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A. Introductionnavigator

  1. Most common cause of acute mono- or oligoarthritis or bursitis
    1. Accounted for ~3.9 million outpatients in US in 2002
    2. Usual initially presentation is monoarticular involvement
    3. Chronic disease may have polyarticular flares
    4. Alcohol, aspirin or diuretic use may precipitate gouty flares
    5. Tophaceous gout usually develops after years of intermittent gout
  2. Gout Variants
    1. Monoarticular disease, episodic
    2. Polyarticular disease, multiple joints and several episodes
    3. Tophaceous gout, often with joint destruction
    4. Hyperuricemia without symptoms (not gout, increased predisposition)
  3. Most patients are men; increased incidence in post-menopausal women
  4. Gout and Uric Acid
    1. Most patients have elevated serum urate (>7.0mg/dL; >416µmol/L)
    2. Gout can occur rarely, however, without hyperuricemia
    3. With serum uric acid >10mg/dL (>0.6 mmol/L), 5 year prevalence of gout is 30%
  5. Etiology
    1. ~85% of patients are uric acid underexcreters
    2. ~10% are overproducers
    3. Hyperproliferative diseases lead to overproduction of uric acid
    4. Hyperproliferative diseases include inflammatory (psoriasis) and neoplastic (leukemia, lymphoma, others) disorders
    5. In men, highest quintiles of meat or seafood intake associated with 1.4-1.5X risk of gout versus lowest quintiles; highest dairy intake associated with reduced risk (0.56X) [4]
    6. Overall protein and purine rich vegetables not associated with gout risk [4]
    7. Alcohol intake positively correlates with gout risk 1.3-2.5X risk [5]
    8. Beer had strongest risk and wine carried no increased risk [5]
    9. Loss of hormone production at menopause may contribute to elevated uric acid
    10. Regardless of etiology, most patients are treated long term by suppression of synthesis
  6. Hyperuricemia [6]
    1. Associated with cardiovascular disease, nephropathy, urolithiasis, gout
    2. Hyperuricemia also associated with diabetes, hypertension, stroke, preelampsia
    3. Treatment only with high risk or history of gout, renal dysfunction
    4. Consider treatment for high levels in patients with severe vascular disease

B. Symptomsnavigator

  1. Presentation
    1. Painful, red swollen joint or bursa
    2. May have appearance of cellulitis or septic joint
    3. Fever, leukocytosis may also occur
    4. Most common initial joint is first MTP ("Podagra")
  2. Formation of uric acid deposits
    1. Tophi may occur in chronic cases
    2. Usually occur in "coldest" areas on body
    3. Cold makes it more likely that monosodium urate will precipitate
    4. Common in distal joints, bursa, pinnae of ears
  3. Drugs associated with Gout Flares
    1. Any drugs which change uric acid concentrations
    2. Aspirin - low doses lower urate, higher doses raise urate
    3. Alcohol - reduces uric acid excretion
    4. Thiazide Diuretics - raise serum uric acid; Other diuretics - lower serum uric acid
    5. Cyclosporine - probably due to decreased GFR and tubular inhibition

C. Pathogenesis [9]navigator

  1. Inflammatory arthritis triggered by crystallization of uric acid
  2. Often associated with hyperuricemia (elevated blood levels of uric acid)
    1. Increased intake of meats leads to elevated urate levels
    2. Consumption of oatmeal and purine rich vegetables does not increase urate levels
    3. Net adenosine triphosphate (ATP) degradation lead to AMP and ADP accumulation
    4. AMP and ADP can be rapidly degraded to uric acid
    5. Ethanol administration increases ATP degradation to AMP
    6. Fructose increases urate levels
  3. Urate is Filtered By the Kidney
    1. Reabsorbed in proximal tubule
    2. Renal urate-anion exchanger (URAT1) responsible for reabsorption of urate
    3. Uricosuric agents inhibit URAT1 (SLC22A12) leading to enhanced urate loss
  4. Urate Crystal Induced Inflammation
    1. Stimulate synthesis and release of various inflammatory mediators
    2. Activate phagocytic cells through phagocytosed particles
    3. Neutrophils are recruited to the site of attack and amplified
    4. Acute gout is self-limited and probably involves T cell type 2 cytokines
    5. Chronic tophaceous gout with joint destruction involves proteases

D. Evaluationnavigator

  1. Joint / Bursa Fluid Analysis is Essential
    1. Rule out infection or superinfection with gram stain and culture
    2. Crystals commonly seen: needle shaped, negatively birefringent (yellow is parallel)
    3. Fluid may contain >50K/µl PMN
    4. Difficult to rule out coinfection even with crystals
    5. Therefore, Gram stain and cultures must be obtained
    6. Synovial fluid from asymptomatic joints in patients with active gout often contain uric acid crystals [6]
    7. herefore, synovial fluid from the knee may be diagnostic and easiest to obtain [7]
    8. Superinfection may occur (usually Staphylococci or Streptococci)
  2. Other Laboratory Tests
    1. Serum urate useful for eventual initiation or adjustment of allopurinol, probenecid
    2. Elevated serum urate level is a risk factor for cardiovascular disease [8]
    3. Serum calcium, phosphate useful for possible CPPD
    4. Complete blood count including white cell count with differential
    5. Blood cultures may be needed in selected cases
    6. Serum TSH for hypothyroid screening (up to 15% gout cases)
  3. Utility of Radiograph
    1. Evaluate for chondrocalcinosis (CPPD; see below)
    2. Bone destruction usually without osteoporosis
    3. Joint effusion with joint space preservation
    4. Asymmetric nodular soft tissue mass (tophus)
    5. Erosions usually eccentric, round or oval in shape
    6. Intraosseous calcification and secondary osteoarthritis
  4. Differential Diagnosis
    1. Septic arthritis
    2. Pseudogout - calcium pyrophosphate dihydrate deposition disease
    3. Uncommon: Hemearthrosis, trauma, pigmented vilonodular synovitis (PVNS)
    4. Hydroxyapatite crystal disease (resolves spontaneously)

E. Conditions Associated with Gout [1]navigator

  1. Insulin Resistance Syndromes (hyperglycemia, diabetes mellitus type 2, metabolic syndrome)
  2. Dyslipidemia: hypertriglyceridemia, low HDL level (metabolic syndrome)
  3. Hypertension
  4. Coronary heart disease
  5. Obesity (usually truncal)
  6. Increased cell turnover disorders: leukemias, chronic anemias

F. Treatment Strategy [1,2]navigator

  1. Depends on stage and symptoms of disease and comorbid conditions
  2. Acute Gout - non-steroidal anti-inflammatory agents (NSAIDs) or glucocorticoids
  3. Initial prevention of recurrent and chronic attacks (interim prophylaxis) - colchicine
  4. Long term prophylaxis: Uric acid lowering agents (often added to low dose colchicine)
  5. Uric acid reduction in patients with symptoms, gout, urate nephropathy, urolithiasis [6]
  6. Consider aggressive uric acid reductions in severe vascular disease

G. Treatment of Acute Gout Attacknavigator

  1. NSAIDs are generally first line
    1. Effective pain control and anti-inflammatory activity
    2. Contradindications include coumadin therapy, GI bleeding/intolerance, renal disease
    3. Caution should be used in patients on high dose diuretics or ACE inhibitors
    4. Examples: Naproxen 500 po bid-tid, Ibuprofen 800mg po tid-qid, others
    5. Naproxen 500mg po bid and prednisolone 35mg po both for 5 days show similar efficacy in acute gouty flare [13]
    6. Avoid salicylates which decrease uric acid excretion and may precipitate attacks
    7. Consider use of concomitant H-2 therapy to protect stomach
    8. COX-2 selective NSAIDS (such as celocoxib, Celebrex®) are safe on stomach
  2. Glucocorticoids
    1. First line therapy in patients intolerant or not improved with NSAIDs
    2. Prednisone - 20-40mg po initially continue for 3-5 days then taper
    3. Prednisolone 35mg qd x 5 days was as effective as naproxen 500mg po bid x 5 days in acute gouty flare [13]
    4. Methylprednisolone 30-40mg iv qd (may divide doses) can be substituted for prednisone
    5. Taper initially to 20mg then 15mg qd and then slowly over 1-2 weeks to prevent subsequent flare
    6. Colchicine begun at 0.6mg po qd-bid during taper should also be started to prevent flare
    7. When colchicine is used this way, gastrointestinal side effects are minimized (as compared with acute high doses)
    8. Low dose prednisone, 5-10mg/d, can also be used as flare prophylaxis (see below)
  3. Colchicine
    1. Now considered 3rd line treatment for acute gout
    2. Very effective for subacute control (flare prevention) at lower doses
    3. Dosing for acute attacks: 0.2-0.6mg po q 1/2-2 hrs until nausea or diarrhea occur
    4. Total acute dose should not exceed 6mg (in first 12-24 hours)
    5. Interim Maintenance: colchicine at 0.6mg po qd-bid for about 1 month as allopurinol or other urate reducer acts
    6. May be useful in patients with chronic constipation and gout since causes diarrhea as a side effect
    7. More effective for interim prophylaxis but caution with long term use [10]
  4. Agents which alter serum urate concentration are contraindicated in acute attacks
    1. Specific uric acid lowering agents: Allopurinol, probenicid, sulfinpyrazone
    2. Other drugs: aspirin (changing dose), thiazides, other diuretics
    3. Initiation of agents may precipitate severe gouty attack, often with tophus formation
    4. If patient is on a uric acid lowering agent and has an acute attack, do not change dose

H. Interim Prophylaxis [2]navigator

  1. Any change (up or down) in serum urate levels can precipitate gouty attacks
    1. Therefore, an agent to prevent attacks must be given prior to starting uric acid lowering therapy
    2. Continue this agent for 3-12 months while uric acid lowering therapy is initiated
    3. Uric acid metabolism and serum levels must be stabilized before stoppping prophylaxis
    4. Naproxen or colchicine have been used in trials [11]
  2. Colchicine
    1. Recommended first line for interim prophylaxis
    2. Dose is 0.6mg po bid; renal insufficiency dose 0.3-0.6mg po qd (creatinine >1.5mg/dL)
    3. Generally well tolerated at these doses
    4. Maintain prophylaxis as urate levels are reduced; discontinue when urate stable
    5. Long term colchicine can cause myopathy, particularly with liver impairment [10]
  3. Other Agents
    1. Low dose NSAIDs - recommend GI protective agent (or COX-2 selective) if used >1 month
    2. Low dose prednisone - well tolerated, minimal side effects at 10mg/day for < 1year
    3. Prednisone use should be preceded by PPD (MTB) test in most patients

I. Long Term Prevention [2,3,8]navigator

  1. Lowering serum uric acid is most effective long term preventatitve strategy
  2. Also permits resolution (slowly) of tophi
  3. Goal Serum Urate Reductions [3]
    1. For uncomplicated gout goal serum urate <6-7mg/dL
    2. For tophaceous gout serum urate <6mg/dL
  4. Uric Acid Lowering Agents
    1. Allopurinol
    2. Febuxostat
    3. Probenecid
    4. Sulfinpyrazone (rarely used)
    5. Losartan (Cozaar®) also has uricosouric activity [9]
    6. HRT in postmenopausal women reduces risk but is no longer routinely recommended
  5. Allopurinol (Zyloprim®)
    1. Inhibitor of xanthine oxidase (XO), primarily reduced form
    2. Reduces blood uric acid concentration
    3. Dose 100-300mg po qd; 100mg po qd in renal insufficiency
    4. Many patients, with normal renal function, will respond to 100mg po qd
    5. Some patients require 800mg/day or more (maximum 1000mg per day)
    6. Caution should be used as allopurinol reactions are serum level dependent
    7. Adverse effects occur in ~20%; discontinuation required in ~5% overall
    8. In patients with rash in whom allopurinol must be used, desensitization may be performed
    9. In some patients with allopurinol allergy, oxopurinol can be obtained
    10. Severe reactions including toxic epidermal necrolysis (TEN) can occur
    11. Allopurinol hypersensitivity syndrome: fever, skin rash, eosinophilia, hepatitis, progressive renal insufficiency and may be fatal
  6. Febuxostat [11,12]
    1. Oral XO inhibitor, blocks both reduced and oxidized forms
    2. Doses 80-120mg reduce urate slighly better than fixed dose allopurinol
    3. Long term safety data not available to date
  7. Probenecid
    1. Increases urinary excretion of uric acid, called a "uricosuric"
    2. Generally effective only in underexcretors (defined by 24 hour urine collection)
    3. Normal urinary excretion of uric acid is 250-750mg/day
    4. Contraindicated in patients with history of uric acid renal stones
    5. Initiate at 500mg po bid and increase as needed
    6. Monitor 24hr urinary uric acid excretion
    7. May be used in conjunction with allopurinol
    8. Will not work in patients with creatinine >2.0mg/dL
    9. Can increase risk of uric acid stones

References navigator

  1. Rott KT and Agudelo CA. 2003. JAMA. 289(21):2857 abstract
  2. Terkeltaub RA. 2003. NEJM. 349(17):1647 abstract
  3. Eggebeen AT. 2007. Am Fam Phys. 76(6):9-1
  4. Choi HK, Atkinson K, Karlson EW, et al. 2004. NEJM. 350(11):1093 abstract
  5. Choi HK, Atkinson K, Karlson EW, et al. 2004. Lancet. 363(9417):1277 abstract
  6. Dicker HE, Dincer AP, Levinson DJ. 2002. Clev Clin J Med. 69(8):594 abstract
  7. Pascual E, Batlle-Gualda E, Martinez A, et al. 1999. Ann Intern Med. 131(10):756 abstract
  8. Fang J and Alderman MH. 2000. JAMA. 283(18):2404 abstract
  9. Choi HK, Mount DB, Reginato AM. 2005. Ann Intern Med. 143(7):499 abstract
  10. Soto O and Hedley-Whyte ET. 2003. NEJM. 349(17):1656 (Case Record) abstract
  11. Becker MA, Schumacher HR, Wrotmann RL, et al. 2005. NEJM. 353(23):2450 abstract
  12. Moreland LW. 2005. NEJM. 353(23):2505 abstract
  13. Janssens HJ, Janssen M, van de Lisdonk EH, et al. 2008. Lancet. 371(9627):1854 abstract