Gouty Arthritis

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 > 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 also 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, CKD, hypothyroidism, psoriasis, sarcoidosis, and lead poisoning.

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.

About 90% of patients with primary gout are men, usually > 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; the acute inflammation of gout is believed to be initiated by the ingestion of uncoated urate crystals by monocytes and synoviocytes.

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 > 13 mg/dL.

Chronic urate nephropathy is caused by the deposition of monosodium urate crystals in the renal medulla and pyramids.

Although progressive CKD 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 CKD (eg, hypertension, NSAID use, alcohol use, lead exposure, and other risk factors for vascular disease).

In a 2020 randomized, controlled trial in patients with CKD and a high risk of its progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR compared with placebo.

Primary HyperuricemiaIncreased Production of Purine– Idiopathic
– Specific Enzyme Defects (eg, Lesch-Nyhan Syndrome, Glycogen Storage Diseases)
Decreased Renal Clearance of Uric Acid– Idiopathic
Secondary HyperuricemiaIncreased Catabolism and Turnover of Purine– Myeloproliferative Disorders
– Carcinoma and Sarcoma (Disseminated)
– Chronic Hemolytic Anemias
– Cytotoxic Drugs
– Psoriasis
– Down Syndrome
Decreased Renal Clearance of Uric Acid– CKD
– Drug-Induced (eg, Thiazides, Low-Dose Aspirin, Cyclosporine, Niacin)
– Ketoacidemia (eg, Diabetic Ketoacidosis, Starvation)
– Hypothyroidism
– Preeclampsia
– Functional Impairment of Tubular Transport
– Hyperlacticacidemia
– Diabetes Insipidus (Vasopressin-Resistant)
– Bartter Syndrome
– Sarcoidosis
– Lead Poisoning
Origin of Hyperuricemia

Diagnostic Essentials

  • 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.

Clinical Findings

Symptoms and Signs

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. 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 (102°F).

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.

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 cause attacks of gouty arthritis (saturnine gout).

Laboratory Findings

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 (neutrophilia) 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. When these are adjacent to a soft tissue tophus, they are diagnostic of gout.

Ultrasonography and dual-energy CT 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 detected by these imaging modalities.

Differential Diagnosis

Acute gout is often confused with cellulitis.

Bacteriologic studies usually exclude acute pyogenic arthritis but rarely, acute gout and pyogenic arthritis can coexist.

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.


Asymptomatic Hyperuricemia

As a general rule, uric acid–lowering drugs should not be instituted until acute gout, renal calculi, or tophi become apparent.

Acute Attack

Treatment of the acute attack focuses on reducing inflammation, not lowering serum uric acid.


Oral NSAIDs in full dose (eg, naproxen 500 mg twice daily or indomethacin 25–50 mg every 8 hours; see Table) 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 < 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 bid 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 significant kidney or liver impairment.

Using 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 especially useful in patients with contraindications to NSAIDs.

Corticosteroids may be given IV (eg, methylprednisolone, 40 mg/day) or po (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.

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.

Anakinra can be used in hospitalized patients with acute gout in whom comorbidities prevent the use of NSAIDs, colchicine, or glucocorticoids.

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.

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, patients with mild CKD or a history of multiple attacks of gout will likely benefit from pharmacologic treatment. In general, the higher the uric acid level and frequency of 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 kidney.

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 Prophylaxis

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 po either od or bid.

Colchicine is renally cleared. Patients who have coexisting moderate CKD should take colchicine only once a day or once every other day to avoid peripheral neuromyopathy and other complications of colchicine toxicity.

In patients with concomitant CAD, chronic colchicine use can reduce major cardiovascular events.

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 CKD (stage 2 or worse).

The American College of Rheumatology guidelines recommend a treat-to-target approach for urate-lowering therapy. In some cases, particularly in patients with tophi or frequent attacks, control of gout may require lowering serum uric acid to < 5 mg/dL or 297.4 mcmol/L.

Lowering serum uric acid levels does not benefit an acute gout flare.

Three classes of agents may lower the serum uric acid—xanthine oxidase inhibitors (allopurinol or febuxostat), uricosuric agents, and uricase (pegloticase).

Xanthine Oxidase Inhibitors

Allopurinol and febuxostat are the preferred first-line agents for lowering urate and have similar efficacy. 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. CKD and concomitant thiazide therapy are risk factors. There is a strong association between allopurinol hypersensitivity and HLA-B58:01, which is a prevalent allele in certain populations. It is recommended to screen for HLA-B58:01 before initiating allopurinol in all persons of Chinese, Thai, and Korean descent, as well as in African-American persons.

The initial daily dose of allopurinol is 100 mg/day po (50 mg/day for those with stage 4 or worse CKD); 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. Despite initial concern that febuxostat was associated with more cardiovascular events than allopurinol, a large, randomized, controlled trial in 2020 showed that the two drugs have similar cardiovascular safety. The initial dose of febuxostat is 40 mg/day po. 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

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) is the uricosuric available in the United States; lesinurad (200 mg/day orally) is also available in some countries. These drugs 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. Probenecid should not be used in patients with a creatinine clearance of < 50 mL/minute due to limited efficacy; contraindications include a history of nephrolithiasis (uric acid or calcium stones) and evidence of high uric acid excretion (ie, > 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.


Pegloticase, a recombinant uricase that must be administered IV (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.

Chronic Tophaceous Arthritis

With rigorous drug adherence, allopurinol, febuxostat, and pegloticase shrink tophi and in time can lead to their disappearance. Resorption of extensive tophi requires maintaining a serum uric acid < 6 mg/dL.

Surgical excision of large tophi offers mechanical improvement in selected deformities.

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 have a more progressive course. In patients whose first attack is after age 50 destructive arthropathy is rarely seen.

Calcium Pyrophosphate Deposition

Calcium pyrophosphate deposition (CPPD) in fibrocartilage and hyaline cartilage (chondrocalcinosis) can cause an acute crystal-induced arthritis (“pseudogout”), a degenerative arthropathy, and a chronic inflammatory polyarthritis (“pseudorheumatoid arthritis”).

CPPD also can be an asymptomatic condition detected as incidental chondrocalcinosis on radiographs.

The prevalence of CPPD increases with age.

Hyperparathyroidism, familial hypocalciuric hypercalcemia, hemochromatosis, and hypomagnesemia confer risk of CPPD, but most cases have no associated condition.

Pseudogout is most often seen in persons aged 60 or older, is characterized by acute, recurrent and rarely chronic arthritis involving large joints (most commonly the knees and the wrists) and is almost always accompanied by radiographic chondrocalcinosis of the affected joints.

The crowned dens syndrome, caused by pseudogout of the atlantoaxial junction associated with “crown-like” calcifications around the dens, manifests with severe neck pain, rigidity, and high fever that can mimic meningitis or polymyalgia rheumatica.

Pseudogout, like gout, frequently develops 24–48 hours after major surgery.

Identification of weakly positively birefringent calcium pyrophosphate crystals in joint aspirates is diagnostic.

NSAIDs are helpful in the treatment of acute episodes.

Colchicine, 0.6 mg po od or bid, is more effective for prophylaxis than for acute attacks.

Aspiration of the inflamed joint and intra-articular injection of triamcinolone, 10–40 mg, depending on the size of the joint, are also of value in resistant cases.

In patients with contraindications to other therapies, the use of anakinra, an IL-1 inhibitor, is an option.

The degenerative arthropathy associated with CPPD can involve joints not usually affected by osteoarthritis (eg, glenohumeral joint, wrist, patellofemoral compartment of the knee).

The “pseudorheumatoid arthritis” of CPPD affects the metacarpophalangeal joints and wrists.

In both conditions, radiographs demonstrate chondrocalcinosis and degenerative changes such as asymmetric joint space narrowing and osteophyte formation.

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