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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

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 ($)

Non-rheum
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
(acute flare)
RESOLVE
(urate-lowering therapy)
MAINTAIN
(treatment to control sUA)
7
•Treat acute flare rapidly with antiinflammatory agent
•Initiate urate-lowering therapy to
achieve sUA <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 sUA normalizes
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
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


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
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.
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
15
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
hypoxanthine
XO
xanthine
urate
XO=xanthine oxidase
Allopurinol and febuxostat inhibit
xanthine oxidase and block uric acid
formation
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Markel A. IMAJ, 2005.
17
Oxypurinol
Allopurinol
Hypersensitivity
Syndrome
allopurinol
Xanthine
Oxidase
oxypurinol
Toxic Epidermal
Necrolysis
StevensJohnson
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
18
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.
19
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?
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.
23
Myth #3

The maximum dose of allopurinol in patients
with renal insufficiency should not exceed
300mg
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.
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
25
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.
27
Allopurinol Use in Renal Insufficiency

Mean baseline dosage


Mean dose for pts who completed study


221.4mg (range 100-400, median 200)
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 parallelgroup 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.
32
Schumacher HR, et al. Arthritis Rheum 2008.
33
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.
35
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:



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

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



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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 CrClbased 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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