Gout

01Definition and overview

Gout is an inflammatory arthritis caused by the deposition of monosodium urate crystals in and around joints, in people with a raised serum urate (hyperuricaemia). Urate dissolves in plasma up to about 400 µmol/L (6.8 mg/dL) at body temperature; above that, crystals can form, more easily in cool, peripheral joints and in damaged cartilage.

Gout develops in stages, and treatment can stop it at any of them:

02Etiology and pathophysiology

Where urate comes from

Uric acid is the end product of purine breakdown in humans. Purines from the body's own turnover of DNA and RNA and, less, from food are broken down to hypoxanthine; xanthine oxidase turns hypoxanthine into xanthine and xanthine into uric acid. Most mammals carry on with uricase, which converts urate to soluble allantoin, but humans and the great apes lost the uricase gene, so our urate levels are higher. At the pH of blood almost all of it is the urate anion.

About two thirds of urate leaves through the kidneys and a third through the gut. The kidney filters urate freely and then reabsorbs about 90 per cent of it, so only 5 to 10 per cent of the filtered load is excreted. Reabsorption runs through transporters in the proximal tubule, chiefly URAT1 and GLUT9; secretion runs through others, including ABCG2, which also excretes urate into the gut. Variants of the genes for GLUT9 and ABCG2 have the largest effects on urate levels of any common genes.

Causes of hyperuricaemia

Oestrogen increases urate excretion, which is why gout is rare in women before the menopause. Gout in a young man, a premenopausal woman or a child suggests a genetic or kidney cause.

How crystals cause a flare

1. 1

   Crystals form

   Above saturation, urate nucleates into needle-shaped crystals on cartilage and in the synovium, helped by cool temperatures, a lower pH, dehydration and damaged cartilage; this is why gout favours the feet and joints already affected by osteoarthritis.
2. 2

   The inflammasome

   A rise or a fall in urate, trauma or an illness sheds crystals into the joint. Macrophages engulf them, which activates the NLRP3 inflammasome: caspase-1 cleaves pro-IL-1β into active IL-1β.
3. 3

   Neutrophils

   IL-1β and chemokines such as IL-8 draw in a flood of neutrophils, which release more cytokines, enzymes and complement: the joint becomes hot, red and swollen within hours.
4. 4

   Resolution

   Untreated, the flare ends within days to two weeks: neutrophils form extracellular traps that bundle crystals and break down cytokines, and anti-inflammatory signals take over. The crystals stay behind.
5. 5

   Chronic disease

   With persistent hyperuricaemia, crystals accumulate in tophi, granulomas of crystals surrounded by macrophages and giant cells, which erode bone and cartilage.

Gout is therefore an autoinflammatory disease, driven by innate immunity rather than by autoantibodies, which is why IL-1 blockers work. Colchicine blocks microtubule assembly in neutrophils, stopping their movement and inflammasome activation.

03Clinical features

The flare

• Sudden onset, often at night or in the early morning, peaking within 24 hours: pain so severe that the bedclothes cannot be tolerated, with red, shiny, swollen skin and sometimes fever.
• Podagra, the first metatarsophalangeal joint, is the first site in about half of patients and is involved at some point in most. Then the midfoot, ankle, knee, wrist, fingers and elbow, and bursae such as the olecranon and prepatellar.
• The first flares involve one joint; later flares can involve several. Polyarticular gout is commoner in older women on diuretics, sometimes in finger joints with Heberden nodes.
• Untreated, a flare lasts 7 to 14 days and may end with peeling of the skin over the joint.
• Triggers: alcohol or a heavy meal, dehydration, surgery or acute illness, trauma, starting a diuretic, and starting or changing urate-lowering therapy.

Chronic gout

• Chronic gouty arthritis: persistent joint pain and swelling between flares, joint damage and deformity.
• Tophi: firm, white-yellow nodules of urate under the skin, on the ear helix, over the olecranon, fingers, toes and Achilles tendon. They can ulcerate and discharge chalky material. They usually appear after 10 years or more of untreated hyperuricaemia, earlier in kidney disease or after transplantation.

The kidney

• Kidney stones: in roughly 10 to 20 per cent of people with gout. Many are uric acid stones, favoured by acid urine, radiolucent on plain X-ray and visible on CT; hyperuricaemia also promotes calcium oxalate stones.
• Acute uric acid nephropathy: urate crystals block the tubules in tumour lysis, after chemotherapy of leukaemias and lymphomas; prevented with hydration, allopurinol or rasburicase (a recombinant uricase).
• Chronic urate nephropathy: interstitial urate deposits; whether hyperuricaemia itself damages the kidney is debated. Chronic kidney disease is far more often the cause of gout than its result.

Gout keeps company with hypertension, chronic kidney disease, obesity, the metabolic syndrome, type 2 diabetes, dyslipidaemia, heart failure and coronary disease, and these comorbidities are looked for in every patient.

What else a red hot joint can be

Calcium pyrophosphate deposition disease is the main crystal alternative. Its acute attacks (pseudogout) mimic gout, often at the knee or wrist, sometimes after surgery or an illness; it also causes a chronic arthritis like osteoarthritis. There is no drug to dissolve calcium pyrophosphate, so treatment is aspiration, intra-articular steroid, NSAIDs or colchicine. Early-onset or widespread disease is screened for a metabolic cause.

04Diagnosis and management

Tests

• Synovial fluid microscopy under compensated polarised light: monosodium urate crystals, needle-shaped, strongly negatively birefringent (yellow when parallel to the compensator's axis), often inside neutrophils. It is the reference test and also possible between flares or from a tophus. The fluid is sent for Gram stain and culture whenever infection is possible.
• Serum urate: a level of 360 µmol/L or more supports the diagnosis, but it falls during a flare and can be normal; if gout is suspected, it is repeated at least 2 weeks after the flare settles. A high urate alone does not make a joint gouty.
• Creatinine and eGFR, glucose or HbA1c, lipids, blood pressure; full blood count and liver tests before treatment. In a flare the CRP, ESR and white cell count are often raised.
• X-ray: normal early; later, well-defined punched-out erosions with sclerotic, overhanging edges and a joint space kept until late, and soft-tissue tophi.
• Ultrasound: the double contour sign, a bright line of urate on the surface of the cartilage, and tophi.
• Dual-energy CT: tells urate from calcium by how it absorbs two X-ray energies, and colour-codes the urate deposits. It helps when aspiration is not possible or negative.

In the UK, gout is suspected in anyone with rapid-onset, severe pain, redness and swelling of the first metatarsophalangeal joint or with tophi, and the diagnosis is often clinical, confirmed by a raised urate; aspiration is considered if the diagnosis is uncertain, and imaging if aspiration is not possible.

The 2015 ACR/EULAR classification criteria

Anyone with at least one episode of swelling, pain or tenderness in a peripheral joint or bursa qualifies for assessment. Urate crystals in a symptomatic joint, bursa or tophus are sufficient to classify gout. Without them, points are added from the clinical picture (the joints involved, the features and time course of the episodes, tophi), the serum urate (with points subtracted for a urate below 240 µmol/L or a crystal-negative aspirate) and imaging (a double contour sign or urate on dual-energy CT, gouty erosions on X-ray); 8 points or more classify gout. The criteria have a sensitivity of 92 per cent and a specificity of 89 per cent.

Treating the flare

Treatment starts as early as possible, ideally within hours, with the drug that best fits the patient's other diseases and medicines:

Rest, elevation and ice packs help. Urate-lowering therapy already taken is continued through a flare; stopping it and restarting causes more flares.

Who needs urate-lowering therapy

Guidance has moved towards treating earlier, because gout progresses while the urate stays high:

Asymptomatic hyperuricaemia is not routinely treated with urate-lowering drugs in Europe, and American guidance advises against it; its causes are addressed.

Treat to target

1. 1

   Explain

   Gout is a lifelong condition caused by crystals, and urate-lowering therapy dissolves them and prevents flares, tophi and joint damage. It is usually continued for life, and flares may increase in the first months.
2. 2

   Start low

   The first-line drugs are xanthine oxidase inhibitors. In the UK, ULT starts at least 2 to 4 weeks after a flare has settled, or during it if flares are frequent; American guidance allows starting during a flare under anti-inflammatory cover.
3. 3

   Prevent flares

   Colchicine 0.5 mg once or twice daily, usually for the first 3 to 6 months or until the target is reached; a low-dose NSAID or prednisolone if colchicine is unsuitable.
4. 4

   Titrate

   The dose rises every 2 to 4 weeks, guided by monthly urate levels, until the target is reached.
5. 5

   Target

   Serum urate below 360 µmol/L (6 mg/dL), and below 300 µmol/L (5 mg/dL) with tophi, chronic gouty arthritis or continuing flares. Once it is reached, the urate is checked at least yearly.

• Allopurinol and febuxostat must not be combined with azathioprine or mercaptopurine without specialist dose reduction, because xanthine oxidase breaks those drugs down and they accumulate, causing severe marrow suppression. Product information advises against the combination; if it cannot be avoided, the azathioprine dose is cut to a quarter with allopurinol, and to a fifth or less with febuxostat, with frequent blood counts.
• HLA-B*58:01 is common in Han Chinese, Korean and Thai people and in some people of African descent, and rare in white Europeans. American guidance recommends testing before allopurinol in patients of South-East Asian or African-American descent; a positive result means another drug.
• The febuxostat warning: in the American CARES trial, in patients with gout and cardiovascular disease, cardiovascular deaths were higher with febuxostat than with allopurinol, and in 2019 European product information told prescribers to avoid it in major cardiovascular disease (previous myocardial infarction, stroke or unstable angina) unless no other option was suitable. The European FAST trial (2020) then found no excess of cardiovascular events or deaths with febuxostat, and since 2022 the product information asks instead for caution and regular monitoring in these patients. UK guidance still offers allopurinol rather than febuxostat to people with major cardiovascular disease.
• Patients are told to stop allopurinol and seek help at once if a rash appears.

Lifestyle and other drugs

• Weight loss in overweight, less alcohol (especially beer and spirits), fewer sugar-sweetened drinks, plenty of fluid, and a healthy, balanced diet. In the UK patients are told that no specific diet has been shown to prevent flares; diet alone lowers urate by only a little, and a strict low-purine diet is not needed.
• Medicines are reviewed: a thiazide or loop diuretic is stopped or replaced where possible. Losartan, fenofibrate and SGLT2 inhibitors lower urate a little and are useful when they are indicated for another reason.
• Cardiovascular risk factors and kidney function are managed.
• Referral to a rheumatologist when the diagnosis is uncertain, treatment fails or is not tolerated, in chronic kidney disease stage 3b to 5, and after organ transplantation.

05Epidemiology

About 56 million people had gout worldwide in 2020, an age-standardised prevalence of about 0.7 per cent that has risen by about a fifth since 1990, and the number is forecast to reach about 96 million by 2050 as populations grow and age. In the UK and other wealthy countries 2 to 4 per cent of adults are affected. It is about three times commoner in men than in women, rises with age, is rare before the twenties and in women before the menopause, and is especially common in Māori and Pacific Islander peoples. High body mass index accounts for about a third of the disability from gout, and kidney dysfunction for about a tenth. Cartilage calcification from calcium pyrophosphate is seen on the knee X-rays of more than a third of people over 80, usually without symptoms.

06Prognosis

Without urate lowering, flares return in most patients within a couple of years and become more frequent, longer and polyarticular; tophi and joint damage follow over years. Reaching the target dissolves the crystals: flares become fewer after the first year and stop in most patients, and tophi shrink over months to years. Treatment fails mainly through poor adherence, too low a dose and missed follow-up.

Gout is a marker of cardiovascular and kidney risk, and people with gout die earlier than those without, mostly from cardiovascular disease, which is why the comorbidities are treated as firmly as the joints. Follow-up checks the serum urate (monthly while titrating, then at least yearly), flares, tophi, kidney function and drug harms.