I. Pathophysiology and epidemiology

  1. A multi-organ disease resulting from inflammation and tissue damage triggered by precipitation of monosodium urate monohydrate (MUS) crystals
  2. Uric acid metabolism
    1. Produced by action of xanthine oxidase on the purines hypoxanthine and xanthine (mostly from breakdown of senescent cells; also some from diet).
    2. Filtered at the glomerulus (filtration inhibited by diuretics)
    3. Secreted by the tubules (secretion inhibited by pyrazinamide, low-dose ASA, and alcohol)
    4. Also reabsorbed by the tubules (reabsorption inhibited by uricosuric drugs--probenecid, sulfinpyrazone, benzbromarone, ASA at doses > 2g/d).
    5. About 33% of uric acid elimination is by bacterial degradation in the gut
  1. Chronic hyperuriciemia is necessary but not sufficient for the development of gout. Note that serum uric acid levels can be temporarily lowered during a gout attack.
  1. Usually idiopathic (> 99%) but can be secondary to:
  1. Increased urate production due to
  1. Rare inherited metabolic disorders causing increased uric acid production (PP-ribose-P synthetase over-activity; hypoxanthine-guanine phosphoribosyltransferase deficiency; G5PD deficiency)
  2. Chronic hemolysis
  3. Increased WBC turnover, e.g. leukemia
  4. High dietary purine content (meats esp. organ meats; meat extracts & gravies; seafood; yeast; beer; legumes; oatmeal; spinach; asparagus; cauliflower; mushrooms)
  1. Impaired renal urate secretion
  1. Chronic renal insufficiency of any cause
  2. Meds which inhibit urate secretion or enhance reabsorption
  1. Diuretics (thiazide and loop)
  2. Cyclosporine
  3. Lead
  4. Low-dose ASA
  5. Pyrazinamide
  6. Ethambutol
  7. Niacin
  8. Alcohol
  1. More common in men than women; very rare before puberty; peak incidence around age 45 for men; for women; more common after menopause
  2. Obesity is a risk factor; unclear why
  3. Hypertension appears to be a risk factor, though this may be be confounded by diuretic use.
    1. Ca-channel blockers and losartan and are associated with reduced risk of gout in pts with hypertension; Diurectics, beta-blockers, ACEIs, and ARBs other than losartan are associated with increased risk of gout in pts with hypertension (BMJ 344:d8190, 2012-JW)

II. Clinical features

  1. Gouty arthritis--an acute, inflammatory arthritis caused by intra-articular precipitation of MUS
  1. Predominantly PMN-mediated
  2. Usually monoarticular; 50% involve the big toe MTP joint ("podagra")
  3. Usually exquisitely tender
  4. Can be accompanied by fever and elevation of WBC and ESR
  5. Can last anywhere from hours to weeks without tx
  6. Can be precipitated by exercise, trauma, physiologic stress e.g. surgery, alcohol, "dietary overindulgence," starvation, or start of uric acid-lowering meds
  7. Serum uric acid levels during acute gout attacks
    1. In an analysis of data from two published studies of 339 pts with acute gout (none of whom had been on allopurinol started in the prior 2 weeks), 14% had serum uric acid < 6mg/dL, and 18% had serum uric acid 6-8mg/dL (J Rheumatol 36:1287, 2009-JW)
  8. In recovery phase, desquamation of overlying skin may occur
  1. Extra-articular manifestations
  1. Deposition of monosodium urate monohydrate crystals in extra-articular locations ("tophi")
  1. In cartilage (including ear), tendon sheaths, bursae, subcutaneous tissues, bone, renal interstitium, and rarely, cardiac valves or conduction system
  2. Usually not ass'd with inflammation
  3. Can cause stiffness and aching due to mechanical impingement on surrounding tissue and even, in rare cases, extensive joint destruction
  1. Can get inflammatory tenosynovitis, bursitis, or cellulitis.
  2. Gouty nephropathy
  1. Deposits of monosodium urate monohydrate in renal interstitium with attendant monuclear and giant cel reaction
  2. Renal failure due to gout is generally mild and slowly progressive
  3. Can rarely get acute oliguric renal failure from bilateral tubular obstruction by uric acid crystals--typically in leukemia or lyphoma (esp. during chemotherapy--tumor lysis syndrome) or in setting of severe volume depletion and acidosis
  1. Uric acid urolithiasis is seen in 10-25% of pts with gout

III. Diagnosis

  1. Gold standard for diagnosis is observation of negatively birefringent, needle-shaped crystals on polarized light microscopy in synovial fluid.
  2. WBC count in synovial fluid is usually 5-50k/mm3 in acute gout
  3. Differential diagnosis for acute gouty arthritis
  1. Pseudogout
  2. Acute rheumatic fever
  3. Rheumatoid arthritis
  4. Traumatic arthritis
  5. Osteoarthritis
  6. Septic arthritis--Consider w/u with synovial fluid culture in acute gout, esp. first episode, to r/o alternate diagnosis of septic arthritis
  7. Cellulitis
  8. Bursitis
  9. Thrombophlebitis
  10. Acute sarcoidosis
  11. Psoriatic arthritis.
  12. Reiter's syndrome

IV. Tx

  1. Tx of acute gouty arthritis
    1. Rest the affected joint
    2. Ice significantly reduces pain (J. Rheum. 29:331, 2002--JW)
    3. NSAIDs (don't use salicylates because decrease tubular secretion of uric acid) until attack subsides
    4. Colchicine PO
      1. Reduces PMN phagocytosis of urate crystals
      2. Traditional dose: 0.6-1.2mg then 0.6mg Q1-2h until attack subsides or side f/x develop (us. 18-24h)
      3. In a study in 575 pts with acute gout of < 12h duration randomized to "low-dose" colchicine (1.2mg then single dose of 0.6mg 1h later), "high-dose" colchicine (1.2mg then 0.6mg Q1h x 6h), or placebo, the effectiveness of the two colchicine regimens were similar, though the high-dose group had sig. higher incidence of diarrhea.  ("Acute Gout Flare Receiving Colchicine Evaluation" ("AGREE") Trial; Arth. Rheum. 62:1060, 2010-AFP)
      4. Reduce dose in pts with renal or hepatic disease
      5. Side f/x include nausea, abdominal cramping, and diarrhea; may also cause alopecia, hepatotoxicity, reversible myopathy, and bone-marrow suppression in high doses
      6. Monitor CBC in pts on long-term colchicine therapy
    5. Colchicine IV--much high er risk of bone marrow suppression, nephrotoxicity, and hepatotoxicity--2mg then 1mg Q6h; max dose 4mg; reduce dose by 50% in elderly or pts with hepatic or renal disease
    6. Systemic Corticosteroids if other meds are contraindicated (prednisone 20-40mg/d or intra-articular steroids)
    7. Don't start hypouricemic therapy during acute attack--doesn't help and may induce a recurrent attack by mobilizing uric acid from the tissues. However, if pt is on hypouricemic tx, don't d/c during acute attacks.
  1. Preventive tx
    1. May result in diminution of tophi as well as prevention of acute attacks
    2. Hypouricemic agents
  1. Criteria for use
  1. Frequent or severe attacks
  2. Severe hyperuricemia
  3. Tophi
  4. Radiographic evidence of urate deposits
  5. Urolithiasis
  6. Urate overexcretion
  1. Try to maintain serum uric acid at < 6mg/dl
  2. The optimal duration of hypouricemic tx is unknown; may experts recommend lifelong tx
  3. Hypouricemic tx may precipitate acute gout (unclear why)
    1. Colchicine 1-2wks before and continue for several months after initiation of hypouricemic tx is commonly used
    2. In a study in 43 pts with gouty arthritis starting allopurinol (100mg/d initially then titrated to uric acid < 6.5mg/dL) randomized to colchicine 0.6mg BID vs. placebo; 6mo incidence of gout flares was sig. lower in colchicine group (33% vs. 77%) (J. Rheum. 31:2429, 2004--JW)
  4. Specific agents--Pts with elevated urinary uric acid excretion are at increased risk for urolithiasis and should be tx'd with a xanthine oxidase inhibitor rather than uricosuric agents; this would be the only reason to check urinary uric acid excretion (normal = 330-600mg/d; don't check during an acute attack b/c won't be accurate)
  1. Xanthine oxidase inhibitors
    1. Allopurinol (300mg QD, may increase to up to 900mg if needed; 100-200mg/d in pts with renal insufficiency)
      1. May cause gastric irritation, diarrhea, skin rash, and rarely, hypersensitivity syndrome (more likely in pts with renal insufficiency) with acute interstitial nephritis, hepatitis, fever, vasculitis, and severe skin injury
      2. In a case-control study of 3,677 pts and 21,868 control, allopurinol use > 3y ass'd with RR for cataracts of 1.53 (sig.) (Arch. Ophth. 116:1652, 1998--JW)
      3. Many advise starting at low dose and escalating slowly
    2. Febuxostat ("Uloric"; a non-purine xanthine oxidase inhibitor)
      1. Labeled for use at 40-80mg/d though higher doses were used in clinical trials
      2. Febuxostat 80-120mg/d was associated with significant reductions in serum uric acid and incidence of gout flares in a 4-year uncontrolled study in 116 pts with chronic gout.  Concimmittant colchicine was used for prophylaxis against flares for first 4wks.  No serious adverse events reported but some pts had transient, mild-moderate elevation of liver function tests (Febuxostat Open-Label Clinical Trial of Urate-Lowering Efficacy and Safety, "FOCUS," reported at the European Congress of Rheumatology, FP News 7/15/06, p. 1)
  2. Uricosuric agents
  1. Ineffective--and more dangerous re: risk of uric acid urolithiasis--if CrCl < 30ml/min
  2. Before starting tx, check to make sure 24h urine uric acid secretion is not high, b/c if it is, tx'ing with a uricosuric agent may raise the risk of uric acid stones as well as uric acid deposition in renal tubules
  3. Consider co-treating with urine alkalinizing agents (e.g. acetazolamide 250mg HS)
  4. Probenecid 500-1000mg BID--effectiveness reduced by salicylates
  5. Sulfinpyrazone 100mg TID-QID--may cause HA, GI upset, rash; effectiveness reduced by salicylates
  1. Pegloticase (Krystexxa)
    1. A uric acid-specific enzyme (urate oxidase; catalyzes oxidation of uric acid to allantoin; reducing serum uric acid concentration).
    2. Administered by IV infusion Q2wks
    3. Contraindicated in pts with glucose-6-phosphate dehydrogenase deficiency
    4. Must premedicate with antihistamines and corticosteroids before infusion
    5. Potential adverse effects include triggering of gout flares (see below re: prevention), infusion reactions, GI upset, ecchymosis, nasopharyngitis, mconstipation, chest pain, and exacerbation of heart failure
    6. To prevent initiation of gout flares when starting treatment, pre-treat with NSAID or colchicine 1wk before starting treatment and continue x 6mos if possible.
    7. In a study in 225 pts with severe gout refractory (or intolerant) to allopurinol, with serum uric acid > 7.9, randomized to pegloticase 8mg IV "biweekly" x 12 vs. pegloticase 8mg IV Qmo, or placebo, incidence of reaching goal uric acid level (< 6.0 mg/dL) was sig. greater in both active-treatment groups than placebo (42% for "biweekly", 35% for monthly, and 0% for placebo) (JAMA 306:711, 2011-JW)
  2. Encourage high fluid intake
  3. Moderation in protein intake
  4. Treat HTN if present
  5. Avoid excessive alcohol intake
  6. Colchicine 0.6-1.2mg/d can be used as preventive monotherapy
  7. Ditto for low-dose NSAIDs