatory Prophylaxis either Prior to ULT oncurrent with ULT Monitor for Side Effects SU (q6-12 mo) Yes No symptoms SU target achieved? Evaluate ongoing gout symptoms and signs No Ongoing symptoms Refractory Hyperuricemia Refractory Gouty rthritis ontinue Gout ttack Prophlyaxis Discontinue Prophylaxis after the greater of: t least 6 months of therapy 3 months after achieving target SU (for gout with no tophi on clinical exam) 6 months after achieving target SU B (for gout with tophus or tophi seen on clinical exam) Maintain serum urate <6.0 mg/dl indefinitely (by non-pharmacologic measures, and any necessary pharmacologic ULT) 10