Introduction

Gout is the most common inflammatory joint disease in men and the most common inflammatory arthritis in older women. It is caused by deposition of monosodium urate crystals in joints and soft tissues following chronic hyperuricaemia. Chronic hyperuricaemia is associated with disorders of purine metabolism due to under excretion or over production of uric acid, the final metabolite of endogenous and dietary purine metabolism. Gout usually presents as a monoarthritis in the first metatarsophalangeal joint (big toe) of the foot and is often referred to as podagra (from the Greek ‘seizing the foot’). Subsequent attacks may be polyarticular. Other commonly affected joints include the mid-foot, ankle, knee, wrist and finger joints. Although the attack is extremely painful, it is usually self-limiting resolving spontaneously in 1–2 weeks. Acute attacks are managed with rest, ice and one of the following pharmacological agents: NSAIDs, colchicine or corticosteroids. Some patients may only ever experience one attack, but often a second attack occurs within 6–12 months, with increased risk of subsequent attacks. Patients with recurrent attacks require long-term prophylaxis with drugs that lower the serum urate level. The drug of choice is usually allopurinol, however, a small percentage of patients are unable to tolerate allopurinol and require treatment with an alternative urate-lowering agent such as febuxostat or a uricosuric agent such as benzbromarone, sulphinpyrazone or probenecid. It is essential that pharmacological measures are combined with non-pharmacological measures such as dietary and lifestyle modification to prevent recurrent attacks. Inappropriate management of gout can result in chronic tophaceous gout with polyarticular, destructive low-grade joint inflammation, joint deformity and tophi.

Epidemiology

Gout is one of the oldest recognised diseases and was identified by the Egyptians in 2460 BC. Hippocrates described it as ‘arthritis of the rich’ due to the association with certain foods and alcohol. Gout affects 1–2% of adults in developed countries, and in recent decades there has been a significant rise in its prevalence and incidence (Zhang et al., 2006). The USA has seen a doubling in the number of cases with the rate of gout increasing to 4.1% in older males. However, unlike the rest of the world, prevalence in the UK appears not to be rising and from 2000 to 2005 remained at 1.4% (Rider and Jordan, 2010). The increasing numbers in many developed countries have been attributed to trends in lifestyle leading to increased risk of gout, for example, obesity, metabolic syndrome, hypertension, alcohol consumption and increased age of the general population. Although the Maori population have a marked genetic predisposition to gout, prior to 1700 they did not experience this inflammatory joint disease. It was changes in diet and lifestyle following European settlement that led to the appearance and increasing prevalence in the country. New Zealand now has probably the highest prevalence in the World with one in eight men affected (Richette and Bardin, 2010). A similar pattern has also been seen in Eastern China, where gout was considered a very rare disease in the 1980s. Changes in diet and lifestyle due to Western influences have seen its prevalence rise to 1.1% in Eastern China in 2008.

In the UK, the presentation of gout in men before the age of 45 years is unusual, but in those over the age of 75 years prevalence is greater than 7% in men and 4% in women (Doherty, 2009; Jordan et al., 2007; Zhang et al., 2006). Gout is predominantly a disease of men with a male to female ratio of 3.6:1. In women, it tends to develop after menopause when levels of oestrogen, a known uricosuric, fall.

Although environmental factors are clearly implicated in the development of gout, studies have shown that inheritance also plays an important role. In recent years, research into the genetic background of gout has identified several renal urate transporters including URAT-1 and GLUT-9 and the genes that encode them, for example, SLC22A12 and SLC2A9, respectively. Polymorphisms in these genes are associated with increased hyperuricaemia and gout (Dalbeth and Merriman, 2009; Doherty, 2009).

Pathophysiology

Uric acid is mainly a by-product from the breakdown of cellular nucleoproteins and purine nucleotides synthesised de novo with about a third coming from the breakdown of dietary purine intake (Fig. 54.1). Uric acid is a weak acid with a pK_a of 5.75, and at the physiological pH of the extra-cellular compartment 98% of uric acid is in the ionised form of urate. This is mainly present as monosodium urate due to the high concentration of sodium in the extra-cellular compartment. Human beings and higher primates lack the enzyme uricase that degrades uric acid to the highly soluble allantoin resulting in higher concentrations of urate close to the level of solubility. Monosodium urate has a solubility limit of 380 µmol/L; when the concentration exceeds 380 µmol/L, there is a risk of precipitation and the formation of monosodium urate crystals.

Fig. 54.1 Purine pathway.

The production of urate is dependent upon the balance between purine ingestion, de novo synthesis in the cells and the actions of xanthine oxidase at the distal end of the purine pathway. Xanthine oxidase is the enzyme that catalyses the oxidation of hypoxanthine, the breakdown product from the catabolism of cellular nucleoproteins and purine nucleotides, to xanthine and xanthine to uric acid.

Gout can be classified as primary or secondary, depending on the presence or absence of an identified cause of hyperuricaemia.

Primary gout is not a consequence of an acquired disorder, but is associated with rare inborn errors of metabolism and isolated renal tubular defects in the fractional clearance of uric acid. A rare group of enzyme defects result in an increased de novo purine synthesis such as hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome), phosphoribosyl pyrophosphate synthetase super activity, glucose-6 phosphatase deficiency and myogenic hyperuricaemia (Table 54.1).

Table 54.1 Causes of primary and secondary gout

Secondary gout is the consequence of the use of specific drugs or develops as a consequence of other disorders. Certain diseases are associated with enhanced nucleic acid turnover, for example, myeloproliferative and lymphoproliferative disorders, psoriasis and haemolytic anaemia, and can lead to hyperuricaemia. Renal mechanisms are responsible for the majority of hyperuricaemia in individuals with over production representing less than 10% of patients with gout. The kidney excretes about two-thirds of the uric acid produced daily with the remainder being eliminated via the biliary tract with subsequent conversion to soluble allantoin by colonic bacterial uricase. Approximately 90% of the daily load of urate filtered by the kidneys is re-absorbed. This re-absorption process is mediated by specific anion transporters such as URAT-1 which is located on the apical side of the renal proximal tubular cells and is an important determinant of urate re-absorption (Richette and Bardin, 2010). The URAT-1 transporter is targeted by a number of drugs including benzbromarone, probenecid, losartan and sulphinpyrazone.

Risk factors

Hyperuricaemia is one of the main risk factors for gout and occurs in about 15–20% of the population (Doherty, 2009). Fortunately, only a minority of individuals with increased serum uric acid levels develop gout suggesting the importance of other contributing factors (Box 54.1).

Presentation and diagnosis

An acute attack of gout has a rapid onset, with pain being maximal at 6–24 h of onset and spontaneously resolving within several days or weeks. The first attack usually affects a single joint in the lower limbs in 85–90% of cases, most commonly the first metatarsophalangeal joint (big toe). The next most frequent joints to be affected are the mid-tarsi, ankles, knees and arms. The affected joint is hot, red and swollen with shiny overlying skin. Even the touch of a sheet on the affected joint is too painful for the patient to bear. The patient may also have a fever, leucocytosis, raised erythrocyte sedimentation rate (ESR), and the attack may also be preceded by prodromal symptoms such as anorexia, nausea or change in mood. Following resolution of the attack, there may be pruritis and desquamation of the overlying skin on the affected joint.

Monosodium urate crystals preferentially form in cartilage and fibrous tissues where they are protected from contact with inflammatory mediators. The deposition of crystals may continue for months or years without causing symptoms; it is only when the crystals are shed into the joint space or bursa that inflammatory reaction occurs precipitating an acute attack of gout. The shedding of crystals can be triggered by a number of factors including direct trauma, dehydration, acidosis or rapid weight loss. The acute phase response associated with intercurrent illness or surgery may also precipitate an attack; during this phase, there is increased urinary urate excretion with a lowering of serum uric acid which leads to partial dissolution of monosodium urate crystals and subsequent shedding of crystals into the joint space.

The shed crystals are phagocytosed by monocytes and macrophages, activating the NACHT–LRR–PYD-containing protein-3 (NALP3) inflammasome and triggering the release of interleukin-1β (IL-1β) and other cytokines, a subsequent infiltration of neutrophils and the symptoms of an acute attack (Dalbeth and Haskard, 2005). The NALP3 inflammasome (cryopyrin) is a complex of intracellular proteins that is activated on exposure to microbial elements, such as bacterial RNA and toxins. Activation of NALP3 leads to the release of caspase-1, which is required for cleavage of pro-IL-1β to active IL-1β (Richette and Bardin, 2009). IL-1β has been shown to be critically associated with the inflammatory response induced by monosodium urate crystals (Rider and Jordan, 2010).

A third of patients will have normal uric acid concentrations during an acute attack of gout due to increased urinary urate excretion. The most appropriate time to measure serum urate for monitoring purposes is when the attack has completely resolved. The gold standard for the diagnosis of gout is the demonstration of urate crystals in synovial fluid or in a tophus by polarised light microscopy (Zhang et al., 2006). Crystals may be found in fluid aspirated from non-inflamed joints, even in those joints which have not previously experienced an attack. The crystals are large (10–20 μm) and needle shaped with a strong, intense, characteristic light pattern under polarised light. In contrast, the calcium pyrophosphate dehydrate crystals associated with pseudo-gout are small rhomboid crystals of low intensity. Gout and septic arthritis may co-exist and in order to exclude septic arthritis synovial fluid is sent for Gram staining and culture.

Course of disease

The course of gout follows a number of stages; initially, the patient may be asymptomatic with a raised serum uric acid level (Fig. 54.2). Some patients may only ever experience one attack, but often a second attack occurs within 6–12 months. Subsequent attacks tend to be of longer duration, affect more than one joint and may spread to the upper limbs. Untreated disease can result in chronic tophaceous gout, with persistent low-grade inflammation in a number of joints resulting in joint damage and deformity. The disease is characterised by the presence of tophi (Fig. 54.3), monosodium urate crystals surrounded by chronic mononuclear and giant-cell reactions. Tophi deposition can occur anywhere in the body, but they are commonly seen on the helix of the ear, within and around the toe or finger joints, on the elbow, around the knees or on the Achilles tendons. The skin overlying the tophi may ulcerate and extrude white, chalky material composed of monosodium urate crystals.

Fig. 54.2 Schematic representation of the stages of gout.

Fig. 54.3 Chronic tophaceous gout.

Treatment

The management of gout can be split into the rapid resolution of the initial acute attack and long-term measures to prevent future episodes (see Box 54.3).

Gout is often associated with other medical problems including obesity, hypertension, excessive alcohol and the metabolic syndrome of insulin resistance, hyperinsulinaemia, impaired glucose intolerance and hypertriglyceridaemia. This contributes to the increased cardiovascular risk and deterioration of renal function seen in patients with gout. Management is not only directed at alleviating acute attacks and preventing future attacks, but also identifying and treating other co-morbid conditions such as hypertension and hyperlipidaemia. Pharmacological measures should be combined with non-pharmacological measures such as weight loss, changes in diet, increased exercise and reduced alcohol consumption.

Management of chronic gout

The presence of hyperuricaemia is not an indication to commence prophylactic therapy. Some patients may only experience a single episode and a change in lifestyle, diet or concurrent medication may be sufficient to prevent further attacks. Patients who suffer one or more acute attacks within 12 months of the first attack should normally be prescribed prophylactic urate-lowering therapy (see Fig. 54.4). There are, however, some groups of patients where prophylactic therapy should be instigated after a single attack. These include individuals with uric acid stones, the presence of tophi at first presentation and young patients with a family history of renal or cardiac disease. The criteria for starting prophylactic therapy for gout is detailed in Box 54.5.

Fig. 54.4 Management of chronic gout in patients requiring urate-lowering therapy.

Box 54.5 Criteria for starting prophylactic therapy for gout

One or more acute attacks within 12 months of the first attack

Tophi present at the first presentation of an acute attack

Presence of uric acid stones

Need to continue medication associated with raised uric acid levels, for example diuretics

Young patients with a family history of renal or cardiac disease

The aim of prophylactic gout treatment is to maintain the serum urate level below the saturation point of monosodium urate (300 μmol/L). If the serum urate is maintained below this level, crystal deposits dissolve and gout is controlled. Prophylactic treatment should not be initiated until an acute attack of gout has completely resolved, usually 2–3 weeks after symptom resolution. Once started, prophylactic treatment should be continued indefinitely even if further acute attacks develop.

Drugs that lower serum uric acid can be classified into three groups according to their pharmacological mode of action (Box 54.6).

Box 54.6 Classification of prophylactic agents used to lower serum urate

Uricostatic agents: allopurinol, febuxostat

Uricosuric agents: benzbromarone, probenecid, sulphinpyrazone

Uricolytic agents: rasburicase, polyethylene glycol-uricase

Uricostatic agents

Uricostatic agents act on the enzyme xanthine oxidase. Xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and subsequently xanthine to uric acid (Fig. 54.1). Hypoxanthine comes from the catabolism of cellular nucleoproteins and purine nucleotides. Blocking the action of this enzyme reduces the production of uric acid. Agents in this group include allopurinol and febuxostat.

Allopurinol

Allopurinol is the prophylactic agent of choice in the management of recurrent gout. In order to become pharmacologically active, allopurinol must be metabolised by the liver to oxypurinol. Oxypurinol has a much longer half-life than allopurinol, 14–16 h compared to 2 h. Both allopurinol and oxypurinol are renally excreted, with oxypurinol undergoing re-absorption from the renal tubule. In patients with reduced renal function, the half-life of oxypurinol is increased with the risk of accumulation and toxicity. It is, therefore, essential that a patient’s renal function is checked prior to the prescribing of allopurinol and the dose adjusted accordingly (Table 54.2).

Table 54.2 Recommended dose of allopurinol in patients with diminished renal function

Creatinine clearance (mL/min)	Dose
0	100 mg three times a week
10	100 mg alternate days
20	100 mg daily
40	150 mg daily
60	200 mg daily
>100	300 mg daily

In patients with normal renal function, the starting dose is 100 mg/day; this is gradually increased in 100-mg increments every 2–3 weeks until the optimal serum urate level (<300 µmol/L) or the maximum dose is reached. The maximum recommended daily dose in patients with normal renal function is 900 mg/day. A decrease in serum urate will occur within a couple of days of introducing allopurinol therapy with a peak effect at 7–10 days. The dissolution of tophi may take up to 6–12 months with effective therapy.

Approximately 3–5% of patients treated with allopurinol suffer from an adverse reaction. Intolerance usually manifests itself as a hypersensitivity reaction within the first 2 months of treatment. Adverse effects reported with allopurinol therapy include rash, fever, worsening renal failure, hepatotoxicity, vasculitis and even death. Severe toxic effects arise in less than 2% of patients. The risk of toxicity increases with renal impairment, age and concurrent drug therapy such as diuretics.

Prior to the availability of febuxostat, allopurinol desensitisation was attempted in patients with a mild hypersensitivity to allopurinol. This involved starting with a very low dose (50 μcg daily) and gradually increasing the dose over a period of several weeks to 100 mg daily. Desensitisation is now only considered where the reaction has been mild and there is an absence of alternative treatment options.

Azathioprine and mercaptopurine are metabolised by xanthine oxidase, co-administration of allopurinol reduces the metabolism of these two medicines leading to accumulation and toxicity. The dose of azathioprine or mercaptopurine should be reduced to approximately a quarter of the normal dose when co-prescribed with allopurinol. In addition, full blood counts should be performed at regular intervals to identify potential toxicity. High-dose allopurinol (>600 mg/day) increases carbamazepine blood levels by approximately one third; the same effect is not associated with lower doses of allopurinol (<300 mg/day).

Febuxostat

Febuxostat is a more selective and potent inhibitor of xanthine oxidase than allopurinol and has no effect on other enzymes involved in purine or pyrimidine metabolism (Lawrence Edwards, 2009). It is licensed for the treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred including a history, or presence of, tophus and/or gouty arthritis. It is recommended as a second-line agent in patients who are intolerant of allopurinol or for whom allopurinol is contraindicated.

Febuxostat is more effective than fixed-dose allopurinol 300 mg in lowering uric acid concentrations in trials of up to 40 months’ duration (Schumacher et al., 2008, 2009). However, a reduction in the incidence of episodes of acute gout has not been demonstrated.

The recommended starting dose for febuxostat is 80 mg once daily. If the serum uric acid is greater than 357 µmol/L, after 2–4 weeks, the dose should be increased to 120 mg once daily. The increased potency and good oral bioavailability of febuxostat leads to rapid decreases in serum uric acid levels permitting the testing of levels 2 weeks after starting therapy or adjusting the dose. No dosage adjustment is necessary in patients with mild or moderate renal impairment; however, there are no current recommendations for use in patients with severe renal impairment, for example creatinine clearance <30 mL/min. In patients with mild hepatic impairment, the dose should not exceed 80 mg daily; the use of febuxostat has not been studied in patients with severe hepatic impairment. Febuxostat should not be given to patients with ischaemic heart disease or congestive heart failure because of cardiovascular side effects. When initiating therapy with febuxostat, gout flare prophylaxis should be prescribed for at least 6 months.

The most common adverse effects include respiratory infection, diarrhoea, headache and liver function abnormalities. It is recommended liver function should be tested in all patients prior to the initiation of therapy and periodically thereafter based on clinical judgement. The use of febuxostat is not recommended in patients concomitantly treated with mercaptopurine or azathioprine and in patients taking theophylline, serum levels of theophylline should be monitored.

Uricosuric agents

Uricosuric agents increase uric acid excretion primarily by inhibiting post-secretory tubular absorption of uric acid from filtered urate in the kidney. They are indicated as second-line agents in those who are urate under-excreters and are dependent on the patient having an adequate level of renal function. These agents should be avoided in patients with urate nephropathy or those who are over producers of uric acid due to the high risk of developing renal stones. Patients receiving a uricosuric agent are required to maintain an adequate fluid intake, and the need for alkalinisation of urine should be considered to prevent urate precipitation

Benzbromarone

Benzbromarone has been shown to be effective in lowering serum urate levels and reducing the time to resolution of tophi (Kumar et al., 2005; Reinders et al. 2009). However, its use was associated with hepatoxicity and it was withdrawn from the UK. It is still possible to obtain benzbromarone on a named patient basis. The risk of hepatotoxicity has been estimated to be 1:17,000 patients. For those who are prescribed benzbromarone, regular liver function tests must be performed during the first 6 months of therapy, and the hepatotoxic risk associated with the medicine should be clearly explained to the patient at the outset.

The dose ranges from 50 to 200 mg daily. It remains active in mild to moderate renal impairment and is indicated where there is a contraindication to other agents used in the management of gout such as allopurinol and febuxostat (see Fig. 54.4). Diarrhoea may be troublesome in approximately 10% of patients.

Sulphinpyrazone

Sulphinpyrazone is effective in reducing the frequency of gout attacks, tophi and plasma urate levels at doses of 200–800 mg/day. It has the same mode of action on the kidney as benzbromarone and probenecid all of which inhibit URAT-1 transporter resulting in reduced urate re-absorption. However, in addition to this, sulphinpyrazone inhibits prostaglandin synthesis resulting in a similar adverse effect profile to NSAIDs, for example gastro-intestinal ulceration, acute renal failure, fluid retention, elevated liver enzymes and blood disorders. The use of sulphinpyrazone is reserved for use in patients with adequate renal function who are underexcretors of uric acid and intolerant or resistant to treatment with allopurinol.

Probenecid

Probenecid monotherapy is less effective than the other agents in this group and generally not recommended. It may have a role as an add-on agent when allopurinol alone is insufficient. Doses of 0.5–2.0 g/day have been used. As with sulphinpyrazone, it is ineffective in renal impairment. Dyspepsia and reflux may be troublesome in some patients, and it can interact with renally excreted anionic drugs. It is no longer marketed in the UK.

Uricolytics

Uricolytic drugs convert uric acid to allantoin through the actions of the enzyme urate oxidase (uricase). Allantoin is more soluble than uric acid and readily excreted by the kidney. Uricolytics are indicated for hyperuricaemia associated with tumour lysis syndrome and are not indicated for other forms of hyperuricaemia.

Rasburicase

Rasburicase, a recombinant form of the enzyme urate oxidase (uricase), is derived from a cDNA code from a modified Aspergillus flavus strain expressed in a modified strain of Saccharomyces cerevisiae. It is licensed to treat tumour lysis syndrome and is given intravenously at a dose of 0.2 mg/kg in short courses for 5–7 days. Rasburicase has a half-life of approximately 19 h. No dosage adjustment is required in patients with renal or hepatic impairment. Rasburicase is generally well tolerated, but adverse effects include fever, nausea, vomiting, rash, diarrhoea, headache, allergic reactions and the development of auto-antibodies.

Polyethylene glycol-uricase (PEG-uricase)

PEG-uricase is a pegylated, recombinant form of uricase. Pegylation of the molecule reduces the risk of patients developing auto-antibodies and lengthens the half-life of the drug. It is effective in reducing tophi. The use of PEG-uricase has been associated with severe infusion reactions in a small minority of patients; this and its high cost are likely to limit its use. It may have a role in severe, refractory cases or as a short-term treatment to remove tophi prior to the initiation of conventional urate-lowering therapies.

Patient care

It is important to inform patients about the disease, its curable nature, the aims of drug therapy and how to prevent and handle flares. The need for dietary and lifestyle changes should also be stressed. The UK Gout Society website can assist in providing patients with information about the condition and how it should be managed (http://www.ukgoutsociety.org/). In over-weight patients, gradual weight loss should be encouraged, very rapid weight loss should be avoided as it can cause ketosis and result in raised uric acid levels with the likelihood of precipitating an attack. Low purine diets are difficult to adhere to; a calorie-restricted diet with low carbohydrate (40% of energy), high protein (30% of energy) and unsaturated fat (30% of energy) should be recommended. The importance of avoiding or reducing alcohol consumption should also be emphasised.

Patients at risk of recurrent attacks should be issued with a suitable NSAID to treat the attack as soon as possible. The patient should be clear on what dose to take, when to initiate therapy, how long to take the medication for and any possible side effects to look out for. The patient should also be advised to avoid certain over-the-counter medicines which may exacerbate an attack, for example the use of aspirin as an analgesic.

Those taking long-term prophylactic therapy need to understand the importance of continuing therapy despite being asymptomatic. They should avoid running out of medication, as a short gap in therapy may precipitate an attack. Patients receiving uricosuric agents should be advised to maintain a fluid intake of at least 2 L/day to reduce the risk of uric acid stone formation in the kidneys.

The authors thank Professor Philip Conaghan, Centre for Musculoskeletal Disease, Leeds Teaching Hospital NHS, for his invaluable comments regarding the structure and content of this chapter.