44. | Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)

Chapter 37 Gout

Manual of Rheumatology and Outpatient Orthopedic Disorders

Chapter 37 Gout

Theodore R. Fields and Nicholas P. Scarpa

Epidemiology
Disease classification
Acute gout
Asymptomatic hyperuricemia
Interval gout
Chronic gout
The prognosis

The first clinical description of a syndrome called podagra, a classic pattern of gout, was in the fifth century b.c. Despite its early recognition, gout continued to plague humankind until the middle of the twentieth century, when practical and effective therapy emerged. The introduction of allopurinol and nonsteroidal antiinflammatory drugs (NSAIDs) has made it possible to alter the course of the disease dramatically.

Gout is a heterogeneous disorder with primary and secondary forms characterized by hyperuricemia and urate crystal-induced arthritis.

I. Epidemiology. In the United States, approximately 12% of family members of gout patients are affected. Ninety percent of primary gout patients are men. The peak age for the first attack of gout is during the fifth decade . Primary gout is thought to be a polygenic disease.

II. Disease classification

Primary gout. In primary gout, hyperuricemia results from a disorder of purine metabolism or from abnormal excretion of uric acid. Most patients with primary gout fall into an idiopathic category because no precise genetic or metabolic defect can be identified. In approximately 1% of the primary gout group , specific enzyme defects have been found. Deficiency of hypoxanthine guanine phosphoribosyltransferase (HGPRT) and increased activity of phosphoribosylpyrophosphate (PRPP) synthetase are the best-characterized forms.
Secondary gout constitutes about 10% of all gout cases. It can result from a variety of disorders that cause hyperuricemia as a result of overproduction or impaired excretion of uric acid (Table 37-1).

Table 37-1. Classification of hyperuricemia

III. Acute gout

Clinical presentation
1. The intense articular inflammation associated with the presence of intracellular monosodium urate crystals in synovial fluid is usually the first and most characteristic manifestation of an acute gouty arthritis. Classically, acute gout presents as a monarthritis (approximately 70% of cases); however, a polyarticular arthritis occurs in a significant percentage of patients. The onset of pain is sudden; within hours it may become excruciating to the point that the weight of bed sheets is intolerable. Weight bearing , even wearing footwear, may become impossible . The intense inflammation and erythema over the affected joint resemble tenosynovitis or cellulitis. Some patients also experience chills and fever with the acute onset.
2. Acute gouty arthritis occurs most commonly in men (95% of cases), with the initial attack occurring in the fourth or fifth decade. Gouty arthritis rarely develops in women before the onset of menopause.
3. Important predisposing factors of an acute gouty attack include diuretic use, recent surgery, alcohol abuse, chronic renal disease, rapid weight reduction, and infection. A positive family history of gout is helpful in supporting a diagnosis of primary gout. In patients taking cyclosporine, an especially rapidly progressing form of gout can develop, often with tophi.
4. The joints most commonly affected include the first metatarsophalangeal joints (podagra), the dorsum of the foot , the ankle, the knee, and occasionally the joints of the upper extremity . Gouty involvement is also seen in Heberden's and Bouchard's nodes, especially in elderly women on diuretics.
Laboratory studies
1. Synovial fluid examination. The most important procedure in establishing the diagnosis of acute gouty arthritis is the examination of the synovial fluid by compensated polarized microscopy.
  1. Principles of polarizing microscopy. The polarizing microscope consists of the usual optics with added polarizer and analyzer lenses that orient white light into a single plane. When a birefringent crystal is examined and rotated into the proper position, it will appear as a bright object against a dark field. When a first-order red compensator is added to the system, the specimen background appears rose (first-order red). Crystals examined with a compensator have characteristic colors that change when they are rotated 90 degrees as a result of the optical properties of the crystals and the compensator's deceleration of a characteristic frequency of light. The complex physics underlying this phenomenon are clearly described elsewhere.
  2. Crystal identification. If carefully sought, urate crystals can be found in the synovial fluids of 85% of acute gout patients. Urate crystals can also often be found in asymptomatic knee and first metatarsophalangeal joints in patients with gout. Urate crystals are slender and needle-shaped and have strong negative birefringence under polarized light. (Calcium pyrophosphate crystals are pleomorphic, are predominantly rhomboid-shaped, and have weakly positive birefringence.) In most joint fluids, urate crystals can be found inside neutrophils; however, in chronic gout, crystals may also be found free in the synovial fluid. Under polarized light, urate crystals appear yellow when parallel to the axis of the red compensator and blue when perpendicular to the axis. (An axis reference line is etched on the housing of the compensator.) The calcium pyrophosphate crystals of pseudogout have the opposite orientation.
2. Biochemical findings. Serum uric acid levels are usually elevated but are normal in about 10% of patients with acute gout. The creatinine and urea nitrogen levels will be elevated if secondary gout attributable to renal failure is responsible for the acute attack. Lead poisoning , which can also cause nephropathy, can be detected by measuring an elevated level of coproporphyrin III or lead in the urine. If one of the genetic enzyme deficiencies of primary gout is suspected, erythrocyte enzymes can be assessed in a few specialized laboratories.
3. Radiographs usually show only soft-tissue swelling in the first attack of gout. With recurrent or chronic disease, tophi and periarticular erosions with overhanging edges can be seen in the affected joints. On rare occasions, magnetic resonance imaging (MRI) can be useful in distinguishing tophi from other soft- tissue lesions.
Differential diagnosis. Of paramount importance in the differential diagnosis of acute monarthritis is septic arthritis. Infection can be excluded only by Gram's stain and appropriate culture of the aspirated synovial fluid. The remainder of the differential diagnosis includes trauma, pseudogout, and atypical rheumatoid arthritis (RA). Although identification of calcium pyrophosphate crystals supports the diagnosis of pseudogout, both gout and pseudogout may coexist. The diagnosis of atypical RA often requires a prolonged period of observation before a clinical pattern of disease consistent with RA emerges.
Treatment. In the eighteenth and nineteenth centuries, physicians were frustrated by the myriad of impotent remedies proposed to cure gout. Today, however, physicians have a choice of treatment remedies that can dramatically alter the courses of acute and gouty arthritis. Detailed information on individual drugs appears in Appendix E. Regardless of the drug regimen chosen , resting the involved joint is an important adjunctive therapy.
1. Indomethacin is better tolerated than oral colchicine. The dosage of indomethacin is 50 mg three times daily until the attack has almost completely resolved, then 50 mg twice daily until the patient is asymptomatic. A therapeutic effect is usually seen in 8 hours. A suppository form of indomethacin has been approved for use in those patients unable to tolerate the oral form.
2. Other NSAIDs have also been used in treating acute gouty arthritis as alternative regimens.
  1. Sulindac. The dosage is 400 mg initially, then 200 mg twice daily, with gradual tapering during 5 days as inflammation subsides.
  2. Naproxen. The dosage is 500 mg initially, then 250 mg q8h, with gradual tapering during 5 days.
  3. Ibuprofen. The dosage is 800 mg initially, then 400 mg q6h, with gradual tapering during 5 days.
3. Colchicine. A therapeutic response to colchicine in the past has been considered diagnostic of acute gout, but it is now recognized to be nonspecific.
  1. Oral colchicine may cause nausea and diarrhea at the doses needed for control of an acute attack and is rarely recommended as first-time therapy. Occasional patients can tolerate five to six 0.6-mg doses PO hourly and may use this regimen. However, side effects usually outweigh therapeutic benefits.
  2. Intravenous colchicine is used infrequently in current practice. It should be avoided if possible in patients with severe renal or hepatic disease. Patients who have received a full IV dose of colchicine should receive no further colchicine (by any route) for 7 days. IV colchicine should not be used in patients with significant leukopenia or decreased marrow reserves , and it should be avoided if the patient is already taking oral colchicine. It should also be avoided in patients on hemodialysis. Some clinicians have stopped using IV colchicine in view of its potential toxicity. Consult current product labeling for dosage and clinical safety information.
4. Allopurinol or probenecid should not be started during an acute gout episode because reduction of the serum uric acid level may be associated with prolongation of the attack.
5. Corticosteroids. Although not the treatment of choice in patients without concomitant medical problems, the side effect profile of steroids makes this class of drugs appropriate in some of the more complex gout cases. Prednisone (20 to 40 mg daily for up to 3 days, with subsequent rapid taper) can be successful. Local steroid injection is an additional therapeutic option.

IV. Asymptomatic hyperuricemia is arbitrarily defined as serum uric acid values that exceed the mean plus two standard deviations in an asymptomatic population. Therefore, by definition, 2.5% of the population will be affected. It should be stressed that most patients with hyperuricemia are asymptomatic and do not acquire renal or articular disease.

Diagnosis. Many clinical laboratories use an auto-analyzer colorimetric technique based on the ability of urate to reduce phosphotungstic acid. For men, the upper limit of a normal uric acid level is 8.0 mg/dL, and for women, it is 6.5 mg/dL. Several common substances, such as caffeine , vitamin C, and acetaminophen, produce spurious uric acid elevations with the colorimetric technique. The true serum uric acid level as measured by the uricase method is approximately 1 mg lower per deciliter than the value measured by the automated technique. Evaluation of the patient with asymptomatic hyperuricemia includes exclusion of drug effects or other conditions listed in Table 37-1. Diuretic therapy is a particularly common cause of uric acid elevation, which usually does not require treatment.
Treatment of asymptomatic hyperuricemia is a subject of controversy. No strong evidence has been offered that asymptomatic hyperuricemia results in chronic renal disease or joint deformity. Factors in the evaluation of the patient that might lead one to consider individualized therapy to lower serum uric acid include a family history of renal stones and the degree of hyperuricemia. Patients with repeated uric acid elevations above 10 mg/dL have an increased risk for development of gout or urolithiasis; probenecid or allopurinol therapy may be warranted. There is no established treatment protocol for lesser degrees of hyperuricemia, but the cost and possible toxicity of long- term allopurinol or uricosuric therapy argue against their routine use in patients with asymptomatic hyperuricemia and uric acid levels below 10 mg/dL. The risk for urolithiasis is less than 1% of patients per year. Although it is proposed that hyperuricemia may be a risk factor for the development of arterial hypertension and other cardiovascular abnormalities, the data are not sufficiently compelling to warrant treatment.

V. Interval gout is characterized by asymptomatic periods between acute gout attacks. Some patients never experience a second attack. In most patients, a second attack occurs within 6 months to 2 years (75% to 80%). Because the second attack or subsequent attacks cannot be predicted , most physicians take a conservative approach initially. Many patients will not need treatment. Factors that influence a decision to treat with uric acid-lowering agents include a history of renal calculi or uric acid excretion greater than 1,000 mg daily (see section IV for a complete discussion).

VI. Chronic gout is characterized by recurrent episodes of oligoarthritis and polyarticular arthritis, joint deformity, tophi, or urolithiasis. With the variety of medications available today for the treatment of hyperuricemia and acute gout attacks, the incidence of tophaceous gout is diminishing steadily.

Physical examination. Joint examination may reveal an asymmetric polyarthritis that can be very deforming and sometimes difficult to distinguish from RA. Tophi occur in approximately 15% of patients. The more common locations of tophi include the olecranon bursae, finger joints, and helix of the ear. To distinguish possible tophi on the helix of the ear from other entities, one may compress a microscope slide against the lesion, and if the lesion appears white in color, it is a tophus. If the lesion appears yellow in color, this usually signifies a sebaceous cyst, and finally, if the color is the same as the surrounding tissue, this represents normal cartilage. Material scraped or aspirated from tophi can be definitively identified with a polarizing microscope as discussed in section III.B.1. Destruction of cartilage by tophi may lead to secondary degenerative joint disease. Other rare locations of tophi that have been described include the vocal cords, heart valves , and spinal column in addition to the conduction system of the heart.
Laboratory studies
1. Serum studies
  1. Uric acid. Elevated uric acid values occur in about 90% of gout patients.
  2. Creatinine. Elevated levels may reflect gout- related nephropathy or primary renal disease.
2. Urine studies. Patients with primary gout can be subdivided into over-excreters of uric acid (15% of patients) and normal excreters based on quantitative urinary excretion of urate. On a regular diet, normal persons will excrete 300 to 800 mg of uric acid daily. The patient should be instructed to avoid alcohol or aspirin ingestion and to eat no more than one moderate serving of meat daily during the 3 days preceding the urine collection. Foods with a very high purine content, such as organ meats (liver and kidney) and anchovies, should also be avoided before the collection. A uric acid collection obtained during an acute gout attack is unreliable as a result of fluctuating serum acid levels not usually seen in the basal state.
3. Radiographs. Soft-tissue swelling and osteopenia may occur as nonspecific early changes on radiographs. As the disease progresses, soft-tissue tophi may be seen as well as punched-out, sharply marginated areas of bony destruction. Pure urate stones are radiolucent, and imaging studies must take this into account.
The differential diagnosis includes RA, osteoarthritis, and pseudogout. At times, it can be exceedingly difficult to distinguish rheumatoid nodules from tophi without the aid of a biopsy specimen or aspirate. The absence of crystals in the synovial fluid distinguishes chronic gout from osteoarthritis . The demonstration of calcium pyrophosphate crystals in synovial fluid as well as chondrocalcinosis on radiography may help to distinguish chronic gouty arthritis from pseudogout.
Complications. Pure urate stones are found in approximately 80% to 90% of all gout patients in whom urolithiasis develops, in comparison with 10% of the general population. Any patient with gout in whom urolithiasis develops should have recovered stones analyzed chemically, and a 24- hour urine specimen should be obtained for determination of uric acid, calcium, and phosphate excretion. Other diseases associated with stone formation include hyperparathyroidism, cystinuria, and renal tubular acidosis, all of which require appropriate serum and urine studies to elucidate the etiology of urolithiasis. The treatment of choice in nephrolithiasis of gout is allopurinol, which lowers both serum and urinary uric acid values. Patients should be encouraged to maintain high urine volumes , and particularly in large over- producers of uric acid, alkalinization of the urine is warranted.
Treatment
1. Patient education. It is important that the patient realize that gout is a chronic disease and that certain life-style modifications, such as maintenance of an ideal weight and moderation of alcohol intake, are important. A purine-restricted diet may be of benefit in some patients, but only small changes in serum uric acid can be attained. Other factors worth emphasizing are ingestion of at least 2 L of fluids daily to help prevent renal stones and avoidance of alcohol and low-dose aspirin, which aggravate hyperuricemia.
2. Drug therapy. The goals of therapy are to prevent renal parenchymal damage and nephrolithiasis and to suppress articular flares. Drug strategy in chronic gout is determined by the pattern of 24-hour urate excretion and the severity of disease.
  1. Colchicine prophylaxis. Colchicine (0.6 mg daily or twice daily) is effective in diminishing the frequency and severity of spontaneous gout flares and flares induced by initial allopurinol and probenecid therapy. Colchicine may be discontinued after a 6-month symptom-free interval if allopurinol or probenecid has been started. Otherwise, it is continued indefinitely. In the elderly and those with impaired renal function, the dose is 0.6 mg daily. In dialysis patients, oral colchicine is generally best avoided. Some clinicians have abandoned long-term colchicine prophylaxis for several reasons. First, colchicine does not lower urate levels or prevent tophi. Second, acute attacks can be handled as described in section III.D, and oral colchicine at times can cause toxicity, including bone marrow suppression and myopathy. Third, no randomized controlled studies are available to demonstrate the benefit of colchicine alone as a preventive agent in interval gout.
  2. Recurrent gout attacks are treated as described earlier (see section III.D ). The patient may be given a supply of indomethacin (the drug of choice for acute attacks) with instructions to take 50 mg q6h at the first sign of a gout prodrome and to call the physician . When indomethacin is self-administered in this manner, a gout attack may be aborted with only two to three doses.
  3. Uricosurics. The goal is to lower urate to approximately 6.0 mg/dL (auto-analyzer measurement). Most commonly, these drugs are used in patients less than 50 years of age.
    1. Indications (all must be present)
      1. Normal urate excreter (<800 mg/24 h).
      2. Normal renal function.
      3. Absence of tophi.
      4. No history of renal calculi.
    2. Administration. Prophylactic colchicine (0.6 mg twice daily) should begin 3 days before therapy. Probenecid is the uricosuric drug of choice. The initial dosage is 250 mg twice daily for 1 week. The dosage is increased to 500 mg two to three times daily depending on serum uric acid response. Adequate hydration must be maintained to prevent uric acid precipitation in renal tubules.
  4. Allopurinol. The goal is to lower urate to approximately 6.0 mg/dL.
    1. Indications (only one need be present)
      1. Hyperexcretion of urate (>800 mg/24 h).
      2. History of renal calculi.
      3. Tophi.
      4. Renal insufficiency and gout.
      5. There is another indication for lowering urate, and uricosuric drugs are ineffective , not tolerated, or contraindicated.
      6. Before cytotoxic therapy for neoplasia.
      7. Continued attacks of gout despite colchicine prophylaxis, uricosuric drugs, or both. The severity of the gout attacks and the presence of radiographic joint damage are taken into consideration in the individual case.
    2. Administration. Prophylactic colchicine (0.6 mg twice daily) can be started 3 days before initiation of allopurinol therapy. Some clinicians avoid oral colchicine in this setting and treat any flares of gout with NSAIDs or corticosteroids. Colchicine is appropriate for patients in whom prevention of gouty attacks during the initiation of the allopurinol therapy is felt to be especially important. When colchicine prophylaxis is used in this setting, it is generally continued for 6 months. The initial allopurinol dosage is 100 mg daily, which is increased weekly until the maintenance dosage of 300 mg daily is reached. Dosages as high as 600 to 800 mg/d may be needed in a few patients to achieve clinical control. If the creatinine clearance is less than 20 mL/min, the toxicity (skin rash, vasculitis, agranulocytosis) of allopurinol increases . The dosage of allopurinol is decreased according to decreased renal function. For a glomerular filtration rate of 20 to 30 mL/min, the dose of allopurinol should be reduced to 100 mg/d.
    3. Allopurinol allergy. Oxypurinol (an active metabolite of allopurinol) has been shown to be as effective as allopurinol and can be used (by special release from the manufacturer) in patients with allopurinol allergy. However, cross-reactive allergy has occurred in as many as 50% of cases. IV and oral desensitization regimens for allopurinol have been published.
  5. Joint aspiration and intraarticular injection of corticosteroid preparations may be indicated for patients with persisting chronic synovitis. The technique and dosage regimen are described in Chapter 4.
  6. Prevention of nephrolithiasis. In patients with renal stones, the following measures may be used.
    1. Urine alkalinization. A urine pH greater than 6.0 can be achieved with one of the following:
      1. Sodium or potassium citrate (Polycitra) (20 mL four times daily). However, compliance with a regimen of dosing four times daily is difficult.
      2. Acetazolamide (500 mg at bedtime).
    2. Large urine volume. The patient should be instructed to drink adequate fluids to produce at least 2 L of urine daily.
  7. Surgical therapy. Surgical removal of large tophi is indicated if they become infected or interfere with joint function.

VII. The prognosis of properly managed gout is excellent , and most patients have a normal life span. Chronic deforming arthritis and periarthritis can occur in long-standing untreated cases. In rare patients with severe tophaceous renal disease, chronic renal failure may develop.

Bibliography

Bomalaski J, Schumacher R. Podagra is more than gout. Bull Rheum Dis 1984;34:6.

Fam AG. Problem gout: clinical challenges, effective solutions. J Musculoskeletal Med 1997;14:63.

Kelley WM, Harris ED. Textbook of rheumatology. Philadelphia: WB Saunders, 1997.

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Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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