Gout

(Get Out the Gout)

Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Bruyere & Primrose FHT
May 2011
 Objectives
 Describe clinical presentation of gout
 Identify drug & non-drug risk factors for
gout
 Compare treatment options for acute gout
attacks
 Describe options for control of
hyperuricemia / prophylaxis of gout attacks
 Describe challenges to treatment in elderly
populations
 Intro – Gout
 Most common
inflammatory arthritis in
elderly
 Increasing prevalence
 Highest 75-85 y.o.
 Men > women, (< 65y.o.)
 Deposition of urate
crystals in tissue
 Gout in women
 Usually > 65 y.o.
 Loss of estrogen induced
uricosuric effect
 First Acute Gouty Attack
 Usually after years of asymptomatic
hyperuricemia
 Monoarticular
Can progress to
polyarticular
 Explosive onset
 Exquisitely painful
 Peaking ~ 6-12hrs
James Gillray(1757-1815), artist - The Gout - London: 1799
 Gouty Arthritis
 Can cause:
 Chemical cellulitis
 Fever

 Mental status

changes
 Leukocytosis

 Elevated CRP and ESR

 Can be mistaken for bacterial cellulitis

 Pathophysiology
 Precipitation of monosodium urate crystals
in avascular tissues
 (cartilage, epiphyseal bone, periarticular bone)
 Hyperuricemia likely asymptomatic for years
 The acute attack - crystals activate plasma
proteases
 Can activate factor XII & C5
 Can adsorb opsonins in area, attracting
phagocytes!
Pathophysiology – Acute Attack

Inflammation lowers Phagocytosis fails

pH in the joint
Urate precipitates
Crystals lyse phagocytes
out of solution - tophi Tophi are released

MORE PHAGOCYTES Enzymes released

ARRIVE - Lactic acid into synovial fluid
is a byproduct Damage tissue,
of phagocytosis activate complement etc
 Pathophysiology – Acute Attack
 A vicious cycle.

 Acute attacks probably self-limited due to

heat of inflammation re-dissolving the
crystals
 Risk Factors
 Purine rich foods &
nutritional supplements
 ?only animal source?
 Drugs
 Thiazides
 Low dose ASA
• (< 1g/day?)
 Niacin
 Cyclosporin
 Pyrazinamide &
ethambutol
 Risk Factors
 Obesity & excessive
weight gain, (especially in
youth)
 Moderate to heavy alcohol
intake
 High blood pressure
 Abnormal kidney function
 Leukemias, lymphomas,
and hemoglobin disorders
 Trauma & Surgery
 Principles of Management
1. Terminate acute attacks
2. Prevent recurrence & reverse complications
 Eliminate urate crystals from joints & tissues
3. Address co-morbid conditions
 Obesity
 Hypertriglyceridemia
 Hypertension
 Diabetes mellitus
 Excessive alcohol
 1) Treatment of Acute Attacks
 Directed at WBC inflammatory response
Options:
NSAIDs
Colchicine
Corticosteroids

 Choice depends on co-morbidities & history

 More importantly – rapidity of treatment selection!
 Keep agent close at all times; start ASAP PRN
• Esp with poor renal function, slower response =
increased drug exposure over course of a flare
 Serum Urate
 Rising urate levels can provoke flare
 For reasons unknown, lowering serum urate
can as well.
• Worse with more rapid or severe changes in urate
• Occurs in ~ 25% of patients

 N.B. Do not alter existing gout meds during

acute flare!
 NSAIDs
 Most common agent used
 Better side effect profile vs colchicine
 Longer duration of action vs colchicine
 Any NSAID, COX-2 selective or non-
selective
 All equivalent relief of pain / inflammation
 NSAIDS
 Choose based on: Toxicity, Cost, Convenience
 CrCL
• Avoid in CKD
 Risk of ADRs
• (N/V/D, GIB, fluid retention, ARF, etc)
 Cost & availability
• Rx vs OTC
 For elderly: Choose shorter half-life (t½)
• Ibuprofen (2-4hrs); diclofenac (2hrs); indomethacin (4.5hrs);
• Avoid in CHF, CKD, peripheral edema, PUD/GERD
• N.B. increased risk of GIB with concurrent ASA, even 81mg!
 Consider adding a PPI
 Colchicine
 Used for centuries
 Most specific agent in use
 Decreases leukocyte motility
• Binds to tubulin and inhibits
microtubule formation, arresting Colchicum autumnale
neutrophil motility (autumn crocus)
 Decreases phagocytosis in joints (meadow saffron)
• Decreases lactic acid production
 OVERALL EFFECT:
 Interruption of inflammatory process

 PO or IV
• Avoid IV - Potentially fatal if mis-dosed!
 Risk of arrhythmia
 Colchicine
 Traditional dosing:
 0.6mg q1-2hrs until:
• Improved sxs
OR
• GI distress
OR
• 10 doses with no effect
 Too rigourous for most patients!
• (Esp elderly) - GI distress in 50-80%!
• Narrow therapeutic window
 Colchicine
 1 mg & 0.6 mg tablets - scored
 Alternative regimens
 1mg loading dose, then 0.5mg q2-6hrs
OR
 0.5 - 1mg TID

OR
 1.2mg initially, then 0.6mg BID

 Most effective w/i first 12hrs of attack

 Dose low! Try TID dosing first
 D/C if GI distress develops
 Colchicine
 Two-thirds of colchicine-treated patients
improved after 48 hours
 Versus 1/3rd on placebo
 All on colchicine developed diarrhea
after a median time of 24 hours
 (mean dose of colchicine 6.7 mg)
 This side effect occurred before relief
of pain in most patients
1) Management of Gout With Colchicine http://www.theberries.ns.ca/Archives/colchicine.html Accessed Nov 1/07
2) Ahern MJ, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-4.
 Colchicine vs NSAIDs
1. Untreated

Bellainy et al. (1987);
2. Placebo group

Ahern el al. (1987);
3. Colchicine
2
 Aliern et al.(1987);
4. Indomethacin
 Ruotsi Vainio (1978);

Options:
1. NSAID + colchicine Day 1,
then D/C the NSAID
2. Colchicine + analgesic (e.g.
Acetaminophen + codeine) on
Day 1
1. N.B. dose of colchicine
needed is lower than what is
currently recommended.
1) Management of Gout With Colchicine http://www.theberries.ns.ca/Archives/colchicine.html Accessed Nov 1/07
2) Ahern MJ, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-4.
 Corticosteroids
 Reserved for:
 Intolerant of NSAIDs or colchicine
 Co-morbidities that prohibit use of other meds
 Good alternative for elderly w/ poor renal function
 Few trials – choice is empiric
 Eg. Prednisone 20-60mg /day PO
• Are lower doses less effective?
 Noted flares in transplant patients on 7.5-15 mg/day
 Methylprednisolone 125mg/day IV or IM q1-4 days prn
• Can give intra-articular – avoid if joint is septic!
• Use smallest gauge needle (esp if on Warfarin)
 Alternative Treatments
 If standard treatments are contraindicated:
 Ice
 Analgesics
• Acetaminophen
• Opioids
 N.B. Will not alter course of flare, but flares
are usually self-limited
 Summary
Treatment of Acute Attacks
 Start treatment A.S.A.P.!
 Avoid NSAIDs in CKD, CHF
 Consider a PPI for NSAIDs + ASA or Hx of PUD
 Avoid / Reduce colchicine dose in CKD, liver dz,
neutropenia, on diuretics, statins, or cyclosporin
 Do not change doses of any med that can alter
urate levels when treating acute attacks
 Consider NSAIDs, colchicine, steroids at low
doses and in combination (different MOA’s)
 2) Preventing Recurrence
 Must eliminate excess body urate
 Else tophi may continue to enlarge
 Destructive, chronic mononuclear cell
inflammatory response that destroys cartilage
and bone, resulting in chronic arthritis
 High likelihood of recurrence
 62% w/i 1 yr
 78% w/i 2 yrs
 90% w/i 5 yrs
Hoskison, KT and Wortmann, RL
Ref: Drugs & Aging 2007;24(1):21-36

 Recommend urate levels < 360 umol/L

 Normal range 140- 340 (Dynacare)

 At > 360umol/L, fluids are supersaturated

and crystal can precipitate
 At < 360umol/L, deposits dissolve,
mobilize and are eliminated
 Recommendations:
Urate Lowering Therapy
 EULAR:
 “with recurrent attacks, arthropathy, tophi or
radiographic changes”
 US Panel:
 “if tophaceous deposits, erosive changes on X-
ray, or > 2 attacks per year”
 Others:
 “After first attack”
• Disease declared, high rate of recurrence
 “Based on frequency of attacks”
• Since second attack may not occur for years
 Preventing Recurrence
 Recall: Lowering urate can precipitate a flare!
 Increased risk w/ more rapid & severe changes
 ~ 25% of patients

 Start 2-3 weeks after flare resolved

 Uricosuric agents - increase excretion
• Probenecid
• Sulfinpyrazone
 Xanthine Oxidase Inh. – decrease production
• Allopurinol – agent of choice
• Febuxostat – new agent (ULORIC™)
 Avoiding Flares - Allopurinol
 Start Allopurinol at low dose and titrate up to
avoid precipitating event
 Eg. 100mg, increasing by 100mg q2-4 weeks to
target dose
 With renal dysfunction:
• 50mg initiation, incr by 50mg
 Febuxostat (ULORIC™)
 A non-purine, selective xanthine oxidase inh.
 More potent than Allopurinol
 Efficacy vs Allopurinol:
 Lower frequency of gout flares
• N.B. Higher frequency of flare with initiation at higher
doses!
 Improved serum urate lowering effect
 Limited RCTs - need more evidence in:
• Renal dysfunction, concomitant use of urate raising
drugs (eg. ASA, thiazides), comparison against non-
fixed doses of Allopurinol
See: Gaffo LA et al. Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evid. 2009; 4:
25–36. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899777/?tool=pubmed Accessed Feb 7th, 2011.
 Febuxostat (ULORIC™)
 Start 40mg daily (+/- food)
 Up to 80mg or 120mg qd
• after 2 weeks if UA > 360 umol/L
 CrCL > 30mL/min – no dose adjustment
 CrCL < 30 mL/min – unstudied – avoid
 Side effects:
 Rash (1% to 2%)
 Liver function abnormalities (5% to 7%)
• F/U LFTs in 2 & 4 months after starting tx
 Arthralgia (1%)
 Cost: 80mg tabs ~ $65/ month;
 (no ODB coverage)

 Treat the same as allopurinol

 Avoiding Flares (2)
 Start prophylaxis before urate lowering
therapy
 Eg. Daily, low dose NSAID or colchicine 2-3
weeks before allopurinol
• Eg. Colchicine 0.5mg or 0.6mg qd or tid
• Eg. Indomethacin 25mg bid
 Continue 3-6 months and/or [urate] < 360
umol/L
 Note Bene (N.B.)
 No prophylaxis without urate lowering tx!
 Acute flare prevented but crystal deposition in
tissue continues!
 Hence no warning signs of continued cartilage
and bone damage and deposition in organs,
especially kidneys!
 Remember: Cochicine is NOT uricosuric!
 Preventing Recurrence
 Allopurinol
 Most common
 Febuxostat
 New kid on the block!
 Improved efficacy
 Lacking sufficient safety data for some populations
 No ODB coverage
 Probenecid or Sulfinpyrazone: (unlikely)
 only if CrcL > 50mL/min
 No hx of kidney stones
 No ASA > 2g/day
• Interference with uricosuric effects
Preventing Recurrence -Allopurinol
 Dosing:  ADRs: (well tolerated)
 50mg to 800mg qd  Common:
(usually 300mg) • GI upset,
 N.B. Only 21-55% attain • Rash
urate < 360 umol/L on  (esp if on Amox/Amp or
“standard” dose Cyclophosphamide)
• Most insufficient doses –
main barrier to control  Rare:
 N.B. Dose adjust for • Blood dyscrasias
renal function • Jaundice
 Dosing according to CrCL • TEN
may not attain control • Hypersensitivity
Syndrome (including
 GOAL: lowest dose to rash)
target urate < 360
umol/L
 If mild rash occurs, hold
and re-challenge
 Preventing Recurrence
Sulfinpyrazone: Probenecid:
 Up to 800mg /day  500mg to 3g /day
divided bid divided bid-tid
 Start: 100mg BID  Start: 250mg BID
• Increase q1wk • Increase by 500mg
 May decrease to q4wk
200mg/d once urate  May decrease by
controlled 500mg q6mo if stable
 ADRs: GI upset, rash > 6 mo till urate starts
to rise
 ADRs: GI upset, rash
 Useless Trivia With Which To
Impress Your Patients
 Urate levels in humans are 10 times higher than
other mammals because we lack the enzyme
uricase!
 PEGlyated-uricase (Pegloticase) – approved in USA for
refractory gout
 Gout Ambika

Taras
Summary of Gout Prevention
 High likelihood of recurrence
 Eliminate excess body urate to prevent chronic
destructive changes
 Colchicine is not uricosuric!
 No prophylaxis without urate lowering therapy!
 Manage risk factors
 Drugs, diet, co-morbidities
 Allopurinol – drug of choice
 Start low, go slow
 May have to push dose to attain control
3) Address Co-Morbid Conditions

 Obesity
 Hypertriglyceridemia
 Hypertension and Diabetes Mellitus
 Excessive Alcohol
 Obesity & Hypertriglyceridemia
 Weight loss independently lowers urate
levels
 Decreased alcohol consumption, regular
exercise and weight reduction will lower
TGs
 Fibrates
• Especially fenofibrate – mild uricosuric effect
 Diet Restriction
 Total diet restriction only lowers urate levels
by ~ 52.9 umol/L (1mg/dL)
 Very unpalatable
 Poor compliance
 Purine sources matter
 Increase with meat & seafood
 Decrease with dairy
• Daily consumption lowers urate levels
 Oatmeal and purine rich vegetables do not
increase risk of gout
• Peas, mushrooms, lentils, spinach, cauliflower
 Dietary sources
High-Purine Content  Meat extracts
 Anchovies  Mincemeat
 Beer  Mussels
 Oysters
 Bouillon (meat based)  Partridge
 Brains  Roe (fish eggs)
 Broth (meat based)  Sardines
 Clams  Scallops
 Consommé  Shrimp
 Sweetbreads
 Goose  Yeast (baker's and brewer's) taken as a
 Grain alcohol supplement
 Gravy
Moderate-Purine Content
 Heart  Beans, dried
 Herring  Fish (except those in the high-purine
 Kidney content list)
 Lobster  Lentils
 Meat (except those in the high-purine
 Mackerel content list)
 Mushrooms
 Hypertension
 ~ 1/3rd with gout have HTN
 Major cardiac risk factor
 Caution with thiazides and ASA!
 N.B. LOSARTAN – mild uricosuric effect!
 Excessive alcohol
 Mechanisms:
1. Purine content of beverage
• BEER! (lots of guanosine)
2. Chronic alcohol stimulates de novo purine biosynthesis
in liver
3. Binge drinking results in lactic acidemia, lowering renal
urate excretion
 Moderate wine ok, but any alcohol is a risk factor
 RR 1.32 (10 - 15 g/day)
 RR 1.49 (15 - 30 g/day)
 RR 1.96 (30 - 50 g/day)
• > 30g/d in females; > 45g/d in males ↑ risk of liver disease
 RR 2.53 (> 50 g/day)
Summary of Lifestyle Modification
 Lose weight
 Lower TG’s (esp with Fenofibrate)
 Lower BP (esp with Losartan)
 Avoid HCTZ and ASA if you can
 Elimination alcohol
 Avoid eating brainsssss
 Patient Education
Urate crystals  Matches
Gout attack  Matches catch fire
Colchicine or NSAIDs  Put out the fire
Treatment delay  More matches catch fire
Prophylactic colchicine  Dampen matches
Allopurinol or Uricosuric  Removes matches from
agent body
Questions?