An In-Depth Topic Review of Gout

1. Definition
2. Pathogenesis
3. Clinical Presentation
4. Laboratory Findings
5. Differential Diagnosis
6. Initial Treatment
7. Long-term Management Issues
8. Prognosis
9. When to Seek Referral to a Specialist
10. Annotated References

I. Definition

Gout is the arthritic syndrome due to the deposition of monosodium urate crystals. The attacks tend to come in discrete episodes, with normal joints in the intervening period, until late stages of the disease. Gout attacks often are monoarticular, but polyarticular episodes can occur.

Primary gout is not associated with an identifiable cause, other than perhaps a family history. Secondary gout refers to the presence of a recognized cause or precipitating factor, such as lymphoma (especially following chemotherapy), the excessive use of alcohol, or the use of diuretics (see Pathogenesis below).

II. Pathogenesis

Gout develops as a result of the build-up of purines in the body, either by decreased excretion (about 90% of cases of primary gout) or by increased production (about 10% of primary gout). When the concentration of urate exceeds its solubility, crystals precipitate, and the crystals are phlogistic. The crystals lead to activation of the classical and alternative pathways of complement, the influx of neutrophils into the joint, and the release of numerous inflammatory cytokines. In those patients who are over-producers of uric acid, their 24-hour urinary uric acid will likely be elevated, and they will be at risk of urate kidney stones as well as gouty attacks.

Gout is associated with atherosclerosis, hypertension and renal insufficiency, but there remains debate as to whether the association is independent. That is, debate exists as to whether patients with renal disease, for example, have elevated serum uric acid levels due purely to their decreased glomerular filtration rate or whether the hyperuricemia itself can damage the kidney (and whether uric acid is a risk factor for hypertension and coronary artery disease). In rats, data suggest that hyperuricemia has a direct effect on renal blood vessels.

Until the age of menopause, women lag far behind men in the incidence of gout. After menopause, the numbers become closer to equal, but still favor men.

Any factors that raise nucleoprotein production will increase its breakdown -- ultimately, by the action of xanthine oxidase -- into uric acid. Factors that decrease the secretion, or increase the reabsorption, of uric acid will likewise increase the risk of gout.

Secondary factors that may contribute to the elevation of serum urate and the development of gout include:

• chronic kidney disease, which impairs urate excretion;
• lead poisoning, which similarly reduces urate excretion;
• use of medications that reduce urate excretion, including diuretics, low-dose aspirin and cyclosporine;
• significant alcohol intake, which both increases urate production and decreases excretion;
• psoriasis, related to increased skin cell turnover and resultant hyperuricemia from nucleoprotein breakdown;
• lymphoma, especially during chemotherapy, due to cell turnover;
• the post-operative state and other physical stresses, such as myocardial infarction and cerebrovascular accident.

III. Clinical Presentation

From a diagnostic and therapeutic point of view, gout is most efficiently seen in three distinct stages: acute gout, inter-critical (between attacks) gout, and chronic tophaceous gout.

A. Acute gout
In about 70% of acute gout attacks, a single joint becomes suddenly inflamed, often with excruciating pain, erythema, swelling and exquisite tenderness. The attack may be accompanied by chills and a low fever. If untreated, the attack generally peaks within 24 hours and may linger for weeks, especially if the patient continues to use the affected joint actively. Those who get one attack of gout will generally get further attacks, usually within 2 years; 62% have a second attack within a year - and 90% within 10 years. However, 10% never experience an attack again.

The first metatarso-phalangeal (MTP) joint is the single most likely joint to be affected by gout, but many other joints can be involved. The mid-foot, ankle and knee are, respectively, the next most common locations, and the olecranon bursa may also be involved. Gout attacks in Heberden's nodes, especially in elderly women, have been frequently described. Gout is sufficiently rare enough in the shoulders and hips as to suggest that a different cause may be present, even in patients with known gouty arthritis.

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Other diseases can also affect the first metatarso-phalangeal joint, such as pseudogout and Reiter's syndrome, (see Differential Diagnosis below), so involvement of this joint does not provide a definitive diagnosis of gout.

B. Inter-critical gout
Patients seen between gouty attacks generally appear normal - with no symptoms and with unremarkable joint examinations. The exception to this is in patients with long-standing gout who develop chronic tophaceous gout. The greatest controversies in the treatment of gout concern patients in the inter-critical phase.

C. Chronic Tophaceous Gout
After multiple gouty attacks, some permanent changes may occur in the joint, including joint damage and large collections of uric acid, or tophi.

Click Thumbnail to Enlarge Multiple tophi in the hands of a patient with long-standing gout.

Tophi can drain the white uric acid crystals to the surface, which presents an infection risk.

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Gout tophi draining to the surface of the skin over a distal inter-phalangeal joint of the finger.

Patients with tophi are often over-producers of uric acid and therefore have elevated 24-hour urinary uric acid and are at risk of kidney stones.

IV. Laboratory Findings

The great majority of patients with gout have hyperuricemia. However, this is not always true, and some patients drop their serum urate levels in the setting of an acute attack.

Since gout is a life-long disease, often requiring life-long therapy, the importance of a definitive diagnosis cannot be over-emphasized. When a patient first presents with possible gout, it is almost always optimal to drain synovial fluid to examine for crystals. The needle-shaped urate crystals, seen as strongly negatively birefringent under polarized light microscopy, confirm the diagnosis. In some cases, the definitive diagnosis is even easier, such as when the patient has a tophus on the ear, where a scrape of the skin will provide material for crystal analysis, or when a tophus is about to break through to the skin - and a 27- or 30-gauge needle can be used to puncture the skin and obtain material for crystal analysis. It has been well-documented that urate crystals can even be found in asymptomatic metatarso-phalangeal joints. It is more difficult to aspirate a joint with minimal fluid, but often the diagnosis of gout can be made from only the tiny drop of serosanguinous fluid at the tip of an aspirating needle.

The 24-hour urinary urate determination is probably underused for assisting in therapeutic decisions in gout. When a patient is identified as a high urate excretor (i.e. an over-producer rather than an under-excretor), this is a significant push toward using allopurinol. Patients who excrete more than 800 mg of urate per 24h are considered over-excretors.

X-rays are often normal early in gout, but in later stages (e.g. chronic tophaceous gout) the x-rays can help distinguish gout from other conditions.

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X-ray changes in chronic tophaceous gout. White arrow = erosion with overhanging edge.

X-rays in gout differ from those in rheumatoid arthritis in that there is no periarticular osteopenia. Erosions are seen in gout, but without surrounding decreased bone density.

V. Differential Diagnosis

Without crystal identification, great caution needs to be taken before making a diagnosis of gout, in view of the chronic treatment implications. The two "major criteria" for the diagnosis of gout are the documentation of urate crystals in either a joint or in a tophus.

Since certain clinical situations preclude crystal identification (e.g. patient refusal of arthrocentesis), "minor criteria" for gout diagnosis have been set up. To make the presumptive diagnosis of gout, six of the following 12 criteria should be present (note the importance of the history of a single joint with rapid and marked inflammation):

1. more than one discrete arthritis attack;
2. maximal inflammation within 24 hours;
3. an episode of monoarticular arthritis;
4. joint erythema;
5. swollen or painful first MTP joint;
6. unilateral inflammation of an MTP joint
7. unilateral inflammation of a tarsal joint
8. possible tophus;
9. hyperuricemia;
10. asymmetric joint swelling in a joint on X-ray;
11. X-ray showing joint cysts and/or erosions without periarticular osteopenia;
12. Joint inflammation with negative culture.

In addition, it's important to differentiate gout from pseudogout. Ideally, the differentiation is made by identifying the calcium pyrophosphate crystals under polarizing microscopy. When this is not possible, some clues to strongly consider pseudogout are:

1. calcifications seen in typical locations for pseudogout, e.g. the knee menisci, the triangular cartilage of the wrist, or surrounding the humeral head;

2. acute arthritis that seems like gout but is in a joint not usually involved by gout, such as the wrists, shoulders or elbows. (Gout is common in the olecranon bursa but rare in the elbow joint itself; osteoarthritis of the knees is much more prominent in the patello-femoral joint than in the medial or lateral compartment.)

VI. Initial Treatment

A number of different treatments are available for the management of acute gout. The options for managing chronic gout are more limited (see Long-Term Management Issues). A way to help patients think about the different approaches to gout treatment has been suggested by Dr. Robert L. Wortmann (see reference "1" below).

1. Medications for Acute Gout
   
   1. Non-steroidal Anti-Inflammatory Drugs (NSAIDs) are the drugs of choice for acute gout. In the past, indomethacin was used due to limited alternatives. Some patients still find this drug to be the most effective, but it appears to cause more gastro-intestinal distress than most other such agents, and it can cause headache and dizziness, especially in the elderly. A variety of NSAIDs, such as sulindac and naproxen, are effective in gout, and the COX-2 inhibitors, such as celecoxib, rofecoxib and valdecoxib are reasonable choices, as is the COX-2 selective agent meloxicam.
   2. Corticosteroids and ACTH, orally, intramuscularly or intravenously, are effective in gout. Studies many years ago suggested that there was a rebound effect in patients who took corticosteroids for gout, with flares on drug discontinuation, but recent studies have not shown this to be the case. A four- or five-day course of tapering doses of prednisone, e.g. 40 mg - 30 mg -20 mg -10 mg - will work in many patients. Some will need a longer course. Patients with ulcer disease or with a history of intolerance to NSAIDs, or those on warfarin, may be good candidates for corticosteroids. Patients with diabetes mellitus or infections are problematic with regard to prednisone therapy, but with close observation and management of the complicating disease, prednisone may still be possible.
   3. Local injection of corticosteroids into a gouty joint is often an excellent alternative for acute monoarticular gout. The systemic risks are quite small, and the treatment is highly effective. In cases where the inflammation is more diffuse, as in the mid-foot, or when polyarticular involvement is present, this treatment may not be practical.
   4. Colchicine can be used orally to treat gout, and this treatment is often effective, although patients commonly develop diarrhea before attacks are resolved. Colchicine is used at 0.6 mg every hour until the attack ends or significant GI toxicity develops. Some patients, by history, have an excellent response to oral colchicine without GI toxicity, and in those patients it is reasonable to continue its use. For other patients, it would be reasonable to try non-steroidal anti-inflammatory agents. However, colchicine can also be given intravenously, but this is used rather rarely now, due to reports of bone marrow suppression and death with this treatment. Such deaths have been essentially confined to patients with renal insufficiency, and the use of intravenous colchicine has to be used with extreme caution, if at all, in such cases. It is not to be used in patients on hemodialysis because colchicine cannot be hemodialyzed. When used in patients with normal renal and hepatic function, 2 g of intravenous colchicine is given, and then 0.5 mg q8h to a maximum of 4 mg. For patients with any decrease in renal or hepatic function, the initial dose is reduced to 1.5 mg, and the total maximal dose to 2.0 mg. By either route, colchicine has the mild advantage of a relative specificity for crystal-induced disease; so a response to this medication helps point toward gout (or pseudogout) as the underlying diagnosis.
      
      

2. Other factors in management of acute gout
   

   1. Resting of the involved joint is important in managing acute gout. When a patient continues to walk on an inflamed metatarso-phalangeal joint, for example, this can prolong the attack.
   2. Timing of treatment is important. The speed of recovery of a gouty joint is often related to how long after the attack begins that the therapy is started. For example, if a patient begins treatment of a gout attack within an hour of its onset, the attack can often be resolved within a day. If the treatment starts after a week of gout, however, it may take a number of days for the attack to resolve.

VII. Long-term Management Issues

A.  Diet

1. Purine intake still plays a role in the management of gout. Although even a very strict low purine diet can only reduce the serum urate by ~1.0 mg, some patients notice a significant reduction in gout attacks when watching their diet carefully (See reference #2 below for diet books that may be helpful to your patients.) The most important dietary advice includes telling patients to avoid foods with very high purine content such as organ meats (liver, kidney, hearts, sweetbreads [thymus and pancreas]), also known as offal, anchovies, salmon, sardines, meat extracts, and gravies.
   
2. Alcohol intake needs to be limited, since alcohol decreases the excretion of uric acid and also increases its production.
   
   
3. Fluid intake of at least 4-5 cups a day can help in preventing kidney stones.
   
   

B. Medications for Inter-Critical Gout

1. General principles: Four alternatives are available prophylaxis during the period between attacks: allopurinol, colchicine, probenecid and sulfinpyrazone.
   
2. Colchicine prophylaxis is still used today, although perhaps less than in the past. Used at 0.6 mg qd or bid, there is evidence for benefit in preventing gout attacks, although the uric acid level is unchanged. Some patients will get diarrhea with 0.6 mg bid, and some of those will be able to tolerate the drug once a day.
3. Uricosurics, e.g. probenecid and sulfinpyrazone, are used to prevent gout attacks in patients who are found not to be at risk of kidney stones. (This will require 24-hour urinary uric acid testing.
   

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      4.  Allopurinol is the only commercially available xanthine oxidase inhibitor. In patients who are overproducers of uric acid, or those who are not appropriate candidates for uricosuric agents, allopurinol is the drug of choice.

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Indications for Allopurinol in Gout

Patients with history of gout and renal stones will clearly need allopurinol. Patients with tophi benefit from allopurinol, and allopurinol is the drug of choice in patients receiving chemotherapy in a setting where transient hyperuricemia and hyperuricosuria are expected. In patients who need allopurinol, but who develop allergy to this agent, oxypurinol, a metabolic breakdown product of allopurinol, is available from the manufacturer on a compassionate use "N of 1" study basis. The allergy cross-reaction rate of allopurinol and oxypurinol is ~ 50%. An intravenous and an oral desensitization protocol are available. Patients who begin on allopurinol will, not uncommonly, develop an increase in gouty attacks in the months following initiation of this medication. For this reason, some rheumatologists will start colchicine prophylaxis along with the allopurinol, and continue the colchicine for the first six months of allopurinol therapy.

5.  General considerations in the management of chronic gout require taking each patient on an individual basis.

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C.  Management of Chronic Tophaceous Gout

1. Allopurinol is essentially always indicated in patients with chronic tophaceous gout.
2. Surgery to remove tophi that are beginning to break through to the skin is sometimes needed and can prevent severe infectious problems and osteomyelitis. Since it can take 18 months or more for allopurinol to lead to tophus resorption, some patients have tophi, which need to be addressed with a more urgent timetable.

D.  Management of Patients with Gout and Kidney Stones

1. Allopurinol is the drug of choice to prevent gout attacks and to reduce urate in the urine.
2. Fluid intake should remain high.
3. Urinary alkalinization, as with potassium citrate combined with citric acid, can increase the solubility of urate and decrease the risk of urate crystallization.

E.  Management of hypertension, obesity, hyperlipidemia, and coronary disease in patients with gout

Gout as a clue to the above conditions is important in that they should be sought in any patient with gout. It remains unclear whether these conditions are the cause of hyperuricemia or whether the hyperuricemia plays a role in their development, but their treatment is clearly indicated.

VIII. Prognosis

1. Response to treatment is generally quite good, and most patients with gout do very well. In those for whom allopurinol is indicated, most tolerate this drug. In those with allopurinol allergy, most can be managed with a desensitization regimen or with the use of oxypurinol (see "B" below). For those patients with a need for allopurinol and an inability to tolerate the drug, it can be quite difficult to manage their gout and difficult to prevent kidney stones.
   
   
2. Future alternatives for gout management include the ultimate commercial availability of oxypurinol for patients who are allopurinol-allergic and the development of a new xanthine oxidase inhibitor that is chemically unrelated to allopurinol (under development). Uricase, the enzyme present is most animal species, but not the great apes and man, effectively lowers uric acid and is available in an intravenous form, FDA-approved for use as a chemotherapy for childhood malignancy. It is not yet a practical alternative for chronic gout.

IX. When to Seek Referral to a Specialist

Most patients with gout can be managed by their primary care physicians. Cases where a rheumatologist may be helpful include:

1. the involved joint is difficult to aspirate;
2. the diagnosis is unclear;
3. the patient has an apparent allergic reaction to allopurinol;
4. the patient continues to have gout attacks despite a prophylactic regimen;
5. the patient has both gout and renal insufficiency;
6. large tophi have already or are threatening to break through the skin.

X. Annotated References

A. Wortmann RL. Effective management of gout: an analogy. Am J Med. 1998 Dec;105(6):513-4. A review article that includes the "match" analogy to help patients understand the management of the various stages of gout.

B. Schneiter J. Gout Hater's Cookbook: Recipes Lower in Purines and Lower in Fat. (Reachment Publications; 2000) In addition to comprehensive lists of foods lower, relatively high, and highest in purines, this book offers nearly 100 low-purine recipes.

C. Schneiter J. Gout Hater's Cookbook II: The Low Purine Diet Cookbook. (Reachment Publications: 2001) More recipes from the same author. This book is useful for your patients, who often find the recommendations about low purine diets confusing and difficult to follow even when well understood.

D. Wallace SL, Singer JZ. Review: Systemic toxicity associated with the intravenous administration of colchicine - Guidelines for use. J Rheumatol 1987;15:495-9. This is an important article on potentially lethal complications of intravenous colchicine; it emphasizes the importance of renal insufficiency as a risk factor for complications.

E. Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome: Unnecessary morbidity and mortality. Arthritis Rheum 1986;29:82-6. This article stresses the importance of renal insufficiency as a risk factor in allopurinol hypersensitivity, and the importance of reducing allopurinol dose in patients with renal insufficiency and of making sure that only patients who meet appropriate criteria get treated with allopurinol.

F. Moriwaki Y, Yamamoto T, Takahashi S, et al. Spot urine uric acid to creatinine ratio used in the estimation of uric acid excretion in primary gout. J Rheum 2001;28:1306-10. This article is part of an ongoing discussion among rheumatologists as to whether spot urinary urate/creatinine ratio can replace 24-hour urinary urate determination.

G. Fam AG, Dunne SM, Iazzetta J, et al. Efficacy and safety of desensitization to allopurinol following cutaneous reactions. Arthritis Rheum 2001;44:231. This article reviews a regimen of oral desensitization to allopurinol, which has had significant success with low risk.