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

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Presentation on theme: "Gout Update 2014 Bernadette C. Siaton, MD Assistant Professor of Medicine University of Maryland School of Medicine Division of Rheumatology and Clinical."— Presentation transcript:

1 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

2 Disclosures none 2

3 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 3

4 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! 4

5 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 Harrold LR, et al. Rheumatology, 2013.

6 Healthcare Utilization Rheumatologists vs. Non-rheumatologists ER visits (Nationwide Sample of 20% of ERs)  0.2% of all ER visits  $166 million in ED charges alone in 2008 RheumNon-rheumP-value Radiographs (%)6531<0.05 Arthrocentesis (%)7534<0.05 Time to improvement (days) Hospitalization (days) Healthcare costs ($) Panush RS, et al. J Clin Rheumatol Apr; 1(2):74-80 Garg R, et al. Semin Arthritis Rheum Jun;40(6):

7 Gout Management Approach 7 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 INITIATE (acute flare) RESOLVE (urate-lowering therapy) 7 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)

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

9 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 Terkeltaub, RA., et al. Arthritis Rheum

10 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 dose32.7% %34.6% Low dose37.8% %31.1% Placebo15.5%n/a27.1%50.0% Adverse EventsHigh DoseLow DosePlacebo All GI Events Diarrhea Nausea Vomiting Terkeltaub, RA., et al. Arthritis Rheum

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

12 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 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

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

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,

15 CrCl (mL/min) Maintenance Dose of Allopurinol 0100mg every 3d 10100mg every 2d 20100mg 40150mg 60200mg 80250mg mg mg mg Maintenance Doses of Allopurinol for Adults based on CrCl Hande KR, et al. Am J Med, Stage 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) 15

16 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,

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

18 Oxypurinol 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 oxypurinol Xanthine Oxidase Stevens- Johnson Syndrome Allopurinol Hypersensitivity Syndrome Toxic Epidermal Necrolysis 18

19 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, Terkeltaub RA, in Primer on the Rheumatic Disease, 13 th 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 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,

21 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,

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

23 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,

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

25 CrCl (mL/min) Maintenance Dose of Allopurinol 0100mg every 3d 10100mg every 2d 20100mg 40150mg 60200mg 80250mg mg mg mg Allopurinol dosing algorithm Hande KR, et al. Am J Med, Stage 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) 25

26 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

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

28 Allopurinol Use in Renal Insufficiency Mean baseline dosage  221.4mg (range , 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 , median 450) Stamp LK, et al. Arthritis Rheum

29 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

30 Allopurinol vs. Febuxostat AllopurinolFebuxostat (Uloric) FDA-approved 1966FDA-approved 2009 Purine-selective XO InhibitorNon-Purine Selective XO Inhibitor Prevents uric acid production Renal MetabolismLiver Metabolism 30

31 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

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

33 Schumacher HR, et al. Arthritis Rheum

34 Adverse Events Any Adverse Event (AE) PlaceboFebuxostat 80mg Febuxostat 120mg Febuxostat 240 mg Allopurinol 300mg Any AE72%68% 73%75% Diarrhea8%6%*7%*13%**6% Hypertension6%5%2%4%1%*** Neurologic sx1%2%* 7%**2% Muscle sx5%1%<1%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

35 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

36 Official treatment guidelines 36

37 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:

38 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 38 Khanna 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 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 39 Khanna 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 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 40 Kanna 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 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 41

42 QUESTIONS? 42


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