Gout is a clinical syndrome resulting from the deposition of monosodium urate monohydrate crystals in tissue from supersaturated extracellular fluid. Tissue deposition of urate leads to the accompanying inflammation and subsequent degeneration of joints and soft tissues.

Available national data suggests that the prevalence of gout is approximately 8.4 cases/1000 persons of all races and both sexes. This corresponds to 2.1 million persons with gout: 1.56 million men and 550,000 women. However these estimates are based on self-reported data as opposed to data derived from physician evaluation.¹

Although hyperuricemia is not a requirement for the diagnosis of gout and its presence in a patient with arthritis does not necessarily imply that diagnosis, the risk of gout increases with the degree and the duration of hyperuricemia.

In males, uric acid production is increased after puberty and in females after the menopause. The predominant cause of hyperuricemia in most patients is under secretion of urate by the kidneys (Table 1).

Only about 10% of patients with gout are over producers of uric acid (Table 2).

The solubility of monosodium urate is a direct function of temperature. At 37°C the maximum solubility of urate in physiologic saline is 6.8 mg per 100 ml, but at 30°C it is only 4.5 mg per 100 ml.² If serum uric acid concentration is increased for a sustained period of time, monosodium urate will come out of solution to form crystals. Micro tophi will subsequently form particularly in the cooler parts of the body such as distal extremities and ears. Sustained hyperuricemia is a risk factor for acute gouty arthritis, tophaceous gout and uric acid nephrolithiasis. However, most patients with hyperuricemia will never have an attack of gout, and no treatment is required although it is prudent to determine the cause of hyperuricemia and correct them if possible.

The description of gout by the English physician Thomas Sydenham holds as true today as it did in the 17th century:

"The victim goes to bed and sleeps in good health. About two o' clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. This pain is like that of dislocation…. Then follow chills and shivers and a little fever. The pain, which was at first moderate, becomes more intense…. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room…."³

Typically, the first attack of acute gout occurs after 15-20 years of asymptomatic hyperuricemia. In males, attacks begin between the ages of 35 to 50 years and in females, attacks begin 15-20 years after menopause. Attacks are typically monoarticular and have a predilection for the lower extremity. Joints commonly affected are the 1^st metatarsophalageal joint (podagra), midfoot, ankle and knee. As time progresses, attacks begin to involve upper extremity and the joints involved are the wrist, the elbow and the small joints of the hand. Upper extremity and polyarticular involvement are more characteristic in the elderly. The typical attack includes the abrupt appearance of redness, swelling, severe pain and disability over several hours which usually resolve over few days to 2 weeks even in untreated patients.⁴ Desquamation of skin over the affected joint may occur following resolution of the acute attack.

An intercritical (between attacks) stage is then entered. These are asymptomatic phases of variable duration that if left untreated will lead to more acute attacks interspersed by shorter asymptomatic phases.

Anywhere between 15-20 years following the initial attack, tophi may be detected if the hyperuricemia is left untreated. Tophi can occur anywhere in the body but are usually seen over the fingers and toes, forearms or in a chronically swollen olecrenon bursa.

The diagnosis can be made by probing with a needle and finding negatively birefringent needle shaped crystals under polarized microscopy. On plain radiographs a tophus will appear as a periarticular soft tissue density with a rim of calcified bone.

Tophaceous gout and chronic arthropathy may co-exist and the clinical picture maybe confused with other chronic polyarthropathies like Rheumatoid Arthritis with nodules. However, the joint involvement in gout will be asymmetric and urate crystals can be identified in the nodules (Figure 1).

Arthrocentesis for polarized microscopy will usually reveal urate crystals and is the best way to confirm the diagnosis. Serum urate levels cannot be used to confirm or exclude gout. Indeed, levels of urate can be normal during an acute attack. Also, gout and infection can co-exist in the same joint and the presence of typical urate crystals does not exclude the possibility of infection.⁴ Even the smallest amount of fluid obtained from the hub of a needle can be examined for crystals. Urate crystals are bright (strongly birefringent), needle shaped and yellow (negatively birefringent) when lying parallel to the axis of the red compensator in a polarising microscope. Even if a polarising microscope is not available, the finding of a needle shaped crystal within a white blood cell should suggest gout (Table 3).³

Radiographs are generally not useful in the diagnosis of acute gouty arthritis. Classic radiographic features of chronic gout are (Figure 2):

• Tophi
• Normal mineralization
• Joint space preservation
• Asymmetric polyarticular distribution
• "Overhanging" edge of cortex
• "Punched out erosion" of bone with sclerotic borders⁵

Goals of treatment are to:

• Abort acute attacks
• Prevent future attacks
• Treat chronic hyperuricemia and tophaceous gout⁴

For aborting an acute attack, treatment options include (Figure 3):

• NSAIDs
• Oral colchicine
• Intra-articular corticosteroids
• Systemic corticosteroids
• Analgesia alone

NSAIDs are a reasonable option for treating an acute attack. Indomethacin, Ibuprofen, Naproxen, Sulindac, Piroxicam and Ketoprofen are all effective in the treatment of acute gout. COX-2 inhibitors have no proven benefits in acute gout and still have renal and hepatic side effects (Table 4).

Risk factors for NSAID use include CrCl of <50ml/min, poorly compensated congestive heart failure, history of or active peptic ulcer disease, anticoagulant therapy and hepatic dysfunction.

Colchicine acts primarily by inhibiting phagocytosis of urate crystals by neutrophils in patients with normal renal function. The usual dose is 0.6mg orally every hour until a maximum of 4.8 mg is given or until gastrointestinal symptoms (nausea, vomiting, diarrhea) develop or until the symptoms of gout resolve. If serum creatinine is >1.6 mg/dl, the dose of colchicine should not exceed 0.6 mg/day.

IV colchinine has the propensity to cause severe bone marrow toxicity, tissue necrosis from extravasation, renal failure, neuromuscular complications and even death due to multiple organ failure. It is generally not recommended.⁴

Corticosteroids
Intra-articular steroids provide rapid relief of symptoms once infection has been ruled out. Intra-articular injections cause minimal side effects and are ideal for monoarticular arthritis affecting the knee, elbow or wrist. Depomedrol 80mg into the knee or 40mg into an ankle or wrist are typically used doses and can be safely injected even in patients on anticoagulants.⁴

Systemic steroids are used when inflammation is polyarticular or if the joints are difficult to inject, such as in the midfoot. Prednisone 35 mg/day or equivalent is tapered over a week.

In the occasional patient with documented gouty arthritis, strong contraindications may exist to all of the above medications. In such situations, analgesia with narcotics alone may be used.⁶

Colchicine can be used either alone or in combination with uric acid lowering drugs to prevent recurrent attacks (Figure 4). Dosages between 0.6 mg and 1.5 mg have been used. If the creatinine is >1.6 mg/dl, the dose of colchicine should not exceed 0.6 mg in a day. Chronic colchicine therapy causes reversible proximal myopathy, axonal neuropathy, bone marrow suppression, nausea, vomiting and diarrhea. Adverse side effects are more likely to occur in the patient with hepatic or renal insufficiency. A rise in creatinine kinase or the development of the above symptoms should lead to discontinuation of colchicine.⁶

Not all patients with gout develop significant joint destruction. A single gouty attack should not be an indication for lifelong therapy. However, patients with recurrent attacks unresponsive to prophylactic colchicine or those patients with tophi require treatment.

Indications for lifelong hypouricemic therapy include:⁶

• Clinical or radiologic tophi
• Gout attacks with unacceptable frequency
• Development of renal stones
• Unexplained renal insufficiency that could be secondary to hyperuricemia

Before starting a new medication, the patient should be encouraged to abstain from alcohol. Starting allopurinol or a uricosuric agent can precipitate an acute attack of gout and one should wait for resolution of the current attack. Also, the patient should ideally be on colchicine prophylaxis or on NSAIDs prior to initiating urate-lowering therapy.

Hence, these drugs are ideally commenced 2 to 3 weeks after an acute attack has resolved. If acute gout occurs after initiating allopurinol or uricosuric agent, these should be continued while the acute attack is being treated. A serum uric acid level less than 6 mg/dl is the goal.⁴

Uricosuric agents attempt to correct under-excretion in most patients. Examples of this class of drugs includes probenecid and sulfinpyrazone. These drugs are generally well tolerated, but they are seldom prescribed today because they have several disadvantages when compared to the xanthine oxidase inhibitors such as allopurinol: they require multiple daily doses, the patient must have a creatinine clearance greater than 30 to 50 ml/min, must be able to consume atleast 2 liters of fluid daily and must not have a history of uric acid renal calculi.^4,6 Typical doses for probenecid are 250 mg bid and sulfinpyrazone is 50 mg bid. It is useful to note that the measurement of a 24-hour urinary excretion rate is of value only if uricosuric therapy is preferred to allopurinol for underexcretors or if the information alters dietary advice/compliance. Most rheumatologists use allopurinol as the initial hypouricemic drug and few recommend this investigation.⁷

Xanthine oxidase inhibitors (eg, allopurinol) act by decreasing production of uric acid. They are effective in patients who overproduce (urinary uric acid > 600 mg/24 hours) or under excrete uric acid. The starting dose should be adjusted for the patient's renal function as follows:(Table 5)⁴

Subsequently, the dose should be adjusted until the serum uric acid level is consistently below 6 mg/dL. Doses as high as 800mg/day may be required in occasional patients. Potential adverse effects of allopurinol include skin rash, fever, bone marrow suppression, dyspepsia, granulomatous hepatitis, vasculitis and xanthine renal calculi. Rarely, the potentially fatal allopurinol hypersensitivity syndrome of rash, eosinophilia, hepatitis with hepatic failure and renal insufficiency may develop. This syndrome is more likely if the patient's dose is not adjusted for the patient's renal function. Allopurinol will potentiate the effect of warfarin and theophylline, and decrease the metabolism of azathioprine. If both allopurinol and azathioprine are to be prescribed, the dose of the latter should be reduced by 25% of its previous value. Also, peripheral blood counts should be monitored closely on this combination.⁴

The Perioperative Patient
Attacks of gout are common in the perioperative period. Fever can occasionally be the initial and most prominent feature. Unless a detailed joint examination is performed, it is easy to miss gout in the intubated or delirious patient. Patients may be unable to take medications by mouth and are at increased risk for renal failure and gastrointestinal bleeding. Intra-articular corticosteroids are the best option for acute gout in this setting. However, intravenous corticosteroids may be another option if the exposure is meant to be brief. Methyl prednisone 30 mg IV followed by a taper over 5 to 7 days is both effective and safe.⁸

The Patient with Renal Insufficiency
For acute attacks, intra-articular or systemic steroids remain good options for terminating acute attacks of gout. For prophylaxis, NSAIDs should be avoided and colchicine used with extreme caution, especially if creatinine clearance is less than 10 ml/min. Do not exceed 0.6 mg/day. Uricosurics are ineffective especially with glomerular filtration rates below 30 ml/min. Allopurinol is usually preferred, but the dose should be initially adjusted to creatinine clearance and increased gradually to achieve the goal serum uric acid.

The Transplant Patient
Transplant patients may develop high serum urate levels, acute gout and tophi within a few years of transplantation, mainly as a result of interference with urate excretion by cyclosporine. Azathioprine and renal insufficiency may also be major issues in transplant recipients. In patients with normal renal function, colchicine, intra-articular or systemic corticosteroids can be used to abort an acute attack. NSAIDs are best avoided in the face of renal insufficiency and/or hyperkalemia. Some form of uric acid lowering therapy is always necessary and allopurinol and uricosuric agents are effective if GFR is > 30 ml/min. More often, allopurinol is preferred with appropriate dose adjustments. Reduce azathioprine dose by 25% of its previous value or discontinue and replace with mycophenolate.⁴

The Patient with Allopurinol Allergy
Rash occurs in about 2% of patients on allopurinol and is more likely in the setting of concurrent treatment with ampicillin. A 25 % mortality rate has been shown to occur with the hypersensitivity syndrome.⁷ In cases of mild intolerance, eg, not associated with toxic epidermal necrolysis or the acute hypersensitivity syndrome, desensitisation with low dose allopurinol challenge may be attempted. If the reaction was severe, uricosuric agents may be considered. If all else fails, patients should be considered for research protocols where access to oxypurinol or urate oxidase may be present.⁴

The Patient with Large Tophi
Aggressive serum uric acid lowering strategies are called for in this situation, usually to levels less than 5 mg/dl. A combination of allopurinol and uricosuric agent may become necessary with a lower than usual dose of probenecid and a higher dose of allopurinol. Prophylaxis with colchicine or NSAIDs should be ongoing until visible tophi are resorbed.

Problems in the management of gout stem mainly from:⁹

• Failure to prescribe colchicine prophylaxis early on in treatment when hyperuricemia fluctuates.
• The initiation of urate lowering therapy when the patient still has acute gouty inflammation.
• Poor compliance

Useful websites:

• www.arthritis.org
• www.rheumatology.org/research/guidelines/refer
• www.niams.nih.gov/hi/topics/gout
• www.rheumatology.og/patients/factsheet/gout.html

1. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis and Rheumatism. 1998;41:778-99.
   
   
2. Boss GR, Seegmiller JE. Hyperuricemia and gout. Classification, complications and management. New England Journal of Medicine. 1979;300:1459-68.
   
   
3. Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. American Family Physician. 1999;59:925-34.
   
   
4. Conn's Current therapy 2002. Method of David Blumenthal, MD. Saunders, The Curtis Center, Independence Square West, Philadelphia, PA 19106-3399.
   
   
5. Buckley TJ. Radiologic features of gout. American Family Physician.1996;54:1232-8.
   
   
6. George TM, Mandell BF. Individualizing the treatment of gout. Cleveland Clinic Journal of Medicine. 1996;63:150-5.
   
   
7. McGill NW. Gout and other crystal-associated arthropathies. Best Practice and Research in Clinical Rheumatology. 2000;14:445-60.
   
   
8. Shaw M, Mandell BF. Perioperative management of selected problems in patients with rheumatic diseases. Rheumatic diseases Clinics of North America. 1999;25:623-648.
   
   
9. Emmerson BT. The management of gout. New England Journal of Medicine. 1996;334:445-51.
   

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