Gout and pseudogout are the 2 most common crystal-induced arthropathies. Gout is caused by monosodium urate monohydrate crystals; pseudogout is caused by calcium pyrophosphate crystals and is more accurately termed calcium pyrophosphate disease.
Patients with gout, particularly women, are at increased risk for vascular disease, according to a retrospective cohort study of 8386 patients with gout and 39,766 matched controls. Multivariate analysis showed that women with gout had a 25% increased risk for any vascular event compared with women without gout (hazard ratio [HR], 1.25) and increased risks for any coronary heart disease (HR, 1.25) and peripheral vascular disease (HR, 1.89). 
Men with gout, compared with those without gout, had a small but significantly increased risk for any vascular event (hazard ratio [HR], 1.06) and an increased risk for any coronary heart disease (HR, 1.08) and peripheral vascular disease (HR, 1.18). Unlike women, men with gout were not at greater risk for angina, transient ischemic attack, and stroke.[1, 2]
Symptoms of gout or pseudogout include the following:
Physical findings may include the following:
Complications of gout include the following:
See Presentation for more detail.
Studies that may be helpful include the following:
Plain radiographs may show findings consistent with gout. Erosions with overhanging edges are generally considered pathognomonic for gout (though also found in other diseases). Characteristics of erosions typical of gout include the following:
Ultrasonographic findings in established gout include the following:
Other imaging modalities that may be considered include the following:
See Workup for more detail.
Gout is managed in the following 3 stages:
Acute treatment of proven crystal-induced arthritis is directed at relief of the pain and inflammation. Agents used in this setting include the following:
Therapy to control the underlying hyperuricemia generally is contraindicated until the acute attack is controlled (unless kidneys are at risk because of an unusually heavy uric acid load).
Long-term management of gout is focused on lowering uric acid levels. Agents used include the following:
Because these agents change serum and tissue uric acid levels, they may precipitate acute attacks of gout. This undesired effect may be reduced by prophylaxis with the following:
Other therapeutic agents that may be considered include the following:
Nonpharmacologic measures that may be warranted are as follows:
See Treatment and Medication for more detail.
Gout. Chronic tophaceous gout in untreated patient with end-stage renal disease.
Gout and pseudogout are the two most common crystal-induced arthropathies. Gout is caused by monosodium urate monohydrate crystals; pseudogout is caused by calcium pyrophosphate (CPP) crystals and is more accurately termed calcium pyrophosphate disease (CPPD). (See Pathophysiology and Etiology.) Gout is one of the oldest diseases in the medical literature,[3, 4] known since the time of the ancient Greeks. Pseudogout, which may be clinically indistinguishable from gout, was recognized as a distinct disease entity in 1962.
Crystal deposition can be asymptomatic, but gout and CPPD can develop into debilitating illnesses marked by recurrent episodes of pain and joint inflammation that result from the formation of crystals within the joint space and deposition of crystals in soft tissue.[5, 6, 7] If untreated, these disorders can lead to joint destruction and, in the case of uric acid crystals, renal damage.
Elevated serum uric acid levels are the principal risk factor for developing gout. lIn study that compared 993 patients with asymptomatic hyperuricemia and 4,241 normouricemic patients, the odds ratio (OR) for developing gout was 32 times higher in the hyperuricemic group than in the normouricemic group. The risk was most striking in men with severe hyperuricemia, in whom the OR for developing gout was 624.8.
Although gout is associated with hyperuricemia, gout attacks are triggered not by a particular level of uric acid but typically by acute changes in the level of uric acid. All individuals with gout have hyperuricemia; however, hyperuricemia is also found in patients taking diuretics and even in those taking niacin or low doses of aspirin.
Gout may be either primary or secondary (see Etiology). Primary gout is related to underexcretion or overproduction of uric acid, often associated with a mix of dietary excesses or alcohol overuse and metabolic syndrome. Secondary gout is related to medications or conditions that cause hyperuricemia, such as the following :
Gout is definitively diagnosed on the basis of demonstration of urate crystals in aspirated synovial fluid, in the absence of another etiology for arthritis. Classic radiographic findings are highly suggestive (see Workup).
Advances in early diagnosis and the availability of definitive treatment have significantly improved the prognosis of gout, as evidenced by the declining incidence of disabling chronic tophaceous gout. However, tophaceous gout may still develop because of misdiagnosis, poor management, medication intolerances, or poor patient adherence.
Gout is managed in the following 3 stages:
Treatment of gout is important to relieve pain; to prevent disease progression; and to prevent deposition of urate crystals in the renal medulla or uric acid crystals in the renal collecting system, which may produce kidney stones or urate nephropathy. (See Treatment.)
Management of pseudogout also involves treatment of the acute attack and prophylaxis. Treatment of the acute phase of pseudogout follows the same approaches as are used in gout, and colchicine is effective for prophylaxis. In contrast with gout, however, no specific therapeutic regimen exists to treat the underlying cause of CPP crystal deposition in pseudogout, except in cases associated with disorders such as hemochromatosis or hyperparathyroidism. (See Treatment.)
Gout can be considered a disorder of metabolism that allows uric acid or urate to accumulate in blood and tissues. When tissues become supersaturated, the urate salts precipitate, forming crystals. In addition, the crystals also are less soluble under acid conditions and at low temperatures, such as occur in cool, peripheral joints (eg, the metatarsophalangeal joint of the big toe).
Urate initially precipitates in the form of needlelike crystals. The light-retarding (phase-shifting) characteristics of urate crystals allow them to be recognized by polarizing microscopy (see the image below).
Gout. Needles of urate crystals seen on polarizing microscopy.
Many conditions and drugs have been associated with an increase in plasma (and subsequent synovial) urate levels, particularly metabolic syndrome. A genetic predisposition for hyperuricemia exists; except in rare genetic disorders, however, the development of gout in hyperuricemic individuals appears to be mediated by environmental factors.[11, 12, 13]
The CPP crystals that produce pseudogout comprise a combination of inorganic pyrophosphate and calcium. The inorganic pyrophosphate is produced in large part by ectonucleotide phosphodiesterase pyrophosphatase (ENPP1), a catalytic enzyme found in chondrocytes of cartilage, and the pyrophosphate is exported potently by the membrane transporter ANKH.
A genetic predisposition exists for pseudogout. However, aging, some metabolic diseases (eg, hyperparathyroidism, hemochromatosis, and hypomagnesemia), and any process that leads to osteoarthritis also can be associated with subsequent CPP crystal deposition and pseudogout.
The presence of urate crystals in the soft tissues and synovial tissues is a prerequisite for a gouty attack. However, these crystals can also be found in synovial fluid or on the cartilage surface in the absence of joint inflammation.
A gout attack may be triggered either by release of crystals (eg, from partial dissolution of a microtophus caused by changing serum urate levels) or by precipitation of crystals in a supersaturated microenvironment (eg, release of urate as a consequence of cellular damage). In either situation, it is believed, naked urate crystals then interact with intracellular and surface receptors of local dendritic cells and macrophages, triggering a danger signal to activate the innate immune system.
This interaction may be enhanced by immunoglobulin G (IgG) binding.[15, 16] Triggering of these receptors, including Toll-like receptors, followed by intracellular signaling by the NLRP3 inflammasome, results in the release of interleukin (IL)-1β, which in turn initiates a cascade of proinflammatory cytokines, including IL-6, IL-8, neutrophil chemotactic factors, and tumor necrosis factor (TNF)-α.[17, 18] Neutrophil phagocytosis leads to another burst of inflammatory mediator production.
Subsidence of an acute gout attack results from multiple mechanisms, including the clearance of damaged neutrophils, change in the properties of urate crystals, and the production of anti-inflammatory cytokines such as IL-1 receptor antagonist (IL-1RA), IL-10, and transforming growth factor (TGF)-β.[16, 19, 20, 21]
Gout develops in the setting of excessive stores of uric acid in the form of monosodium urate. Uric acid is an end-stage by-product of purine metabolism. Humans remove uric acid primarily by renal excretion. When excretion is insufficient to maintain serum urate levels below the saturation level of 6.8 mg/dL, hyperuricemia may develop, and urate can crystallize and deposit in soft tissues.
About 90% of patients with gout develop excess urate stores because of an inability to excrete sufficient amounts of uric acid in the urine (underexcretion). Most of the remaining patients either overconsume purines or produce excessive amounts of uric acid endogenously (overproduction). A few have impaired intestinal elimination of uric acid.
In rare cases, overproduction of uric acid is the result of a genetic disorder, such as the following :
Overproduction of uric acid may also occur in disorders that cause high cell turnover with release of purines that are present in high concentration in cell nuclei. These disorders include myeloproliferative and lymphoproliferative disorders, psoriasis, and hemolytic anemias. Cell lysis from chemotherapy for malignancies, especially those of the hematopoietic or lymphatic systems, can raise uric acid levels, as can excessive exercise and obesity.
Causes of secondary gout due to underexcretion of uric acid include renal insufficiency, lead nephropathy (saturnine gout), starvation or dehydration, certain drugs, and chronic abuse of ethanol (especially beer and hard liquor). These disorders should be identified and corrected, if possible.
Certain comorbid conditions are associated with a higher incidence of gout, including the following[23, 24] :
Foods that are rich in purines include anchovies, sardines, sweetbreads, kidney, liver, and meat extracts. Consumption of fructose-rich foods and beverages (eg, those sweetened with high-fructose corn syrup) is associated with an increased risk of gout in both men and women.[25, 26]
The heritability of serum urate levels is estimated at 63%. Genome-wide association studies (GWAS) have identified several candidate loci associated with chronically elevated serum urate concentrations and gout.[28, 29, 30, 31]
In particular, 3 genes are noted to have a strong association with hyperuricemia. The locus with the strongest evidence of association is the glucose transporter 9 (GLUT9) gene, commonly referred to as the solute carrier 2A9 (SLC2A9), the product of which alters the renal excretion of uric acid. Some of the variants are associated with a protective effect, whereas others convey a higher risk of gout.
The urate transporter 1 (URAT1) gene is involved with the urate-organic anion exchanger. Several mutations in this gene have been associated with gout.
Polymorphisms in the ABCG2 gene, which is located on chromosome 4 and codes for an intestinal urate transporter, are strongly associated with high serum uric acid concentrations and gout. Elevation of uric acid levels is greater in men than in women with the minor allele of rs2231142 in ABCG2.[28, 30]
Although genetic factors have been strongly associated with hyperuricemia, environmental and other state-of-health factors are responsible for the majority of the gout burden in developed countries.[32, 33] A study of 514 male twin pairs did show a strong concordance in hyperuricemia among monozygotic (MZ) twins (53%) as compared with dizygotic (DZ) twins (24%), but it did not show a significant difference between MZ and DZ twins with regard to the lifetime prevalence of gout.
Individual gout flares are often triggered by acute increases or decreases in urate levels that may lead to the production, exposure, or shedding of crystals. Changes in urate levels can result from acute alcohol ingestion, acute overindulgence in foods high in purines, rapid weight loss, dehydration, or trauma.
Similarly, flares can be precipitated by additions of or changes in dosage of medications that raise or lower uric acid levels. Medications that increase uric acid levels via effects on renal tubular transport include loop and thiazide diuretics, niacin, low-dose aspirin, and cyclosporine A.[34, 35, 36] Agents that lower levels of uric acid include radiocontrast dyes, xanthine oxidase inhibitors (eg, allopurinol and febuxostat), and uricosurics (eg, probenecid).
Although the pathophysiology, clinical presentation, and acute-phase treatment of gout and pseudogout are very similar, the underlying causes of the 2 diseases are very different. Many cases of pseudogout in elderly people are idiopathic, but pseudogout has also been associated with trauma and with many different metabolic abnormalities, the most common of which are hyperparathyroidism and hemochromatosis.
Risk factors for pseudogout include use of loop diuretics (but not thiazide diuretics) and proton pump inhibitors, which cause hypomagnesemia. Pseudogout attacks have been reportedly induced by etidronate disodium therapy and angiography.[37, 38]
Pseudogout has been recognized as having an underlying genetic component; however, comorbid conditions (such as osteoarthritis) and environmental factors are thought to play a much stronger role. Some disorders that can lead to secondary pseudogout, such as hemochromatosis, do have a clear genetic cause. These patients should be properly evaluated and counseled.
Gout affects 8.3 million people in the United States; prevalence among adults is estimated to be 3.9%, on the basis of data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES). Prevalence is approximately 20% in patients with a family history of gout. It is estimated that more than 2 million people in the United States take medication to decrease serum uric acid levels.
Gout has become increasingly common in the United States as the population has grown older and heavier. From 1990 to 1999, the incidence rose 40%. Estimates for the number of US adults with self-reported gout in the previous year rose from 2.1 million in 1995 to 3 million in 2008. In 2008, gout accounted for 174,823 emergency department (ED) visits in the US, or approximately 0.2% of all ED visits.
The frequency of pseudogout varies with age. The annual incidence of acute attacks of arthritic pain and swelling is about 1.3 per 1000 adults, but nearly 50% of adults develop radiographic changes typical of CPPD by age 80 years.
Attacks of gout have been noted to occur more frequently in the spring and less frequently in the winter. The reason for this is unknown.
Gout has a worldwide distribution. The prevalence varies widely from country to country. Regional differences may reflect environmental, dietary, and genetic influences.
In the United Kingdom from 2000 to 2007, the incidence of gout was 2.68 per 1000 person-years—4.42 in men and 1.32 in women, and increasing with advancing age. In Italy, the prevalence of gout rose from 6.7 per 1000 population in 2005 to 9.1 per 1000 population in 2009, increasing with age and 4 times higher in men. In the Maori people of New Zealand, studies from the 1970s found that 0.3% of men and 4.3% of women were affected.[47, 48]
Gout has a male predominance.[26, 49] The estimated prevalence of gout is 5.9% in men and 2% in women. This difference is largely a consequence of age at onset; estrogenic hormones have a mild uricosuric effect, and gout is therefore unusual in premenopausal women. For pseudogout, the male-to-female ratio is approximately 50:50.
The predominant age range of gout is 30-60 years. Usually, uric acid levels are elevated for 10-20 years before the onset of gout. In men, uric acid levels rise at puberty, and the peak age of onset of gout in men is in the fourth to sixth decade of life. However, onset may occur in men in their early 20s who have a genetic predisposition and lifestyle risk factors. In women, uric acid levels rise at menopause, and peak age of onset is in the sixth to eighth decade of life.
The rate of gout is almost 5 times higher in persons aged 70-79 years than in those younger than 50 years. The higher prevalence of gout in elderly persons may also reflect an increased prevalence of metabolic syndrome, high rates of diuretic treatment for hypertension and chronic heart failure, and the use of low-dose aspirin.
Earlier onset of gout occurs in patients with renal insufficiency or a genetic abnormality of purine metabolism (eg, hypoxanthine-guanine phosphoribosyltransferase deficiency or phosphoribosylpyrophosphate synthetase superactivity). Cyclosporine A can cause an accelerated form of gout, even in premenopausal women, that can present after only a few years of hyperuricemia, particularly if the patient is also receiving diuretics.
Gout has an increased prevalence in some populations but is rare in others. For example, the frequency of gout is higher in populations such as the Chamorros and Maori and in the Blackfoot and Pima tribes. Many Maori and other Polynesian women have a genetic defect in renal urate handling that places them at risk for hyperuricemia and gout. However, racial differences may at least in part reflect differences in diet, which has a large influence on the clinical expression of gout.
In the United States, the incidence of gout is 3.11 per 1000 person-years in African Americans and 1.82 per 1000 person-years in whites; the excess risk can be partly explained by a higher frequency of incident hypertension. In contrast, clinically recognized gout is extremely rare among blacks living in Africa.
Gout is associated with considerable morbidity, with acute episodes often causing incapacitation. However, gout that is treated early and properly carries an excellent prognosis if patient adherence to treatment is good.
With early treatment, gout should be totally controlled. If attacks recur, successful uric acid adjustment (requiring lifelong use of urate-lowering medication) usually suppresses further activity. During the first 6-24 months of urate-lowering therapy, acute attacks of gout often occur more frequently.[56, 57]
Chronic injury to intra-articular cartilage leaves the joints more susceptible to subsequent joint infections. Draining tophi can become secondarily infected. Untreated chronic tophaceous gout can lead to severe joint destruction and, rarely, renal impairment. Deposition of monosodium urate crystals in the kidney can result in inflammation and fibrosis, leading to reduced renal function or chronic nephropathy. Rarely, gout can produce spinal cord impingement when deposition in tissues produces a local mass.
Acute attacks of pseudogout usually resolve within 10 days. Prognosis for resolutions of acute attacks is excellent. Some patients experience progressive joint damage with functional limitation. CPPD also can cause chronic arthritis that can resemble osteoarthritis or rheumatoid arthritis.
Hyperuricemia and gout are associated with an increased overall likelihood of mortality. Whether this is directly attributable to hyperuricemia or gout or to gout-associated diseases (eg, insulin resistance, type 2 diabetes mellitus, abdominal obesity, hypercholesterolemia, or hypertension) has been much debated.[59, 60, 61]
Although no evidence has shown that gout or hyperuricemia causes any of these disorders, elevated urate levels have been shown to correlate with elevated blood pressure in adolescents. Among middle-aged men, hyperuricemia is a significant independent risk factor for death from cardiovascular disease. A meta-analysis found an independent association between gout and cardiovascular mortality as well as all-cause mortality.
In a 2010 study, Kuo et al demonstrated that gout, but not hyperuricemia, is associated with higher risk of death from all causes and cardiovascular diseases. Analysis of 1383 deaths among 61,527 Taiwanese subjects showed in individuals with gout compared with those who had normal uric acid levels, the hazard ratio (HR) of all-cause mortality was 1.46 and the adjusted HR of cardiovascular mortality was 1.97. Among individuals with hyperuricemia, the HR of all-cause mortality was 1.07 and the adjusted HR of cardiovascular mortality was 1.08.
An analysis of nationwide data on more than 200,000 English patients indicates that individuals with gout are at increased risk for both heart attack and stroke. The rate ratio for myocardial infarction in patients with gout was 1.82. Rate ratios for stroke were 1.71 for all stroke, 1.68 for ischemic stroke, 1.69 for hemorrhagic stroke, and 2.00 for stroke of unspecified type. Risks were elevated in both men and women and were higher in the younger age groups.[65, 66]
Patients with severe hyperuricemia should avoid foods with high purine content. Moderation in food and alcohol consumption is advised. Early recognition of acute gout attacks is critical, in that intervention with medication is much more effective earlier in the attack.
For patient education information, see the Arthritis Center, as well as Gout. Online information and pamphlets on gout are also available from the Arthritis Foundation.
The spontaneous onset of excruciating pain, edema, and inflammation in the metatarsal-phalangeal joint of the great toe (podagra; see the image below) is highly suggestive of acute crystal-induced arthritis. Podagra is the initial joint manifestation in 50% of gout cases; eventually, it is involved in 90% of cases. Podagra is not synonymous with gout, however: it may also be observed in patients with pseudogout, sarcoidosis, gonococcal arthritis, psoriatic arthritis, and reactive arthritis.
Gout. Acute podagra due to gout in elderly man.
Other than the great toe, the most common sites of gouty arthritis are the instep, ankle, wrist, finger joints, and knee. In early gout, only 1 or 2 joints are usually involved. Consider the diagnosis in any patient with acute monoarticular arthritis of any peripheral joint except the glenohumeral joint of the shoulder.
The most common sites of pseudogout arthritis are large joints, such as the knee, wrist, elbow, or ankle. Case reports have documented carpal tunnel syndrome as an initial presentation of pseudogout. Case reports of calcium pyrophosphate (CPP) crystals forming masses in the spinal ligamentum flavum have been documented. These have led to both single-level and multilevel myelopathy.
Although crystal-induced arthritis is most commonly monoarticular, polyarticular acute flares are not rare, and many different joints may be involved simultaneously or in rapid succession. Multiple joints in the same limb often are involved, as when inflammation begins in the great toe and then progresses to involve the midfoot and ankle.
Gout attacks begin abruptly and typically reach maximum intensity within 8-12 hours. Affected joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable. The onset of symptoms in pseudogout can resemble acute gout or be more insidious and may occur over several days.
Untreated, the first attacks resolve spontaneously in less than 2 weeks. A history of intermittent inflammatory arthritis, in which the joints return to normal between attacks, is typical of crystalline disorders and is characteristic of gouty arthritis early in its course.
Gout initially presents as polyarticular arthritis in 10% of patients. Elderly women, particularly women with renal insufficiency who are taking a thiazide diuretic, can develop polyarticular arthritis as the first manifestation of gout. These attacks may occur in coexisting Heberden and Bouchard nodes. Such patients may also develop tophi more quickly, occasionally without prior episodes of acute gouty arthritis.[68, 69, 70]
The pattern of symptoms in untreated gout changes over time. The attacks can become more polyarticular. More proximal and upper-extremity joints become involved. Attacks tend to occur more frequently and last longer.
Eventually, patients may develop chronic polyarticular arthritis, sometimes nearly symmetrical, that can resemble rheumatoid arthritis. Indeed, chronic polyarticular arthritis that began as an intermittent arthritis should prompt consideration of a crystalline disorder in the differential diagnosis.
Acute flares of gout can result from situations that lead to increased levels of serum uric acid, such as the consumption of beer or liquor, overconsumption of foods with high purine content, trauma, dehydration, or the use of medications that elevate levels of uric acid. Acute flares of gout also can result from situations that lead to decreased levels of serum uric acid, such as the use of radiocontrast dye or medications that lower the levels of uric acid, including allopurinol and uricosurics.
Patients with gout have as much as 1000 times more uric acid in the body as unaffected individuals do and are almost twice (1.97 times) as likely to develop renal stones as healthy individuals are ; therefore, they may have a history of renal colic and hematuria. Indeed, renal stones may precede the onset of gout in 14% of affected patients. Whereas 52% of these patients may have stones composed entirely of uric acid, 20% may develop calcium oxalate or sometimes calcium phosphate stones.
Because gout is frequently present in patients with the metabolic syndrome (eg, insulin resistance or diabetes, hypertension, hypertriglyceridemia, and low levels of high-density lipoproteins) and because the presence of these associated disorders can lead to coronary artery disease, these problems should be sought and treated in patients diagnosed with gout.
It is important to ask about a history of peptic ulcer disease, renal disease, or other conditions that may complicate the use of the medications used to treat gout.
Fever, chills, and malaise do not distinguish cellulitis or septic arthritis from crystal-induced arthritis, because all 3 illnesses can produce these signs and symptoms. A careful history may uncover risk factors for cellulitis or septic arthritis, such as possible exposure to gonorrhea, a recent puncture wound over the joint, or systemic signs of disseminated infection.
Patients experiencing an acute attack of gout or pseudogout most often present with involvement of a single joint. However, all joints must be examined to determine whether the patient’s arthritis is monoarticular or polyarticular. Involved joints have all the signs of inflammation: swelling, warmth, erythema, and tenderness.
The erythema over the joint may resemble cellulitis; the skin may desquamate as the attack subsides. The joint capsule becomes quickly swollen, resulting in a loss of range of motion of the involved joint.
Patients may be febrile during an acute gout attack, particularly if it is polyarticular. However, it is important to look for sites of infection that may have seeded the joint and caused an infectious arthritis resembling or coexisting with acute gouty arthritis.
Migratory polyarthritis is a rare presentation. Polyarticular gout commonly involves the small joints of the fingers and toes, as well as the knees. An inflammatory synovial effusion may be present. Uncommonly, acute gout may present as carpal tunnel syndrome.
Posterior interosseous nerve syndrome is a rare compression neuropathy that manifests as inability to extend the fingers actively. The syndrome has been reported in a patient with elbow swelling from an attack of pseudogout; in this case, treatment with intra-articular steroids led to resolution of the nerve palsy.
Patients with established gout may have chronic arthritis. Affected joints evidence tenderness and swelling, with or without redness, warmth, or joint damage.
Although gout typically causes joint inflammation, it can also cause inflammation in other synovial-based structures, such as bursae and tendons. Tophi are collections of urate crystals in the soft tissues. They tend to develop after about a decade in untreated patients who develop chronic gouty arthritis. Tophi may develop earlier in older women, particularly those receiving diuretics.[68, 69, 70]
Tophi are classically located along the helix of the ear, but they can be found in multiple locations, including the fingers, the toes, the prepatellar bursa, and along the olecranon, where they can resemble rheumatoid nodules (see the images below). Rarely, a creamy discharge may be present.[74, 75] The finding of an apparent rheumatoid nodule in a patient with a negative rheumatoid factor assay or a history of drainage from a nodule should prompt consideration of gout in the differential diagnosis.
Gout. Tophaceous deposits in ear.
Gout. Tophaceous deposits on elbow.
Gout. Chronic tophaceous gout in untreated patient with end-stage renal disease.
The folklore surrounding gout has also involved the eye, and before the 20th century, a myriad of common and unusual ocular symptoms were falsely ascribed to gout. Medical science has since documented eye involvement as a rare but definite aspect of gout. All manifestations of gout in the eye are secondary to deposition of urate crystals within the ocular tissue.[77, 78]
Tophi have been described in the eyelids.[79, 80, 81] Conjunctival nodules containing needlelike crystals have been described within the interpalpebral areas, sometimes associated with a mild marginal keratitis. Band keratopathy with refractile, yellow crystals in the deep corneal epithelial cells and at the level of the Bowman membrane are not uncommon.
Blurring of vision from the corneal haze or a foreign body sensation due to epithelial breakdown may occur. Gout rarely can be associated with anterior uveitis; Duke-Elder mentions this as a cause of hemorrhagic iritis in his classic Text Book of Ophthalmology. Scleritis and tendinitis have also been described. Besides the cornea, the iris, anterior chamber, lens, and sclera have been found to harbor urate crystals; on postmortem examination, urate crystals have also been found in tarsal cartilage and in the tendons of extraocular muscles.[77, 78]
Complications of gout include the following:
Arthrocentesis of the affected joint is mandatory for all patients with new-onset acute monoarthritis and is very strongly recommended for those with recurrent attacks whose diagnosis has never been proved by microscopic visualization of crystals. Tophi also may be aspirated for crystal analysis under polarizing microscopy.
A prior history of gout or pseudogout does not rule out the possibility of acute septic arthritis. In fact, the latter is more common in patients with a history of crystal-induced arthritis. Septic arthritis must be diagnosed and treated promptly, because irreversible damage can occur within 4-6 hours and the joint can be completely destroyed within 24-48 hours.
Send joint fluid for fluid analysis, including cell count and differential, Gram stain, culture and sensitivity, and microscopic analysis for crystals. If crystals are seen, their shape and appearance under polarized light are diagnostic.
In gout, crystals of monosodium urate (MSU) appear as needle-shaped intracellular and extracellular crystals. When examined with a polarizing filter and red compensator filter, they are yellow when aligned parallel to the slow axis of the red compensator but turn blue when aligned across the direction of polarization (ie, they exhibit negative birefringence). Negatively birefringent urate crystals are seen on polarizing examination in 85% of specimens.
Microscopic analysis in pseudogout shows calcium pyrophosphate (CPP) crystals, which appear shorter than MSU crystals and are often rhomboidal. Under a polarizing filter, CPP crystals change color depending upon their alignment relative to the direction of the red compensator. They are positively birefringent, appearing blue when aligned parallel with the slow axis of the compensator and yellow when perpendicular.
In crystal arthritis, the white blood cell (WBC) count in the synovial fluid is usually 10,000-70,000/µL. However, it may be as low as 1000/µL or as high as 100,000/µL.
Even in the presence of crystals in the joint fluid, blood cultures are indicated if any sign of systemic toxicity is present. Septic arthritis can occur in patients with active crystalline arthropathy.
Gouty attacks are not related to serum levels of uric acid. Thus, an elevated serum uric acid level does not prove the diagnosis of acute gout, though hyperuricemia is present in 95% of cases, and a normal level does not exclude the diagnosis. Renal uric acid excretion should be measured in high-risk patients, including those with renal calculi, a strong family history of gout, and a first attack before age 25 years.
Pseudogout attacks can be triggered by many metabolic abnormalities. Thus, patients who have an initial attack of arthritis with CPP crystals should have a workup that includes a chemistry screen; serum magnesium, calcium, and iron levels; and thyroid function tests.
The WBC count in peripheral blood is usually elevated, with a left shift during acute attacks. The erythrocyte sedimentation rate (ESR) usually is elevated during acute attacks.
Imaging studies of the affected joint or joints are indicated. Patients with new onset of acute gout usually have no radiographic abnormalities. In established disease, radiographs may reveal punched-out erosions or lytic areas with overhanging edges.
Magnetic resonance imaging (MRI) is capable of detecting crystal deposits but is not part of any routine evaluation for acute arthritis. MRI can be very useful in determining the extent of the disease and may help in the differential diagnosis.
Patients with pseudogout usually have degenerative joint changes evident on imaging studies. In addition, they may have calcifications in the soft tissues, tendons, or bursae.
When a patient presents with acute inflammatory monoarticular arthritis, aspiration of the involved joint is critical to rule out an infectious arthritis and to attempt to confirm a diagnosis of gout or pseudogout on the basis of identification of crystals (see the image below). Minute quantities of fluid in the shaft or hub of the needle are sufficient for synovial fluid analysis.
Gout. Fluid obtained from tophaceous deposit in patient with gout.
Urate crystals are shaped like needles or toothpicks with pointed ends (see the first image below). Under polarizing light microscopy, urate crystals are yellow when aligned parallel to the axis of the red compensator and blue when aligned across the direction of polarization (ie, they exhibit negative birefringence). Finding negatively birefringent urate crystals (see the second image below) firmly establishes the diagnosis of gouty arthritis.
Gout. Needles of urate crystals seen on polarizing microscopy.
Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from acutely inflamed joint.
Pseudogout crystals (CPP) are rod-shaped with blunt ends and are positively birefringent. Thus, pseudogout crystals are blue when aligned parallel to the slow ray of the compensator and yellow when they are perpendicular.
Crystals must be distinguished from birefringent cartilaginous or other debris. Debris may have fuzzy borders and may be curved, whereas crystals have sharp borders and are straight. As alkalization reduces uric acid crystal solubility and the enzyme uricase can “dissolve” these crystals, reduction by addition of sodium hydroxide or uricase to suspected gout crystal can be helpful.
Corticosteroids injected into joints have a crystalline structure that can mimic either MSU or CPP crystals. They can be either positively or negatively birefringent.
The sensitivity of a synovial fluid analysis for crystals is 84%, with a specificity of 100%. If gout remains a clinical consideration after negative analysis findings, the procedure can be repeated in another joint or with a subsequent flare. Crystals may be absent very early in a flare.
Although the sensitivity of this test is inferior, aspiration of synovial fluid from previously inflamed joints that are not currently inflamed may reveal urate crystals. Such crystals are generally extracellular.
Synovial fluid should also be sent for cell count. During acute attacks, the synovial fluid is inflammatory, with a WBC count higher than 2000/µL (class II fluid) and possibly higher than 50,000/µL, with a predominance of polymorphonuclear neutrophils, though low WBC counts are occasionally found.
Synovial fluid glucose levels are usually normal, whereas they may be depressed in septic arthritis and occasionally in rheumatoid arthritis. Measurement of synovial fluid protein has no clinical value.
Crystalline arthritis and infectious arthritis can coexist. Indeed, infectious arthritis is more common in previously damaged joints, which may occur in patients with chronic gouty arthritis. Consequently, in patients with acute monoarticular arthritis, send synovial fluid for Gram stain and culture and sensitivity.
The pathologic specimens must be processed anhydrously. MSU is water-soluble and dissolves in formalin; therefore, only the ghosts of urate crystals may be seen if formalin is used. Absolute (100%) alcohol–fixed tissue is best for identification of urate crystals.
Once a diagnosis of gout is established by confirmation of crystals, repeat aspiration of joints with subsequent flares is not necessary unless infection is suggested or the flare does not respond appropriately to therapy for acute gout.
Measurement of serum uric acid is the most misused test in the diagnosis of gout. The presence of hyperuricemia in the absence of symptoms is not diagnostic of gout. In addition, as many as 15% of patients with symptoms from gout may have normal serum uric acid levels at the time of their attack. Thus, the diagnosis of gout can be missed if the joint is not aspirated. Remember that situations that decrease uric acid levels can trigger attacks of gout. In such cases, the patient’s medical records may reveal prior elevations of uric acid.
Approximately 25% of the population has a history of elevated serum uric acid, but only a minority of patients with hyperuricemia develop gout. Thus, an abnormally high serum uric acid level does not indicate or predict gout. As noted, gout is diagnosed by the presence of urate crystals in the synovial fluid or soft tissues. More important, some patients who present with a hot swollen joint and an elevated serum uric acid level in fact have infectious arthritis, which may be mismanaged if their synovial fluid is not examined.
Asymptomatic hyperuricemia generally should not be treated. However, patients with levels higher than 11 mg/dL and overexcretion of uric acid are at increased risk for renal stones and renal impairment; therefore, renal function should be monitored in these individuals.
The level of serum uric acid does correlate with the risk for developing gout. The 5-year risk for developing gout is approximately 0.6% if the level is below 7.9 mg/dL, 1% if it is 8-8.9 mg/dL, and 22% if it is higher than 9 mg/dL.
A 24-hour urinary uric acid evaluation is generally performed if uricosuric therapy is being considered. If patients excrete more than 800 mg of uric acid in 24 hours while eating a regular diet, they are overexcretors and thus overproducers of uric acid. These patients (approximately 10% of patients with gout) require allopurinol instead of probenecid to reduce uric acid levels. Furthermore, patients who excrete more than 1100 mg in 24 hours should undergo close renal function monitoring because of the risk of stones and urate nephropathy.
In patients in whom probenecid is contraindicated (eg, those with a history of renal stones or renal insufficiency), a 24-hour urine test of uric acid excretion need not be performed, because the patient clearly will need allopurinol.
Blood studies may reveal abnormalities associated with gout or common comorbid conditions. In addition, abnormal results on renal function or liver function studies may affect the selection of therapy.
Obtaining an accurate measure of the patient’s renal function before deciding on therapy for gout is important. The glomerular filtration rate can be estimated by using formulas such as the Modification of Diet in Renal Disease (MDRD) Study equation or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Serum creatinine evaluation alone can underestimate renal dysfunction in elderly patients or in patients with low muscle mass.
The WBC count may be elevated in patients during the acute gouty attack, particularly if it is polyarticular. Hypertriglyceridemia and low levels of high-density lipoprotein (HDL) are associated with gout. Glucose measurement is useful because patients with gout are at increased risk for the development of diabetes mellitus.
Pseudogout attacks can be triggered by many metabolic abnormalities. Thus, patients who have an initial attack of arthritis with CPP crystals should have a workup that includes a chemistry screen; serum magnesium, calcium, iron and iron-binding levels; and thyroid function tests.
Plain radiographs may show findings consistent with gout, but these findings are not diagnostic. Early in the disease, radiographs are often normal or show only soft-tissue swelling. Radiographic findings characteristic of gout, which generally do not appear within the first year of disease onset, consist of punched-out erosions or lytic areas with overhanging edges (see the image below). Haziness suggestive of tophi can be seen in late gout, and tophi may calcify.
Gout. Radiograph of erosions with overhanging edges.
Erosions with overhanging edges generally are considered pathognomonic for gout but also can be found in amyloidosis, multicentric reticulohistiocytosis, and type IIA hyperlipoproteinemia. Characteristics of erosions that are typical of gout but not of rheumatoid arthritis include the following:
Another characteristic of erosions typical of gout is sclerotic borders, sometimes called cookie-cutter or punched-out borders. In addition, erosions in gout may be distributed asymmetrically among the joints, with strong predilection for distal joints, especially in the lower extremities (see the images below).
Gout. Plain radiograph showing typical changes of gout in first metatarsophalangeal joint and fourth interphalangeal joint.
Gout. Plain radiograph showing chronic tophaceous gouty arthritis in hands.
At the first attack, sites affected with gout may be anechoic on ultrasonography. Later, diffuse enhancement may be evident on the articular cartilage surface. Chondrocalcinosis show up as a thin, hyperechoic band within hyaline cartilage and punctuated pattern on fibrocartilage.
Ultrasonographic findings in established gout include the following[90, 91, 92] :
Ultrasonography may demonstrate urate crystal deposition in tissues of asymptomatic patients with hyperuricemia. Pineda et al found double-contour signs in the first metatarsal-phalangeal joints of 25% of 50 asymptomatic patients with hyperuricemia but in none of 52 normouricemic subjects.
In a study by DeMiguel et al, ultrasonography identified urate crystal deposition in 11 of 26 patients who had asymptomatic hyperuricemia for 2-28 years (average, 6.2 years), affecting the knee in 9 cases and the first metatarsal-phalangeal joint in 6. These results document that asymptomatic gout may not be as innocuous as was once believed.
Plain radiography and computed tomography (CT) are complementary for recognizing erosions in gout. Dual-energy CT, using a renal stone color-coding protocol, assesses chemical composition, labeling urate deposits in red.
In a study comparing CT imaging versus a history of urinary tract calculus for identification of nephrolithiasis in gout patients, 62% of the patients with CT-documented scans had no history of urolithiasis. In 383 male patients with primary gout, CT scanning confirmed nephrolithiasis in 103 (26.9%), whereas the history of urinary tract calculus was positive in only 65 (17%). The authors concluded that the prevalence of urolithiasis cannot be accurately determined on the basis of patients’ histories.
MRI is not part of any routine evaluation for acute arthritis. MRI evidence of edema is minimal in gout, unless concomitant osteomyelitis is present. However, MRI with gadolinium is recommended when tendon sheath involvement must be evaluated and when osteomyelitis is in the differential diagnosis. Large deposits of crystals may be seen in bursae or ligaments. MRI examination of erosions reveals tophi but no bone edema or synovitis.
Tophi usually have low or intermediate signal intensity on T1-weighted spin echo images. Signal intensity also tends to be low on T2-weighted images. In the absence of inflammation, the tophi are sharply delineated. Presence of inflammation results in increased perilesional signal intensity. Tophi and the surrounding area of inflammation enhance with gadolinium.
Chronic tophaceous gouty deposits frequently show large pale pink acellular areas, which represent dissolved urate crystals, surrounded by histiocytes and multinucleated giant cells (see the image below).
Gout. Hematoxylin and eosin (H&E) stain, low power, showing abundant pale pink areas surrounded by histiocytes and multinucleated giant cells.
The crystals are water-soluble and thus are dissolved during routine tissue processing. If there are a large number of crystals, however, some may survive processing and appear as pale brown-gray refractile material (see the image below), or they may be seen on unstained sections. The urate crystals are easily seen on polarized light.
Gout. H&E stain, high power, showing that most urate crystals have been dissolved but that some pale brown-gray crystals did survive processing.
Pseudogout also demonstrates pale pink areas that may be surrounded by histiocytes and multinucleated giant cells. On higher-power views, however, the crystals are purple and rhomboid and therefore can be distinguished from gout on routine histology (see the images below).
H&E stain, medium power, of pseudogout with pale pink fibrocartilage in upper portion and purple crystals of calcium pyrophosphate in lower portion.
Pseudogout. H&E stain, high power, under polarized light to highlight rhomboidal crystals.
Pseudogout. H&E stain, high power, of calcium pyrophosphate crystals, demonstrating their rhomboidal structure.
Gout is managed in the following 3 stages:
In 2012, the American College of Rheumatology (ACR) published guidelines on the treatment and prophylaxis of acute gouty arthritis and the management of hyperuricemia.[101, 102]
As a general rule, asymptomatic hyperuricemia should not be treated, though ultrasonographic studies have demonstrated that urate crystal deposition into soft tissues occurs in a minority of patients with asymptomatic hyperuricemia.[93, 94] Patients with levels higher than 11 mg/dL who overexcrete uric acid are at risk for renal stones and renal impairment; therefore, renal function should be monitored in these individuals.
Urate-lowering therapy appears to reduce the incidence of kidney damage in gout. In a retrospective study of 16,186 patients with initial serum uric acid levels above 7 mg/dL, Levy and colleagues found that patients with gout who remained on urate-lowering therapy were less likely to develop kidney damage leading to chronic kidney disease than those who were untreated. All patients were followed for 36 months from their first documented high serum uric acid level.
Patients who achieved a serum uric acid level below 6 mg/dL had a 37% improvement in renal outcomes (P < .0001). The hazard ratio for kidney damage was 1.08 (95% confidence interval, 0.76–1.52) in patients who received urate-lowering therapy more than 80% of the time and was 1.27 (95% confidence interval, 1.05–1.55) in those who received urate-lowering therapy less than 80% of the time.
Tophi should not be surgically removed unless they are in a critical location or drain chronically. Surgery may be indicated for tophaceous complications, including infection, joint deformity, compression (eg, cauda equina or spinal cord impingement), and intractable pain, as well as for ulcers related to tophaceous erosions. Delayed healing is noted in 50% of patients.
Treatment of the acute phase of pseudogout is identical to that of acute gout. In patients with idiopathic pseudogout, a deterrent regimen of colchicine may be used. If an underlying metabolic problem is responsible for pseudogout, the arthritis may be cured when the underlying problem is addressed.
The temptation to treat patients without a proven diagnosis must be resisted. Septic arthritis may clinically resemble gout or pseudogout, and unrecognized septic arthritis can lead to loss of life or limb. Distinguishing septic arthritis from crystal-induced arthritis is not possible without an examination of joint fluid.
Acute treatment of proven crystal-induced arthritis is directed at relief of the pain and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine, and adrenocorticotropic hormone (ACTH) are treatment options. The choice is based primarily on whether the patient has any concomitant health problems (eg, renal insufficiency or peptic ulcer disease). Colchicine, a classic treatment, is now rarely indicated.
When comorbid conditions limit the use of NSAIDs or colchicine, a preferred option may be an intra-articular steroid injection, particularly when a large, easily accessible joint is involved. Septic arthritis must be reasonably excluded.
Therapy to control the underlying hyperuricemia generally is contraindicated until the acute attack is controlled (unless kidneys are at risk because of an unusually heavy uric acid load). Starting therapy to control hyperuricemia during an acute attack may intensify and prolong the attack. If the patient has been on a consistent dosage of probenecid or allopurinol at the time of the acute attack, however, the drug should be continued at that dosage during the attack.
Furthermore, control of hyperuricemia generally is not pursued for a single attack. If attacks are recurrent or evidence of tophaceous or renal disease is present, therapy for control of hyperuricemia is indicated.[104, 105, 106]
NSAIDs are the drugs of choice in most patients with acute gout who do not have underlying health problems. Although indomethacin is the NSAID traditionally chosen for acute gout, most of the other NSAIDs can be used as well. Select an agent with a quick onset of action. Do not use aspirin, because it can alter uric acid levels and potentially prolong and intensify an acute attack. Low-dose aspirin alters uric acid levels, increasing the risk of gout attacks and requiring close uric acid monitoring when aspirin is added to a uric acid/gout treatment regimen.
Cyclooxygenase-2 (COX-2) inhibitors have been used with success, but patients may require higher dosages than are typically used.
Avoid NSAIDs in patients with a history of peptic ulcer disease or gastrointestinal (GI) bleeding, those with renal insufficiency or abnormal hepatic function, those taking warfarin (a selective COX-2 inhibitor can be used), and those in the intensive care unit (ICU) who are predisposed to gastritis. Limit NSAID use in elderly patients, because of the potential for adverse central nervous system (CNS) effects. Use NSAIDs cautiously in patients with diabetes and those who are receiving concomitant angiotensin-converting enzyme (ACE) inhibitors.
To control the acute attack, NSAIDs are prescribed at full dosage for 2-5 days. Once the acute attack is controlled. the dosage is reduced to approximately one half to one fourth of that amount. Taper the dosage over approximately 2 weeks. Gout symptoms should be absent for at least 2 days before the NSAID is discontinued.
Although colchicine was once the treatment of choice for acute gout, it is now less commonly used than NSAIDs because of its narrow therapeutic window and risk of toxicity.[109, 110] To be effective, colchicine therapy is ideally initiated within 36 hours of onset of the acute attack. When used for acute gout in classic hourly dosing regimens (no longer recommended), colchicine causes adverse GI effects, particularly diarrhea and vomiting, in 80% of patients.
Dosing recommendations for colchicine in the treatment of acute gout have undergone modifications as awareness of its toxicities has increased. Newer recommendations trend toward lowered daily and cumulative doses.[109, 111]
The regimen currently favored consists of 1.2 mg of colchicine, followed by 0.6 mg 1 hour later to initiate treatment of the early gout flare. In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Terkaltaub et al found that this regimen yielded both maximum plasma concentration and early gout flare efficacy comparable with those of high-dose colchicine (4.8 mg total over 6 hours), with a safety profile indistinguishable from that of placebo.
Data from 7 separate drug-to-drug interaction (DDI) studies suggests colchicine dose reductions of 33-66% for treatment of acute gout and 50-75% for prophylaxis when colchicine is given in combination with the extended-release calcium channel blockers verapamil and diltiazem or with the numerous P-gp and/or CYP3A4 inhibitors (eg, clarithromycin and cyclosporine); in addition, patients should avoid grapefruit juice. Dosages of colchicine did not have to be adjusted when the drug was used in combination with azithromycin.
Colchicine should generally be avoided if the glomerular filtration rate (GFR) is lower than 10 mL/min, and the dose should be decreased by at least half if the GFR is lower than 50 mL/min. Colchicine should also be avoided in patients with hepatic dysfunction, biliary obstruction, or an inability to tolerate diarrhea.
A clinical response to colchicine is not pathognomonic for gout. Responses may also occur in patients with pseudogout, sarcoid arthropathy, psoriatic arthritis, or calcific tendonitis.
In February 2008, the US Food and Drug Administration (FDA) ruled that intravenous (IV) colchicine can no longer be produced or shipped in the United States, because of its toxicities. Consequently, IV colchicine is no longer advocated for the treatment of acute gout in the United States.
Corticosteroids can be given to patients with gout who cannot use NSAIDs or colchicine. Steroids can be given orally, IV, intramuscularly (IM), or intra-articularly. Using parenteral corticosteroids confers no advantage unless the patient cannot take oral medications.
Prednisone can be given at a dose of approximately 40 mg for 1-3 days, which is then tapered over approximately 2 weeks (tapering more rapidly can result in a rebound flare). Monitor closely for corticosteroid effects. If treatment continues for more than 2 weeks, consider measures to prevent osteoporosis.
Intra-articular long-acting (depot) corticosteroids are particularly useful in patients with a monoarticular flare to help reduce the systemic effects of oral steroids. Ensuring that the joint is not infected before injecting intra-articular corticosteroids is particularly important.
An alternative to corticosteroid administration is to give ACTH (40 IU subcutaneously, with repeat dosing as needed) to induce production of corticosteroid by the patient’s own adrenal glands. Such a regimen does not depend on the patient for proper tapering of prednisone.
If the patient does not have an adequate response to initial therapy with a single drug, ACR guidelines advises that adding a second appropriate agent is acceptable. Using combination therapy from the start is appropriate for an acute, severe gout attack, particularly if the attack involves multiple large joints or is polyarticular. Acceptable regimens include any of the following, in full or prophylactic doses as appropriate :
When a patient experiences a first attack of gout, any medication regimens that may have contributed to the gout attack must be altered, and any predisposing medical conditions or habits must be addressed. Patients should be instructed to go on a diet if obese, to stop drinking beer, and to avoid purine-rich foods.
In many cases, patients who have a first attack of gout should undergo therapy with agents that lower uric acid, given the high risk for further inflammatory attacks and the potential for destructive tophaceous deposition in the bone, synovium, and kidney, even without episodes of acute inflammation. If the first attack is not severe, however, some rheumatologists advocate waiting for a second attack before initiating such therapy; not all patients experience a second attack, and some patients may require convincing that they need life-long therapy.
The risk of a second attack of gout after the first attack is 62% after 1 year, 78% after 2 years, and 93% after 10 years. The decision to begin therapy depends partly on the baseline serum uric acid levels (>9 mg/dL denotes a higher risk for recurrent gouty arthritis and tophi).
ACR guidelines recommend pharmacologic urate-lowering therapy for patients with gout who have 1 or more tophi on clinical examination or imaging study or have frequent attacks of acute gouty arthritis (≥2 attacks per year). Less robust evidence supports pharmacologic therapy for patients with chronic kidney disease of stage 2 or worse or a past history of urolithiasis.
Long-term management of gout is focused on lowering uric acid levels. The goal of therapy is to reduce serum uric acid levels to below 6 mg/dL, at minimum. In many cases, lowering uric acid levels to less than 5 mg/dL is necessary to improve the signs and symptoms of gout. ACR guidelines recommend that once palpable tophi and all acute and chronic gout symptoms have resolved, serum uric acid levels should be maintained below 6 mg/dL indefinitely.
In contrast, Perez-Ruiz et al have proposed that once dissolution of existing urate crystals has been achieved, less stringent control may suffice to prevent formation of new crystals. In their prospective cohort study of 211 patients from whom urate-lowering therapy was withdrawn either after 5 years if no tophus was present at baseline or 5 years after resolution of the last tophus, no patient who maintained an average serum urate level lower than 7 mg/dL developed a crystal-proven recurrence of gout.
Avoiding the use of medications that elevate uric acid in patients with gout is prudent. Thus, in patients with hypertension, other agents are preferable to a thiazide diuretic, provided that blood pressure can be managed easily with a single drug. Low-dose aspirin is also uricosuric. The angiotensin-receptor blocker (ARB) losartan should be considered, because it is uricosuric at 50 mg/day. However, medications that elevate uric acid can still be used, if required, by making appropriate adjustments of allopurinol or probenecid doses.
Urinary excretion amounting to less than 800 mg per 24-hour period on an unrestricted diet is considered underexcretion. Underexcreting patients are candidates for uricosuric therapy with probenecid. The dosage is increased at monthly intervals until the uric acid level is lowered to target. Urinary alkalization (eg, with potassium citrate) and ingestion of copious amounts of fluid are adjunctive recommendations.
In patients with gout who have renal disease, ACR guidelines recommend xanthine oxidase inhibitor therapy with either allopurinol or febuxostat as the first-line pharmacologic approach. Probenecid can be used in patients who have contraindications to or are intolerant of at least 1 of those first-line agents, or it may be combined with a xanthine oxidase inhibitor if the inhibitor does not lower uric acid sufficiently. Probenecid could also be used for those patients who consider the risks of xanthine oxidase inhibitors to be too high.
The ACR advises, however, that monotherapy with probenecid is not a first-line choice in patients with a creatinine clearance of less than 50 mL/min. In addition, drug interactions may occur with probenecid (see Medication).
Because allopurinol, febuxostat, and probenecid change serum and tissue uric acid levels, they may precipitate acute attacks of gout. To reduce this undesired effect, colchicine or low-dose NSAID treatment is provided for at least 6 months. In patients who cannot take colchicine or NSAIDs, low doses of prednisone can be considered. When used prophylactically, colchicine can reduce such flares by 85%. Patients with gout may be able to abort an attack by taking a single colchicine tablet at the first twinge of an attack.
The standard dosage of colchicine for prophylaxis is 0.6 mg twice daily, but lower dosages have also been suggested. Significant dosage reduction is critical for patients who are also taking calcium channel blockers (eg, verapamil or diltiazem) and any of the large number of P-gp or CYP3A4 inhibitors (eg, clarithromycin or cyclosporine). In patients with renal insufficiency, the dosing frequency may have to be decreased to once daily or every other day.
Adverse GI effects are uncommon with this dosage, occurring in only 4% of patients. This stands in contrast to the 80% risk of adverse GI effects with the classic hourly colchicine regimen for the treatment of acute gout.
Even in prophylactic doses, however, long-term use of colchicine can lead to marrow toxicity and to neuromyopathy, with elevated levels of creatine kinase and resulting muscle weakness. Colchicine-induced neuromyopathy is a particular risk in patients with renal insufficiency.
If the patient develops a gout flare after beginning therapy with a uric acid–lowering agent, the agent should not be discontinued, because discontinuance will only cause another flux in the uric acid level, which may prolong and intensify the attack.
Allopurinol blocks xanthine oxidase and thus reduces the generation of uric acid. Approximately 3-10% of patients taking allopurinol develop symptoms of intolerance, such as dyspepsia, headache, diarrhea, or pruritic maculopapular rash.
Less frequently (1% of cases), patients taking allopurinol can develop severe allopurinol hypersensitivity syndrome, which carries a mortality of 20-30%. Features of this syndrome include fever, toxic epidermal necrolysis, bone marrow suppression, eosinophilia, leukocytosis, renal failure, hepatic failure, and vasculitis. Corticosteroids are often used to treat severe allopurinol hypersensitivity syndrome.
Severe allopurinol hypersensitivity syndrome is more likely to occur in patients with renal insufficiency, those who are taking a thiazide diuretic, and those started on allopurinol at a dosage of 300 mg/day. In addition, strong associations have been found between severe allopurinol hypersensitivity reactions and carriage of the HLA–B*5801 allele.
ACR guidelines recommend considering screening for HLA–B*5801 carriage, using a polymerase chain reaction–based test, in selected high-risk patients before starting allopurinol. Patients at particularly high risk are known to include those of Han Chinese or Thai descent; Koreans are also at risk, if they have stage 3 or worse chronic kidney disease. It is unclear whether such precautions are necessary with a 100-mg starting dose of allopurinol. Additionally, availability of this test may be an issue.
Severe allopurinol hypersensitivity syndrome may present as Stevens-Johnson syndrome or as drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after initiation of allopurinol. The underlying mechanism is thought to be a cell-mediated immune reaction to allopurinol and its metabolites. Although the frequency is only is 0.4%, the rate of organ failure and death is high. Treatment is with IV N- acetylcysteine and steroids.
Allopurinol should immediately be discontinued in patients who develop pruritus or a rash consistent with allopurinol hypersensitivity.
In most patients, start allopurinol at 100 mg/day (50 mg/day in patients with renal insufficiency). Stamp et al have proposed that the risk of allopurinol hypersensitivity may be reduced by starting allopurinol at a dose of 1.5 mg per unit of estimated GFR.
Adjust the dosage upward every 2-5 weeks according to the uric acid level until the goal of a uric acid level of 6 mg/dL or less is achieved. Once the target uric acid level has been achieved and maintained for 6 months, discontinue colchicine prophylaxis, unless the patient has 1 or more tophi on clinical exam.
Previously, adjusting the allopurinol maintenance dosage to the creatinine clearance rate was recommended for patients with renal insufficiency. However, Vázquez-Mellado et al found no increase in the prevalence of adverse reactions to allopurinol in patients who were started at an adjusted dosage but subsequently had their dosage raised to meet therapeutic targets.
ACR guidelines advise that the dosage of allopurinol can be raised above 300 mg/day, even in patients with renal impairment, provided that the patient receives adequate education and monitoring for drug toxicity (including measurement of transaminase levels). The maximum dosage of allopurinol approved by the US Food and Drug Administration (FDA) is 800 mg/day, but the maximum dosage should be lower in patients with chronic kidney disease.
Beware of drug interactions. For example, allopurinol prolongs the half-life of azathioprine and 6-mercaptopurine. It enhances the bone marrow toxicity of cyclophosphamide. Patients taking concomitant ampicillin are at an increased risk of rash.
Allopurinol can be used in combination with probenecid. However, note that probenecid increases the excretion of allopurinol.
In a retrospective 24-month study of gout patients who had been prescribed allopurinol, Riedel et al found that only 18% of them filled all their prescriptions throughout the entire follow-up period and thus were presumably compliant; 10.4% filled only a single prescription. In contrast, Rees et al reported that when patients receiving urate-lowering therapy were given a predominantly nurse-delivered intervention that included education and individualized lifestyle advice, 92% achieved target serum uric acid levels at 1 year.
Febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol in patients with gout.[126, 127] Febuxostat is administered orally and is metabolized mainly in the liver. In contrast, allopurinol and its metabolites are excreted primarily by the kidney. Therefore, febuxostat can be used in patients with renal impairment with no dosage adjustment. It is more expensive than allopurinol.
The CONFIRMS trial demonstrated the efficacy and safety of febuxostat in lowering hyperuricemia. By 6 months, the primary endpoint—a serum uric acid level of less than 6.0 mg/dL—was achieved in 45% of subjects on febuxostat 40 mg/day, 67% on febuxostat 80 mg/day, and 42% on allopurinol. In subjects with renal impairment, the primary endpoint was achieved in 50% of subjects on febuxostat 40 mg/day, 72% on febuxostat 80 mg/day, and 42% on allopurinol. Adverse event rates were low and similar in all groups.
In patients aged 65 years or older, the primary endpoint was achieved in 62% on febuxostat 40 mg/day, 82% on febuxostat 80 mg/day, and 47% on allopurinol. These figures remained essentially unchanged in subjects with mild-to-moderate renal impairment.
In African-American subjects, the primary endpoint was reached in 47% on febuxostat 40 mg/day, 68% on febuxostat 80 mg/day, and 43% on allopurinol. Similar rates were seen in subjects with renal impairment. Adverse event rates in both subgroups were comparable with those in the overall trial.
The efficacy and safety of febuxostat in women was demonstrated in the CONFIRMS trial and in 2 other trials comparing febuxostat and allopurinol: FACT (Febuxostat Versus Allopurinol Controlled Trial) and APEX (Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat). Achievement of a uric acid level below 6.0 mg/dL rose with increasing daily doses of febuxostat doses, from 54.3% in patients receiving 40 mg to 100% in those receiving 240 mg, compared with 45.9% with allopurinol. Results were similar in subjects with renal impairment.
Nonrecombinant urate-oxidase (uricase) is used in Europe to prevent severe hyperuricemia induced by chemotherapy in patients with malignancies, as well as in selected patients with treatment-refractory gout. Short-term use of such agents in patients with severe tophaceous gout could debulk the total-body urate load, allowing maintenance with probenecid or allopurinol.
In 2009, the FDA approved recombinant uricase (rasburicase) for the prevention of tumor lysis syndrome. However, it is highly immunogenic and may cause anaphylaxis.
In 2010, a polyethylene-glycol–conjugated uricase (pegloticase) was approved by the FDA for gout. Pegloticase, which enzymatically catalyzes the oxidation of uric acid to allantoin, is an IV biologic agent to be considered when adjustment of contributing medications (eg, diuretics) and treatment with allopurinol, febuxostat, and uricosuric agents are insufficient to achieve appropriate reduction of serum uric acid levels.
The European Medicines Agency (EMA) is now weighing approval of pegloticase in Europe. Approval was recommended by an expert advisory committee.
Adverse effects of pegloticase include anaphylaxis, infusion reactions, gout flares, and exacerbation of congestive heart failure. At present, substantial expense compromises its cost-effectiveness as an initial approach. The ACR guidelines do not recommend pegloticase as a first-line approach.
Benzbromarone is an effective uricosuric agent available on a restricted basis only outside the United States. However, it has been withdrawn because it causes fulminant hepatotoxicity.
Vitamin C, with its uricosuric effect, may reduce the serum concentration of uric acid. In one study, 500 mg/day for 2 months reduced uric acid by a mean of 0.5 mg/dL in patients without gout. However, gout patients appear to be less responsive to such a low dose of ascorbate. Vitamin C treatment should be avoided in patients with nephrolithiasis, urate nephropathy, or cystinuria.
In an open-label pilot study of 10 patients with refractory acute gout treated with the interleukin (IL)-1 antagonist anakinra, pain was substantially reduced in all patients within 2 days, without side effects. Clinical signs of inflammation had disappeared in 9 of 10 patients by day 3 of treatment.
The lipid-lowering drug fenofibrate, a fibric acid derivative, lowers serum uric acid levels while reducing very-low-density lipoprotein (VLDL), total cholesterol, and triglyceride levels. However, the creatinine level increases, and all effects are negated once the drug has been discontinued.
In 2010, an 8-week, single-blind, double-dummy, dose-ranging study showed that the selective IL-1β antibody canakinumab yielded fast and lasting relief of pain in patients with acute gouty arthritis flares refractory to treatment with NSAIDs or colchicine. However, in June 2011, canakinumab was denied approval by the FDA. (See FDA Panel Says No to Canakinumab for Gout Attacks.)
Because uric acid is a breakdown product of purine, high-purine foods should be either avoided or consumed only in moderation. Foods very high in purines include organ meats such as sweetbreads (eg, pancreas and thymus), smelt, sardines, and mussels. Foods moderately high in purines include anchovies, trout, haddock, scallops, mutton, veal, liver, bacon, salmon, kidneys, and turkey.
Purines are found in all protein foods. All sources of purines cannot and should not be eliminated.
Overall, purine restriction generally reduces serum uric acid levels by no more than 1 mg/mL, with modest impact, and diets with very low purine content are not palatable. Diet modifications alone are rarely able to lower uric acid levels sufficiently to prevent accumulation of urate, but they may help lessen the triggers of acute gout attacks.
Patients with gout should avoid excess ingestion of alcoholic drinks, particularly beer, because alcohol use elevates uric acid levels and thus can precipitate attacks of gout. Indeed, heavy drinkers are much more likely to have recurrent gout attacks, even with allopurinol therapy. Moderate wine intake is not associated with increased development of incident gout, but excesses of any form of alcohol in gout patients are associated with acute gout flares.
Patients should avoid sodas and other beverages or foods sweetened with high-fructose corn syrup. They should also limit their use of naturally sweet fruit juices, table sugar, and sweetened beverages and desserts, as well as table salt. Patients taking colchicine should avoid grapefruit and grapefruit juice.
Maintaining a high level of hydration with water (at least 8 glasses of liquids per day) may be helpful in avoiding attacks of gout. In view of the association of gout with atherosclerosis, the diagnosis of gout may afford a particularly good opportunity for the clinician to advise a low-cholesterol, low-fat diet if such a diet is otherwise appropriate for the patient. Although a diet of this type may help uric acid levels, such advice should be given primarily to help prevent atherosclerosis.
Weight reduction in patients who are obese can improve hyperuricemia. Ketosis-inducing diets (eg, fasting) should be avoided, however.
Because acute attacks are already sufficiently limiting of activity, additional limitations of activity are not necessary. The patient should avoid trauma to the affected joint; otherwise, they should be active.
Rheumatologists should be involved in the care of patients with difficult gout, as advised in the ACR guidelines. They can establish the diagnosis with arthrocentesis and synovial fluid analysis for crystals. They also are skilled in the management of this disorder, and consultation may be helpful for patients with an acute gout attack that does not respond to NSAIDs within 2 days or to colchicine within 1 day, as well as for patients with refractory hyperuricemia.
Rheumatology or orthopedic consultation is indicated for any patient with septic arthritis or for any patient in whom a septic arthritis cannot be ruled out.
After diagnosis and treatment of an acute gouty arthritis episode, the patient should return for a follow-up visit in approximately 1 month to be evaluated for therapy to lower serum uric acid levels.
If uric acid–lowering therapy is begun, patients should be seen within 2 weeks to ensure that no untoward toxicity has developed and then every 1-2 months while medication dosages are adjusted to achieve the target uric acid level of 5-6 mg/dL. Once this level is achieved and maintained, patients can be seen every 6-12 months and their serum uric acid monitored to help assess efficacy and adherence.
Acute inflammation due to gout can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or colchicine. NSAIDs are the most commonly used drugs in acute gout.
Over the long term, gout is treated by decreasing tissue stores of uric acid with the xanthine oxidase inhibitors allopurinol or febuxostat or with the uricosuric agent probenecid. Because agents that lower uric acid can precipitate attacks of gout, low-dose colchicine is typically used as prophylaxis (usually for 6 months) when such therapy is initiated.
If these measures, along with adjustment of contributing medications (eg, diuretics), do not result in appropriate reduction of serum uric acid levels, uric acid−lowering treatment is escalated as recommended in the 2012 American College of Rheumatology (ACR) gout guidelines.[101, 102]
Other agents lower uric acid levels as a secondary effect. The angiotensin-receptor blocker (ARB) losartan is moderately uricosuric at 50 mg/day. The lipid-lowering agent fenofibrate reduces serum urate 19% and increases clearance by 36% at 200 mg/day.
Clinical Context: Naproxen is used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of the enzyme cyclooxygenase, resulting in prostaglandin synthesis.
Clinical Context: Ketoprofen is used for the relief of mild-to-moderate pain and inflammation. Small doses are initially indicated in small and elderly patients and in those with renal or liver disease. Individual doses greater than 75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observe the patient for response.
Clinical Context: Diclofenac inhibits prostaglandin synthesis by decreasing activity of the enzyme cyclooxygenase, which in turn decreases formation of prostaglandin precursors.
Clinical Context: Indomethacin has been the NSAID traditionally used to treat acute inflammation in gout, though other NSAIDs are effective in this setting as well. Like all NSAIDs, indomethacin blocks cyclooxygenase and thereby reduces the generation of prostaglandins.
Clinical Context: Unlike most NSAIDs, which inhibit both COX-1 and COX-2, the selective COX-2 inhibitor celecoxib offers the possibility of relieving inflammation and pain, but with a lower risk of GI side effects. It has been suggested that COX-2 expression in monocytes is induced in response to urate crystals.
Several studies have found that selective COX-2 inhibitors are comparable to other NSAIDs for treating acute gouty arthritis. However, celecoxib requires particularly high doses to provide pain relief comparable to that provided by indomethacin in acute gout.
Selective COX-2 inhibitors may increase the risk of cardiac disease; 1 drug in this class, rofecoxib, has already been removed from the market for this reason. Celecoxib is currently under investigation for associated risk of accelerated cardiac disease. Curiously, the risk appears to be associated with ingestion of 200 mg twice daily, but not with ingestion of 400 mg once daily.
As a class, NSAIDs are the drugs most widely used to treat the pain and inflammation of acute gout attacks in patients who can safely take these medications. Although NSAID effects on pain tend to be patient-specific, naproxen and indomethacin are common choices. Nevertheless, the choice of an NSAID is a matter more of habit than of science. Use of concomitant gastric protection with misoprostol or consideration of a cyclooxygenase-2 (COX-2)–specific NSAID might be considered if the patient has gastrointestinal (GI) risk or is older than 51 years.
To control the attack as quickly and safely as possible (recalling that it takes 5 half-lives to reach steady state), consider using an NSAID with a short half-life (eg, ketoprofen, ibuprofen, or diclofenac). Use the maximum dosage of NSAID, and taper over approximately 10-14 days, depending on patient response.
Clinical Context: Colchicine inhibits microtubules and may thereby inhibit phagocytosis, neutrophil mobility, and chemotaxis. It also may inhibit generation of prostaglandins. The traditional approach of giving colchicine until vomiting or diarrhea appears is not appropriate; these are signs of toxicity. Instead, 1.2 mg is given orally, followed by 0.6 mg after 1 hour. Dose reduction is required for coingestion of interacting drugs (eg, P-gp or CYP3A4 inhibitors).
Clinical Context: Probenecid lowers tissue stores of uric acid by increasing net renal excretion of uric acid through inhibition of tubular reabsorption. Some authorities recommend alkalizing the urine when starting probenecid to reduce the risk for renal stone formation. Probenecid is indicated for long-term management of hyperuricemia associated with gout.
Uricosuric agents lower uric acid levels by inhibiting renal tubular reabsorption of uric acid, thereby increasing net renal excretion of uric acid. These agents increase the risk of renal stones, with about a 9-10% risk for probenecid. They should not be started during an attack of acute gouty arthritis. The goal of therapy is to lower serum uric acid to approximately 5-6 mg/dL without causing renal stones.
Clinical Context: Oral prednisone can be given to abort an attack of gout. By reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity, this agent may decrease inflammation. Steroid dose packs that clearly label the dose to be taken each day can be convenient for some patients.
Clinical Context: Intra-articular use is considered by some as the treatment of choice for pseudogout and for acute gouty attacks in patients who cannot be given NSAIDs, colchicine, or high-dose systemic corticosteroids.
Clinical Context: Corticotropin stimulates endogenous production of corticosteroids and directly and rapidly acts on peripheral leukocyte activation. It decreases inflammation by suppressing migration of PMNs and reversing increased capillary permeability.
Corticosteroids are potent and effective anti-inflammatory drugs that can be used to treat acute gout in patients who cannot tolerate NSAIDs or colchicine. They can be given orally, intramuscularly (IM), intravenously (IV), or intra-articularly. Adrenocorticotropic hormone (ACTH) also acts in gout, in part by inducing adrenal steroids. No intrinsic advantage to treating with IV corticosteroids exists unless the patient cannot take oral medications.
The short-burst corticosteroid regimen used to treat an acute flare of gout is generally well tolerated. Nevertheless, patients may experience the adverse effects seen with long-term steroid use.
In patients with only 1 or 2 involved joints, intra-articular corticosteroids are a safe and effective treatment option, once infection has been excluded. Water-soluble steroids (eg, dexamethasone) are teleologically inappropriate for use as a depot steroid treatment.
Clinical Context: Allopurinol reduces production of uric acid, thereby allowing the body to dispose of excess uric acid stores. It is the most effective therapy for lowering serum uric acid. Most patients achieve the target uric acid level of 5 mg/dL at a dosage of 300-400 mg/day. A lower dosage is used if renal insufficiency is present.
Clinical Context: Febuxostat is a potential alternative to allopurinol.[126, 127] Like allopurinol, febuxostat is a xanthine oxidase inhibitor that prevents uric acid production and lowers elevated serum uric acid levels. Unlike allopurinol, it is a thiazolecarboxylic acid derivative, not a purine base analogue. Febuxostat physically blocks the channel to the molybdenum-pterin active site of xanthine oxidase and is metabolized by liver oxidation and glucuronidation.
Common adverse events include upper respiratory tract infections, arthralgias, diarrhea, headache, and liver function abnormalities. Atrioventricular block or atrial fibrillation and cholecystitis also have been reported. As with other uricosuric agents, initiation of febuxostat may precipitate gouty attacks.[42, 141]
Inhibition of xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine, reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines. This results in the reduction of the tissue stores of uric acid. The goal of therapy is to lower the serum uric acid level to approximately 5-6 mg/dL. These agents should not be started during an attack of acute gouty arthritis without adequate control of the gouty inflammation.
Clinical Context: Pegloticase is a pegylated uric acid–specific enzyme that is a polyethylene glycol conjugate of recombinant uricase. It achieves its therapeutic effect by catalyzing oxidation of uric acid to allantoin, thereby lowering serum uric acid levels. Pegloticase is indicated for gout in adults refractory to conventional therapy (ie, when serum uric acid levels have not normalized and either signs and symptoms are inadequately controlled with xanthine oxidase inhibitors or uricosurics at maximum appropriate doses or xanthine oxidase inhibitors are contraindicated).
The dosage is 8 mg IV every 2 weeks. Complications include anaphylaxis, infusion reactions, flare of gout attacks in 63-86% of patients and nephrolithiasis in 13-14%, along with arthralgias, nausea, dyspepsia, muscle spasms, pyrexia, back pain, diarrhea, and rash.[142, 143] Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a contraindication.
Uricase facilitates conversion of urate to allantoin. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys. Thus, hyperuricemia is reduced, with little risk of acute kidney injury.
Clinical Context: Cosyntropin is an adrenocorticotropic hormone (corticotropin) that stimulates the production and release of endogenous steroids. It is an effective treatment of acute crystal-induced arthritis in postoperative patients and in other patients who cannot take oral medications.
Corticotropic hormones stimulate synthesis and release of corticosteroid hormones. They are principally used in diagnostic tests to differentiate primary adrenal insufficiency from secondary adrenal insufficiency. They have limited therapeutic value in conditions responsive to corticosteroid therapy, for which a corticosteroid should be the drug of choice.