ESSENTIALS OF DIAGNOSIS
Acute, monoarticular arthritis, often of the first MTP joint; recurrence is common.
Polyarticular involvement more common in patients with longstanding disease.
Identification of urate crystals in joint fluid or tophi is diagnostic.
Dramatic therapeutic response to NSAIDs.
With chronicity, urate deposits in subcutaneous tissue, bone, cartilage, joints, and other tissues.
Gout is a metabolic disease of a heterogeneous nature, often familial, associated with abnormal deposits of urate in tissues and characterized initially by a recurring acute arthritis, usually monoarticular, and later by chronic deforming arthritis. Urate deposition occurs when serum uric acid is supersaturated (ie, at levels greater than 6.8 mg/dL [404.5 mcmol/L]). Hyperuricemia is due to overproduction or underexcretion of uric acid—sometimes both. The disease is especially common in Pacific islanders, eg, Filipinos and Samoans. Primary gout has a heritable component, and genome-wide surveys have linked risk of gout to several genes whose products regulate urate handling by the kidney. Secondary gout, which may have a heritable component, is related to acquired causes of hyperuricemia, eg, medication use (especially diuretics, low-dose aspirin, cyclosporine, and niacin), myeloproliferative disorders, plasma cell myeloma, hemoglobinopathies, chronic kidney disease, hypothyroidism, psoriasis, sarcoidosis, and lead poisoning (Table 20–4). Alcohol ingestion promotes hyperuricemia by increasing urate production and decreasing the renal excretion of uric acid. Finally, hospitalized patients frequently suffer attacks of gout because of changes in diet, fluid intake, or medications that lead either to rapid reductions or increases in the serum urate level.
Table 20–4.Origin of hyperuricemia. ||Download (.pdf) Table 20–4. Origin of hyperuricemia.
Increased production of purine
Specific enzyme defects (eg, Lesch-Nyhan syndrome, glycogen storage diseases)
Decreased renal clearance of uric acid (idiopathic)
Increased catabolism and turnover of purine
Carcinoma and sarcoma (disseminated)
Chronic hemolytic anemias
Decreased renal clearance of uric acid
Chronic kidney disease
Drug-induced (eg, thiazides, low-dose aspirin, cyclosporine, niacin)
Hyperketoacidemia (eg, diabetic ketoacidosis, starvation)
Functional impairment of tubular transport
Diabetes insipidus (vasopressin-resistant)
About 90% of patients with primary gout are men, usually over 30 years of age. In women, the onset is typically postmenopausal. The characteristic lesion is the tophus, a nodular deposit of monosodium urate monohydrate crystals with an associated foreign body reaction. Tophi are found in cartilage, subcutaneous and periarticular tissues, tendon, bone, the kidneys, and elsewhere. Urates have been demonstrated in the synovial tissues (and fluid) during acute arthritis; indeed, the acute inflammation of gout is believed to be initiated by the ingestion of uncoated urate crystals by monocytes and synoviocytes. Once inside the cells, the gout crystals are processed through Toll-like receptors and activate NALP-3 inflammasomes that in turn release a variety of chemotactic agents and cytokines capable of mediating inflammation. The precise relationship of hyperuricemia to gouty arthritis is still obscure, since chronic hyperuricemia is found in people who never develop gout or uric acid stones. Rapid fluctuations in serum urate levels, either increasing or decreasing, are important factors in precipitating acute gout. The mechanism of the late, chronic stage of gouty arthritis is better understood. This is characterized pathologically by tophaceous invasion of the articular and periarticular tissues, with structural derangement and secondary degeneration (osteoarthritis).
Uric acid kidney stones are present in 5–10% of patients with gouty arthritis. Hyperuricemia correlates highly with the likelihood of developing stones, with the risk of stone formation reaching 50% in patients with a serum urate level greater than 13 mg/dL. Chronic urate nephropathy is caused by the deposition of monosodium urate crystals in the renal medulla and pyramids. Although progressive chronic kidney disease occurs in a substantial percentage of patients with chronic gout, the role of hyperuricemia in causing this outcome is controversial, because many patients with gout have numerous confounding risk factors for chronic kidney disease (eg, hypertension, NSAID use, alcohol use, lead exposure, and other risk factors for vascular disease).
Acute gouty arthritis is sudden in onset and frequently nocturnal. It may develop without apparent precipitating cause or may follow rapid increases or decreases in serum urate levels. Common precipitants are alcohol excess (particularly beer), changes in medications that affect urate metabolism, and, in the hospitalized patient, fasting before medical procedures. The MTP joint of the great toe is the most susceptible joint (“podagra”), although others, especially those of the feet, ankles, and knees, are commonly affected (Figure 20–2). Gouty attacks may develop in periarticular soft tissues such as the arch of the foot. Hips and shoulders are rarely affected. More than one joint may occasionally be affected during the same attack; in such cases, the distribution of the arthritis is usually asymmetric. As the attack progresses, the pain becomes intense. The involved joints are swollen and exquisitely tender and the overlying skin tense, warm, and dusky red. Fever is common and may reach 39°C. Local desquamation and pruritus during recovery from the acute arthritis are characteristic of gout but are not always present. Tophi may be found in the pinna of the ears, feet, olecranon and prepatellar bursae, and hands. They usually develop years after the initial attack of gout.
Typical inflammatory changes of gout at first MTP joint (podagra). (Used, with permission, from Richard P. Usatine, MD, in Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H. The Color Atlas of Family Medicine, 2nd ed. McGraw-Hill, 2013.)
Asymptomatic periods of months or years commonly follow the initial acute attack. After years of recurrent severe monoarthritis attacks of the lower extremities and untreated hyperuricemia, gout can evolve into a chronic, deforming polyarthritis of upper and lower extremities that mimics rheumatoid arthritis.
Chronic lead intoxication may result in attacks of gouty arthritis (saturnine gout).
Although serial measurements of the serum uric acid detect hyperuricemia in 95% of patients, a single uric acid determination during an acute flare of gout is normal in up to 25% of cases. A normal serum uric acid level, therefore, does not exclude gout, especially in patients taking urate-lowering drugs. During an acute attack, the peripheral blood white cell count is frequently elevated. Identification of sodium urate crystals in joint fluid or material aspirated from a tophus establishes the diagnosis. The crystals, which may be extracellular or found within neutrophils, are needle-like and negatively birefringent when examined by polarized light microscopy.
Early in the disease, radiographs show no changes. Later, punched-out erosions with an overhanging rim of cortical bone (“rat bite”) develop (eFigure 20–5). When these are adjacent to a soft tissue tophus, they are diagnostic of gout. Ultrasonography can be used to confirm the diagnosis of gout. Tophi that are too small to appreciate on physical examination and smaller deposits of urate crystals can frequently be imaged by ultrasonography.
Gouty erosion at the first metatarsal phalangeal joint of the right foot. (Used, with permission, from Nicole Richman, MD.)
Acute gout is often confused with cellulitis. Bacteriologic studies usually exclude acute pyogenic arthritis but rarely, acute gout and pyogenic arthritis can co-exist. Pseudogout is distinguished by the identification of calcium pyrophosphate crystals (positive birefringence) in the joint fluid, usually normal serum uric acid, and the radiographic appearance of chondrocalcinosis.
Chronic tophaceous arthritis may resemble chronic rheumatoid arthritis; gout is suggested by an earlier history of monoarthritis and is established by the demonstration of urate crystals in a suspected tophus. Likewise, hips and shoulders are generally spared in tophaceous gout. Biopsy may be necessary to distinguish tophi from rheumatoid nodules. A radiographic appearance similar to that of gout may be found in rheumatoid arthritis, sarcoidosis, plasma cell myeloma, hyperparathyroidism, or Hand-Schüller-Christian disease.
A. Asymptomatic Hyperuricemia
As a general rule, uric acid–lowering drugs should not be instituted until acute gout, renal calculi, or tophi become apparent. Epidemiologic studies suggest that treating asymptomatic hyperuricemia slows the progression of chronic kidney disease, but there are no definitive studies on this point.
Treatment of the acute attack focuses on reducing inflammation, not lowering serum uric acid. Indeed, sudden reduction of serum uric acid often precipitates further episodes of gouty arthritis.
Oral NSAIDs in full dose (eg, naproxen 500 mg twice daily or indomethacin 25–50 mg every 8 hours; see Table 5–5) are effective treatment for acute gout and should be continued until the symptoms have resolved (usually 5–10 days). Contraindications include active peptic ulcer disease, impaired kidney function, and a history of allergic reaction to NSAIDs.
Oral colchicine is an appropriate treatment option for acute gout, provided the duration of the attack is less than 36 hours. For acute gout, colchicine should be administered orally as follows: a loading dose of 1.2 mg followed by a dose of 0.6 mg 1 hour later for a total dose of 1.8 mg the first day; thereafter 0.6 mg twice per day is used until resolution. Patients who are already taking prophylactic doses of colchicine and have an acute flare of gout may receive the full loading dose (1.2 mg) followed by 0.6 mg 1 hour later (before resuming the usual 0.6 mg once or twice daily) provided they have not received this regimen within the preceding 14 days (in which case, NSAIDs or corticosteroids should be used). Colchicine dose should be reduced or avoided altogether if there is kidney or liver impairment. The use of oral colchicine during the intercritical period to prevent gout attacks is discussed below.
Corticosteroids often give dramatic symptomatic relief in acute episodes of gout and will control most attacks. They are most useful in patients with contraindications to the use of NSAIDs. Corticosteroids may be given intravenously (eg, methylprednisolone, 40 mg/day) or orally (eg, prednisone, 40–60 mg/day). Corticosteroids can be given at the suggested dose for 5–10 days and then simply discontinued or given at the suggested initial dose for 2–5 days and then tapered over 7–10 days. If the patient’s gout is monoarticular or oligoarticular, intra-articular administration of the corticosteroid (eg, triamcinolone, 10–40 mg depending on the size of the joint) is very effective. Because gouty and septic arthritis can coexist, albeit rarely, joint aspiration and Gram stain with culture of synovial fluid should be performed when intra-articular corticosteroids are given.
4. Interleukin-1 inhibitors
Anakinra (an interleukin-1 receptor antagonist) and canakinumab (a monoclonal antibody against interleukin-1 beta) have efficacy for the management of acute gout, but these drugs have not been approved by the FDA for this indication.
C. Management Between Attacks
Treatment during symptom-free periods is intended to minimize urate deposition in tissues and to reduce the frequency and severity of recurrences. Potentially reversible causes of hyperuricemia are a high-purine diet, obesity, alcohol consumption, and use of certain medications (Table 20–4). Patients with a single episode of gout who have normal kidney function and are able to lose weight and stop drinking alcohol are at low risk for another attack and may not require long-term medical therapy. In contrast, individuals with mild chronic kidney disease or with a history of multiple attacks of gout are likely to benefit from pharmacologic treatment. In general, the higher the uric acid level and the more frequent the attacks, the more likely that long-term medical therapy will be beneficial. All patients with tophaceous gout should receive urate-lowering therapy.
Excessive alcohol consumption can precipitate attacks and should be avoided. Beer consumption appears to confer a higher risk of gout than does whiskey or wine. Although dietary purines usually contribute only 1 mg/dL to the serum uric acid level, moderation in eating foods with high purine content is advisable. Patients should avoid organ meats and beverages sweetened with high fructose corn syrup. A high liquid intake and, more importantly, a daily urinary output of 2 L or more will aid urate excretion and minimize urate precipitation in the urinary tract.
2. Avoidance of hyperuricemic medications
Thiazide and loop diuretics inhibit renal excretion of uric acid and, if possible, should be avoided in patients with gout. Similarly, niacin can raise serum uric acid levels and should be discontinued if there are therapeutic alternatives. Low doses of aspirin also aggravate hyperuricemia.
Colchicine can be used when urate-lowering therapy is started to suppress attacks precipitated by abrupt changes in the serum uric acid level. The usual dose is 0.6 mg orally either once or twice a day. Colchicine is renally cleared. Patients who have coexisting moderate chronic kidney disease should take colchicine only once a day or once every other day in order to avoid peripheral neuromyopathy and other complications of colchicine toxicity.
4. Reduction of serum uric acid
Indications for urate-lowering therapy in a person with gout include frequent acute arthritis (two or more episodes per year), tophaceous deposits, or chronic kidney disease (stage 2 or worse). The American College of Rheumatology guidelines recommend a treat-to-target approach for urate-lowering therapy. The minimum goal of urate-lowering therapy is a serum uric acid at or below 6 mg/dL or 357 mcmol/L (ie, below the level at which serum is supersaturated with uric acid, thereby allowing urate crystals to solubilize); in some cases, control of gout may require lowering serum uric acid to less than 5 mg/dL or 297.4 mcmol/L. Lowering serum uric acid levels is not of benefit for the treatment of an acute gout flare.
Three classes of agents may be used to lower the serum uric acid—xanthine oxidase inhibitors (allopurinol or febuxostat), uricosuric agents, and uricase (pegloticase).
A. XANTHINE OXIDASE INHIBITORS
Allopurinol and febuxostat are the preferred first-line agents for lowering urate. They reduce plasma uric acid levels by blocking the final enzymatic steps in the production of uric acid. Allopurinol and febuxostat should not be used together, but they can be tried sequentially if the initial agent fails to lower serum uric acid to the target level or if it is not tolerated. The most frequent adverse effect with either medication is the precipitation of an acute gouty attack; thus, patients generally should be receiving prophylactic doses of colchicine.
Hypersensitivity to allopurinol occurs in 2% of cases, usually within the first few months of therapy, and it can be life-threatening. The most common initial sign of hypersensitivity is a pruritic rash that may progress to toxic epidermal necrolysis, particularly if allopurinol is continued; vasculitis and hepatitis are other manifestations. Patients should be instructed to stop allopurinol immediately if a rash develops. Chronic kidney disease and concomitant thiazide therapy are risk factors. There is a strong association between allopurinol hypersensitivity and HLA-B*5801, which is a prevalent allele in certain East Asian populations. Current recommendations are to screen for HLA-B*5801 prior to initiating allopurinol in all persons of Han Chinese and Thai descent and in Koreans with stage 3 or worse chronic kidney disease.
The initial daily dose of allopurinol is 100 mg/day orally (50 mg/day for those with stage 4 or worse chronic kidney disease); the dose of allopurinol should be titrated upward every 2–5 weeks to achieve the target serum uric acid level. A typical dose of allopurinol is 300 mg, but most patients require greater than 300 mg daily to achieve the target uric acid level. The maximum daily dose is 800 mg.
Allopurinol interacts with other drugs. The combined use of allopurinol and ampicillin causes a drug rash in 20% of patients. Allopurinol can increase the half-life of probenecid, while probenecid increases the excretion of allopurinol. Thus, a patient taking both drugs may need to use slightly higher than usual doses of allopurinol and lower doses of probenecid.
Febuxostat can also rarely cause hypersensitivity reactions, and those with previous hypersensitivity to allopurinol appear to have slightly higher risk. It can be given without dose adjustment to patients with mild to moderate kidney disease. However, abnormal liver tests may develop in 2–3% of patients taking febuxostat. In addition, febuxostat is associated with a higher rate of fatal and nonfatal cardiovascular events than allopurinol. The FDA advises that febuxostat be reserved for patients in whom allopurinol is ineffective or contraindicated, and there is an FDA boxed warning regarding febuxostat’s higher risk of death. The initial dose of febuxostat is 40 mg/day orally. If the target serum uric acid is not reached in 4 weeks, the dose of febuxostat can be increased to 80 mg/day and then to the maximum dose of 120 mg/day.
Uricosuric drugs lower serum uric acid levels by blocking the tubular reabsorption of filtered urate, thereby increasing uric acid excretion by the kidney. Probenecid (0.5 g/day orally) and lesinurad (200 mg/day orally) are the uricosurics of choice in the United States, and are typically reserved for patients who cannot achieve a serum uric acid of less than or equal to 6.0 mg/dL with allopurinol or febuxostat alone. Lesinurad carries an FDA black box warning that acute kidney injury can occur with treatment, especially when lesinurad is used without a xanthine oxidase inhibitor; it is contraindicated in patients with a creatinine clearance of less than 45 mL/min. Probenecid can be added to a xanthine oxidase inhibitor or used as monotherapy. Probenecid should not be used in patients with a creatinine clearance of less than 50 mL/min due to limited efficacy; contraindications include a history of nephrolithiasis (uric acid or calcium stones) and evidence of high uric acid excretion (ie, greater than 800 mg of uric acid in a 24-hour urine collection). To reduce the development of uric acid stones (which occur in up to 11%), patients should be advised to increase their fluid intake and clinicians should consider prescribing an alkalinizing agent (eg, potassium citrate, 30–80 mEq/day orally) to maintain a urinary pH > 6.0.
Nonprimate mammals do not develop gout because they have an enzyme—uricase—that ensures that purine metabolism does not end with urate but the much more soluble metabolite, allantoin. In humans, the gene for uricase has been inactivated by a missense mutation, so purine metabolism dead ends with the production of uric acid. Pegloticase, a recombinant uricase that must be administered intravenously (8 mg every 2 weeks), is indicated for the rare patient with refractory chronic tophaceous gout. Pegloticase carries an FDA black box warning, which advises administering the drug only in health care settings and by health care professionals prepared to manage anaphylactic and other serious infusion reactions.
D. Chronic Tophaceous Arthritis
With rigorous medical compliance, allopurinol, febuxostat, or pegloticase shrinks tophi and in time can lead to their disappearance. Resorption of extensive tophi requires maintaining a serum uric acid below 6 mg/dL. Surgical excision of large tophi offers mechanical improvement in selected deformities.
E. Gout in the Transplant Patient
Hyperuricemia and gout commonly develop in many transplant patients because they have decreased kidney function and require drugs that inhibit uric acid excretion (especially cyclosporine and diuretics). Treating acute gout in these patients is challenging. Often the best approach for monoarticular gout—after excluding infection—is injecting corticosteroids into the joint. For polyarticular gout, increasing the dose of systemic corticosteroid may be the only alternative. Since transplant patients often have multiple attacks of gout, long-term relief requires lowering the serum uric acid with allopurinol or febuxostat. (Kidney dysfunction seen in many transplant patients makes uricosuric agents ineffective.) Both allopurinol and febuxostat inhibit the metabolism of azathioprine and should be avoided in patients who take azathioprine.
Without treatment, the acute attack may last from a few days to several weeks. The intervals between acute attacks vary up to years, but the asymptomatic periods often become shorter if the disease progresses. Chronic gouty arthritis occurs after repeated attacks of acute gout, but only after inadequate treatment. The younger the patient at the onset of disease, the greater the tendency to a progressive course. Destructive arthropathy is rarely seen in patients whose first attack is after age 50.
Patients with gout have an increased incidence of hypertension, kidney disease, diabetes mellitus, hyperlipidemia, and cardiovascular disease.
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