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

Disclosures

none

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!
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):74-80

Garg R, et al. Semin Arthritis Rheum. 2011 Jun;40(6):501-11.

Gout Management Approach

INITIATE
(acute flare)

Treat

acute flare rapidly with antiinflammatory agent

Initiate

RESOLVE
(urate-lowering therapy)

MAINTAIN
(treatment to control sUA)

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

Myth #1

Acute gout flares are treated with 1 tablet of

colchicine hourly until the patient develops
diarrhea or gets better.

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.

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

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
Maintenance Dose of
on CrCl
CrCl (mL/min)
Allopurinol

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.

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

hypoxanthine

XO

xanthine

XO

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
allopurin
ol

Xanthin
e
Oxidase

Allopurinol
Hypersensit
ivity
Syndrome

oxypurino
l

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
< of6allopurinol in patients with renal
DosesUA
reduction
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

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

<6 for 3 months then q3 months

Stamp LK, et al. Arthritis Rheum 2011.

sUA

26

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.

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

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.

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
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.

34

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
The choice of pharmacologic agent depends on severity of the
Arthritis
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

41

QUESTIONS?

bsiaton@medicine.umaryland.edu
42