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Gout
Ryan B. Feeney, PharmD
Michael C. Barros, PharmD, BCPS, BCACP
Paul N. Williams, MD, FACP
image BASICS
DESCRIPTION
  • Gout is an inflammatory arthritis related to a hyperuricemia (serum uric acid [SUA] level >6.8 mg/dL) (1).
  • Acute gouty arthritis can affect ≥1 joints; the first metatarsophalangeal joint is most commonly involved at presentation (podagra).
  • Although hyperuricemia is necessary for the development of gout, it is not the only determining factor.
  • Characterized by deposition of monosodium urate (MSU) crystals that accumulate in joints and soft tissues, resulting in acute and chronic arthritis, soft-tissue masses called tophi, urate nephropathy, and uric acid nephrolithiasis
  • After an initial flare, a second flare occurs in ˜60% of patients within 1 year and 78% within 2 years of the initial attack (2).
  • Management involves treating acute attacks and preventing recurrent disease by long-term reduction of SUA levels through pharmacology and lifestyle adjustments
EPIDEMIOLOGY
Incidence
Annual incidence of gout (3):
  • Uric acid 7 to 8.9 mg/dL is 0.5%.
  • Uric acid >9 mg/dL is 4.5%.
Prevalence
  • Increasing prevalence over the past decades (3)
  • 2007 to 2008 prevalence of gout in the United States (3)
    • Men 5.8% (6.1 million)
    • Women 2.0% (2.2 million)
  • 2008 prevalence of hyperuricemia in the United States (3)
    • Men 21.2% (SUA >7.0 mg/dL)
    • Women 21.6% (SUA >5.7 mg/dL)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Hyperuricemia results from urate overproduction, underexcretion, or often a combination of the two.
  • Gout occurs when MSU, a product of purine metabolism, precipitates out of solution and accumulates in joints and soft tissues.
  • Transient changes in urate solubility caused by local temperature decrease, trauma, or acidosis may lead to an acute gouty attack.
  • Urate crystals that precipitate trigger an immune response.
  • Left untreated, this crystal deposition leads to permanent joint damage and tophus formation.
Genetics
  • Phosphoribosyl pyrophosphate (PRPP) deficiency and hypoxanthine-guanine-phosphoribosyltransferase (HGPRT) deficiency (Lesch-Nyhan syndrome) are inherited enzyme defects associated with overproduction of uric acid.
  • Polymorphisms in the URAT1 and SLC 2A9 (GLUT9) renal transporters are hereditary enzyme defects resulting in primary underexcretion of uric acid.
RISK FACTORS
  • Age >40 years
  • Male gender
  • Increased purine uptake (meats and seafood)
  • Alcohol intake (especially beer)
  • High fructose intake
  • Obesity
  • Hyperuricemia
  • Congestive heart failure
  • Coronary artery disease
  • Dyslipidemia
  • Renal disease
  • Organ transplant
  • Hypertension
  • Hyperinsulinemia
  • Metabolic syndrome
  • Diabetes mellitus
  • Urate-elevating medications:
    • Thiazide diuretics: ethambutol
    • Loop diuretics (less of a risk vs. thiazides)
    • Niacin
    • Calcineurin inhibitors (cyclosporine and tacrolimus)
    • Acetylsalicylic acid (not recommended in high doses)
GENERAL PREVENTION
  • Maintain optimal weight.
  • Regular exercise
  • Diet modification (purine-rich foods)
  • Reduce alcohol consumption (beer and liquor).
  • Maintain fluid intake and avoid dehydration.
COMMONLY ASSOCIATED CONDITIONS
  • Hypertension
  • Dyslipidemia
  • Nontraumatic joint disorders
  • Heart disease
  • Urinary tract disease
  • Diabetes mellitus
  • Metabolic syndrome
  • Obesity
  • Renal disease
image DIAGNOSIS
PHYSICAL EXAM
  • Examine suspected joint(s) for tenderness, swelling, and range of motion (ROM).
  • Assess for presence of firm nodules known as tophi.
  • In patients with chronic gout, tophi can frequently be found in the helix of the ear, over the olacrenon process, or on the Achilles tendon.
  • Patients with untreated chronic gout can have evidence of joint inflammation and deformity.
DIFFERENTIAL DIAGNOSIS
Acute bursitis, tendonitis, septic arthritis, pseudogout (calcium pyrophosphate deposition disease), cellulitis, osteoarthritis
DIAGNOSTIC TESTS & INTERPRETATION
  • SUA (may be normal during an acute flare)
  • CBC (can see elevation of WBC during an acute gout flare)
  • Synovial fluid analysis: urate crystals (negatively birefringent under polarizing microscopy), cell count (WBC usually 2,000 to 5,000 cells/mm3); culture to rule out infection. Some guidelines suggest that gout can be diagnosed clinically without synovial fluid analysis.
  • Screen for uric acid overproduction—24-hour urinary uric acid in those patients with gout onset before the age of 25 years or had a history of urolithiasis (1)[C].
  • Radiograph is normal early in disease but can reveal
    • Swelling in acute gout
    • Periarticular erosions with periosteum overgrowth in chronic gout
  • Urate kidney stones are radiolucent and thus invisible on radiograph.
image TREATMENT
GENERAL MEASURES
Topical ice as needed (4)[B]
MEDICATION
  • Acute treatment
    • General principles:
      • Acute gouty arthritis attacks should be treated with pharmacologic therapy (4)[C].
      • Pharmacologic treatment should be initiated within 24 hours of acute gout attack onset (4)[C].
      • Ongoing pharmacologic urate-lowering therapy should not be interrupted during an acute gout attack (4)[C].
      • Choice of agent is based on severity of pain and the number of joints involved (4).
    • Mild/moderate gout severity (≤6 of 10 on visual analog pain scale, particularly for an attack involving only one or a few small joints or one to two large joints)
      • NSAIDs:
        • Naproxen (Naprosyn, Anaprox, Aleve): 750 mg followed by 250 mg q8h for 5 to 8 days (4)[A]
        • Indomethacin (Indocin): 50 to 150 mg/day for 2 to 7 days (4)[A]
        • Sulindac (Clinoril): 200 mg BID for 7 to 10 days (4)[A]
        • Celecoxib (Celebrex)
        • Not FDA approved but can be considered in selected patients with contraindications or intolerance to NSAIDs (4)[B].
          • Dose at 800 mg once followed by 400 mg on day 1, then 400 mg BID for 1 week (4)[B]
      • Corticosteroids
        • Those with an acute flare involving one to two large joints can consider intra-articular corticosteroids; can consider using PO corticosteroids in combination.
        • For other acute flares, use PO corticosteroids:
          • Prednisone (Sterapred): 0.5 mg/kg/day for 5 to 10 days followed by discontinuation (4)[A] or alternately 2 to 5 days at full dose followed by tapering for 7 to 10 days and then discontinuing (4)[C]
          • Methylprednisolone (Medrol) dose pack (4)[C]
          • Triamcinolone acetonide (Trivaris): 60 mg IM single dose followed by oral corticosteroids (4)[C]
      • P.423

      • Colchicine (Colcrys)
        • Used for gout attacks where the onset was <36 hours prior to treatment initiation (4)[A]
        • Begin a loading dose of 1.2 mg followed by 0.6 mg 1 hour later, followed by 0.6 mg once or twice daily 12 hours later, until the gout attack resolves (4)[C].
        • Dose reduction recommended in moderate to severe kidney disease and in those on inhibitors of cytochrome P450 3A4 and P-glycoprotein (clarithromycin, erythromycin, cyclosporine, and disulfiram) (4).
    • Severe gout (≥7 of 10 on visual analog pain scale, involving ≥4 joints with arthritis involving >1 region, or involving three separate large joints)
      • Initial combination therapy is an option and includes the use of full doses of the following (4)[C]:
        • Colchicine and NSAIDs
        • PO corticosteroids and colchicine
        • Intra-articular steroids with all other modalities
    • For patients not responding to initial pharmacologic monotherapy, add a second agent (4)[C].
  • Chronic treatment
    • Indications for pharmacologic urate-lowering therapy include any patient with
      • Tophus or tophi by clinical exam or imaging study (1)[A]
      • Frequent attacks of acute gouty arthritis (≥2 attacks/year) (1)[A]
      • Chronic kidney disease (CKD) stage 2 or worse (1)[C]
      • Past urolithiasis (1)[C]
    • Treat to the serum urate:
      • Minimum serum urate target is <6 mg/dL (1)[A].
      • Serum urate target may need to be <5 mg/dL to improve gout signs and symptoms (1)[B].
    • Urate-lowering agents can be prescribed during an acute attack provided that effective anti-inflammatory prophylaxis has been initiated prior to urate-lowering therapy (1)[C].
    • Anti-inflammatory prophylaxis required when initiating urate-lowering therapy include the following:
      • First line
        • Low-dose colchicine: 0.6 mg once or twice daily (4)[A]
        • Low-dose NSAIDs with proton pump inhibitor if indicated: naproxen 250 mg PO BID (4)[C]
      • Second line: Use of colchicine and NSAIDs both are not tolerated, contraindicated, or ineffective:
        • Low-dose prednisone or prednisolone at ≤10 mg/day (4)[C]
      • Treatment duration for the greater of
        • At least 6 months (4)[A] or
        • 3 months after achieving serum urate appropriate for the patient with no tophi on exam (4)[B], or for 6 months after achieving serum urate appropriate for the patient with ≥1 tophi on exam (4)[C]
    • Pharmacologic urate-lowering agents:
      • Allopurinol (Zyloprim): xanthine oxidase inhibitor (1)[A]
        • Starting dose should be no higher than 100 mg/day (1)[B]
        • Starting dose should be 50 mg/day in stage 4 CKD or worse
        • Gradually titrate the dose upward q2-5wk to appropriate maximum dose (1)[C]
        • Dose can be >300 mg/day, even with renal impairment, as long as accompanied by patient education and monitoring of drug toxicity; maximum FDA-approved dosage is 800 mg/day (1)[B].
        • Regularly monitor for allopurinol hypersensitivity syndrome (AHS), pruritus, rash, elevated hepatic transaminases, and eosinophilia.
        • Screening for the HLA-B*5801 allele for AHS should be performed in those of Korean descent with stage 3 CKD or worse and Han Chinese or Thai descent irrespective of renal function (1)[A].
      • Febuxostat (Uloric): selective xanthine oxidase inhibitor (1)[A]
        • No renal or hepatic adjustments needed for mild-to-moderate hepatic or renal impairment
        • Starting dose 40 mg/day; may be titrated to 80 mg/day
        • In select instances, may dose up to 120 mg/day (not FDA approved) (1)[A]
      • Probenecid: uricosuric agent (1)[B]
        • Alternative first line urate-lowering therapy; use if at least one xanthine oxidase inhibitor is contraindicated or not tolerated (1)[B].
        • May be used in addition to allopurinol or febuxostat if serum urate target not achieved
        • Multiple drug interactions exist, as well as risk of urolithiasis with this agent.
        • Not recommended if creatinine clearance (CrCl) is <50 or with patient history of urolithiasis (1)[C].
        • Starting dose is 250 mg BID; gradually titrate to 2,000 mg/day
  • Other treatment
    • Acute treatment: adrenocorticotropic hormone (ACTH): 25 to 40 IU SC (4)[A]; especially in those NPO
    • Pegloticase in select severe instances (1)
SURGERY/OTHER PROCEDURES
Large tophi that are infected or interfering with joint motion may need to be surgically removed.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • SUA q2-5wk while titrating urate-lowering treatment to goal (1)[C]
  • Regularly monitor CBC, renal function, liver function test, and urinalysis.
DIET
  • General lack of evidence regarding specific recommendations, although the American College of Rheumatology has outlined the following (1)[C]:
  • General measures:
    • Weight loss for obese patients
    • Healthy overall diet
    • Exercise
    • Smoking cessation
    • Stay well hydrated
  • Avoid
    • Organ meats high in purine content (sweetbreads, liver, kidney) (1)[A]
    • High-fructose corn syrup-sweetened sodas, other beverages, or foods
    • Alcohol overuse (>2 servings per day for men and >1 serving per day for women) (1)[A]
    • Any alcohol use in gout during periods of frequent gout attacks or advanced gout under poor control
  • Limit
    • Serving sizes of beef, lamb, pork, and seafood with high purine content such as sardines and shellfish (1)[B]
    • Servings of naturally sweetened fruit juices
    • Table sugar and sweetened beverages and desserts
    • Table salt, including in sauces and gravies
    • Alcohol (particularly beer) in all gout patients (1)[B]
  • Encourage
    • Low-fat or nonfat dairy products
    • Vegetables
PATIENT EDUCATION
  • Dietary and lifestyle modifications (1)[B]
  • Patient instructions on initiating treatment on signs and symptoms of an acute gout attack without the need to consult health care provider for each attack (1)[B]
  • Discussion that gout is caused by excess uric acid and that effective urate-lowering therapy is essential treatment (1)[B]
PROGNOSIS
Gout can usually be successfully managed with proper treatment.
REFERENCES
1. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431-1446.
2. Doghramji PP. Managing your patient with gout: a review of treatment options. Postgrad Med. 2011;123(3):56-71.
3. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10): 3136-3141.
4. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res. 2012;64(10):1447-1461.
Codes
&NA;
ICD10
  • M10.9 Gout, unspecified
  • M10.00 Idiopathic gout, unspecified site
  • M10.30 Gout due to renal impairment, unspecified site
Clinical Pearls
&NA;
  • MSU crystals found in synovial fluid aspirate are pathognomonic for gout.
  • Acute gout and sepsis can coexist.
  • Asymptomatic hyperuricemia does not require treatment.
  • Losartan possesses uricosuric properties, therefore it may be an excellent agent if patient is hypertensive.