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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 Immunology

1 February 2014

1

Disclosures

none

2

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

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

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.

Healthcare Utilization

Rheum Non-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

Healthcare costs ($) 8756 14750

Panush RS, et al. J Clin Rheumatol. 1995 Apr; 1(2):74-80Garg R, et al. Semin Arthritis Rheum. 2011 Jun;40(6):501-11.

Gout Management Approach

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•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)

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•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)

Myth #1

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

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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 2010.9

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 76.9 23.0 13.6

Nausea 17.3 4.1 5.1

Vomiting 17.3 0 0


Improvement in pain @ 24 hours

Terkeltaub, RA., et al. Arthritis Rheum 2010.

High-dose

Low-dose

placebo

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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)


Myth #2

You cannot use allopurinol in patients with renal insufficiency

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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. 14

CrCl (mL/min)Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg

Maintenance Doses of Allopurinol for Adults based on CrCl

Hande KR, et al. Am J Med, 1984.

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)

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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. 16

Pathophysiology

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hypoxanthine urate xanthineXO XO

XO=xanthine oxidase

Allopurinol and febuxostat inhibit xanthine oxidase and block uric acid formation

Markel A. IMAJ, 2005.17

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

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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.

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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, 2006.20

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. 21

Is recommended dose of allopurinol enough?

Dalbeth N, et al. J Rheum, 2006.

19% (recommended) vs 38% (higher than recommended) reached sUA <6, p <0.01

22

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, 2006.23

Myth #3

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

24

CrCl (mL/min)Maintenance Dose of

Allopurinol

0 100mg every 3d

10 100mg every 2d

20 100mg

40 150mg

60 200mg

80 250mg

100 300mg

120 350mg

140 400mg

Allopurinol dosing algorithm

Hande KR, et al. Am J Med, 1984.

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)

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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. 26

Allopurinol Use in Renal Insufficiency

Stamp LK, et al. Arthritis Rheum 2011.27

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. 28

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 2011.29

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 Prevents uric acid production

Renal Metabolism Liver Metabolism

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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. 31

Proportion of subjects with last 3 monthly sUA <6

Schumacher HR, et al. Arthritis Rheum 2008.32

Adverse Events

Any Adverse Event (AE)

Placebo Febuxostat 80mg

Febuxostat 120mg

Febuxostat 240 mg

Allopurinol 300mg

Any AE 72% 68% 68% 73% 75%

Diarrhea 8% 6%* 7%* 13%** 6%

Hypertension 6% 5% 2% 4% 1%***

Neurologic sx 1% 2%* 2%* 7%** 2%

Muscle sx 5% 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


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


Official treatment guidelines

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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 individual37

Zhang W, et al. Ann Rheum Dis. 2006; 65: 1312-1324.37

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 . 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

39 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

40 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

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QUESTIONS?

[email protected]

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