Hyperuricemia & Gout

Question 1

What is Gout?

Answer 1

Gout is an inflammatory arthritis resulting from deposition of uric acid crystals
(monosodium urate) in tissues and fluids within the body.
Key terms:
○ Hyperuricemia: elevated serum urate concentration (>416 µmol/L in men &
>357 µmol/L in women)
○ Acute arthritis: deposition of urate crystals in synovial fluid leukocytes,
leading to an inflammatory response
○ Tophi: deposits of monosodium urate crystals in tissues in & around joints

Question 2

Epidemiology

Answer 2

● “Disease of Kings”
○ One of the first clinical syndromes to be defined
● Increasing incidence due to lifestyle changes
○ Now seen in areas with traditionally low rates of gout (e.g. China)
Affects more males than females
○ Incidence increases with age
■ Peak age for diagnosis 40-50 in males, >60 in females
● Genetic component:
○ familial link along with environmental factors

Estrogen helps the uric acid actually be excreted in the urine
Pos menopausal for females

Question 3

Course of Illness: Early

Answer 3

Asymptomatic
Hyperuricemia
Only ~25% go
on to develop
acute gout

Acute Gouty Arthritis

Intercritical Gout

Advanced Gout(chronic tophaceous)

20% of the North American population has hyperuricemia. But again, only about a quarter of those go on to actually develop the, the acute gout or have any type of complication

Question 4

What is Uric Acid?

Answer 4

Adenosine
Inosine
Hypoxanthin
–>
Xanthine
Oxidase
–>
Guanosine
Guanine
Xanthine
–>
Xanthine
Oxidase
–>
Uric Acid
–> (not in humans)
Allantoin (soluble)

Question 5

Pathophysiology: Hyperuricemia

Answer 5

Overproduction of Uric Acid
>1000 mg/d

● Primary
○ Idiopathic
○ Genetic enzyme abnormalities
● Secondary
○ Excessive dietary intake
○ Increased tissue breakdown
■ Myeloproliferative or
lymphoproliferative disorders
■ Hemolytic diseases
■ Psoriasis

Underexcretion of Uric Acid
< 600 mg/d
● Primary
○ Idiopathic (~90% gout pts)
● Secondary
○ Decreased renal function
○ Metabolic acidosis
○ Dehydration
■ enhances Na+ and UA
reabsorption in proximal
tubul

90% of patients don’t excrete enough uric acid for an unknown reason.

So about a third of uric acid is excreted in the gut, two-thirds through the kidney. And our body actually tries really hard to keep the uric acid for some reason. It’s filtered and then it’s reabsorbed and then it’s secreted and then it’s reabsorbed again. So about 90% of the uric acid that we produce is actually reabsorbed back into our system.

decreased renal function is definitely going to have an impact on the level of uric acid in the system. As does metabolic acidosis, with more uric acid being retained and shifting towards that precipitation in the tissues state and dehydration

Question 6

Factors Associated with [SUA] / Risk Acute Gout

Answer 6

Diet Related:
* Meat, Seafood
* Alcohol
* High fructose content

Disease Related:
* CVD (IHD, HF)
* CKD
* Nephrolithiasis
* Metabolic syndrome
* Obesity (BMI >30)
* Insulin resistance
* Hyperlipidemia (­TG)
* Hypertension

Drug Related:
* Increase SUA:
* Salicylates <1g/day
* Diuretics (thiazide, loop)
* Niacin
* Cyclosporine, tacrolimus
* Cytotoxic chemotherapy
* Decrease SUA:
* allopurinol, febuxostat,
probenecid

Some Things May Also Lower Risk: * Dairy
* Coffee (incl. decaffeinated)
* Vitamin C

ow doses of salicylates, so low dose aspirin, diuretics, thiazides, loops, anything that’s, that’s again impacting that that kidney flow. Niacin, vitamin B, cyclosporin, tacrolimus, and cytotoxic chemotherapy

losartan, interestingly, as a bonus benefit in terms of it being an anti-hypertensive, it can also increase that uric acid secretion a little bit.

Question 7

Course of Illness: Acute Flare

Answer 7

Asymptomatic
Hyperuricemia

Acute Gouty Arthritis
* Usually monoarticular
* Resolves spontaneously
in 7-10 days
If someone enters that phase of acute gouty arthritis, they usually have one joint that’s impacted and if left alone, it will resolve.

Intercritical Gout
- , if patients are consistently having sort of A gout flare, gout flare every few months, a couple times a year sort of thing. Eventually patients are symptom-free between those specific attacks. But again, because they’re having them so frequently that crystal may be depositing in joints, so likes to look for damaged joints

Advanced
Gout
(chronic tophaceous)
- Eventually late in the disease course.Patients are no longer asymptomatic at all. So they have enough going on in those joints that have been particularly impacted by the gout that they’re uncomfortable.

usually 10-12 years after that initial flare, they may have visible tophi that are causing them some challenges even with function

Question 8

Clinical Presentation: Acute Gout

Answer 8

● Rapid onset of exquisite pain with warmth, swelling, erythema
○ Pain escalates over 8-12h period
○ Severity (VAS 0-10)
■ Mild £4, Moderate 5-6, Severe ³7
■ “Bed Sheet Sign”

● Usually monoarticular (85%)
○ More than half the time in the big toe! (called podagra)
○ Other joints: midfoot, ankle, heel, knee
■ Wrist, fingers, elbows, achilles tendon may be affected later in disease course

Question 9

Acute Gout: Classic Triad

Answer 9

Presumptive diagnosis of gout if:
1. Hyperuricemia present
2. Acute monoarticular arthritis
3. Gratifying clinical response to colchicine
■ complete resolution of symptoms within 48hr
■ no recurrence for at least 1 week
Gout <—> increase uric acid

if we have lab work and we see that the serum uric acid is elevated, That’s a checkmark, although it doesn’t have to be elevated for someone to have gout.

. If they’re presenting acutely with one joint, that’s inflamed. Again. Good signal,
somebody can have elevated uric acid and never have an attack of gout.

Question 10

Clinical Presentation

Answer 10

see slide 17
new onset gout vs long standing gout

Question 11

Course of Illness: Ongoing

Course of Illness: Late

Answer 11

Symptom free, but:
* Urate crystal deposition
continues
* Tophi increase in size

Course of Illness: Late
- No longer Pain Free!
*affected joints
uncomfortable, swollen U

• Uncommon overall
  *occurs >10y after initial flare

Question 12

Chronic Tophaceous Gout

Answer 12

ok

Question 13

Complication

Gouty Nephropathy

Answer 13

Gouty Nephropathy
● Uric acid nephrolithiasis
○ kidney stones occur in 15% patients with gout
○ depends on:
■ SUA
■ acidity of urine (pH<6 decreases UA solubility)
■ urinary uric acid concentration
○ can lead to acute renal failure 2° ureter obstruction
● Interstitial renal disease (urate nephropathy)
○ long-term deposition of urate crystals in renal parenchyma
■ microtophi with giant-cell inflammatory reaction
○ early signs: proteinuria, inability to concentrate urine

kidney stones can affect up to 15% of patients with gout. Exact same reasons. So that balance of the level of serum uric acid, but also the level actually in the urine itself. The urine is more acidic, so it’s more likely to precipitate in that acidic environment.

could lead to an acute kidney injury. You’ve got a blocked outflow. Then interstitial renal disease, much more rare, but literally gout or those crystals forming in the parenchyma. So in the meat of the kidney itself. And clearly that would cause a lot of damage. I

Question 14

Complications
Cardiovascular Disease

Answer 14

○ Hyperuricemia is associated with increased risk of CVD
■ gout is a chronic systemic inflammatory condition
○ Patients with gout have higher prevalence of CV risk factors
○ Management:
■ tight control of traditional CV risk factors (screen per national guidelines)
■ tight control of systemic inflammation (acute and chronic therapy)
■ cohort data suggests colchicine and allopurinol use (chronic management) may also
reduce risk

Question 15

How is Gout Diagnosed?

Answer 15

● History & Physical Exam
○ Clinical findings as discussed
● Laboratory Findings
○ Hyperuricemia (generally >400umol/L)
○ Leukocytosis (­PMNs)
○ ­ ESR and CRP
○ Synovial Fluid:
■ WBC ~15,000-20,000cells/uL (PMNs)
■ Intracellular MSU crystals present
Ø 100% Definitive diagnosis
● Diagnostic Imaging
○ Early: none, maybe soft tissue swelling
○ Intermediate: microtophi (asymmetric) on previously affected joints
○ Late: bony erosions (punched out marginal erosions)

Usually high serum uric acid but not always

we do see elevated white count. We see a predominance of neutrophils in that we see an elevated CRP or ESR

here’s a few little crystals here and you can see their needle shaped

Question 16

Differential Diagnosis

Answer 16

● Septic arthritis
● Pseudogout
○ calcium pyrophosphate dihydrate crystals
○ calcium hydroxyapatite crystals
● Trauma
● Cellulitis
● Erosive OA
● Early polyarticular disease
○ spondyloarthropathies
○ rheumatoid arthritis

Question 17

Mo (he/him) is a 53 year old regular patient who is describing an acute onset
of red, swollen, and painful big toe. He states the pain began in the middle of
the night and it hurts so badly he is having difficulty ambulating.
● PMHx: T2DM
● SHx: nonsmoker, 1-2 glasses of wine/week
● ROS: 5’10”, 275lbs
○ Otherwise unremarkable
● Medications:
○ ECASA 81mg daily
○ Metformin 850mg BID
● You check Netcare and see that his bloodwork was just reported:
○ SUA: 470 µmol/L
What factors support a gout diagnosis?

Answer 17

Consistent with typical patient that may present with gout
ü Male
ü Over 30 years old
● Consider the classic triad:
ü Hyperuricemia
ü Acute monoarticular arthritis (present - he has podagra: red swollen painful big toe)
? Gratifying clinical response to colchicine (we do not know yet)
● Other typical signs / comorbidities:
○ Pain started in the middle of the night
○ Obese, T2DM
● For definitive diagnosis MSU crystals must be identified
● Often patients will be diagnosed using a presumptive diagnosis when they have
classic history of previous flares

Question 18

Goals of Therapy

Answer 18

● CURE!
● Terminate acute gouty arthritis flare
● Manage pain
○ >20% within 24 hours
○ >50% at 24 hours
● Prevent subsequent gouty arthritis flares
● Lower serum urate (<360umol/L)
● Reduce or eliminate tophi
● Treat risk factors (to prevent recurrence)
● Prevent complications
● Prevent and/or manage adverse effects of therapy

Question 19

Non-Pharmacologic Therapy

Answer 19

● Avoid contact with affected joint as much as possible
● Rest, elevate, ice
○ may reduce pain by up to 3/10 points on VAS
● Dietary
○ Restrict purine and high fructose corn syrup intake
■ more effective for chronic prophylaxis
● NHPs
○ none demonstrated to be of benefit in RCTs

Question 20

Approach to Treatment: Acute

Answer 20

● KEY is to initiate therapy within 24h (ideally 12h) of symptom onset
● Monotherapy usually effective (and thus is most common)

● Consider combination therapy:
○ Initially if:
■ severe pain (³7/10 VAS)
■ affecting large joints
■ polyarticular
○ If no response to initial monotherapy:
■ <20% improvement in pain in 24h
■ <50% improvement in pain at ³24h
○ Regimens include:
■ Colchicine + NSAID
■ Colchicine + oral steroid
■ IA steroid + colchicine or NSAID or oral steroid

Question 21

Colchicine

Answer 21

● Efficacy
○ Onset: within hours
○ Effective in 2/3 of patients
■ most effective if begun within 12h of acute flare
○ May also see used at lower daily doses for prevention
■ if so, should NOT be used for flares
● Recall - MOA:
○ Inhibits β-tubulin polymerization into microtubules, thereby preventing
activation, degranulation, and migration of neutrophils
Ø Effective anti-inflammatory

incredibly effective anti-inflammatory, but does nothing with respect to the long-term progression of gout.

but they’re not impacting that pathophysiology for the long-term complications of gout. So you saw in that triad this is effective in two-thirds of patients.
may also see this at lower doses for prevention or during sort of bridging therapy when folks are starting on chronic therapy. And if that is so, we should not be using it for flares.

● Dose:
○ 1.2mg po STAT, followed by 0.6mg po 1h later
■ Use only within 36h of flare onset (delay reduces success of therapy)
■ Renal Dose Adjustment (for this regimen only)
● CrCl <30mL/min: No dose adjustment, but avoid if used in past 14 days
● Dialysis: 0.6mg once only; avoid if used in past 14 days
○ Alternate Regimen:
■ 1.2mg po STAT then 0.6mg po daily to BID until flare resolved for >24-48h
(must adjust for renal impairment)
■ Maximum 6mg per treatment course

recommended dose now for colchicine is two tablets, 1.1, 0.2 mg immediately followed by one tablet an hour later
if at 24 h, that gout isn’t down less than 50%, then we may need to think about doing something else

If patients have reduced renal function, we don’t need to adjust this particular therapy, but we do need to think about adjusting colchicine if it’s used in for any longer period of time. (more than 2 doses)

Question 22

AGREE Trial

Answer 22

Trial Type MC, DB, PC RCT (N=184)
Population
Known gout (³2 flares in past year)

Regimens
Low Dose: 1.2mg, 0.6mg in 1h, then PLA q1h x5h (total 1.8mg)
High Dose: 1.2mg then 0.6mg q1h x6h (total 4.8mg)
(allowed stable dose of urate-lowering therapy, rescue NSAID)

Follow Up 48 hours

Outcome 1° decrease Pain >/=50% within 24h: 38 vs 33% (p<0.05)
* Rescue NSAID: 31.1 v 34.6%
Safety:
* Overall AE: 36 v 77%
* Diarrhea: 23 v 77%
* Severe Diarrhea: 0 v 17%

Ø Low dose colchicine resulted in similar benefit with fewer adverse events compared to high dose colchicine
Ø Regimen should lead to fewer serious AE and drug interactions

Question 23

Colchicine
● Adverse Effects:

DI

Answer 23

○ Dose-dependent GI – nausea, vomiting, cramping, diarrhea
■ Maximum dose 6mg per treatment course (traditional dosing)
● deaths related to CV collapse, respiratory depression at doses as low as 7mg
○ Serious (Rare):
■ Myelosuppression (neutropenia > thrombocytopenia, pancytopenia, aplastic anemia)
■ Neuromuscular (rhabdomyolysis; reversible peripheral neuropathy)
■ Liver failure

● Drug Interactions:
○ CYP 3A4 and P-gp inhibitors – reduce dose
■ strong inhibitor: 0.6mg stat
● avoid further doses for 3 days
■ moderate inhibitor: 0.6-1.2mg stat
● avoid further doses for 3 days

Question 24

NSAIDs

Flashback: Consider Risk for Toxicity

Answer 24

May be less effective than colchicine

● Dose:
○ High dose x 24-72 hours, then lower doses until symptoms resolved x1-2d
■ Indomethacin
● 75mg x1à 50mg Q6h x2d à 50mg q8h x1d à 25mg q8h x1d
● 50mg TID until pain tolerable, then taper
■ Naproxen
● 750mg STAT à 500mg BID x4-5d
■ Celecoxib
● 800mg STAT + 400mg in 12h à 400mg BID x7d
○ Caution in CKD (and HF, PUD, CAD, HTN, etc)

● Efficacy:
○ Mainstay of therapy due to excellent efficacy & minimal toxicity with shortterm use
Ø Reduce pain and swelling in acute gout flares
○ Indomethacin favoured from a historical perspective, but any NSAID will have
comparable efficacy

Question 25

Corticosteroids

Answer 25

Dose:
○ Prednisone PO
■ 30-50mg daily x 3-5 days, no taper required (evidence-based dosing based on RCTs)
■ ³0.5mg/kg daily x5-10 days, no taper required
■ ³0.5mg/kg daily x2-5 days, taper over 7-10d (may prevent risk of re-flare upon discontinuation)
○ Methylprednisolone IM
■ 0.5-2mg/kg x1
● Efficacy:
○ Useful when contraindications to NSAIDs, colchicine exist
○ Comparable to NSAIDs
○ Use oral therapy when >2 joints involved (vs. IA)

Steroids are useful when patients can’t take colchicine or NSAIDS. Their effectiveness has been shown to be similar to NSAIDS

think about using a systemic steroids if there are more than two joints involved.

Question 26

Intraarticular Corticosteroids

Answer 26

● Dose: (dependent on size of joint)
○ Triamcinolone acetonide
■ large joint: 10-40mg
■ small joint: 2.5-5mg
○ Methylprednisolone
■ large joint: 20-80mg
■ small joint: 4-10mg
● Efficacy:
○ Use if <1-2 (large) joints affected
○ No RCTs, data limited to case series which do show effectiveness (high risk of
bias)
○ Generally used in combination with oral steroid, NSAID, or colchicine

Question 27

Anakinra & Canakinumab

Answer 27

MOA: IL-1 inhibitor (involved in inflammatory response)
● Dose:
○ Anakinra (Kineret®) 100mg subcut daily x3d
○ Canakinumab (Ilaris®)150mg subcut x1
● Efficacy:
○ Off label use - consider for treatment of severe gout flares refractory or
with contraindications to other treatments
○ Current infection is a contraindication to IL-1 inhibitor use

L-1 the cytokine of action in gout attacks

Both off label
expensive, not covered by prov drug plan