Gout Update 2014 Bernadette C. Siaton, MD Assistant Professor of Medicine University of Maryland School of Medicine Division of Rheumatology and Clinical Immunology 1 February 2014

Disclosures none

Objectives Review FDA-approved dosing guidelines for colchicine (Colcrys) Evaluate the safety of allopurinol in the setting of chronic kidney disease Compare efficacy of available xanthine oxidase inhibitors (allopurinol vs. febuxostat) in treatment of gout Review the EULAR and ACR management guidelines for gout

5 Gout Commandments Hyperuricemia ≠ Gout Goal sUA < 6 Use prophylaxis for at least 3 months after initiating gout therapy Do not stop gout medication unless patient is showing evidence of drug toxicity or adverse reaction Ask your friendly rheumatologist for help!

Gout Management –the Score Card 52.8% of PCP provided optimal medication treatment for acute attack 3.4% of PCPs would appropriately treat inter-critical gout in the setting of CKD 16.7% provided optimal care for chronic tophaceous gout Primary Care and ER Physicians are first line for acute gouty attacks Education needed to optimize outcomes and limit toxicity Need for formal guidelines for rheumatology referral Random sample of primary care doctors in the US, 883 respondents (41% response rate) 63% private practice, 52% >16 years in practice Harrold LR, et al. Rheumatology, 2013.

Healthcare Utilization Rheumatologists vs. Non-rheumatologists ER visits (Nationwide Sample of 20% of ERs) 0.2% of all ER visits $166 million in ED charges alone in 2008 Rheum Non-rheum P-value Radiographs (%) 65 31 <0.05 Arthrocentesis (%) 75 34 Time to improvement (days) 3.6 6.6 0.06 Hospitalization (days) 7.4 14.7 0.08 Healthcare costs ($) 8756 14750 Panush RS, et al. J Clin Rheumatol. 1995 Apr; 1(2):74-80 Garg R, et al. Semin Arthritis Rheum. 2011 Jun;40(6):501-11.

Gout Management Approach INITIATE (acute flare) Treat acute flare rapidly with anti-inflammatory agent Initiate urate-lowering therapy to achieve sUA <6 Use concomitant anti-inflammatory prophylaxis for up to 6 mo to prevent mobilization flares RESOLVE (urate-lowering therapy) Continue urate lowering therapy to control flares and avoid crystal deposition Prophylaxis use for at least 3-6 months until sUA normalizes MAINTAIN (treatment to control sUA) 7

Myth #1 Acute gout flares are treated with 1 tablet of colchicine hourly until the patient develops diarrhea or gets better.

AGREE study: Acute Gout Flare Receiving ColchicinE Evaluation High vs. Low Dose Colchicine for Gout Flare Randomized, double-blind, placebo-controlled study Low 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 medication 184 patients intent-to-treat analysis Patients 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.

AGREE study: Acute Gout Flare Receiving ColchicinE Evaluation Colchicine Dose % >50% reduction in pain P value vs. placebo Adverse Event Rate % needing rescue medications High dose 32.7% 0.034 76.9% 34.6% Low dose 37.8% 0.005 36.5% 31.1% Placebo 15.5% n/a 27.1% 50.0% Adverse Events High Dose Low Dose Placebo All GI Events 76.9 25.7 20.3 Diarrhea 23.0 13.6 Nausea 17.3 4.1 5.1 Vomiting Terkeltaub, RA., et al. Arthritis Rheum 2010.

Improvement in pain @ 24 hours High-dose Low-dose placebo Terkeltaub, RA., et al. Arthritis Rheum 2010.

Take home points Low-dose colchicine had similar efficacy to high-dose colchicine with lower adverse effect profile Colchicine now has FDA-approved dosing based on creatinine clearance CrCl 30-80 ml/min = 0.6mg daily CrCl <30 ml/min = 0.3mg daily HD = 0.6mg twice weekly (not dialyzable) Terkeltaub, RA., et al. Arthritis Rheum 2010.

Myth #2 You cannot use allopurinol in patients with renal insufficiency

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.

Maintenance Doses of Allopurinol for Adults based on CrCl CrCl (mL/min) Maintenance Dose of Allopurinol 100mg every 3d 10 100mg every 2d 20 100mg 40 150mg 60 200mg 80 250mg 100 300mg 120 350mg 140 400mg Stage 1 renal damage with normal GFR (GFR > 90 ml/min) Stage 2 Mild CKD (GFR = 60-89 ml/min) Stage 3 Modererate CKD (GFR = 30-59 ml/min) Stage 4 Severe CKD (GFR = 15-29 ml/min) Stage 5 End Stage CKD (GFR <15 ml/min) Hande KR, et al. Am J Med, 1984.

What did doctors take home? Guidelines made in order to prevent allopurinol hypersensitivity Allopurinol should not be used in renal insufficiency Hande KR, et al. Am J Med, 1984.

Pathophysiology XO XO hypoxanthine xanthine urate XO=xanthine oxidase Allopurinol and febuxostat inhibit xanthine oxidase and block uric acid formation 17 Markel A. IMAJ, 2005.

Oxypurinol Allopurinol Hypersensitivity Syndrome Xanthine Oxidase allopurinol oxypurinol Toxic Epidermal Necrolysis Stevens-Johnson Syndrome Oxypurinol, allopurinol metabolite, cleared by kidney and accumulates in patients with renal failure Oxypurinol inhibits xanthine oxidase Increased oxypurinol related to risk of allopurinol hypersensitivity syndrome

Allopurinol Hypersensitivity Syndrome 2% of all allopurinol users develop cutaneous rash Frequency of hypersensitivity 1 in 260 DRESS syndrome Drug Reaction, Eosinophilia, Systemic Symptoms 20% mortality rate Life threatening toxicity: vasculitis, rash, eosinophilia, hepatitis, progressive renal failure Treatment: early recognition, withdrawal of drug, supportive care Steroids, N-acetyl-cysteine, dialysis prn Markel A. IMAJ, 2005. Terkeltaub RA, in Primer on the Rheumatic Disease, 13th ed. 2008.

Relationship between recommended allopurinol dose and sUA < 6 Dose reduction of allopurinol in patients with renal insufficiency may lead to under-treatment and persistent hyperuricemia Dalbeth, et al. created allopurinol calculator Performed retrospective chart review of 250 patients with ACR criteria for gout Divided into 4 groups: no allopurinol lower than recommended allopurinol dose recommended allopurinol dose higher than recommended allopurinol dose Dalbeth N, et al. J Rheum, 2006.

Results 227/250 (90.8%) were taking allopurinol Mean allopurinol dose was 214mg/day 9.7% took lower than recommended doses 70.9% took recommended doses 19.4% took higher than recommended doses 4/250 (1.6%) developed hypersensitivity All took recommended doses Dalbeth N, et al. J Rheum, 2006.

Is recommended dose of allopurinol enough? 19% (recommended) vs 38% (higher than recommended) reached sUA <6, p <0.01 Dalbeth N, et al. J Rheum, 2006.

Is recommended dose of allopurinol enough? Limitations: Retrospective study Homogenous population (Maori/Pacific Islanders) Cannot judge medication compliance Conclusions: Allopurinol dosing according to published guidelines has NOT led to adequate control of hyperuricemia Dalbeth N, et al. J Rheum, 2006.

Myth #3 The maximum dose of allopurinol in patients with renal insufficiency should not exceed 300mg

Allopurinol dosing algorithm CrCl (mL/min) Maintenance Dose of Allopurinol 100mg every 3d 10 100mg every 2d 20 100mg 40 150mg 60 200mg 80 250mg 100 300mg 120 350mg 140 400mg Stage 1 renal damage with normal GFR (GFR > 90 ml/min) Stage 2 Mild CKD (GFR = 60-89 ml/min) Stage 3 Modererate CKD (GFR = 30-59 ml/min) Stage 4 Severe CKD (GFR = 15-29 ml/min) Stage 5 End Stage CKD (GFR <15 ml/min) Hande KR, et al. Am J Med, 1984.

Allopurinol Use in Renal Insufficiency Objective: Determine the safety and efficacy of increasing allopurinol dose above the proposed guidelines for patients with gout Prospective study of patients on allopurinol ≥ 1 month 81.9% European, 14.4% Maori or Pacific Island Descent Saw patients monthly and titrated allopurinol until sUA <6 for 3 months then q3 months Stamp LK, et al. Arthritis Rheum 2011.

Allopurinol Use in Renal Insufficiency Stamp LK, et al. Arthritis Rheum 2011.

Allopurinol Use in Renal Insufficiency Mean baseline dosage 221.4mg (range 100-400, median 200) Mean dose for pts who completed study 335.7mg (range 0-600, median 350) Mean dose for pts who achieved sUA <6 359.7mg (range 150-600, median 450) Stamp LK, et al. Arthritis Rheum 2011.

Conclusions Doses above recommended dose are effective for lowering sUA with few adverse events Patients with renal impairment tolerated allopurinol doses higher than CrCl-based doses and achieved sUA <6 Monitor sUA regularly and treat-to-target sUA <6 Limitations of study: self-selected patients who were already on allopurinol → minimize incidence of toxicity Stamp LK, et al. Arthritis Rheum 2011.

Allopurinol vs. Febuxostat Febuxostat (Uloric) FDA-approved 1966 FDA-approved 2009 Purine-selective XO Inhibitor Non-Purine Selective XO Inhibitor Prevents uric acid production Renal Metabolism Liver Metabolism

Allopurinol vs. Febuxostat Phase III, randomized, double-blind, allopurinol and placebo-controlled parallel-group trial Primary end point: proportion of subjects with the last 3 monthly sUA <6 regardless of whether or not subject completed the study Randomized 2:2:1:2:1 febuxostat 80mg: 120mg: 240mg: allopurinol: placebo Schumacher HR, et al. Arthritis Rheum 2008.

Proportion of subjects with last 3 monthly sUA <6 Schumacher HR, et al. Arthritis Rheum 2008.

Schumacher HR, et al. Arthritis Rheum 2008.

Adverse Events Any Adverse Event (AE) Placebo Febuxostat 80mg Allopurinol 300mg Any AE 72% 68% 73% 75% Diarrhea 8% 6%* 7%* 13%** 6% Hypertension 5% 2% 4% 1%*** Neurologic sx 1% 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 ≤ 0.05 Schumacher HR, et al. Arthritis Rheum 2008.

Discussion Febuxostat effectively reduced sUA <6 Allopurinol dose fixed instead of titrated Patients with impaired renal function did not achieve sUA <6 with recommended allopurinol dose of 100mg AE profile similar across treatment groups except for diarrhea and dizziness higher in febuxostat 240mg group Schumacher HR, et al. Arthritis Rheum 2008.

Official treatment guidelines

Treatment: Summary of EULAR Recommendations Therapeutic goal of urate-lowering therapy is sUA <6.0 mg/dL Urate lowering therapy indications: Recurrent gout attacks Tophi and/or radiographic changes on initial presentation Address associated risk factors and comorbidities – tailor to the individual 37 Zhang W, et al. Ann Rheum Dis. 2006; 65: 1312-1324.

2012 ACR Management Guidelines Lifestyle Modification for all patients with gout Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering pharmacologic therapy Target sUA <6 at minimum, sUA <5 better Starting 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 sUA Khanna D, et al. Arthritis Care Res . 2012 Oct;64(10):1431-46

2012 ACR Management Guidelines Consider HLA screening for HLA-B*5801 in certain populations considered high risk for allopurinol hypersensitivity syndrome Koreans with stage 3 CKD or worse Han Chinese Thai descent Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when sUA not at target by XOI alone Pegloticase appropriate for severe refractory disease or intolerance of standard regimens Khanna D, et al. Arthritis Care Res. 2012 Oct;64(10):1431-46

2012 ACR Management Guidelines for Acute Gouty Arthritis The choice of pharmacologic agent depends on severity of the attack Monotherapy for mild/moderate attack Combination therapy for severe attack or those refractory to monotherapy Acceptable combination therapy approaches include Colchicine and NSAIDS Oral steroids and colchicine Intra-articular steroids with all other modalities Continue current therapy during flare Patient education on signs of flare for self treatment Kanna D, et al. Arthritis Care Res (Hoboken). 2012 Oct;64(10):1447-61

Take Home Points Goal sUA < 6, and use concurrent prophylaxis Colchicine has FDA-approved dosing guidelines for chronic kidney disease Allopurinol doses above recommended CrCl-based dose is effective with minimal adverse effect Febuxostat is an excellent alternative for patients with renal insufficiency Other treatment alternatives exist, please refer to your friendly rheumatologist for difficult cases

QUESTIONS? bsiaton@medicine.umaryland.edu