Gout

What is gout?

The pathogenesis of gout is well understood. If serum urate concentrations persistently exceed the physiological saturation threshold of urate (around 380 μmol/L; 1 μmol/L=0.02 mg/dL), monosodium urate crystals form and deposit, particularly in cartilage, bone, and periarticular tissues of peripheral joints. Continuing crystal deposition is clinically silent, with about 10% of people with hyperuricaemia developing clinical gout.1

The first acute attack of gout occurs when crystals are shed from the articular cartilage into the joint space. It is usually monoarticular and typically affects the lower limb. Involvement of the first metatarsophalangeal joint (“podagra”) is common and occurs in 56-78% of first attacks.2 The mid-foot, ankle, knee, finger joints, wrist, and elbow are also commonly affected.2 The shoulder, hips, and spine are rarely affected. Acute attacks are characterised by sudden onset, severe joint pain—which reaches peak intensity within 12-24 hours and is associated with swelling and erythema—and then complete resolution within one to two weeks.3

The time between acute attacks is termed the intercritical period. If untreated, a second acute attack often occurs within two years. Recurrent attacks may become more frequent and affect different joints or more than one joint. Chronic tophaceous gout can be a consequence of untreated gout and is associated with progressive joint damage, chronic pain and disability, and clinically evident subcutaneous tophi (hard, impacted monosodium urate crystals (fig 1⇓). Tophi mainly occur on the fingers, olecranon processes, toes, Achilles’ tendons, knees, and occasionally the helix of the ears.

Fig 1 Tophi affecting the interphalangeal joints of the left hand (A) and right second toe (B). Note asymmetry of swelling and yellow-white discoloration

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Who gets gout?

Gout usually affects men aged 40 years and over and women over 65 years.4 It increases with age, affecting 7% of men aged over 75 in the United Kingdom.4 The incidence and prevalence of gout are rising because of an ageing population, increasing prevalence of the metabolic syndrome, and possibly dietary changes.

Uric acid is the relatively insoluble endproduct of purine metabolism. Around 70% of uric acid derives from the breakdown of endogenous purines, with the remaining 30% from dietary purines. Most uric acid (around 70%) is excreted through the kidney, the remainder through the gut.5 Hyperuricaemia is caused by reduced renal elimination (most commonly) or increased production (or both). Epidemiological studies show that the metabolic syndrome and its components (insulin resistance, obesity, hyperlipidaemia, and hypertension) are strongly associated with gout (box 1).4 6 7 A large cross-sectional study found a 62.8% prevalence of the metabolic syndrome in people with gout compared with 25.4% in those without gout (adjusted odds ratio 3.05, 95% confidence interval 2.0 to 4.6).8

Although associations between gout and dietary factors—including alcoholic drinks and purine-rich foods—have been recognised for centuries, these have only recently been examined in high quality prospective studies (box 1).9 10 The risk of developing gout is directly related to alcohol consumption (multivariate relative risk 1.17 per 10 g alcohol intake/day, 95% confidence interval 1.11 to 1.22).9 The risk is high for beer (2.51, 1.77 to 3.55) and spirit consumption (1.60, 1.19 to 2.16), but not for wine (1.05). Compared with the lowest fifth of consumption, the relative risk of developing gout in the highest fifth was 1.41 (1.07 to 1.86) for red meat and 1.51 (1.17 to 1.95) for seafood.10 Dairy products are protective (0.54, 0.42 to 0.74). Sugar sweetened soft drinks, especially those with fructose (1.85, 1.08 to 3.16) increase the risk of gout, whereas consumption of caffeinated and decaffeinated coffee (0.41, 0.19 to 0.88) is thought to be protective.11 12

Gout often runs in families, and this is possibly related to lifestyle and genetic factors. Patients may inherit a genetic predisposition to gout, with several rare enzymatic defects known to be a cause. A twin study estimated the hereditability of renal clearance and fractional excretion of urate to be 60% and 87%, respectively.13 Putative mutations affecting several genes involved in renal urate transport have been proposed to influence developing hyperuricaemia and gout including SLC22A12, SLC2A9 (GLUT9), ABCG2, and SLC17A3, although work is ongoing.14

Drugs are often implicated in the pathogenesis of gout (box 1). A recent systematic review including 13 original studies found a trend towards a higher risk for acute gout in patients taking loop and thiazide diuretics, although the magnitude of risk and independence were not consistent.15 Although no randomised controlled trials (RCTs) have tested cessation of chronic diuretic use in people with gout, consider cessation or reduction when the indication is hypertension rather than cardiac or renal failure.16 17 Low dose aspirin (75-150 mg/day) has well recognised urate retaining properties, but this is thought to be clinically insignificant, and low dose aspirin should continue if needed for cardiovascular prophylaxis.

Is gout associated with any other diseases?

Gout is increasingly being viewed as more than just a joint disease. Comorbidity including hypertension (74%), hyperlipidaemia, chronic kidney disease (20%), osteoarthritis, obesity (53%), diabetes (26%), congestive heart failure (11%), and ischaemic heart disease (14%) is common and often unrecognised and undertreated.6 7 8 18 Comorbidity may adversely affect diagnosis, limit management options, and contribute to long term adverse clinical outcomes.

How is gout diagnosed and assessed?

For patients presenting with classic symptoms (rapid onset, podagra, swelling, erythema) a clinical diagnosis is usually accurate.3 Figure 2⇓ shows likelihood ratios for different clinical features. Podagra has high sensitivity (0.96, 0.91 to 1.01) and specificity (0.97, 0.96 to 0.98), performing better than pain, swelling, and erythema. A definitive diagnosis requires confirmation of the presence of monosodium urate crystals in synovial fluid or tophi. Although joint aspiration is not needed when the presentation is classic, aspiration and examination of synovial fluid for crystals can be useful when presentation is atypical or involves other joints, during either the acute attack or the intercritical period. It also allows differentiation from the main differential diagnoses of acute calcium pyrophosphate crystal arthritis (pseudogout) and septic arthritis.3 A systematic review highlights the high degree of interobserver reliability (κ 0.35-0.63) for identifying monosodium urate crystals in synovial fluid, emphasising the need for training and quality control.19

Fig 2 Likelihood ratio and 95% confidence interval (CI) for various features in the diagnosis of gout. MSU=monosodium urate. Reproduced, with permission, from the Annals of the Rheumatic Diseases3

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Serum uric acid concentrations, although important when “treating to target,” are less useful in the diagnosis of gout. Two large population based cohorts found that, although the risk of clinical gout increases with increasing concentrations of serum urate, not all people with hyperuricaemia develop gout.20 21 There is no evidence to support drug treatment of people with asymptomatic hyperuricaemia. Patients with confirmed gout may have normal serum urate concentrations, especially during an acute attack, when concentrations are often reduced because renal urate excretion increases during the acute phase.22

It is also useful to screen for comorbidity by requesting urea and electrolytes, estimated glomerular filtration rate, glucose, and lipids. Measuring and dealing with problems of blood pressure, body mass index, smoking, alcohol use, and cardiovascular risk should form part of a comprehensive gout assessment.

Imaging is not usually needed to diagnose gout. Plain radiographs are often normal, although radiographic evidence of asymmetrical swelling and subcortical cysts without erosion may be useful to diagnose chronic gout.3 A systematic review concluded that ultrasound is a promising diagnostic tool, but further research is needed to assess the responsiveness, reliability, and feasibility of using this modality routinely.23 The “double contour” sign—hyperechoic enhancement of the superficial margin of the articular cartilage—is an ultrasound finding thought to be specific to gout (sensitivity 44%, specificity 99%) that is also seen in 25% of patients with asymptomatic hyperuricaemia.23 24 25

How are acute attacks of gout treated?

Treatment of acute gout aims to provide rapid relief of joint pain and swelling. First line oral drugs are usually non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine.16 There is no evidence that any one NSAID is more effective than another. A systematic review commented on the poor quality of existing NSAID trials in acute gout, with the exception of two moderately sized RCTs, which found an equivalent effect of indometacin 50 mg three times daily and etoricoxib 120 mg daily on pain.26 27 28 More recently, two well conducted trials have found indometacin (50 mg three times daily for two days, then 25 mg three times daily for three days) and naproxen 500 mg twice daily to be as effective as oral prednisolone.29 30 Indometacin was associated with more gastrointestinal adverse events, however, and is best avoided.29

British Society for Rheumatology and American College of Rheumatology guidelines suggest using a fast acting NSAID, such as naproxen, at full dose. Caution is needed, however, in people with heart failure, ischaemic heart disease, renal insufficiency, or a history of gastrointestinal ulcers, bleeds, or perforations.17 31 Continue treatment until the attack has resolved (typically a few days to two weeks).

Colchicine is a naturally occurring alkaloid that inhibits leucocytic phagocytosis of monosodium urate crystals, the inflammasome, and cell mediated immune responses. It has traditionally been used in high doses (1 mg initially, followed by 500 µg every two to three hours until pain relief is obtained). Although a small trial showed the effectiveness of high dose regimens over placebo, all participants randomised to receive colchicine developed diarrhoea or vomiting (or both).32 Lower doses of colchicine are as effective and better tolerated than high dose regimens.

A recent well conducted moderately sized RCT found at least a 50% reduction in pain within 24 hours in 33% of participants treated with high dose colchicine (1.2 mg initially and then 600 µg hourly for six hours). There was also a 38% reduction in those treated with low dose colchicine (1.2 mg initially, followed by 600 µg after one hour) and a 16% reduction in those receiving placebo.33 Diarrhoea affected 77% of the high dose group, 23% of the low dose group, and 14% receiving placebo. The British National Formulary recommends 500 µg two to four times daily.34 Although no head to head comparison between colchicine and a NSAID exists, oral NSAIDs are generally considered to be the first line treatment for acute gout, with colchicine reserved for those with contraindications to, or intolerance of, NSAIDs.17 Several drugs can increase the risk of colchicine toxicity (box 2).

Corticosteroids provide a further treatment option. Although there are no RCTs,35 expert consensus agrees that joint aspiration and intra-articular injection of corticosteroids is a rapid and highly effective treatment for acute gout.16 17 The diagnosis can be confirmed by microscopy of aspirated fluid, and such treatment is probably best practice in a hospital setting. However, the necessary skills to perform aspiration and injection might not be present in all settings, particularly primary care. Intramuscular or oral corticosteroids provide a useful option, particularly when there are contraindications to NSAIDs and colchicine and more than one joint is affected or joint injection is not possible.16 31 Two high quality RCTs found that oral prednisolone at doses of 30-35 mg daily for five days are as effective as NSAIDs.29 30

Rest and cooling of the joint are also effective for acute gout. A small RCT found that the application of topical ice in combination with oral prednisolone and colchicine reduces pain more effectively than combined prednisolone and colchicine alone.36

How is gout managed in the long term?

Long term management of gout aims to prevent formation of new monosodium urate crystals and cause existing crystals to dissolve by lowering serum urate below the physiological saturation threshold. This will cause acute attacks to cease and tophi to resolve, as well as prevent long term joint damage. Urate lowering is best achieved by combining non-drug based and drug based interventions. Individualised patient education is a fundamental component of management and should focus on the causes and consequences of hyperuricaemia and gout,37 the importance of urate lowering, and how this can be achieved.