1. 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

2. Disclosures
none

3. 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

4. 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!

5. 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
Random sample of primary care doctors in the US, 883 respondents (41% response rate)
63% private practice, 52% >16 years in practice
Harrold LR, et al. Rheumatology,

6. Healthcare Utilization
Rheumatologists vs. Non-rheumatologists
ER visits (Nationwide Sample of 20% of ERs)
0.2% of all ER visits
$166 million in ED charges alone in 2008
Rheum
Non-rheum
P-value
Radiographs (%) 65 31
<0.05
Arthrocentesis (%) 75 34
Time to improvement (days)
3.6
6.6
0.06
Hospitalization (days)
7.4
14.7
0.08
Healthcare costs ($)
8756
14750
Panush RS, et al. J Clin Rheumatol Apr; 1(2):74-80
Garg R, et al. Semin Arthritis Rheum Jun;40(6):

7. Gout Management Approach
INITIATE
(acute flare)
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
RESOLVE
(urate-lowering therapy)
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) 7

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

9. 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
Patients given a blister pack, called the call-center to confirm flare -4 cardinal signs present. Kept journal of pain scores then returned to study center within 4 hours and had several visits.
Terkeltaub, RA., et al. Arthritis Rheum 2010.

10. 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
23.0
13.6
Nausea
17.3
4.1
5.1
Vomiting
Terkeltaub, RA., et al. Arthritis Rheum 2010.

11. Improvement in pain @ 24 hours
High-dose
Low-dose
placebo
Terkeltaub, RA., et al. Arthritis Rheum 2010.

12. 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 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.

13. Myth #2
You cannot use allopurinol in patients with renal insufficiency

14. 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.

15. Maintenance Doses of Allopurinol for Adults based on CrCl
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
Stage 1 renal damage with normal GFR
(GFR > 90 ml/min)
Stage 2 Mild CKD (GFR = ml/min)
Stage 3 Modererate CKD (GFR = ml/min)
Stage 4 Severe CKD (GFR = ml/min)
Stage 5 End Stage CKD (GFR <15 ml/min)
Hande KR, et al. Am J Med, 1984.

16. 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.

17. 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.

18. Oxypurinol
Allopurinol Hypersensitivity Syndrome
Xanthine
Oxidase
allopurinol
oxypurinol
Toxic Epidermal 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

19. 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

20. 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.

21. 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.

22. 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.

23. 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.

24. Myth #3
The maximum dose of allopurinol in patients with renal insufficiency should not exceed 300mg

25. Allopurinol dosing algorithm
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
Stage 1 renal damage with normal GFR
(GFR > 90 ml/min)
Stage 2 Mild CKD (GFR = ml/min)
Stage 3 Modererate CKD (GFR = ml/min)
Stage 4 Severe CKD (GFR = ml/min)
Stage 5 End Stage CKD (GFR <15 ml/min)
Hande KR, et al. Am J Med, 1984.

26. 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.

27. Allopurinol Use in Renal Insufficiency
Stamp LK, et al. Arthritis Rheum 2011.

28. Allopurinol Use in Renal Insufficiency
Mean baseline dosage
221.4mg (range , 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 , median 450)
Stamp LK, et al. Arthritis Rheum 2011.

29. 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.

30. Allopurinol vs. Febuxostat
Febuxostat (Uloric)
FDA-approved 1966
FDA-approved 2009
Purine-selective XO Inhibitor
Non-Purine Selective XO Inhibitor
Prevents uric acid production
Renal Metabolism
Liver Metabolism

31. 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.

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

33. Schumacher HR, et al. Arthritis Rheum 2008.

34. Adverse Events Any Adverse Event (AE) Placebo Febuxostat 80mg
Allopurinol 300mg
Any AE
72%
68%
73%
75%
Diarrhea 8%
6%*
7%*
13%** 6%
Hypertension 5% 2% 4%
1%***
Neurologic sx 1%
2%*
7%**
Muscle sx
<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.

35. 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.

36. Official treatment guidelines

37. 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 ; 65:

38. 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
Khanna D, et al. Arthritis Care Res Oct;64(10):

39. 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 Oct;64(10):

40. 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
Kanna D, et al. Arthritis Care Res (Hoboken) Oct;64(10):

41. 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

42. QUESTIONS?