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Gout Pascal Richette, Thomas Bardin Lancet 2010; 375: 318–28 Published Online August 18, 2009 DOI:10.1016/S01406736(09)60883-7 See Editorial page 254 Université Paris 7, UFR Médicale, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Fédération de Rhumatologie, Paris, France (P Richette MD, Prof T Bardin MD) Correspondence to: Dr Pascal Richette, Fédération de Rhumatologie, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, France [email protected]

Gout is a common arthritis caused by deposition of monosodium urate crystals within joints after chronic hyperuricaemia. It affects 1–2% of adults in developed countries, where it is the most common inflammatory arthritis in men. Epidemiological data are consistent with a rise in prevalence of gout. Diet and genetic polymorphisms of renal transporters of urate seem to be the main causal factors of primary gout. Gout and hyperuricaemia are associated with hypertension, diabetes mellitus, metabolic syndrome, and renal and cardiovascular diseases. Non-steroidal anti-inflammatory drugs and colchicine remain the most widely recommended drugs to treat acute attacks. Oral corticosteroids could be an alternative to these drugs. Interleukin 1β is a pivotal mediator of acute gout and could become a therapeutic target. When serum uric acid concentrations are lowered below monosodium urate saturation point, the crystals dissolve and gout can be cured. Patient education, appropriate lifestyle advice, and treatment of comorbidities are an important part of management of patients with gout.

Introduction Gout, “the king of diseases and the disease of kings”,1 was one of the earliest disorders to be recognised as a clinical entity. It was first identified by the Egyptians in 2640 BCE, and written evidence of the disease dates back to Hippocratic writings from about 400 BCE.2,3 The most accurate early description of an acute attack of gout was made by Sydenham, an English physician, writing about himself in 1683.2,3 Crystals from tophi were first described during the 18th and 19th centuries, and in the mid 20th century the role of excess urate production and impaired excretion in the pathogenesis of hyperuricaemia were reported. Finally, McCarty and Hollander3 showed that crystals from the synovial fluid of patients with gout were composed of monosodium urate. Nowadays, gout is probably the best understood and most manageable of all common systemic rheumatic diseases.4 Most frequently it causes recurrent attacks of acute arthritis and sometimes can lead to chronic arthropathy, tophi depositions, and renal disease. Gout is a disorder of purine metabolism and results from urate crystal deposition in and around the joints caused by

Search strategy and selection criteria We searched the Cochrane library, Medline, and EmBase for reports published in English from Jan 1, 1998, to Nov 30, 2008 with the search terms “gout”, “hyperuricemia”, “uric acid”, “urate”, “purine”, and “tophus”. We also searched for “gout” or “hyperuricemia” combined with the terms “epidemiology”, “pathogenesis”, “genetic”, “pathophysiology”, “diagnosis”, “kidney stones”, “metabolic syndrome”, “diabetes”, “hypertension”, “cardiovascular”, and “treatment”. We mainly selected reports from the past 10 years but did not exclude commonly referenced and highly cited older publications. We also searched the reference lists of publications identified and selected articles we judged relevant. Some review articles and book chapters were also included to provide comprehensive overviews that are beyond the scope of this Seminar. The reference list was modified during the peer-review process.

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longstanding hyperuricaemia. Hyperuricaemia is a risk factor for gout but most people remain asymptomatic throughout their lives. In the past 10 years, the epidemiology of gout seems to have changed and great advances in the understanding of this disease have been made. We review data for epidemiology, pathophysiology, and diagnosis, and discuss present and future treatment for this disorder that is frequently inappropriately managed.5

Epidemiology Data show a rise in the prevalence of gout that is potentially attributable to shifts in diet and lifestyle, improved medical care, and increased longevity.6 In England, rates of gout increased from 0·3% to 1·0% of the total population between 1970 and 1990,7 and a similar trend was reported in the USA during the 1990s—especially for men older than 75 years in whom rates nearly doubled from 2·1% in 1990 to 4·1% in 1999.8 From 2000 to 2005 in the UK, 1·4% of people were estimated to have gout.9 Gout is the most prevalent inflammatory arthritis in developed countries, especially in elderly men. It has become frequent in other parts of the world such as China, Polynesia, New Zealand, and urban sub-Saharan Africa.6,10–12 In New Zealand the rise has been even greater in the Māori population than in the European population. In 1992, in Māori people the prevalence of gout, not recognised before colonisation, was 6·4%.11 In eastern China, where gout was regarded as a very rare disease in 1980, the prevalence in 2008 was estimated at 1·14%, after changes in lifestyle and dietary behaviour.12 The prevalence of gout is much higher in men than in women and rises with age. In women it mainly develops after menopause—the fall in oestrogen, which is uricosuric, increases uricaemia. Postmenopausal hormone use is associated with lowered serum urate concentrations.13 Alcohol and dietary excess have long been associated with gout. The prevalence of gout in men increases with high consumption of meat, seafood, and fructose, and intake of beer and spirits, whereas vegetables with a high purine content and moderate wine www.thelancet.com Vol 375 January 23, 2010

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consumption have no effect.14,15 Rates of gout are heightened with raised body-mass index but fall with loss of weight.16 Consumption of dairy products, vitamin C, and coffee, including decaffeinated coffee, is associated with decreased uricaemia or prevalence of gout, or both.15,17,18

Pathophysiology Uric acid is the final metabolite of endogenous and dietary purine metabolism. It is a weak acid with pKa of 5·75 (pH at which uric acid and urate concentrations are equal). At a physiological pH of 7·4 in the extracellular compartment, 98% of uric acid is in the ionised form of urate.19 Because of the high concentration of sodium in the extracellular compartment, urate is largely present as monosodium urate, with a low solubility limit of about 380 μmol/L. When urate concentrations exceed 380 μmol/L, risk of monosodium urate crystal formation and precipitation increases. In urine, which is acidified along the renal tubule, urinary urate is converted to low solubility uric acid.1,20 The human diet contains little urate. Urate is produced mainly in the liver and to a lesser extent in the small intestine. Its production depends on the balance between purine ingestion, de-novo synthesis in cells, recycling, and the degradation function of xanthine oxidase at the distal end of the purine pathway (figure 1).20–22 Some diseases including myeloproliferative and lymphoproliferative disorders, psoriasis, and haemolytic anaemia are associated with enhanced turnover of nucleic acid, which in turn can lead to hyperuricaemia. Another cause of overproduction of uric acid relates to acceleration of ATP degradation to AMP, a precursor of uric acid (figure 1). This overproduction can arise with excessive alcohol or fructose consumption.1,23 Human beings and higher primates do not have the enzyme uricase that degrades uric acid to the highly soluble allantoin. Therefore, in people, urate concentrations are much higher than are those of most non-primate mammals, fish, and amphibians that have uricase. Consequently, the physiological concentration of urate in people is close to its limit of solubility. The gastrointestinal tract excretes a third and the kidney about two-thirds of the uric acid produced daily. Renal mechanisms are responsible for hyperuricaemia in about 90% of individuals because impaired excretion of renal uric acid is the main mechanism underlying the rise in the urate pool.20,24 Patients with gout need urate concentrations of 120–180 μmol/L higher than do those without gout to achieve similar uric acid excretion rates.1,25 Patients who overproduce uric acid represent less than 10% of those with gout.1 About 90% of the daily load of urate filtered by the kidneys is reabsorbed, and this process is mediated by specific anion transporters, including URAT1 (SLC22A12). This transporter localises to the apical side of the renal proximal tubular cells and is an important determinant of urate reabsorption.26,27 www.thelancet.com Vol 375 January 23, 2010

Importantly, URAT1 is a drug target because it is inhibited by benzbromarone, probenecid, losartan, and sulfinpyrazone, which explains the uricosuric effect of these drugs (figure 1).26,28,29 The protein GLUT9 (SLC2A9) was reported to function as an efflux transporter of urate from tubular cells30 and to affect serum urate concentration.31–33 In tissues, formation of monosodium urate crystals depends on several factors—particularly on local concentration of urate.21 Solubility of urate in joint fluids depends on the articular hydration state, temperature, pH, concentration of cations, and presence of extracellular matrix proteins such as proteoglycans, collagens, and chondroitin sulphate.21,34 Variation in these factors might explain the predilection of gout in the first metatarsophalangeal joint (a peripheral joint with low temperature) and osteoarthritic joints (joints with decreased collagen and proteoglycan content), and the nocturnal onset of pain (because of intra-articular dehydration).34–36 Monosodium urate crystals are pro-inflammatory stimuli that can initiate, amplify, and sustain an intense inflammatory response.34,35 Most often released from preformed deposits in the joints, they can be phagocytosed by monocytes as particles, thus triggering a typical inflammatory response through release of pro-inflammatory mediators such as interleukin 1β, tumour necrosis factor α, and interleukin 8.37 Mechanisms by which urate Ribose-5-phosphate PRPPS Nucleic acids

PRPP

GMP

IMP

Guanosine

Inosine

Nucleic acids AMP Adenosine

APRT

HGPRT Guanine

PRPP

Hypoxanthine XO

Adenine

PRPP

Allopurinol Febuxostat

Xanthine XO Uric acid Probenecid Benzbromarone Losartan Fenofibrate

Uricase PEG-uricase

Allantoin

Renal excretion

Figure 1: Purine synthesis, salvage, and degradation Xanthine oxidase (XO) is the enzyme that catalyses the oxidation of hypoxanthine to xanthine, and xanthine to uric acid. It is inhibited by allopurinol and febuxostat. Purine bases derived from nucleic acids are re-used. The enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) salvages hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP). In a similar salvage pathway, adenine phosphoribosyl transferase (APRT) converts adenine to adenosine monophosphate (AMP). HGPRT deficiency and phosphoribosylpyrophosphate (PRPP) synthetase (PRPPS) superactivity are a cause of secondary gout. The gene for uricase has been inactivated in humans. Adapted with permission from Torres RJ et al.22 PEG-uricase=polyethylene glycol-modified uricase.

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A

B

Figure 2: Deposits of uric acid (tophi) in the helix of the ear (A) and within the skin overlying the finger joints (B)

Panel 1: EULAR recommendations for the diagnosis of gout*51 • In acute attacks the rapid development of severe pain, swelling, and tenderness that reaches its maximum within just 6–12 h, especially with overlying erythema, is highly suggestive of crystal inflammation, although not specific for gout • For typical presentations of gout (such as recurrent podagra with hyperuricaemia) a clinical diagnosis alone is reasonably accurate but not definitive without crystal confirmation • Identification of monosodium urate crystals in synovial fluid or tophus aspirates allows a definitive diagnosis of gout • A routine search for monosodium urate crystals is recommended in all synovial fluid samples obtained from undiagnosed inflamed joints • Identification of these crystals from asymptomatic joints might allow definite diagnosis in intercritical periods • Gout and sepsis can coexist, so gram stain and culture of synovial fluid should still be done when septic arthritis is suspected even if monosodium urate crystals are identified • Although the most important risk factor for gout, serum uric acid concentrations do not confirm or exclude gout because many people with hyperuricaemia do not develop gout, and during acute attacks serum concentrations might be within the normal range • Renal uric acid excretion should be measured in selected patients with gout, especially those with a family history of young-onset gout, with onset of gout at younger than 25 years, or with renal calculi • Although radiographs can be useful for differential diagnosis and might show typical features in chronic gout, they are not useful for confirmation of diagnosis of early or acute gout • Risk factors for gout and associated comorbidity should be assessed, including features of metabolic syndrome (obesity, hyperglycaemia, hyperlipidaemia, and hypertension) *Recommendations are based on research evidence and the opinion of rheumatologists.

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crystals activate cells in the joint cavity have been partly explained.38,39 Monosodium urate crystals could activate monocytes via the toll-like receptor (TLR) pathway and the inflammasome. Recognition of extracellular monosodium urate crystals by TLR2 and TLR4 expressed by macrophages could induce interleukin 1 transcription, and TLR2 and TLR4 signal transduction relies on MyD88, an adaptor protein.38,40–42 The second component of activation is CD14—a phagocyte-expressed pattern recognition receptor that functionally interacts with both TLR2 and TLR4, and which could bind crystals and promote this urate-induced inflammation.43 Researchers of studies that have major implications for therapeutics have established that phagocytosed intracellular crystals are detected in the cytoplasm by the NALP3 inflammasome in monocytes or macrophages. The result is activation of caspase-1, which initiates interleukin-1β maturation and secretion.44 In turn, interleukin-1β secretion produces various pro-inflammatory mediators, which elicit neutrophil influx into the joints. Results of in-vivo studies37,42,44 have confirmed that interleukin 1β and its pathway is crucially associated with the inflammatory response induced by monosodium urate, suggesting that interleukin 1β is a pivotal mediator of inflammation in acute gout and a key therapeutic target.

Genetics and clinical features Urate concentrations vary greatly between individuals, and although environmental factors are clearly implicated, results of studies45 have shown that inheritance also plays a part. Heritability of serum uric acid concentration accounts for about 60% of variability.46 Genome-wide studies31–33,47,48 have identified substantial associations between polymorphisms in the GLUT9 (SLC2A9) gene, urate concentrations, and gout, and a polymorphism in the URAT1 (SLC22CA12) gene was confirmed as a genetic risk factor for hyperuricaemia in Chinese men.49 Two new loci have been identified—ABCG2 and SLC17A3—which also show an association with uric acid concentrations and risk of gout.50 The natural history of articular gout is typically composed of three periods: asymptomatic hyperuricaemia, episodes of acute attacks of gout with asymptomatic intervals, and chronic gouty arthritis.1 Chronic hyperuricaemia is the most important risk factor for gout.51 Risk of acute gout rises with urate concentration. The yearly incidence of gout is 0·5% in people with a serum urate concentration between 420 μmol/L and 530 μmol/L, and 4·5% in those with a serum urate of 540 μmol/L or higher. In patients with urate concentrations of 540 μmol/L or more the cumulative incidence of gouty arthritis is 22% after 5 years.6,52 However, many people with high serum urate never develop gout. Acute gouty arthritis most often begins with one joint affected in the lower limbs (85–90% of cases)—usually the first metatarsophalangeal joint—which is classically www.thelancet.com Vol 375 January 23, 2010

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termed podagra. The next most frequent locations are the midtarsi, ankles, knees, and arms. The initial attack is rarely polyarticular (3–14% of cases), and acute attacks seldom affect the shoulders or hips.1,53,54 Onset is abrupt, and the affected joint is erythematous, warm, swollen, and tender. The most important differential diagnosis is septic arthritis. Untreated gout mostly resolves within a few days. As inflammation disappears, the skin over the joint often peels. Only one episode happens in some patients, but patients often have a second attack within 6 months to 2 years. Subsequent attacks frequently last longer than does the first attack, affect several joints, and spread to the upper limbs, especially the arms and hands.1,53 Several factors that might trigger acute attacks include alcohol intake,55 meat and seafood consumption,15 fasting, trauma, and surgery.56,57 Different drugs can also precipitate acute gout by raising or lowering uric acid concentrations. Use of diuretic drugs increases risk of gout attacks,58 and the occurrence of arthritis shortly after initiation of urate-lowering therapy is well established.59 When left untreated acute attacks of gout can lead to chronic gout, which is characterised by chronic destructive polyarticular involvement with low-grade joint inflammation, joint deformity, and tophi—monosodium urate crystals surrounded by chronic mononuclear and giant-cell reactions.53,60 Tophaceous gout develops within 5 years of onset of gout in 30% of untreated patients.60 Tophi are frequently seen in the helix of the ear (figure 2A), over the olecranon processes, on the Achilles tendons, within and around the toe or finger joints (figure 2B), around the knees, and within the pre-patellar bursae.1,53 Sometimes the skin overlying the tophus ulcerates and extrudes white, chalky material composed of monosodium urate crystals. Tophi are painless and rarely become infected.53 Function and health-related quality of life can be severely affected with chronic gout.61–64 Tophi deposition can happen anywhere in the body and sometimes leads to unusual features. Tophi are usually identified in subcutaneous tissue of the skin but can also take the form of intradermal superficial collections resembling pus in the finger pad.65,66 Spinal involvement can lead to nerve root or cord compression35,67 and might also mimic epidural infection.35,68 Tophi can be seen in the flexor tendons of the hand, the carpal tunnel, and even in the median nerve, which leads to carpal tunnel syndrome.69,70 Other rare locations are the eyes,71 breast,72 vocal cords,73 heart,74 and colon.75

Diagnosis and imaging The European League Against Rheumatism (EULAR) developed recommendations51 in 2006, on the basis of both clinical practice and the best available evidence for diagnosis of gout. Panel 1 lists the ten key recommendations. Analysis of synovial fluid or tophus www.thelancet.com Vol 375 January 23, 2010

A

B

5 μM

5 μM

C

D

5 μM

5 μM

Figure 3: Identification of monosodium urate crystals from synovial fluid (A) Light microscopy. (B) Under polarised light. (C) Under compensated polarised light, crystals parallel to the axis of slow vibration. (D) Under compensated polarised light, crystals perpendicular to the axis of slow vibration.

10 μm

Figure 4: Microscopic analysis of an aspirate from a tophus Compensated polarised microscopy of numerous birefringent, needle-shaped monosodium urate crystals.

aspirate is a key diagnostic method for gout because identification of monosodium urate crystals in these samples enables a definite diagnosis to be made (figures 3 and 4).51,76 Aspiration of the small first metatarsophalangeal joint is of special interest because most patients with gout have had or will have at least one 321

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Figure 5: Uratic arthropathy Soft tissue swelling over the proximal interphalangeal joints of the second and third fingers, and typical extra-articular erosions at the margins of these joints.

episode of podagra. Although aspiration of this joint is often thought of as painful and difficult to do, it is well tolerated with a 25-gauge needle and can provide enough synovial fluid samples for crystal identification. Use of a thin 29-gauge needle can also yield sufficient samples with lessened discomfort.77 In clinical practice most synovial fluid is aspirated from inflamed joints. Monosodium urate crystals can be identified in synovial fluid obtained from asymptomatic joints, especially the knees and the first metatarsophalangeal joint.51,76,78 Once aspirated, this fluid should be examined rapidly at room temperature because formation and solubility of crystals are affected by temperature and pH.79 These crystals are easily detected with an ordinary light microscope, but use of a compensated polarising microscope is needed for a definite identification of negatively birefringent crystals. Monosodium urate crystals appear as thin, needle-shaped structures with pointed ends. They can be seen both intracellularly and extracellularly (figure 3A). Under direct polarised light, they are strongly birefringent and appear very bright against the black background (figure 3B). Under compensated polarised light, they are yellow when aligned parallel to the slow vibration and blue when aligned perpendicular to the slow vibration of a compensator (figure 3C, 3D, and figure 4).1,53 Notably, gout and septic arthritis can coexist within the same joint.80 Thus, synovial fluid should be analysed for bacteria when septic arthritis is suspected, even if monosodium urate crystals are in the joint.51,54 A third of patients have normal uric acid concentrations during an acute attack of gout.81,82 Quantification of excretion rates of urinary uric acid enables identification of patients with overexcretion, defined as 24-h urinary uric acid excretion exceeding 700–1000 mg per day with a regular diet.83 This measurement is not useful for diagnosis of primary gout in routine practice, because in 322

most patients with gout and hyperuricaemia the concentration of uric acid in their urine is within the normal range.21,51 However, it could be useful for identification of patients at risk of uric acid nephrolithiasis,83 and could help for therapeutic purposes when uricosuric therapy is considered. Overexcretion of uric acid in a young patient with gout suggests an underlying enzyme defect.84 Radiographs of joints affected by acute attacks are not useful for diagnosis of recent gout because generally acute gout will not show abnormal findings on plain radiography for many years, apart from non-specific soft-tissue swelling overlying the inflamed joint.51,85 By contrast, patients who have had years of intermittent episodic arthritis and those with chronic gout might show characteristic features, mainly the consequences of tophus infiltration into bone, on radiography.86 Eccentric nodular soft-tissue prominence accompanies soft-tissue deposition of urate and is usually visible late in the evolution of disease. Bone erosions are key features and are at first extra-articular. They are typically punched out, occurring along the long axis of the bone, with overhanging edges and sclerotic rims (figure 5).87 The joint space is very well preserved until late in the course of disease.87,88 Ultrasonography, CT, and MRI are emerging techniques that could be used for diagnosis and assessment of gout.89 Ultrasonography can detect tophaceous material and erosions, and deposition of monosodium urate crystals on cartilaginous surfaces, which appear as a hyperechoic, irregular band over the superficial margin of the cartilage.38,90–92 On MRI, tophi usually show low-signal intensity on both T1-weighted and T2-weighted images and a variable enhancement pattern.93 MRI is of particular interest for investigation of spinal involvement in gout. CT allows for very good visualisation of bone erosion and tophi.94,95 All these techniques are presently being assessed for their ability to monitor disease progression and treatment response in gout.

Primary and secondary gout Gout can be classified as primary or secondary, depending on the presence or absence of an identified cause of hyperuricaemia.1,53 Thus, primary gout is not a consequence of an acquired disorder or the result of a congenital defect. Other conditions often accompany primary gout, including obesity, alcohol consumption, hypertension, and hypertriglyceridaemia, which should be carefully assessed.1,51,53 Secondary gout is the consequence of use of specific drugs or develops in the course of other disorders such as lead intoxication, renal failure,1,53 and particularly in the rare familial juvenile hyperuricaemic nephropathy and the autosomaldominant medullary cystic kidney disease.20 Gout is associated with use of several drugs, including diuretics, low-dose aspirin, and drugs often used in organ transplantation (panel 2).6 Diuretics are one of the most www.thelancet.com Vol 375 January 23, 2010

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important causes of secondary hyperuricaemia, which arises through a combination of volume depletion and decreased renal tubular secretion of uric acid.58 However, development of gout might depend on the condition for which diuretics are prescribed rather than as a result of the drugs.96,97 Aspirin has a bimodal effect on renal processing of uric acid. At high doses (>3 g per day) aspirin is uricosuric, but at low doses (