Gout

• Gout is an inflammatory arthritis caused by deposition and accumulation of monosodium urate crystals in tissues, mainly synovium, cartilage and skin with or without symptoms as a result of long standing hyperuricemia.
• 90% of gout is due to under excretion and 10% is due to increased synthesis.
• The stages of gout are hyperuricemia, asymptomatic gout, acute gout, inter-critical gout and chronic gout.
• It is often associated with metabolic syndrome with insulin resistance, hypertension and diabetes mellitus.
• Gout and asymptomatic hyperuricemia is associated with significantly elevated risk of chronic lifestyle diseases such as obesity, hypertension, ischaemic heart disease, type 2 diabetes, chronic kidney disease etc.
• Nephropathy and disorders associated with increased cell turnover can be associated.

Metabolism

• Uric acid is the end metabolite of purine metabolism in humans.
• In other species, presence of the enzyme called uricase converts uric acid into highly water soluble allantoin.
• In humans, the uricase gene is inactivated by the presence of 2 mutations.
• The level of uric acid in humans is 10 times higher than other species due to the absence of uricase.
• It is a weak acid and at the physiologic pH exists in the ionic form called urate.
• Uric acid levels depend on the dietary intake, synthesis and excretion.
• The limit of solubility of urate is 6.8mg/dL.
• When exceeded, urate crystal deposition occurs in tissues.
• Solubility of urate is determined by the following factors
  • pH
  • Body temperature
  • Level of hydration
  • Presence of nucleation factors
  • Concentration of cations

Clinical Features

• Episodic urate crystal induced acute inflammation of joints, tendons and bursa is the classic picture of acute gout.
• Acute attack which peaks within just 6–12 hours with overlying erythema is highly suggestive of crystal inflammation though not specific for gout.
• In recurrent podagra with hyperuricemia, a clinical diagnosis is reasonably accurate but not definitive without crystal confirmation.
• Lower limbs are more commonly affected than upper limbs.
• Peripheral joints are more commonly affected than central joints.
• First metatarsophalangeal joint is the site of presentation (Podagra) in more than 50% of cases. Other sites of first attack are the tarsal joints ankle and knee.
• More than 80% of the site of first episode is in the lower limbs.
• The first episode is monoarticular in 90%.
• Polyarticular onset is seen in less than 1%.
• Olecranon bursa is the commonest site of first attack in the upper limb.
• First metatarsophalangeal joint is affected in more than 80% of patients with uncontrolled or untreated gout.
• Acute attacks are preceded by prodromal symptoms such as mild pain, limitation of motion and discomfort.
• Acute attacks have an abrupt onset with rapid development of acute inflammation with excruciating pain during the first 24-48 hours.
• Provocative factors for acute attacks include severe dietary restriction, high purine diet, local trauma and initiation of treatment.
• Sudden drop in uric acid level results in disintegration of solid aggregations leading to local inflammation.
• Macroscopic collections of urate crystals is called tophi. More commonly seen in areas subjected to pressure or friction.
• Limitation of joint movement is due to accumulation of tophaceous deposits in the joints and periarticular tissues.
• Intraarticular tophi may present with mechanical symptoms mimicking meniscus tear or loose body.
• Rupture of intradermal tophi may mimic pustules.
• Persistent joint swelling is called chronic gouty arthritis. It is due to chronic granulomatous inflammation induced by urate crystals. X-rays usually show only minimal destruction, but MRI or USG show extensive soft tissue deposits.

Natural history of untreated gout

• More than 75% develop subsequent acute attacks.
• Frequency of attacks increase in 50%.
• Severity of attack increases in 30%.
• Polyarticular involvement develops in 40%.
• Tophaceous burden increases.

Investigations

Diagnostic investigations are done for

o          Confirmation of gout.

o          Determination of burden of disease.

o          Identification of complications.

o          Identification of other associated rheumatic conditions.

Confirmation of diagnosis

• Demonstration of MSU crystals in synovial fluid or tophus aspirates is the gold standard for the diagnosis of gout.
• Synovial fluid should be send for total count, differential count, analysis, gram stain, bacterial culture and biochemical analysis.
• MSUC are water soluble and is dissolved if preserved in formalin, hence tissue samples to be examined for urate crystals should be fixed in 100% alcohol.
• In all synovial fluid samples obtained from inflamed joints for diagnosis, search for MSU crystals.
• During the intercritical period, definite diagnosis can be made by identification of MSU crystals in the asymptomatic joints.
• Gout and sepsis may coexist, hence do gram staining and culture
• Serum uric acid levels alone do not confirm or exclude gout, as many with hyperuricemia do not develop gout, and the serum levels may be normal in many with acute attack.
• In those with a family history of young onset gout, onset of gout under age 25, or with renal calculi determine the renal uric acid excretion.

Determination of burden of disease

• Number of acute exacerbations.
• Number and location of joints ever involved by acute attacks.
• Presence, size, and location of superficial tophi.
• Persistence of pain, joint swelling, limitation of motion, and deformities.
• Short 4-joint USG of both knees and first metatarsophalangeal joints.

Look for comorbidities such as obesity, hyperglycaemia, hyperlipidaemia and hypertension.

Imaging

• Conventional x-ray
• Ultrasonography
• Three-dimensional (3D) multislice imaging via computed tomography (CT),
• Dual-energy computed tomography (DECT)
• Magnetic resonance imaging (MRI)

Radiography

• Radiographs are not useful in confirming the diagnosis of early or acute gout.
• Play a minor role in diagnosis.
• Nonspecific initially.
• Acute gout attack produces soft tissue swelling.
• Asymmetric erosive arthropathy especially of the first MTPJ is the characteristic appearance of chronic gouty arthritis.
• Gouty deposits cause well corticated erosions with typical overhanging margins.
• New bone formation can be seen in the form sclerosis, osteophytes, bony spurs and, rarely, periosteal deposition and ankylosis.

CT Scan

• Multislice helical CT scanning can show tophaceous deposits with a typical density of 160–170 Hounsfield units. They are found close to the erosions extending into the soft tissues.

Dual Energy CT

• Uses 2 X-ray tubes arranged perpendicular to each other using different voltages. It has the potential to detect intra-articular and extra-articular urate crystals which would have been otherwise undetectable.

High resolution ultrasound scan.

• Serial high resolution ultrasound may be used to assess response to treatment.
• Highly sensitive for detection of erosions.
• Double contour sign seen

Diagnosis Criteria

Rome criteria – 1963

(2 of 4 required for diagnosis)

• Serum uric acid > 7mg/dl in males and >6mg/dl in females
• Tophus
• Urate crystals demonstrated in the synovial fluid
• History of recurrent attacks of joint swelling of abrupt onset which resolves within 2 weeks.

New York criteria – 1968

• Demonstration of urate crystals in the synovial fluid or tissue.

OR

More than 2 of the following criteria.

• Tophi
• History or observation of podagra.
• History or observation of at least 2 attacks of painful limb swelling of abrupt onset which resolves within 1-2 weeks.
• History or observation of good response to colchicine within 24 hours.

ACR Criteria- 1977

• Urate crystals in the synovial fluid.

OR

• Tophus demonstrated by microscopy or tissue biopsy.

OR

At least 6 of the following 12

• More than one attack of acute arthritis.
• Maximum amount of symptoms developed within 24 hours.
• First MTPJ swollen or painful.
• Unilateral first MTPJ attack.
• Unilateral tarsal joint attack.
• Redness over the joint.
• Suspected tophus.
• Symmetric joint swelling on the radiograph.
• Subcortical cysts without erosions on the x-ray.
• Negative bacterial culture of joint aspirate during the attack.

Differential diagnosis

• Psuedogout
• Rheumatoid arthritis
• Infectious arthritis
• Acute pyrophosphate arthritis
• Spondylarthropathies

Treatment

• Treatment is divided into control of acute attack and long term control of chronic gout.
• Aim of treatment in chronic gout is to reduce uric acid levels by non-pharmacologic and pharmacologic interventions.
• Nonpharmacologic measures include weight reduction, restriction of alcohol and dietary modifications.
• The goal of treatment in acute gout is control of pain and inflammation safely and at the earliest.
• Mainstay of treatment of acute gout is anti-inflammatory drugs.
• Anti-inflammatory drugs may be NSAIDS, steroids or colchicine.
• Patient should rest the inflamed joint and apply ice packs.
• Oral colchicine with or without NSAIDs is recommended as first-line treatment for acute gout.
• Colchicine should be started within 24 hours of onset. It is not given after 36hours of onset.

Diet restrictions

• Weight reduction reduces de novo synthesis of adenosine which results in decreased uric acid levels.
• Relative risk of gout is 1 in those with normal BMI, 2 in the overweight and 3 in the obese.
• Dietary intake of purine have a significant influence on serum uric acid level.
• Bioavailability of purine in foods depend on its cellularity and the metabolic and transcriptional status of the cells.
• High levels of meat intake associated with 40% increase in the incidence of gout.
• High levels of fish intake associated with 50% increase in the incidence of gout.
• Vegetables with high levels of purine content do not have a significant effect on the serum uric acid levels.
• Restricted purine intake in healthy males result in 30% reduction in uric acid levels.
• Diary consumption lower risk of gout.
• Coffee consumption lower risk of gout.
• Alcoholic beverages especially beer is associated with increased risk of gout as it has high levels of guanosine. Alcohol causes degradation of ATP to AMP, metabolic acidosis and dehydration leading to increase in uric acid levels.
• Relative risk of gout is 2.5 in those taking beer.
• Fructose increases uric acid levels as it leads to conversion of ATP in liver to AMP. Hence soft drink consumption should be reduced.
• Thiazides, loop diuretics, cyclosporine and low-dose aspirin cause uric acid retension.

Urate lowering therapy (URL)

• Drugs available
  • Xanthine oxidase inhibitors
    • Allopurinol
    • Febuxostat
  • Uricosuric drugs
    • Probenecid
    • Benzbromarone
    • Sulfinpyrazone
  • Recombinant uricase
    • Pegloticase
  • Asymptomatic hyperuricemia is not an indication for drug treatment.
  • Drug treatment indications
    • Recurrent acute attacks >2 per year
    • Tophaceous gout
    • Chronic gouty arthropathy
    • Recurrent nephrolithiasis
    • Patients undergoing chemotherapy
  • URL is not given during acute attacks as sudden lowering of urate levels can lead to disintegration of tophi leading to worsening or prolongation of attack.
  • Goal range of urate is <6mg/dL.
  • Goal range is <5mg/dL for those with tophi.
  • Serum levels are lowered slowly at a rate of 1-2mg/dL per month.
  • Serum uric acid levels are measured every 2 weeks during the first month and then every 2 months for first 6 months. Once target level is achieved it is monitored every 6 months.
  • Xanthine oxidoreductase is a dimeric enzyme that exist in 2 forms. Xanthine oxidase and xanthine dehydrogenase.
  • Xanthine oxidase catalyses conversion of xanthine to hypoxanthine and conversion of hypoxanthine to uric acid.
  • Allopurinol and febuxostat inhibit xanthine oxidase.
  • First line of treatment is febuxostat or allopurinol.
  • Febuxostat preferred in presence of impaired renal function.
  • Allopurinol
    • Starting dose of 100mg per day if glomerular filtration rate is normal.
    • Dose increased by 100mg every 2-4 weeks till target range is achieved.
    • Maximum dose – 800mg/day.
    • Target level achieved only in 40-50%.
    • Side effects- Toxic epidermal necrolysis, Steven Johnson syndrome, Acute hepatic syndrome with fever, rash, hepatitis and renal filure.
    • Side effects are more likely with those with impaired renal function.
  • Febuxostat
    • Thiazolecarbolic acid derivative.
    • Inhibits both forms of xanthine oxidoreductase.
    • Metabolism is hepatic. Hence no dose adjustment required in presence of renal impairment.
    • Dosage 40-120mg/day.
    • Higher cardiovascular events have been reported with febuxostat but not confirmed.
  • Uricosuric agents
    • 90% of gout is due to impaired excretion.
    • Inhibit proximal tubule urate reabsorption.
    • Cannot be used in those with renal impairment or nephrolithiasis.
    • Probenecid usually started at a dose of 250mg twice daily. Maximum dose is 2000mg per day.
  • Pegloticase
    • Recombinant porcine uricase.
    • Single dose lowers uric acid to undetectable levels for several weeks.
    • 8mg Biweekly infusions for 6 months reduce body urate pool.
    • Immunogenicity can lead to lose of efficacy and immune reactions
    • Loss of efficacy precedes immune reaction, hence urate levels should be measured before and after infusion.
    • Should not be combined with other urate lowering drugs to avoid missing of loss of efficacy due to antibodies.
    • Gout flare ups and immune reactions are frequent.