Gout Update 2014 Bernadette C Siaton MD Assistant

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 1

Disclosures n none 2

Objectives n n 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 3

5 Gout Commandments n n n Hyperuricemia ≠ Gout Goal s. UA < 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! 4

Gout Management –the Score Card n n n 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 formal guidelines for rheumatology referral Harrold LR, et al. Rheumatology, 2013.

Healthcare Utilization n Rheumatologists vs. Non-rheumatologists Rheum P-value Radiographs (%) 65 31 <0. 05 Arthrocentesis (%) 75 34 <0. 05 Time to improvement (days) 3. 6 6. 6 0. 06 Hospitalization (days) 7. 4 14. 7 0. 08 8756 14750 Healthcare costs ($) n Non-rheum ER visits (Nationwide Sample of 20% of ERs) q q 0. 2% of all ER visits $166 million in ED charges alone in 2008 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) RESOLVE (urate-lowering therapy) MAINTAIN (treatment to control s. UA) 7 • Treat acute flare rapidly with antiinflammatory agent • Initiate urate-lowering therapy to achieve s. UA <6 • Use concomitant anti-inflammatory prophylaxis for up to 6 mo to prevent mobilization flares • Continue urate lowering therapy to control flares and avoid crystal deposition • Prophylaxis use for at least 3 -6 months until s. UA normalizes 7

Myth #1 n Acute gout flares are treated with 1 tablet of colchicine hourly until the patient develops diarrhea or gets better. 8

AGREE study: Acute Gout Flare Receiving Colchicin. E Evaluation n n n High vs. Low Dose Colchicine for Gout Flare Randomized, double-blind, placebo-controlled study Low dose colchicine (1. 8 mg total over 1 h) High dose colchicine (4. 8 mg total over 6 h) Primary end point: >50% pain reduction in 24 hours without rescue medication 184 patients intent-to-treat analysis Terkeltaub, RA. , et al. Arthritis Rheum 2010. 9

AGREE study: Acute Gout Flare Receiving Colchicin. E 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 76. 9 23. 0 13. 6 Nausea 17. 3 4. 1 5. 1 Vomiting 17. 3 0 0 Terkeltaub, RA. , et al. Arthritis Rheum 2010. 10

Improvement in pain @ 24 hours High-dose Low-dose placebo Terkeltaub, RA. , et al. Arthritis Rheum 2010. 11

Take home points n n 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 q q q Cr. Cl 30 -80 ml/min = 0. 6 mg daily Cr. Cl <30 ml/min = 0. 3 mg daily HD = 0. 6 mg twice weekly (not dialyzable) Terkeltaub, RA. , et al. Arthritis Rheum 2010. 12

Myth #2 n You cannot use allopurinol in patients with renal insufficiency 13

Allopurinol and Renal Insufficiency n 1984 Hande, et al published “Severe allopurinol toxicity: Description and guidelines for prevention in patients with renal insufficiency” q “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. 14

Maintenance Doses of Allopurinol for Adults based on Cr. Cl 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. Cr. Cl (m. L/min) Maintenance Dose of Allopurinol 0 100 mg every 3 d 10 100 mg every 2 d 20 100 mg 40 150 mg 60 200 mg 80 250 mg 100 300 mg 120 350 mg 140 400 mg 15

What did doctors take home? n n Guidelines made in order to prevent allopurinol hypersensitivity Allopurinol should not be used in renal insufficiency Hande KR, et al. Am J Med, 1984. 16

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

Oxypurinol Allopurinol Hypersensitivity Syndrome allopurinol Xanthine Oxidase oxypurinol Toxic Epidermal Necrolysis Stevens. Johnson Syndrome n n n 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 18

Allopurinol Hypersensitivity Syndrome n n n 2% of allopurinol users develop cutaneous rash Frequency of hypersensitivity 1 in 260 DRESS syndrome q 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 q Steroids, N-acetyl-cysteine, dialysis prn Markel A. IMAJ, 2005. Terkeltaub RA, in Primer on the Rheumatic Disease, 13 th ed. 2008. 19

Relationship between recommended allopurinol dose and s. UA < 6 n Dose reduction of allopurinol in patients with renal insufficiency may lead to under-treatment and persistent hyperuricemia n Dalbeth, et al. created allopurinol calculator n Performed retrospective chart review of 250 patients with ACR criteria for gout n Divided into 4 groups: q q no allopurinol lower than recommended allopurinol dose higher than recommended allopurinol dose Dalbeth N, et al. J Rheum, 2006. 20

Results n 227/250 (90. 8%) were taking allopurinol q q n Mean allopurinol dose was 214 mg/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 q All took recommended doses Dalbeth N, et al. J Rheum, 2006. 21

Is recommended dose of allopurinol enough? 19% (recommended) vs 38% (higher than recommended) reached s. UA <6, p <0. 01 Dalbeth N, et al. J Rheum, 2006. 22

Is recommended dose of allopurinol enough? n Limitations: q q q n Retrospective study Homogenous population (Maori/Pacific Islanders) Cannot judge medication compliance Conclusions: q Allopurinol dosing according to published guidelines has NOT led to adequate control of hyperuricemia Dalbeth N, et al. J Rheum, 2006. 23

Myth #3 n The maximum dose of allopurinol in patients with renal insufficiency should not exceed 300 mg 24

Allopurinol dosing algorithm 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. Cr. Cl (m. L/min) Maintenance Dose of Allopurinol 0 100 mg every 3 d 10 100 mg every 2 d 20 100 mg 40 150 mg 60 200 mg 80 250 mg 100 300 mg 120 350 mg 140 400 mg 25

Allopurinol Use in Renal Insufficiency n Objective: q Determine the safety and efficacy of increasing allopurinol dose above the proposed guidelines for patients with gout n Prospective study of patients on allopurinol ≥ 1 month n 81. 9% European, 14. 4% Maori or Pacific Island Descent n Saw patients monthly and titrated allopurinol until <6 for 3 months then q 3 months Stamp LK, et al. Arthritis Rheum 2011. s. UA 26

Allopurinol Use in Renal Insufficiency Stamp LK, et al. Arthritis Rheum 2011. 27

Allopurinol Use in Renal Insufficiency n Mean baseline dosage q n Mean dose for pts who completed study q n 221. 4 mg (range 100 -400, median 200) 335. 7 mg (range 0 -600, median 350) Mean dose for pts who achieved s. UA <6 q 359. 7 mg (range 150 -600, median 450) Stamp LK, et al. Arthritis Rheum 2011. 28

Conclusions n Doses above recommended dose are effective for lowering s. UA with few adverse events n Patients with renal impairment tolerated allopurinol doses higher than Cr. Cl-based doses and achieved s. UA <6 n Monitor s. UA regularly and treat-to-target s. UA <6 n Limitations of study: self-selected patients who were already on allopurinol → minimize incidence of toxicity Stamp LK, et al. Arthritis Rheum 2011. 29

Allopurinol vs. Febuxostat Allopurinol 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 30

Allopurinol vs. Febuxostat n n n Phase III, randomized, double-blind, allopurinol and placebo-controlled parallelgroup trial Primary end point: proportion of subjects with the last 3 monthly s. UA <6 regardless of whether or not subject completed the study Randomized 2: 2: 1 q febuxostat 80 mg: 120 mg: 240 mg: allopurinol: placebo Schumacher HR, et al. Arthritis Rheum 2008. 31

Proportion of subjects with last 3 monthly s. UA <6 Schumacher HR, et al. Arthritis Rheum 2008. 32

Schumacher HR, et al. Arthritis Rheum 2008. 33

Adverse Events Any Adverse Event (AE) Placebo Febuxostat 80 mg Febuxostat 120 mg Febuxostat 240 mg Allopurinol 300 mg Any AE 72% 68% 73% 75% Diarrhea 8% 6%* 7%* 13%** 6% Hypertension 6% 5% 2% 4% 1%*** Neurologic sx 1% 2%* 7%** 2% Muscle sx 5% 1% <1%*** *Statistically significant versus febuxostat 240 mg p ≤ 0. 05 **Statistically significant versus allopurinol p ≤ 0. 05 ***Statistically significant versus placebo p ≤ 0. 05 Schumacher HR, et al. Arthritis Rheum 2008. 34

Discussion n n Febuxostat effectively reduced s. UA <6 Allopurinol dose fixed instead of titrated Patients with impaired renal function did not achieve s. UA <6 with recommended allopurinol dose of 100 mg AE profile similar across treatment groups except for diarrhea and dizziness higher in febuxostat 240 mg group Schumacher HR, et al. Arthritis Rheum 2008. 35

Official treatment guidelines 36

Treatment: Summary of EULAR Recommendations n n Therapeutic goal of urate-lowering therapy is s. UA <6. 0 mg/d. L Urate lowering therapy indications: q q n 37 Recurrent gout attacks Tophi and/or radiographic changes on initial presentation Address associated risk factors and comorbidities – tailor to the individual Zhang W, et al. Ann Rheum Dis. 2006; 65: 1312 -1324. 37

2012 ACR Management Guidelines Lifestyle Modification for all patients with gout n n Xanthine Oxidase Inhibitor (XOI) first-line urate-lowering pharmacologic therapy n Target s. UA <6 at minimum, s. UA <5 better n Starting dose of allopurinol should be 100 mg, less in CKD with titration above 300 mg prn if needed (even in CKD) n Continue prophylaxis for 3 (no tophi) – 6 months (tophi) after achieving target s. UA 38 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 n considered high risk for allopurinol hypersensitivity syndrome q Koreans with stage 3 CKD or worse q Han Chinese q Thai descent n Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when s. UA not at target by XOI alone n Pegloticase appropriate for severe refractory disease or intolerance of standard regimens Khanna D, et al. Arthritis Care Res. 2012 Oct; 64(10): 1431 -46 39

2012 ACR Management Guidelines for Acute Gouty Arthritis The choice of pharmacologic agent depends on severity of the attack q Monotherapy for mild/moderate attack q Combination therapy for severe attack or those refractory to monotherapy Acceptable combination therapy approaches include q Colchicine and NSAIDS q Oral steroids and colchicine q Intra-articular steroids with all other modalities Continue current therapy during flare Patient education on signs of flare for self treatment n n 40 Kanna D, et al. Arthritis Care Res (Hoboken). 2012 Oct; 64(10): 1447 -61

Take Home Points n n n Goal s. UA < 6, and use concurrent prophylaxis Colchicine has FDA-approved dosing guidelines for chronic kidney disease Allopurinol doses above recommended Cr. Clbased 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 41

QUESTIONS? bsiaton@medicine. umaryland. edu 42