Gout

Source: 20th Edition Harrison’s Principles of Internal Medicine

- metabolic disease
- affected: middle-aged → elderly men & postmenopausal women
- results from an ↑i body pool of urate with hyperuricemia.
- characterization: episodic acute arthritis/chronic arthritis → caused by → deposition of monosodium urate crystals, CT tophi, risk for deposition in kidney interstitium or uric acid nephroliyhiasis.

Acute and Chronic Arthritis

- Acute arthritis : most common early clinical manifestation of gout.
- one joint is affected initially.
- polyarticular acute gout → ocur in subsequent episodes.
- often involved: metatarsophalangeal joints of the 1st toe.
- commonly affected: tarsal joints, ankles, & knees
- elderly patients/advanced disease → finger joints may be involved.
- Inflamed Herberden’s or Bouchard’s nodes: 1st manifestation of gouty arthritis.
- 1st episode of acute gouty arthritis: begins at NIGHT with dramatic joint pain & swelling.
- joints rapidly become → warm, red, & tender with a clinical appearance that often mimics that of cellulitis.
- early attacks: within 3-10 days
- precipitate acute gouty arthritis: a.) dietary excess d.) excessive ethanol ingestion
b.) trauma e.) hypouricemic therapy
c.) surgery f.) serious medical illness (MI & stroke)
- After many acute mono- or oligoarticular attacks → gouty patients may present with a chronic nonsymmetric synovitis → causing → potential confusion with rheumatoid arthritis.
- Chronic gouty arthritis: only manifestation; manifest as periarticular tophaceous deposits in the absence of synovitis.
- women: represent only 5-20% of all patient with gout.
- most women with gouty arthritis: postmenopausal & elderly → have → osteoarthritis & arterial hypertension → causes → mild renal insufficiency & receiving DIURETICS.
- premenopausal gout is RARE.
- precocious gout (young women) → caused by ↓d renal urate clearance & renal insufficiency.

Laboratory Diagnosis
- presumptive diagnosis → should be confirmed by NEEDLE ASPIRATION of acutely or chronically involved joints or tophaceous deposits.
- present with similar clinical features: a.) acute septic arthritis
b.) crystalline-associated arthropathies
c.) needle-shaped monosodium urate (seen intracellularly & extracellularly)
- compensated polarized light → crystals are brightly birefringent with negative elongation.
- synovial fluid leukocyte counts → ↑e from 2000 to 6000/uL.
- effusions appear cloudy → due to the ↑i numbers of leukocytes.
- large amounts of crytals → produce a thick pasty or chalky joint fliud.
- bacterial infection can coexist with urate crystals in synovial fluid.
- suspicion of septic arthritis → joint fluid must be cultured.
- Monosodium urate crystals → demonstrated in the 1st metatarsophalangeal joint & knees (not acutely involved with gout).
- arthrocentesis: useful technique to establish the diagnosis of gout between attacks.
- serum uric acid levels → can be normal or ↓L at the time of acute attack
- inflammatory cytokines → can be URICOSURIC & effective initiation of hypouricemic therapy (can precipitate attack) → this limits the value of serum uric acid determinations for diagnosis of gout.
- serum urate levels → always ↑e; important to use to follow the course of hypouricemic therapy.

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 - 24-h urine collection for uric acid
- useful in assessing the risk of stones.
- elucidating overproduction or underexcretion of uric acid.
- deciding whether it may be appropriate to use a uricosuric therapy.
- excretion of >800 mg of uric acid/24-h (regular diet) → causes of overproduction of purine should be considered.
- list of laboratories that should be obtained due to possible pathologic sequelae of gout: a.) urinalysis d.) WBC count
b.) serum creatinine e.) liver function test
c.) hemoglobin f.) serum lipids

Radiographic Features
- characteristic radiographic features of advanced chronic tophaceous gout: a.) cystic changes
b.) well-defined erosions with sclerotic margins (often with overhanging bony edges)
c.) soft tissue masses
- ultrasound → aid earlier diagnosis by showing a double contour sign overlying the articular cartilages.
- dual-energy computed tomography (CT) → show specific features establishing the presence of urate crystals.

Treatment
- Acute Gouty Arthritis
- mainstay of treatment during acute attacks: administration of anti-inflammatory drugs (NSAIDs, colchine, or glucocorticoids).
- NSAIDs → used most often in individuals without comorbid conditions.
- colchine & NSAIDs → poorly tolerated & dangerous in elderly, presence of renal insufficiency, and GI disorders.
- icepack applications & rest of the involved joints → can be HELPFUL.
- colchine (orally) → traditional & effective treatment if used early in an attack.
- useful regimens: one 0.6-mg tablet given every 8 h (subsequent tapering)
1.2 mg followed by 0.6 mg in 1 h (subsequent day dosing depending on response)
- the drug must temporarily discontinued at the 1st sign of LOOSE STOOLS & symptomatic treatment must be given for the diarrhea.
- NSAIDs (full anti-inflammatory doses) → effective in 90% of patients; resolution of signs & symptoms usually occurs in 5-8 days.
- most effective drugs (short-half life) → a.) indomethacin, 25-50 mg tid d.) diclofenac, 50 mg tid
b.) naproxen, 500 mg bid e.) celecoxib, 800 mg → followed by → 400 mg 12 h later → then → 400 mg bid
c.) ibuprofen, 800 mg tid
- glucocorticoids (intramuscular injection or orally)
- i.e., prednisone, 30-50 mg/d → initial dose; gradually tapered with the resolution of the attack; effective in polyarticular gout.
- single joint/few involved joints → intraarticular triamcinolone acetonide, 20-40 mg or methylprednisolone, 25-50 mg → effective & well tolerated.
- inflammasome & IL-1B (acute gout) → daily anakinra → used when other treatments have failed or were contraindicated.

- Hypouricemic Therapy
- ultimate control of gout: requires correction of basic underlying defect (hyperuricemia)
- attempts to normalize serum uric acid to <300-360 umol/L (5.0-6.0 mg/dL) → prevent recurrent gouty attacks & eliminate tophaceous deposits → critical & ental commitment to hypouricemic
regimens & medications that are generally required for life.
- should be considered when hyperuricemia cannot be corrected by simple means a.) control of body weight d.) limitation of ethanol use
b.) ↓L purine diet e.) ↓d use of fructose-containing foods & beverages
c.) ↑i liquid intake f.) avoidance of diuretics
- decision to initiate hypouricemic therapy is made taking into consideration a.) the number of attacks (urate lowering → maybe cost effective after 2 attacks)
b.) serum uric acid levels (progression is more rapid in >535 umol/L [>9.0 mg/dL])
c.) patient willingness to commit lifelong therapy
d.) presence of uric acid stones
- urate-lowering therapy → should be initiated in any patient who already has tophi or chronic gouty arthritis.

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- uricosuric agents (probenecid) → used in patients with good renal function who underexcrete uric acid with <600 mg in a 24-h urine sample.
- urine volume → should be maintained by ingestion of 1500 mL of water everyday.
-Probenecid → started at a dose of 250 mg twice daily & ↑i gradually as needed up to 3 g per day to achieve and maintain a serum uric acid leve of <6 mg/dL.
- NOT EFFECTIVE in patients with serum creatinine levels >177 umol/L (2mg/dL).
- Benzbromarone (uricosuric drug) → more effective in patients with chronic kidney disease
- Lesinurad → approved in patients already on xanthine oxidase inhibitor as an adjuvant at 200 mg/day.
- some agents used to treat common comorbidities : a.) losartan
b.) fenofibrate
c.) amlodipine
- allopurinol (xanthine oxidase inhibitor) → most commonly used hypouricemic agent; best drug to ↓L serum urate, urate stone formers, patients with renal disease.
- can be given in a single morning dose → usually 100 mg initially & ↑i up to 800 mg if needed.
- in patient with chronic renal disease → initial allopurinol dose should be ↓L & adjusted depending on the serum creatinine concentration
E.g., creatinine clearance: 10 mL/min → one generally would use 100 mg daily.
- doses can be ↑i to reach the TARGET URATE LEVEL of <6 mg/dL.
- toxicity: recognized ↑i in patients who use thiazide diuretics in patients → allergic to penicillin & ampicillin → and Asians expressing HLA-B*58:01.
- most serious side effects include: a.) life-threatening toxic epidermal necrolysis d.) granulomatous hepatitis
b.) systemic vasculitis e.) renal failure
c.) bone marrow suppression
- patients with mild cutaneous reactions to allopurinol can reconsider the use a.) uricosuric agent
b.) undergo an attempt at desensitization to allopurinol
c.) take febuxostat ( new, chemically unrelated specific xanthine oxidase inhibitor)
- febuxostat → approved in the US at 40 or 80 mg once a day; does not require dose adjustment in mild to moderate renal disease.
- pegloticase (pegylated uricase) → available for patients who do not tolerate or fail full doses of other treatments
- given IV usually at 8 mg every 2 weeks; can ↓L serum uric acid in up to 50% of such patients.
- urate-lowering drugs → not initiated during acute attacks
- low-dose colchine → initiated to ↓d the risk of the flares that often without anti-inflammatory treatment (occur with urate lowering).
- colchicine anti-inflammatory prophylaxis (doses of 0.6 mg one to two times daily)
 Given along with the hypouricemic therapy until the patient is → normouricemic & without gouty attacks for 6 months; as long as tophi are present.
 Should no be used in dialysis patients
 Given in lower doses to patients with renal disease or with P glycoprotein or CYP3A4 inhibitors such as (clarithromycin → ↑i toxicity to colchicine).