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15 Pearls of Gout Management:
how to be the best gout doctor ever!
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Obesity epidemic +High fructose corn syrup
Stamp et al, Arth & Rheum, 63(2)
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Fructose
Fructose 1- phosphate
Inosine
Uric acid
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Increasing prevalence of gout
Y-axis = prevalence per 1000 individuals
Wallace, et al, J Rheum, 31(8):1582
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Prevalence of gout
1990s: “Gout is the 2nd most
common inflammatory arthritis”
Today: Gout is THE MOST
COMMON inflammatory arthritis
2008 Prevalence: 1 out 25 adults 1 out of 16 men 1 out of 8 elderly
Gout Epidemic!
National Health and Nutrition Examination Survey (NHANES) data
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Obesity
Obesity increases sUA -increases urate synthesis -decreased renal excretionBMI 30-34.9 = RR 2.33 for goutBMI ≥ 35 = RR 2.97
Marasini, J of Rheum, 36(4), 2009Choi et al, Arch of Int Med, 165(7), 2005
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HypertensionObesity
Choi et al, Arch Int Med, 165, 2005Choi et al, BMJ, 334, 2012Feig et al, JAMA, 300 (8), 2008
-Harvard: 47,150 men over 12 years-HTN→ RR 2.31 new onset gout-diuretics→ RR 1.7
-another study: diuretics RR 2.36 losartan RR .71
-Baylor study: 30 adolescents: HTN + sUA ≥ 6 allopurinol 400 mg qd vs placebo 4 weeks 1/3 normal BP on allopurinol 1/30 normal BP on placebo
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Hypertension
Dyslipidemia
Obesity
Gelber A, Rheumatology News, January 2010
-JHH: 1216 men, average age 22 yo-followed 45 years-those with top quintile cholesterol, average of 217 mg/dl-60% higher prevalence of gout over next 45 years adjusted for BMI and HTN
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Hypertension
Chronic kidney disease
Dyslipidemia
Obesity
-25-40% of gout pts have CKD
-Gout tx allop→ improved GFR 267 pts, over 5 years 74 ml/min → 80 ml/min
-Gout tx febuxostat→ 1 mg/dl improvement in sUA → 1 ml/min incr. in GFR
Johnson RJ et al, Hypertension, vol 41, 2003Jo et al., J of Rheum Dis, 18(1), 2011Whelton et al, J of Clin Rheum, 17(1), 2011
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Hypertension
Chronic kidney disease
Insulin resistance/DM type II
Dyslipidemia
Obesity
-22% of men with DM II have gout -41% of men > 65yo have DM II-New onset DM II RR in pts with gout = 1.34-Insulin resistance increases sUA hyperinsulinemia decreases renal clearance-Gout and DMII share genetic risk factors
Suppiah et al, New Zealand Med Journal, 121(1283), 2008Choi et al, Rheumatology, 47(10, 2008Marasini, J of Rheum, 36(4), 2009Lai et al, Rheumatology (Oxford), 2011
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Hypertension
Chronic kidney disease
Insulin resistance/DMII
Cardiovascular disease
Dyslipidemia
Obesity
≥ 20% have a very high 5 year risk for CVD event
-additional 15% were at high risk-Men with gout = 30% increase in CVD death in 6 yrs-Another 6 yr study: RR for CV death = 1.97-Gout = independent risk factor for CVD
Colvine K. et al, New Zealand Med Journal, 121(1285), 2008Krishnan et al, Archives Int Med, 10(26), 2008Kuo et al, Rheumatology, 49(1), 2010
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Hypertension
Chronic kidney disease
Insulin resistance/DMIICardiovascular disease
Dyslipidemia
Obesity
Pearl 1: Every gout patient needs a good PCP
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Does hyperuricemia cause metabolic syndrome?
Rats fed high fructose diet Normally develop metabolic syndrome
Prophylactic allopurinol or a uricosuric agent No change in dietary intake ↓ weight gain ↓ HTN ↓ triglyceride elevations ↓ hyperinsulinemia
[sUA] proportional to amount of vasoconstriction
Nakagawa et al, Am J of Phys - Renal Physiology, 290(3), 2006
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Definition of hyperuricemia
Hyperuricemia is sUA > 6.8 mg/dL At a pH of 7.4 Urate limit of solubility = 6.8 mg/dL
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Pearl 2:Normal sUA ≤ 6.8 mg/dL
(ignore what the lab sheet says)
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Is it gout?
Try to make a crystal proven diagnosis Most hyperuricemics don’t have gout 1/3 of acute gout flares have normal sUA 1/3 of polyarticular gout patients have +RF
When gout is “diagnosed” clinically Sensitivity = 70% Specificity = 79%
Malik et al: J of Clinical Rheum, 15(1), 2009
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Pearl 3:Make a crystal-proven
diagnosis whenever possible
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1st:Stop Acute Gout Attacks ASAP
Anti-inflammatory Drugs NSAIDS
Use around the clock, maximum doses No NSAID better than another Most gout patients can’t take NSAIDs
low eGFR Elevated BP GI issues
Colchicine Corticosteroids
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Stop Acute Gout Attacks ASAP
Anti-inflammatory Drugs NSAIDS Colchicine (Colcrys)
.6 mg tablets 2 tablets ASAP Then 1 more tablet 1 hour later
Corticosteroids
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Stop Acute Gout Attacks ASAP
Anti-inflammatory Drugs NSAIDS Colchicine Corticosteroids
Oral Prednisone 40 mg qam for 7 days
Intramuscular 1cc depoMEDROL + 1cc dexamethasone IM buttock
Intra-articular Safest steroid approach
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Pearl 4:Some patients (severe gout)
may need more than one type of therapy for acute gout attacks
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In all gout patients:
Rx weight loss Educate patient about gout Adjust cardiovascular meds
Stop non-critical diuretics Rx losartan Rx fenofibrate
Rx vitamin C Rx gout diet
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Stop non-critical diuretics
Loop diuretics (furosemide) Thiazide diuretics (HCTZ)
HCTZ increases sUA .8 – 1.53 mg/dl
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Rx losartan Uricosuric
Works even if CKD ↑s urine pH (prevents stones)
Not other ARBs Decreases sUA .32 mg/dl – 1.33 Probably dose related
Handler, Hypertension, 12(9), 2010
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Rx fenofibrate An even stronger uricosuric! English study:
Added to allopurinol → 19% addition reduction in sUA Korean group = 23% decrease Chinese study:
200 mg/d→ sUA decreased 28% Japanese study:
300 mg/d: sUA 7.0 mg/dL→ 5.2 mg/dL (26%)
Feher et al, Rheumatology (Oxford), 42(2), 2003Lee, Korean J of Int Med, 2006Li, J of Peking Univ, 41(5), 2009Noguchi, J of Atherosclerosis and Thrombosis, 11(6), 2004
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Rx Vitamin C 1000 mg a day
Vit C is uricosuric Vit C 500 mg qd
Normal subjects Decreased sUA .5 mg/dL
Another 20 year study, men Vit C 500 mg/d = RR for gout .83 Vit C 1000 – 1499 mg/d = .66 Vit C ≥ 1500 mg/d = .55
Huang et al, Arthritis & Rheum, 52(6), 2005
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Rx a gout diet
Decreases sUA 1.0 – 1.7 mg/dL
Dussein, Ann of Rheum Disease, 59(7)2000Choi et al, NEJM, 350(11), 2004
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Rx a gout diet
Decrease intake of meat purines Eat in moderation Smaller quantities at a time
Choi, NEJM, 350(11), 2000
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Rx a gout diet
Decrease intake of meat purines No restrictions in vegetables
High purine vegetables don’t cause gout when eaten in moderation
Choi, NEJM, 350(11), 2000
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Rx a gout diet
Decrease intake of meat purines No restrictions in vegetables Consume more dairy products
Increased dairy = Lower gout prevalence
Choi, NEJM, 350(11), 2000
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Rx a gout diet
Decrease intake of meat purines No restrictions in vegetables Consume more dairy products Drink plenty of fluids
Avoid volume depletion
Choi, NEJM, 350(11), 2000
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Rx a gout diet Decrease intake of meat purines No restrictions in vegetables Consume more dairy products Drink plenty of fluids Avoid beer and hard liquor
1 beer a day RR for gout = 1.5 Beer = high in guanosine Beer → volume depletion and lactic acidosis
Choi, NEJM, 350(11), 2000
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Rx a gout diet
Decrease intake of meat purines No restrictions in vegetables Consume more dairy products Drink plenty of fluids Avoid beer and hard liquor
Liquor 2 shots a day or more RR = 1.6
Choi, NEJM, 350(11), 2000
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Rx a gout diet
Decrease intake of meat purines No restrictions in vegetables Consume more dairy products Drink plenty of fluids Avoid beer and hard liquor
Wine 8 oz a day = No increase in gout
Choi, NEJM, 350(11), 2000
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Rx a gout diet
Decrease intake of meat purines No restrictions in vegetables Consume more dairy products Drink plenty of fluids Avoid beer and hard liquor Avoid high fructose corn syrup foods
HFCS→ inosine → ↑ sUA levels HFCS→ increases fat production
Choi, Lancet, 363(9417), 2004
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Pearl 5: In all gout patients
Adjust cardiovascular meds Stop non-critical loop and thiazide diuretics Rx losartan in HTN regimen Rx fenofibrate in dyslipidemia regimen
Rx vitamin C 1000 mg a day Rx a gout diet Rx weight loss Educate patient about gout
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Next question to address :
Rx urate lowering therapy or not?
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Urate lowering meds:Review urate metabolism
Purines from meats, beer, fructose, and body cell turnover
Uric acid
Xanthine oxidase
Renal excretion
Overproduction10% of gout patients
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Urate lowering meds:Review urate metabolism
Purines from meats, beer, fructose, and body cell turnover
Uric acid
Xanthine oxidase
Renal excretion
Underexcretion90% of gout patients
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Urate lowering meds:Uricosurics
Purines from meats, beer, fructose, and body cell turnover
Uric acid
Xanthine oxidase
Renal excretion
Excretion=Uricosurics
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Urate lowering meds:Uricosurics
Purines from meats, beer, fructose, and body cell turnover
Uric acid
Xanthine oxidase
Renal excretion
Excretion=UricosuricsVitamin CLosartanFenofibrate
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Urate lowering meds:Uricosurics
Purines from meats, beer, fructose, and body cell turnover
Uric acid
Xanthine oxidase
Renal excretion
Excretion=UricosuricsLosartanFenofibrateVitamin C
Probenecid
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Urate lowering meds:Xanthine oxidase inhibitors
Purines from meats, beer, fructose, and body cell turnover
Uric acid
Xanthine oxidase AllopurinolFebuxostat (Uloric)
Renal excretion
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Urate lowering meds:Uricase
Purines from meats, beer, fructose, and body cell turnover
Uric acid Allantoin
Xanthine oxidase
Renal excretion
Pegloticase (Krystexxa)Uricase
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Next question to address:
Rx urate lowering therapy or not? End organ damage or large body stores of UA?
Joint damage Renal insufficiency Nephrolithiasis Tophi on PE
The above require a xanthine oxidase inhibitor Allopurinol Febuxostat (Uloric)
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Pearl 6: Rx allopurinol or febuxostat
to anyone with gout and:
Joint damage Renal insufficiency Nephrolithiasis Tophi
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Pearl 7: Prophylactic anti-inflammatory before urate lowering medicine
Anti-inflammatory drugs NSAIDs, daily full dose (eg , meloxicam 15 mg qd) Colchicine (Colcrys) 0.6 mg bid
If CKD ↓ to 0.6 mg qd after stable on urate lowering med
Prednisone, lowest dose needed E.g. 2.5 – 7.5 mg a day
May need a combination in severe patients Stop 6 – 12 months after sUA is at goal
Or after all tophi resolved
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Pearl 8: Don’t use prophylaxis without concomitant urate lowering tx
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Pearl 9: Don’t start or stop urate
lowering tx during an attack
Wait about 2 weeks after attack resolved
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Pearl 10: Gout “Treat to Target” goal=
sUA < 6.0 mg/dL European League Against Rheumatism
Minimum requirement Want to do even better?
Strive for sUA < 5.5 mg/dL sUA < 5.0 mg/dL if tophi or joint damage
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Allopurinol
Initial dosing If normal renal function = 300 mg qd If decreased renal function = 50-100 mg qd
CHECK sUA 2 weeks later Adjust dose up until sUA < 6.0
Maximum dose of allopurinol is 800 mg qd NOT 300 mg
“If you get a rash, stop it and call me”
Dalbeth et al, Seminars in Dialysis, 20(5), 2007
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Allopurinol dosing in CKD
Initial dosed based on renal function CKD use 50 – 100 mg qd
Increase every 2 weeks based on sUA Goal = sUA ≤ 6.0 mg/dL
Don’t base maintenance doses on eGFR! Gout patients with CKD are undertreated!
Using allopurinol above the dose based on creatinine clearance is effective and
safe in patients with chronic gout, including those with renal impairment
Stamp et al, Arth & Rheum, 63(2), 2011
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Pearl 11: Allopurinol Dose ≠
300 mg qd
Allopurinol dose = 50 mg –
800 mg qd
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Febuxostat (Uloric)
Initial dosing 40 mg qd
CHECK sUA 2 weeks later If sUA > 6.0 mg/dL Increase to 80 mg qd
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If allopurinol/febuxostat not initially required:
If first attack, or 2 widely spaced Follow using advice in pearl 5
If ≥ 2 attacks, especially 2 in a year Get a 24 hour urine uric acid
UA > 800 mg/24 hours = overproducer (10%) Use allopurinol or febuxostat
UA < 800 mg/24 hours = underexcretor (90%) Use probenecid
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Probenecid
Start 250 mg bid with meals Effective within 2 hours Same time as postprandial diuresis
Food increases urine pH = less stones Liquid increases urine flow = less stones
Increase q 2 weeks until sUA < 6.0 Increase by 250 to 500 mg increments Maximum dose = 3000 mg per day Caution patient to stay hydrated
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Probenecid
Consider alkalinizing urine to prevent stones Acetazolamide 250 mg qAM
During the first week of adding probenecid One week after increasing the dose
Want urine pH >6.5 at least part of the day
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Pearl 12: Use more probenecid
Safer than allopurinol 90% of gout is due to underexcretion
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Pearl 13: Check sUA level every 2 weeks on urate lowering
meds Check sUA 2 weeks after adding
allopurinol, febuxostat, or probenecid Increase dose ASAP if sUA > 6.0 Repeat sUA 2 weeks later after each dose
Repeat until target sUA reached
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Difficult gout case:
Gout patient on: Allopurinol 800 mg qd eGFR = 50 ml/min sUA = 7.1
What to do next?
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Difficult gout case:
Gout patient on: Allopurinol 800 mg qd eGFR = 50 ml/min sUA = 7.5
What to do next? Add Probenecid
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Pearl 14: Add Probenecid to allopurinol if sUA
goal not achieved
Allopurinol (100-400mg/d) + probenecid (250mg bid)
25% additional reduction in sUA Even works if CKD
Stocker et al, Clinical Pharmacokinetics, 47(2), 2008Stocker et al, J of Rheum, 38(5), 2010
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Pearl 15: After 5 years of gout control:
target sUA < 6.8 mg/dL 211 patients
5 years after tophi gone 5 years of urate lowering tx with sUA < 6.0 Urate lowering tx stopped Then followed for average of 3 years Those who had sUA < 7.0 had not gout attacks
Especially those with weight loss, on losartan or fenofibrate
After 5 years of no tophi & sUA < 6.0 Taper down urate meds
Perez-Ruiz, Arth and Rheum, 65(12), 2011
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15 Pearls of Gout Tx:Important Points
1) Normal sUA ≤ 6.8 mg/dL
2) Treat to Target is sUA < 6.0 mg/dL1) Strive for much lower if tophi
2) Monitor sUA regularly life long
3) Use Vitamin C, losartan, fenofibrate, diet
4) Check sUA every 2 weeks after urate lowering therapy added
1) Adjust dose of medicine ASAP if sUA > 6.0
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