Gout is a rapid onset crystal-induced arthritis and is the most common form of inflammatory arthritis. Characterised by intense pain and swelling, acute attacks typically affect the first metatarsal-phalangeal joint (MTP of the great toe). If chronic, gout may affect other mainly peripheral joints including ankles, knees and fingers amongst others. It is uncommon for gout to affect more central joints such as hips.

It is triggered following prolonged hyperuricaemia due to purine breakdown which results in the accumulation of monosodium urate (MSU) crystals in the joint. When aspirated, this synovial fluid can be viewed under polarizing light microscopy to confirm the diagnosis.

Gout most commonly affects men with a first attack experienced between the ages of 30 and 50. Increased alcohol intake, being obese, metabolic syndrome, being of African American origin and family history are all well-established risk factors.

Gout can cause incapacitation during an acute attack and many patients experience repeat attacks, although the frequency of these flares is reduced if a treatment plan is adhered to. NSAIDs or colchicine are first-line for an acute attack whilst allopurinol is used as first-line prophylaxis to reduce occurrence of flares.

Gout develops when excessive serum levels of uric acid results in the precipitation of monosodium urate crystals.

Well known risk factors for gout include:

• Gender
  • Men are more likely to develop gout.
  • A woman's risk of gout increases following the menopause.
• Age
  • Most commonly, the first attack of gout occurs between the ages of 30 and 50.
  • Risk increases with age.
• Diet
  • A diet high in purines includes foods such as meat, seafood and fructose-containing foods.
  • These purines are metabolised to uric acid in the body and so increased consumption of such foods increases the risk of gout.
• Alcohol - much like diet, the role of alcohol in gout is linked to purine metabolism.
• Metabolic syndrome
• Medications associated with increased risk of gout:
  • Loop and thiazide diuretics
  • Low dose aspirin
  • Levodopa
• Chronic kidney disease
  • Physiologically, the kidneys flush out uric acid. If kidneys are impaired, uric acid will build up in the body.
  • The reverse also happens that persistently high serum uric acid damage the kidneys.

Although a rheumatological presentation, gout is considered a disorder of metabolism which results in the accumulation of uric acid via the pathway:

• Increased uric acid production/decreased excretion → elevated serum uric acid → deposition of MSU crystals in joints → inflammatory response = gout flare.

Increased uric acid production/decreased excretion

• Purines play an important role in serum uric acid balance. They are metabolised into uric acid via a multi-step pathway involving the enzyme xanthine oxidase hence the efficacy of the use of allopurinol (a xanthine oxidase inhibitor) as prophylactic treatment for gout.
• Purines are obtained from the diet. This is why diet plays a large role in management - reduced purines = reduced serum uric acid = reduced risk for gout. Dietary items high in purines include:
  • Alcohol
  • Red meat
  • Organ meat e.g. liver/kidney.
  • Sweetened beverages due to their fructose content (a precursor for purines).

Elevated serum uric acid

• Hyperuricaemia is split into primary and secondary hyperuricaemia but is more simply considered to occur via two pathways:
  • Insufficient uric acid clearance e.g. kidney disease.
  • Excess uric acid production e.g. excessive ingestion of purine containing foodstuffs.

Crystal deposition

• As uric acid levels increase, they may form a precipitate of crystals which deposit at peripheral joints. These crystals are needle-like and negatively birefringent under polarised light. When these crystal deposits become so large, they can be felt and seen as bumps under the skin called tophi.
• Tophi occur in joints, bones, cartilage and tissues around the joint and are responsible for many of the bone-related complications of gout.

Gout flares

• An attack of gout is triggered by either:
  • The release of these crystals from deposits = increase in serum uric acid levels.
  • The initial precipitation of crystals = decrease in serum uric acid levels.
• Both deposition and release of crystals activate the innate immune system triggering interleukins and pro-inflammatory cytokines release. This provides an inflammatory response presenting as a flare of gout.
• As illustrated, flares are triggered by a sudden change in serum uric acid. This is why the following may trigger a flare:
  • Rapid weight loss or fasting as excess lactic acid builds up and prevents excretion of uric acid.
  • Use of radio-contrast dyes can lower uric acid levels and so result in a flare.
  • Medication changes.

In contrast to many forms of arthritis, gout develops rapidly reaching maximal severity within 24 hours, and resolves within 5-15 days. Rarely, gout symptoms may appear gradually. 70% of first presentations involve the first MTP however gout may affect other peripheral joints including:

• Other joints of the feet, ankle and knee
• Joints of the hand, wrist and elbow.
• It rarely affects more central joints such as hip and spine.

Typical features of an affected joint include:

• Intense pain - often described as a stabbing and contact with the joint is very painful. May prevent patient from sleeping.
• Erythema - red and warm to the touch, gout may often resemble cellulitis.
• Joint swelling and tenderness resulting in a reduced range of movement.

Systemic symptoms may include:

• Tophi
  • In chronic gout, MSU crystals may deposit to form small hard lumps called tophi in the tissues surrounding the joint, cartilage and in the joints themselves.
  • They may form elsewhere including feet, knees, wrists, ears, fingers, kidneys and sclerae.
• Eye involvement - MSU crystals deposited in cornea (very rare)

Diagnosing gout for the first time can be achieved primarily using clinical features and patient history. If clinical features do not confidently suggest gout, a synovial fluid aspiration of the affected joint will confirm the diagnosis.

It appropriate to arrange serum uric acid measurements 4-6 weeks following the first presentation of suspected gout. They are also useful in chronic gout for monitoring purposes (higher levels correlate to a higher risk of gout). Additionally, radiology may evidence extra-articular features in chronic gout.

Investigations are outlined in more detail below.

Clinical diagnosis

• NICE guidelines state that if a patient presents with features suggestive of gout and there are no suspicions of other conditions such as septic arthritis, a clinical diagnosis can be made with no need for investigations.
• The European League Against Rheumatism (EULAR) recommend that the clinical diagnosis be supported by the following features:
  • Mono-articular involvement of a foot/ankle joint
  • Previous episodes of a similar nature
  • Rapid onset
  • Erythema
  • Male
• They stress that whilst suggestive of gout, these features are by no means specific.
• If making a clinical diagnosis, screen for cardiovascular risk and risk of kidney disease.

Synovial fluid analysis

• NICE advise aspiration is not indicated unless:
  • Diagnosis of gout is unsure.
  • Septic arthritis is suspected.
• Fine-needle aspiration of the affected joint is considered the gold standard as the presence of MSU crystals is 100% specific for gout. Usually, synovial fluid in gout will contain WBC at a level greater than 2000/µL
• It can also be used to differentiate between gout and pseudogout.
• Additionally, SF analysis allows the exclusion of an infective arthritis.

Serum uric acid

• Hyperuricaemia is NOT diagnostic of gout however, increased levels do correlate with increased risk of developing gout.
• Serum uric acid should be measured 4-6 weeks following an acute gout attack to confirm hyperuricemia.
  • Serum uric acid reference ranges vary between trusts and so it would be advisable to look on the trust intranet to be certain. They tend to be around 200-430µmol/L in males and 140-360µmol/L in females.
  • It is considered to be raised when levels are above 360µmol/L
  • The absence of hyperuricaemia does not exclude gout.
• Given the correlation between higher serum uric acid levels and risk of gout, it can be useful in monitoring response to urate lowering therapy in a patient with chronic gout.

Other bloods to consider

• U&Es: renal function should be measured to ensure appropriate dose of allopurinol.
• FBC: WBC may be raised
• Fasting glucose and lipid profile: gout is associated with metabolic syndrome.

Radiology - useful in chronic gout

• X-rays
  • X-rays are usually normal unless the disease is at an advanced stage.
  • In chronic gout, joint effusion is usually the earliest sign. Later, x-rays show punched out lytic lesions, sclerotic margins and outlines of tophi. Tophi are lumps caused by MSU crystal deposition.
• Ultrasound: tophi present in chronic gout can be observed via ultrasound appearing hyperechoic (white appearance).

Septic arthritis

• The most important differential diagnosis to exclude is septic arthritis.
• If patient is systemically unwell and presenting with a painful, swollen joint of rapid onset, septic arthritis must be excluded.
  • Patients should be referred immediately for joint aspiration and culture to determine diagnosis.
• May be more likely if risk factors for infection are present e.g. intravenous drug use

Pseudogout

• Pseudogout presents very similarly to gout but few clinical features differentiate the two:
  • Pseudogout is more likely to affect larger joints such as the knee .
  • Pseudogout is more likely in the elderly.
  • It typically presents with a less intense pain.
  • Chondrocalcinosis may be identified on x-ray.
• It is definitively distinguished by rhomboid shaped positively birefringent calcium pyrophosphate crystals in the synovial fluid but often this is not a feasible test.

Cellulitis

• The red swollen appearance of gout lends itself to a differential diagnosis of cellulitis.
• Given the risk of septic arthritis, it is appropriate to perform a fine needle aspiration of the joint despite the possibility of cellulitis which would usually contraindicate such an investigation.

Rheumatoid arthritis (RA)

• Chronic gout may be confused with RA despite mono-articular RA being rare. Distinguishing features include:
  • The onset of pain in RA is usually more gradual than gout.
  • Rheumatoid nodules may be present however are easily confused with tophi.
  • If patient experiences recurrent flares, this is more suggestive of gout.
• Rheumatoid factor may be present in both RA and gout so is not useful to distinguish the two. Anti-CCP is much more specific for RA but has relatively low sensitivity.
• Synovial fluid analysis would show inflammation in RA but no MSU crystals which would be present in gout.

Gout is typically managed in the community setting with differing approaches for acute and chronic gout. The goal of treatment to manage an acute attack is to reduce pain and inflammation of the affected joint and ensure it's function is rapidly restored, whilst long term management of gout aims to prevent flares and reduce joint erosion.

NICE guidelines for the management of gout are based upon the European League Against Rheumatism's (EULAR) evidence-based recommendations. Management of an acute attack includes NSAIDs and colchicine as first-line agents and corticosteroids if NSAIDs and colchicine are contraindicated. Long term control includes lifestyle advice and a range of pharmacological options but most commonly serum urate-lowering therapy allopurinol as first-line and febuxostat if allopurinol is not tolerated.

Acute attack management

If untreated, an acute attack may spontaneously resolve within 2 weeks but EULAR recommend they should be treated as soon as possible.

Management includes:

• Self-care - patient should be advised to keep joint elevated to reduce inflammation, limit any trauma to joint and keep it cool (consider using an ice-pack)
• Prescription of either of the first line treatments recommended by NICE: colchicine or NSAIDs such as indomethacin. Choice is based on patient preference, renal function and any co-morbidities.
  • Aspirin is not indicated as it may increase uric acid levels. This is because it prevents excretion of uric acid from the kidneys.
  • Aspirin may be prescribed in cases of cardiovascular disease and stroke as the benefits outweigh the risk of potentially inducing a gout flare.
• Corticosteroids:
  • A short course of oral corticosteroids such as prednisolone may be used if a patient cannot tolerate NSAIDs.
  • Intra-articular corticosteroids can also be used.

Long-term control

EULAR recommends allopurinol as the first-line urate lowering therapy with target uric acid levels of 360µmol/L or less.

• It is a xanthine oxidase inhibitor metabolising xanthine to uric acid. This results in reduced deposition of MSU crystals in joints hence the application for gout.
• It is generally well tolerated but side effects may include:
  • Common side-effects - skin rash (may indicate Stevens-Johnson Syndrome) and joint paint/swelling
  • Rare side effects - drug hypersensitivity syndrome (signs include eosinophilia, lymphadenopathy, fever and multi-organ involvement)
• *NOTE* Allopurinol should not be commenced during an acute attack as it may worsen it and so should be started 1-2 weeks after an acute attack. As it may also precipitate another acute attack, the British Society for Rheumatology recommends prophylactic colchicine (or NSAID if colchicine not tolerated) should be prescribed alongside for up to six months to avoid this.

Second-line therapy is febuxostat and is used for those who do not tolerate allopurinol.

• It is a non-purine xanthine oxidase inhibitor.
• Check liver function prior to commencing treatment.

Preventative lifestyle measures

• Patients should be educated about risk factors and encouraged to reduce consumption of alcohol. Alcohol is a source of purines which are metabolised into uric acid by the body.
• Patients should attempt to maintain a healthy weight and eat a healthy low-purine diet. They should be advised to limit meat, seafood and fructose-containing foods/drinks as these are high in purines.

If gout is not well controlled, it may result in the development of a range of co-morbidities/presentations. Many of these are a result of the chronically elevated levels of serum uric acid and subsequent systemic effects.

Complications include:

• Tophi
  • As mentioned previously, tophi form when MSU crystals deposit to form hard lumps. They can form in tissues, bone and cartilage and if large and painful may impact a patients ability to perform daily tasks.
  • Tophi are usually a sign of chronic gout, their presence indicates that there are likely to be MSU crystal deposits elsewhere in the body.
• Bone complications
  • Repeated attacks of gout and the presence of tophi all contribute to bone erosion and weakening of joints resulting in degenerative arthritis. In the most serious of cases, surgery will be required to rectify this damage.
  • A 2018 population-based study found that gout conferred a 20% increased risk of osteoporosis.
• Renal complications
  • Kidney stones may occur due to deposits of MSU crystals in the urinary tract as a result of hyperuricaemia. They can disrupt the flow of urine, cause pain and make the patient more susceptible to an infection of the urinary tract or kidney.
  • Although kidney disease is a risk factor for gout, gout can also cause kidney disease. Although not fully understood, it is believed kidney disease may result due to the passage of MSU crystals through kidneys causing scarring. This scarring then reduces functionality of the kidneys.
• Mental health conditions
  • Resultant from the chronic pain and incapacitation, patients may be unable to work of complete activities of daily living.
  • Cumulatively, this may impact a patient's mental well-being and they should be supported appropriately.

Many of these complications can be avoided if serum uric acid levels are kept within range.