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DISCLOSURES: 2011 ACR Guidelines Task Force Robert Terkeltaub MD Preliminary Recommendations: • GRANT SUPPORT: VA, NIH

MANAGEMENT OF GOUT: • CONSULTANT: • URATE-LOWERING THERAPY (ULT) Takeda, Savient, ARDEA, BioCryst, URL, •CHRONIC TOPHACEOUS GOUTY ARTHROPATHY Regeneron, Novartis, Pfizer, Metabolex, Nuon, Chugai, Ajanta, Prescription Solutions Robert Terkeltaub, MD SPEAKER: None VAMC/University of California San Diego

GOUT CASE SCENARIOS: Chronic Tophaceous Gouty Arthropathy: To replicate mild, moderate, severe in-office presentations of gout (#’s 1-6: intermittent symptoms without and with tophi; CASE SCENARIOS #’s 7-9: chronic tophaceous gouty arthropathy) Disease CASE Characteristics NOT A DISEASE CLASSIFICATION SCHEME Severity SCENARIO Tophus or Tophi detected CASE •Stable disease Symptoms Frequency on Physical SCENARIO Mild •Simple chronic tophaceous gouty arthropathy 7 Exam •Affecting 1 Intermittent NO Infrequent Symptoms (< 1 attack/yr) 1 symptoms •Stable disease NO Frequent Symptoms (2-6 attacks/yr) 2 Moderate •Simple chronic tophaceous gouty arthropathy 8 NO Very Frequent Symptoms (> 7 attacks/yr) 3 •Affecting 2-4

Intermittent •Chronic tophaceous gouty arthropathy of >4 joints symptoms YES Infrequent Symptoms (< 1 attack/yr) 4 Severe OR 9 YES Frequent Symptoms (2-6 attacks/yr) 5 • ≥1 unstable, complicated, severe articular tophus or tophi

YES Very Frequent Symptoms (> 7 attacks/yr) 6

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CASE SCENARIOS: CASE SCENARIOS: MILD Chronic Tophaceous Gouty Arthropathy SEVERE Chronic Tophaceous Gouty Stable, simple tophus limited to one joint (Scenario #7) Arthropathy: Numerous, Complicated, or Unstable Tophi (Scenario #9) • Lack of drainage • Lack of aggressive connective tissue mass or • Tophi affecting more than 4 joints destructive effects • Lack of high risk of infection OR • Stable in size, or slow growth • One or more Tophi demonstrating • Lack of severe chronic, tophaceous joint inflammation  Drainage  Aggressive mass or connective MODERATE Chronic Tophaceous Gouty tissue destructive effects Arthropathy  High risk of infection  Very rapid growth Stable, simple tophi affecting 2-4 joints  Severe, chronic tophaceous joint (Scenario #8) inflammation

Summary of Gout Management Options and Objectives in Varying Disease Severity Outline of preliminary gout Case Scenarios 1-9 CASE SCENARIOS management recommendations: No tophi on >1Tophi detected on exam exam Intermittent Symptoms CTGA • Diagnostic, Imaging, Co-Morbidity Considerations Measure 1 2 3 4 5 6 7 8 9 • General Management Principles for all Patients Diet, alcohol, weight management, and co-morbidity and + + + + + + + + + medication review Target serum urate should be lowered sufficiently to improve signs and symptoms of gout + + + + + + + + + ULT Domain PHARMACOLOGIC ULT • Principles of Non-pharmacologic and Pharmacologic ULT First line: SINGLE AGENT XOI titrated to maximum +§ + + + + + + + + appropriate dose (Alternative: Probenecid) • Approach to Refractory Disease serum urate target not achieved

Combination ORAL XOI+URICOSURIC ULT at maximum § appropriate doses + + + + + + + + + serum urate target not achieved Chronic Tophaceous Gouty Arthropathy Domain PEGLOTICASE − − + − +¶ + + + + § Finding of a tophus or tophi on imaging study, or CKD 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.

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High Resolution Ultrasound: Summary Preliminary Recommendations in Preliminary Recommendation as Diagnosis of Gout that Impact on Therapy Imaging Approach in Gout “DOUBLE CONTOUR SIGN”: • The diagnosis of gout should be definitive before Accepted by TFP as evidence for urate crystal deposition initiation of ULT in all case scenarios

• Recommended measures for diagnosis of gout extend beyond clinical classification criteria, PROXIMAL DISTAL synovial fluid aspiration/crystal analysis

• 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 General Recommendations for Preliminary Recommendations on Imaging MANAGEMENT OF ALL PATIENTS with Gout Measures in Supporting Diagnosis of Gout  Primary Principle: Communicate and educate patients on and with the Potential to Impact on Therapy treatment objectives and adherence • Assess gout symptom severity and tophus burden C – High resolution ultrasound finding of “Double Contour Sign” is a valid and useful measure to detect urate crystal deposition C • Consider cause(s) of C – High resolution ultrasound findings suggestive of tophus or tophi C • Diagnose and treat co-morbidities C – Plain radiography findings such as erosion C C – Advanced imaging (eg, CT, dual energy CT [DECT]): C • Communicate and initiate diet, lifestyle recommendations • Eliminate non-essential prescription of specific serum urate-

C High resolution ultrasound finding of “Double Contour Sign” by itself elevating medications NOT an appropriate indication for pharmacologic ULT − Thiazide and loop diuretics − Niacin − Calcineurin inhibitors

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Preliminary Specific Recommendations: • Achieve optimal BMI Specific Recommendations: GENERAL HEALTH, DIET, LIFESTYLE • Healthy overall diet • Exercise C CO-MORBIDITY CHECKLIST for Gout patients MEASURES IN GOUT PATIENTS: • Smoking cessation Appropriate to consider, and, if indicated, evaluate: C for all grades C • Stay well hydrated Avoid Limit Encourage • Serum urate-elevating medications • Organ meats high in purine *Serving Sizes of: • Low fat or non fat dairy content products • Hypertension • Beef, Lamb, Pork • Lean meat • Vegetables

• Metabolic syndrome, Type 2 Diabetes Mellitus • Seafood with high purine content (eg sardines) • CKD, renal disease • Shellfish • Excessive Alcohol Use • High fructose corn syrup- • Naturally sweet fruit juices sweetened drinks or foods • Table sugar, and sweetened • Obesity, Dietary Factors beverages and desserts • Hyperlipidemia, Modifiable risk factors for CAD or stroke • Table salt, including in sauces and gravies • History of urolithiasis • Alcohol including beer • Coffee (caffeinated or • In selected cases, potential genetic and acquired causes of • Concentrated binges of decaffeinated) caffeinated beverages overproduction including coffee • Lead toxicity *Specifically advise: Total limit of 6 ounces per day of meat or high purine seafood (combined total no more than 6 ounces per day) LACK OF CONSENSUS: Ascorbate, cherries, nuts, legumes

Preliminary: Indications for Initiate 1st line ULT AND Treat to SUA target Pharmacologic ULT Initiate Xanthine Oxidase Inhibitor A Uricosuric agent A Pharmacologic

OR Anti-inflammatory Any patient with established diagnosis of gouty and Allopurinol Febuxostat Probenecid Prophylaxis A •Tophus or tophi by clinical exam or imaging study A •Frequent attacks of gouty arthritis (≥ 2 per year) A •CKD Stage 2- 5, ESRD C Monitor for Yes No SUA target achieved? Refractory Hyperuricemia •Uric acid urolithiasis C •Side Effects C •SUA (q6-12 mo) C Ongoing Evaluate ongoing gout symptoms and symptoms Refractory Gouty Arthritis Yes signs Continue Gout Attack Prophlyaxis C No symptoms Define SUA target

Ultimately Discontinue Prophylaxis Maintain serum urate <6.0 mg/dL indefinitely Start pharmacologic Start Pharmacologic A (by non-pharmacologic ULT A + Gout Attack Prophylaxis measures, and any necessary pharmacologic ULT) C

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Summary Preliminary Recommendations for MANAGEMENT OF HYPERURICEMIA Preliminary Recommendations for in Gout SUA TARGET WITH ULT in Gout

• Xanthine Oxidase Inhibition (XOI) endorsed as primary first line • Goal of ULT is SUA target, at a minimum, of pharmacologic ULT A < 6mg/dL in all case scenarios • Probenecid endorsed as alternative first line therapy A

• Pharmacologic ULT can be started during an acute gout attack, providing that effective anti-inflammatory management has been • Target Serum Urate should be lowered sufficiently achieved B (to be defined in talk by D Khanna) to improve signs and symptoms of gout, which

• Monitor serum urate regularly C may involve lowering to below 5 mg/dL B

Velocity of Tophus Reduction Summary Preliminary Recommendations Accelerates as Serum Urate drops for ALLOPURINOL IN ULT for Gout Below 5 mg/dL • Prior to initiation, consider HLA-B*5801 in selected high risk patients for severe hypersensitivity C (eg, Han Chinese; Asians with CKD stage 3-5)

• Starting dose <100 mg/d, and lower than 100 mg/d in stage 4 or worse CKD C • Gradually titrate maintenance dose upwards every 2-5 weeks to appropriate maximum dose, in order to treat to chosen SUA target C • Dose can be raised >300 mg/d with monitoring for drug toxicity (eg, pruritis, rash, elevated hepatic transaminases) A Perez-Ruiz F et al. Arthritis Rheum 47:356-60, 2002

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Meta-Analysis: Summary Preliminary Recommendations HLA-B*5801 Linkage to Severe for URICOSURIC ULT in Gout Allopurinol Hypersensitivity Reactions (AHS/DRESS, SJS, TEN) • History of urolithiasis contra-indicates primary uricosuric ULT C Somkrua R, et al. BMC Med Genet. 2011 Sep 9;12(1):118. Association of HLA-B*5801 Allele and Allopurinol-Induced • Urinary uric acid should be measured before uricosuric ULT C SJS and TEN: Systematic Review and Meta-analysis. • Elevated 24hr urine uric acid or high urine uric acid on spot urine collection contra-indicates uricosuric ULT C • Matched-control studies: • Continue to monitor urinary uric acid during uricosuric ULT C OR 96.60, 95%CI 24.49-381.00, p<0.001 • Consider urine alkalinization (eg, K+ CITRATE), with monitoring of • Population-control studies: urine pH C OR 79.28, 95%CI 41.51-151.35, p< 0.001 LACK OF CONSENSUS: UNDISSOCIATED URINE URIC ACID ASSAY : 21

Specific Preliminary Recommendations for CHOICE OF URICOSURIC ULT in Gout Initiate 1st line ULT AND Treat to SUA target Initiate Pharmacologic Xanthine Oxidase Inhibitor Uricosuric agent PROBENECID FIRST CHOICE AMONG URICOSURICS A Anti-inflammatory OR USE PROBENECID ONLY AFTER FAILURE OF >1 OTHER ULT C Allopurinol Febuxostat Probenecid Prophylaxis

• If CrCl <50, other ULTs favored over probenecid C Monitor for Yes SUA target No Refractory • Consider other agents with uricosuric effects (eg, FENOFIBRATE, achieved? •Side Effects Hyperuricemia LOSARTAN, ASCORBATE) where appropriate B •SUA (q6-12 mo) • Addition of uricosuric to XOI drug is an effective therapeutic approach C

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Pegloticase: Preliminary Summary Summary Preliminary Recommendations Recommendations for REFRACTORY or DIFFICULT TO TREAT for REFRACTORY or DIFFICULT TO TREAT Gout patients Gout patients • Attempt upwards dose titration of a Xanthine Oxidase • Pegloticase appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, inhibitor (XOI) when serum urate target has not been met A conventional and appropriately dosed ULT A • LACK OF CONSENSUS: • If upward titration of initial ULT agent does not meet target Appropriate duration of pegloticase therapy relative ‒Consider ADDING URICOSURIC (if on XOI) B to intended and achieved decrease in symptoms ‒Consider CHANGING XOI C and signs of gout, including decrease in tophus size ‒Consider ADDING XOI (if on Uricosuric) C • Pegloticase therapy not recommended as first line ULT agent for any case scenarios

Preliminary: Additional gout management options HIGHLIGHTS OF PRELIMINARY and objectives in CHRONIC KIDNEY DISEASE(CKD) SYSTEMATIC GOUT/HYPERURICEMIA and END STAGE RENAL DISEASE (ESRD) MANAGEMENT RECOMMENDATIONS:

• CKD STAGE 2-5 OR ESRD patient with gout: • Ultrasound: Useful Imaging Modality in Symptomatic Gout ‒ Sufficient indication for first line pharmacologic ULT in any • Specific Co-Morbidity and Diet Advice Checklists Established gout patient C • Pharmacologic ULT Algorithm Developed • For specific scenario of a DIALYSIS patient with gout: • Consensus: “SUA Target to Improve Gout Symptoms and Signs” ‒ Serum urate should not be measured during dialysis • Allopurinol: Starting Dose, Selective Pharmacogenomics session C • Combination Oral ULT Endorsed for Broad Case Scenarios • Pegloticase Recommendations in Distinct Case Scenarios ‒ Hemodialysis is often associated with reduction of symptomatic arthritis in those with pre-existing gout • Specific Recommendations for Management of Refractory Disease C Developed in: ‒ For dialysis patients with hyperphosphatemia, sevelamer Chronic Tophaceous Gouty Arthropathy should be considered in ULT C Gout CKD Stage 3 or Worse

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Issues and Limitations in Assessing Limitations in Assessing Evidence Outcomes Evidence in these for these Gout Domains Domains in Gout • Add-on vs. Substitution vs. “All Comers” 1 Agent Rx • Outcomes, Clinical Activity, Response Criteria Uneven, Poorly • “Real World” Patients (eg. selection due to prior failure of Defined, or Surrogate: allopurinol therapy) vs. Industry-Sponsored Clinical Trials eg, Clinical Activity (Gout Attack Frequency, Severity, Duration) Serum Urate (eg, <6, <5), Joint Damage, QOL • Non-titrated Allopurinol vs. Titrated Febuxostat • QOL Instruments: Variable, Evolving • Placebo Comparator, Low Numbers/Duration: Pegloticase • Index Tophus: Visible Resolution or Size Reduction Velocity: • Cross-Sectional, Prospective, or Retrospective Designs Criteria, Differing Tophus Sites, ? Role of Imaging

• Epidemiology, and Internet-Based Case Crossover Studies vs. • Imaging: Not Yet Utilized in Outcomes Analyses Prospective, Controlled Clinical Trials: eg, Diet, Alcohol, SUA, Disease Activity

Serum Urate Reduction Using Allopurinol Dose Escalation Above Previous Renal Dose Adjustment in Gout, Including Those With Renal Impairment Extra slides Stamp L, et al. ARTHRITIS & RHEUMATISM Vol. 63, No. 2, February 2011, pp 412–421

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Evidence Reviewed: High Risk Populations re Specific Recommendations: HLA-B*5801 Linkage to Severe Allopurinol URINE URIC ACID SCREENING FOR Hypersensitivity Reactions SELECTED GOUT PATIENTS (AHS/DRESS, SJS, TEN) Examples: HLA-B*5801 Prevalence Odds Ratio of Severe Reaction • Gout onset before age 25 C Han Chinese: 9% ~580:1 • History of urolithiasis Koreans: 12.2% ~380:1 with CKD stage 3-5 C Thai: >6% >100:1

Comparison to Caucasians: Caucasians: 1-3% in most Up to ~80:1 (lower negative predictive value)

HLA-B*5801 screening endorsed for high risk groups: • PCR screening (followed by sequencing for inconclusive results (in ~10% of PCR tests))

Evidence for Urinary Uric Acid Monitoring Velocity of Tophus Reduction Before and During Uricosuric Therapy Accelerates as Serum Urate drops Below 5 mg/dL

Perez-Ruiz and colleagues, Arthritis & Rheum, 2003 Perez-Ruiz F et al. Arthritis & Rheum 47:356-60, 2002

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Initiate 1st line ULT therapy Initiate Pharmacologic Anti-inflammatory Xanthine Oxidase Inhibitor A Uricosuric agent A Prophylaxis A either Allopurinol OR Febuxostat Probenecid • Prior to ULT OR • Concurrent with ULT

Monitor for Yes Refractory Hyperuricemia SUA target achieved? No •Side Effects C •SUA (q6-12 mo) C Evaluate ongoing Ongoing symptoms Refractory Gouty Arthritis gout symptoms and Continue Gout Attack signs Prophlyaxis C No symptoms

Discontinue Prophylaxis after the greater of: Maintain serum urate • At least 6 months of therapy A <6.0 mg/dL indefinitely OR (by non-pharmacologic • 3 months after achieving target SUA C measures, and any necessary (for gout with no tophi on clinical exam) pharmacologic ULT) C • 6 months after achieving target SUA B (for gout with tophus or tophi seen on clinical exam)

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