15 Pearls of Gout Management:

how to be the best gout doctor ever!

Obesity epidemic +High fructose corn syrup

Stamp et al, Arth & Rheum, 63(2)

Fructose

Fructose 1- phosphate

Inosine

Uric acid

Increasing prevalence of gout

Y-axis = prevalence per 1000 individuals

Wallace, et al, J Rheum, 31(8):1582

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

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

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

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

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

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

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

Hypertension

Chronic kidney disease

Insulin resistance/DMIICardiovascular disease

Dyslipidemia

Obesity

Pearl 1: Every gout patient needs a good PCP

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

Definition of hyperuricemia

Hyperuricemia is sUA > 6.8 mg/dL At a pH of 7.4 Urate limit of solubility = 6.8 mg/dL

Pearl 2:Normal sUA ≤ 6.8 mg/dL

(ignore what the lab sheet says)

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

Pearl 3:Make a crystal-proven

diagnosis whenever possible

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

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

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

Pearl 4:Some patients (severe gout)

may need more than one type of therapy for acute gout attacks

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

Stop non-critical diuretics

Loop diuretics (furosemide) Thiazide diuretics (HCTZ)

HCTZ increases sUA .8 – 1.53 mg/dl

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

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

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

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

Rx a gout diet

Decrease intake of meat purines Eat in moderation Smaller quantities at a time

Choi, NEJM, 350(11), 2000

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

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

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

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

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

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

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

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

Next question to address :

Rx urate lowering therapy or not?

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

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

Urate lowering meds:Uricosurics

Purines from meats, beer, fructose, and body cell turnover

Uric acid

Xanthine oxidase

Renal excretion

Excretion=Uricosurics

Urate lowering meds:Uricosurics

Purines from meats, beer, fructose, and body cell turnover

Uric acid

Xanthine oxidase

Renal excretion

Excretion=UricosuricsVitamin CLosartanFenofibrate

Urate lowering meds:Uricosurics

Purines from meats, beer, fructose, and body cell turnover

Uric acid

Xanthine oxidase

Renal excretion

Excretion=UricosuricsLosartanFenofibrateVitamin C

Probenecid

Urate lowering meds:Xanthine oxidase inhibitors

Purines from meats, beer, fructose, and body cell turnover

Uric acid

Xanthine oxidase AllopurinolFebuxostat (Uloric)

Renal excretion

Urate lowering meds:Uricase

Purines from meats, beer, fructose, and body cell turnover

Uric acid Allantoin

Xanthine oxidase

Renal excretion

Pegloticase (Krystexxa)Uricase

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)

Pearl 6: Rx allopurinol or febuxostat

to anyone with gout and:

Joint damage Renal insufficiency Nephrolithiasis Tophi

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

Pearl 8: Don’t use prophylaxis without concomitant urate lowering tx

Pearl 9: Don’t start or stop urate

lowering tx during an attack

Wait about 2 weeks after attack resolved

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

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

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

Pearl 11: Allopurinol Dose ≠

300 mg qd

Allopurinol dose = 50 mg –

800 mg qd

Febuxostat (Uloric)

Initial dosing 40 mg qd

CHECK sUA 2 weeks later If sUA > 6.0 mg/dL Increase to 80 mg qd

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

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

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

Pearl 12: Use more probenecid

Safer than allopurinol 90% of gout is due to underexcretion

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

Difficult gout case:

Gout patient on: Allopurinol 800 mg qd eGFR = 50 ml/min sUA = 7.1

What to do next?

Difficult gout case:

Gout patient on: Allopurinol 800 mg qd eGFR = 50 ml/min sUA = 7.5

What to do next? Add Probenecid

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

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

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