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
 Rheumatologists vs. Non-rheumatologists
Rheum Non-rheum P-value
Radiographs (%) 65 31 <0.05
Arthrocentesis (%) 75 34 <0.05
Time to improvement 3.6 6.6 0.06
(days)
Hospitalization (days) 7.4 14.7 0.08
Healthcare costs ($) 8756 14750

 ER visits (Nationwide Sample of 20% of ERs)

 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 •Treat acute flare rapidly with anti-
(acute flare) inflammatory agent

•Initiate urate-lowering therapy to

achieve sUA <6
RESOLVE •Use concomitant anti-inflammatory
(urate-lowering therapy) prophylaxis for up to 6 mo to prevent
mobilization flares

•Continue urate lowering therapy

MAINTAIN to control flares and avoid crystal
(treatment to control sUA) deposition
•Prophylaxis use for at least 3-6
months until sUA normalizes 7

7
Myth #1

 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
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
% >50% % needing
Colchicine reduction in P value vs. Adverse rescue
Dose pain placebo Event Rate 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
 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. 12

Myth #2

 You cannot use allopurinol in patients with

renal insufficiency

13
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

 Maintenance Doses of Allopurinol for
Adults based on CrCl
Maintenance Dose of
CrCl (mL/min) Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
Stage 1 renal damage with normal GFR 40 150mg
(GFR > 90 ml/min)
Stage 2 Mild CKD (GFR = 60-89 ml/min) 60 200mg
Stage 3 Modererate CKD (GFR = 30-59 ml/min)
Stage 4 Severe CKD (GFR = 15-29 ml/min) 80 250mg
Stage 5 End Stage CKD (GFR <15 ml/min)
100 300mg
120 350mg
140 400mg

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

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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

XO XO
hypoxanthine xanthine urate

XO=xanthine oxidase

Allopurinol and febuxostat inhibit

xanthine oxidase and block uric acid
formation
17

Markel A. IMAJ, 2005.

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Oxypurinol
Allopurinol
Hypersensitivity
Syndrome
Xanthine
Oxidase Toxic Epidermal
allopurinol oxypurinol
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

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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.
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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?

19% (recommended) vs 38% (higher than recommended) reached

sUA <6, p <0.01
Dalbeth N, et al. J Rheum, 2006. 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.

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Myth #3

 The maximum dose of allopurinol in patients

with renal insufficiency should not exceed
300mg

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 Allopurinol dosing algorithm

Maintenance Dose of
CrCl (mL/min) Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
Stage 1 renal damage with normal GFR 40 150mg
(GFR > 90 ml/min)
Stage 2 Mild CKD (GFR = 60-89 ml/min) 60 200mg
Stage 3 Modererate CKD (GFR = 30-59 ml/min)
Stage 4 Severe CKD (GFR = 15-29 ml/min) 80 250mg
Stage 5 End Stage CKD (GFR <15 ml/min)
100 300mg
120 350mg
140 400mg

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

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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.

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 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.

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Allopurinol vs. Febuxostat
Allopurinol
FDA-approved 1966
Purine-selective XO Inhibitor
Prevents uric acid production
Renal Metabolism
Febuxostat (Uloric)
FDA-approved 2009
Non-Purine Selective XO
Inhibitor
Prevents uric acid production
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
Schumacher HR, et al. Arthritis Rheum 2008.
33
 Adverse Events
Any Adverse Placebo Febuxostat Febuxostat Febuxostat Allopurinol
Event (AE) 80mg 120mg 240 mg 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

Schumacher HR, et al. Arthritis Rheum 2008.

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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.

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Official treatment guidelines

36
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.

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

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
 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?

bsiaton@medicine.umaryland.edu

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