3 ObjectivesReview FDA-approved dosing guidelines for colchicine (Colcrys)Evaluate the safety of allopurinol in the setting of chronic kidney diseaseCompare efficacy of available xanthine oxidase inhibitors (allopurinol vs. febuxostat) in treatment of goutReview the EULAR and ACR management guidelines for gout
4 5 Gout Commandments Hyperuricemia ≠ Gout Goal sUA < 6 Use prophylaxis for at least 3 months after initiating gout therapyDo not stop gout medication unless patient is showing evidence of drug toxicity or adverse reactionAsk your friendly rheumatologist for help!
5 Gout Management –the Score Card 52.8% of PCP provided optimal medication treatment for acute attack3.4% of PCPs would appropriately treat inter-critical gout in the setting of CKD16.7% provided optimal care for chronic tophaceous goutPrimary Care and ER Physicians are first line for acute gouty attacksEducation needed to optimize outcomes and limit toxicityNeed for formal guidelines for rheumatology referralRandom sample of primary care doctors in the US, 883 respondents (41% response rate)63% private practice, 52% >16 years in practiceHarrold LR, et al. Rheumatology,
6 Healthcare Utilization Rheumatologists vs. Non-rheumatologistsER visits (Nationwide Sample of 20% of ERs)0.2% of all ER visits$166 million in ED charges alone in 2008RheumNon-rheumP-valueRadiographs (%)6531<0.05Arthrocentesis (%)7534Time to improvement (days)3.66.60.06Hospitalization (days)7.414.70.08Healthcare costs ($)875614750Panush RS, et al. J Clin Rheumatol Apr; 1(2):74-80Garg R, et al. Semin Arthritis Rheum Jun;40(6):
7 Gout Management Approach INITIATE(acute flare)Treat acute flare rapidly with anti-inflammatory agentInitiate urate-lowering therapy to achieve sUA <6Use concomitant anti-inflammatory prophylaxis for up to 6 mo to prevent mobilization flaresRESOLVE(urate-lowering therapy)Continue urate lowering therapy to control flares and avoid crystal depositionProphylaxis use for at least 3-6 months until sUA normalizesMAINTAIN(treatment to control sUA)7
8 Myth #1Acute gout flares are treated with 1 tablet of colchicine hourly until the patient develops diarrhea or gets better.
9 AGREE study: Acute Gout Flare Receiving ColchicinE Evaluation High vs. Low Dose Colchicine for Gout FlareRandomized, double-blind, placebo-controlled studyLow dose colchicine (1.8mg total over 1 h)High dose colchicine (4.8mg total over 6 h)Primary end point: >50% pain reduction in 24 hours without rescue medication184 patients intent-to-treat analysisPatients given a blister pack, called the call-center to confirm flare -4 cardinal signs present. Kept journal of pain scores then returned to study center within 4 hours and had several visits.Terkeltaub, RA., et al. Arthritis Rheum 2010.
10 AGREE study: Acute Gout Flare Receiving ColchicinE Evaluation Colchicine Dose% >50% reduction in painP value vs. placeboAdverse Event Rate% needing rescue medicationsHigh dose32.7%0.03476.9%34.6%Low dose37.8%0.00536.5%31.1%Placebo15.5%n/a27.1%50.0%Adverse EventsHigh DoseLow DosePlaceboAll GI Events76.925.720.3Diarrhea23.013.6Nausea18.104.22.168VomitingTerkeltaub, RA., et al. Arthritis Rheum 2010.
11 Improvement in pain @ 24 hours High-doseLow-doseplaceboTerkeltaub, RA., et al. Arthritis Rheum 2010.
12 Take home pointsLow-dose colchicine had similar efficacy to high-dose colchicine with lower adverse effect profileColchicine now has FDA-approved dosing based on creatinine clearanceCrCl ml/min = 0.6mg dailyCrCl <30 ml/min = 0.3mg dailyHD = 0.6mg twice weekly (not dialyzable)Terkeltaub, RA., et al. Arthritis Rheum 2010.
13 Myth #2You cannot use allopurinol in patients with renal insufficiency
14 Allopurinol and Renal Insufficiency 1984 Hande, et al published “Severe allopurinol toxicity: Description and guidelines for prevention in patients with renal insufficiency”“Avoidance of allopurinol or use of reduced doses in patients with renal insufficiency according to proposed guidelines should be adequate to inhibit uric acid production in most patients and may reduce the incidence of life-threatening allopurinol toxicity.”Hande KR, et al. Am J Med, 1984.
15 Maintenance Doses of Allopurinol for Adults based on CrCl CrCl (mL/min)Maintenance Dose of Allopurinol100mg every 3d10100mg every 2d20100mg40150mg60200mg80250mg100300mg120350mg140400mgStage 1 renal damage with normal GFR(GFR > 90 ml/min)Stage 2 Mild CKD (GFR = ml/min)Stage 3 Modererate CKD (GFR = ml/min)Stage 4 Severe CKD (GFR = ml/min)Stage 5 End Stage CKD (GFR <15 ml/min)Hande KR, et al. Am J Med, 1984.
16 What did doctors take home? Guidelines made in order to prevent allopurinol hypersensitivityAllopurinol should not be used in renal insufficiencyHande KR, et al. Am J Med, 1984.
17 Pathophysiology XO XO hypoxanthine xanthine urate XO=xanthine oxidase Allopurinol and febuxostat inhibit xanthine oxidase and block uric acid formation17Markel A. IMAJ, 2005.
18 OxypurinolAllopurinol Hypersensitivity SyndromeXanthineOxidaseallopurinoloxypurinolToxic Epidermal NecrolysisStevens-Johnson SyndromeOxypurinol, allopurinol metabolite, cleared by kidney and accumulates in patients with renal failureOxypurinol inhibits xanthine oxidaseIncreased oxypurinol related to risk of allopurinol hypersensitivity syndrome
19 Allopurinol Hypersensitivity Syndrome 2% of all allopurinol users develop cutaneous rashFrequency of hypersensitivity 1 in 260DRESS syndromeDrug Reaction, Eosinophilia, Systemic Symptoms20% mortality rateLife threatening toxicity: vasculitis, rash, eosinophilia, hepatitis, progressive renal failureTreatment: early recognition, withdrawal of drug, supportive careSteroids, N-acetyl-cysteine, dialysis prnMarkel A. IMAJ, 2005.Terkeltaub RA, in Primer on the Rheumatic Disease, 13th ed
20 Relationship between recommended allopurinol dose and sUA < 6 Dose reduction of allopurinol in patients with renal insufficiency may lead to under-treatment and persistent hyperuricemiaDalbeth, et al. created allopurinol calculatorPerformed retrospective chart review of 250 patients with ACR criteria for goutDivided into 4 groups:no allopurinollower than recommended allopurinol doserecommended allopurinol dosehigher than recommended allopurinol doseDalbeth N, et al. J Rheum, 2006.
21 Results 227/250 (90.8%) were taking allopurinol Mean allopurinol dose was 214mg/day9.7% took lower than recommended doses70.9% took recommended doses19.4% took higher than recommended doses4/250 (1.6%) developed hypersensitivityAll took recommended dosesDalbeth N, et al. J Rheum, 2006.
22 Is recommended dose of allopurinol enough? 19% (recommended) vs 38% (higher than recommended) reachedsUA <6, p <0.01Dalbeth N, et al. J Rheum, 2006.
23 Is recommended dose of allopurinol enough? Limitations:Retrospective studyHomogenous population (Maori/Pacific Islanders)Cannot judge medication complianceConclusions:Allopurinol dosing according to published guidelines has NOT led to adequate control of hyperuricemiaDalbeth N, et al. J Rheum, 2006.
24 Myth #3The maximum dose of allopurinol in patients with renal insufficiency should not exceed 300mg
25 Allopurinol dosing algorithm CrCl (mL/min)Maintenance Dose of Allopurinol100mg every 3d10100mg every 2d20100mg40150mg60200mg80250mg100300mg120350mg140400mgStage 1 renal damage with normal GFR(GFR > 90 ml/min)Stage 2 Mild CKD (GFR = ml/min)Stage 3 Modererate CKD (GFR = ml/min)Stage 4 Severe CKD (GFR = ml/min)Stage 5 End Stage CKD (GFR <15 ml/min)Hande KR, et al. Am J Med, 1984.
26 Allopurinol Use in Renal Insufficiency Objective:Determine the safety and efficacy of increasing allopurinol dose above the proposed guidelines for patients with goutProspective study of patients on allopurinol ≥ 1 month81.9% European, 14.4% Maori or Pacific Island DescentSaw patients monthly and titrated allopurinol until sUA <6 for 3 months then q3 monthsStamp LK, et al. Arthritis Rheum 2011.
27 Allopurinol Use in Renal Insufficiency Stamp LK, et al. Arthritis Rheum 2011.
28 Allopurinol Use in Renal Insufficiency Mean baseline dosage221.4mg (range , median 200)Mean dose for pts who completed study335.7mg (range 0-600, median 350)Mean dose for pts who achieved sUA <6359.7mg (range , median 450)Stamp LK, et al. Arthritis Rheum 2011.
29 ConclusionsDoses above recommended dose are effective for lowering sUA with few adverse eventsPatients with renal impairment tolerated allopurinol doses higher than CrCl-based doses and achieved sUA <6Monitor sUA regularly and treat-to-target sUA <6Limitations of study: self-selected patients who were already on allopurinol → minimize incidence of toxicityStamp LK, et al. Arthritis Rheum 2011.
30 Allopurinol vs. Febuxostat Febuxostat (Uloric)FDA-approved 1966FDA-approved 2009Purine-selective XO InhibitorNon-Purine Selective XO InhibitorPrevents uric acid productionRenal MetabolismLiver Metabolism
31 Allopurinol vs. Febuxostat Phase III, randomized, double-blind, allopurinol and placebo-controlled parallel-group trialPrimary end point: proportion of subjects with the last 3 monthly sUA <6 regardless of whether or not subject completed the studyRandomized 2:2:1:2:1febuxostat 80mg: 120mg: 240mg: allopurinol: placeboSchumacher HR, et al. Arthritis Rheum 2008.
32 Proportion of subjects with last 3 monthly sUA <6 Schumacher HR, et al. Arthritis Rheum 2008.
34 Adverse Events Any Adverse Event (AE) Placebo Febuxostat 80mg Allopurinol 300mgAny AE72%68%73%75%Diarrhea8%6%*7%*13%**6%Hypertension5%2%4%1%***Neurologic sx1%2%*7%**Muscle sx<1%<1%****Statistically significant versus febuxostat 240mg p ≤ 0.05**Statistically significant versus allopurinol p ≤ 0.05***Statistically significant versus placebo p ≤ 0.05Schumacher HR, et al. Arthritis Rheum 2008.
35 Discussion Febuxostat effectively reduced sUA <6 Allopurinol dose fixed instead of titratedPatients with impaired renal function did not achieve sUA <6 with recommended allopurinol dose of 100mgAE profile similar across treatment groups except for diarrhea and dizziness higher in febuxostat 240mg groupSchumacher HR, et al. Arthritis Rheum 2008.
37 Treatment: Summary of EULAR Recommendations Therapeutic goal of urate-lowering therapy is sUA <6.0 mg/dLUrate lowering therapy indications:Recurrent gout attacksTophi and/or radiographic changes on initial presentationAddress associated risk factors and comorbidities – tailor to the individual37Zhang W, et al. Ann Rheum Dis ; 65:
38 2012 ACR Management Guidelines Lifestyle Modification for all patients with goutXanthine Oxidase Inhibitor (XOI) first-line urate-lowering pharmacologic therapyTarget sUA <6 at minimum, sUA <5 betterStarting dose of allopurinol should be 100mg, less in CKD with titration above 300mg prn if needed (even in CKD)Continue prophylaxis for 3 (no tophi) – 6 months (tophi) after achieving target sUAKhanna D, et al. Arthritis Care Res Oct;64(10):
39 2012 ACR Management Guidelines Consider HLA screening for HLA-B*5801 in certain populations considered high risk for allopurinol hypersensitivity syndromeKoreans with stage 3 CKD or worseHan ChineseThai descentCombination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alonePegloticase appropriate for severe refractory disease or intolerance of standard regimensKhanna D, et al. Arthritis Care Res Oct;64(10):
40 2012 ACR Management Guidelines for Acute Gouty Arthritis The choice of pharmacologic agent depends on severity of the attackMonotherapy for mild/moderate attackCombination therapy for severe attack or those refractory to monotherapyAcceptable combination therapy approaches includeColchicine and NSAIDSOral steroids and colchicineIntra-articular steroids with all other modalitiesContinue current therapy during flarePatient education on signs of flare for self treatmentKanna D, et al. Arthritis Care Res (Hoboken) Oct;64(10):
41 Take Home Points Goal sUA < 6, and use concurrent prophylaxis Colchicine has FDA-approved dosing guidelines for chronic kidney diseaseAllopurinol doses above recommended CrCl-based dose is effective with minimal adverse effectFebuxostat is an excellent alternative for patients with renal insufficiencyOther treatment alternatives exist, please refer to your friendly rheumatologist for difficult cases