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
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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!
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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






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 <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):74-80
Garg 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.
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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
Terkeltaub, RA., et al. Arthritis Rheum 2010.
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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)
Terkeltaub, RA., et al. Arthritis Rheum 2010.
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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.
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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.
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Pathophysiology
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hypoxanthine urate xanthine
XO XO
XO=xanthine oxidase
Allopurinol and febuxostat inhibit
xanthine oxidase and block uric acid
formation
Markel A. IMAJ, 2005.
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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, 13
th
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.

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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

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

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

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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 individual
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Zhang W, et al. Ann Rheum Dis. 2006; 65: 1312-1324.
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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
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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
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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


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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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