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The pathogenesis of gout

July 1, 2008|Cleveland Clinic Journal of Medicine
H. Ralph Schumacher, Jr, MD
Author and Disclosure Information

H. Ralph Schumacher, Jr, MD
Professor of Medicine, University of Pennsylvania, Philadelphia, PA

Correspondence: H. Ralph Schumacher, Jr, MD, VA Medical Center, 151K, University and Woodland Avenues, Philadelphia, PA 19104; schumacr@mail.med.upenn.edu

Dr. Schumacher reported that he has received research grant support and consulting/advisory fees from TAP Pharmaceutical Products and Savient Pharmaceuticals as well as consulting/advisory fees from Pfizer, Regeneron, and Xoma.

Dr. Schumacher received honoraria for participating in the symposium that formed the basis of this supplement and for writing this article. The honoraria were paid by Fallon Medica LLC, a medical communication company, on behalf of TAP Pharmaceutical Products, the underwriter of this supplement. TAP had no input on the content of presentations at the symposium or on this article.

This article is based on Dr. Schumacher’s lecture on this subject at the symposium that formed the basis of this supplement. Dr. Schumacher reported that he prepared his lecture, Fallon Medica transcribed his lecture, and he alone developed the transcript into this article without assistance from undeclared contributors. The article underwent formatting and nonsubstantive copyediting by Fallon prior to submission to the Journal.

ABSTRACT

An elevated serum urate level, together with local factors, can result in the deposition of urate crystals into the joints. Once crystals are deposited into a joint, they can be released into the joint space and initiate an inflammatory cascade causing acute gouty arthritis. These acute flares resolve, but the crystals remain in the joint. The way to ultimately correct the underlying metabolic problem of hyperuricemia and the crystal deposition is to lower the serum urate level and dissolve the crystal deposits. This will stop both the acute attacks and the progressive joint damage.

KEY POINTS

  • A serum urate level of approximately 6.8 mg/dL is the concentration at which urate crystals begin to precipitate. The higher the urate level, the more likely that crystals will deposit into joints.
  • Local factors that combine with hyperuricemia to contribute to the development of gout are trauma, irritation, reduced temperature, and prior joint disease.
  • Because acute attacks of gout typically resolve spontaneously, especially early in the disease course, evaluating the efficacy of acute therapies can be difficult.
  • Lowering the serum urate to less than 6 mg/dL will dissolve crystals out of the joints, ultimately preventing acute gout attacks and joint damage.

ACUTE GOUTY ARTHRITIS

Figure 1. Synovial tissue of a patient with acute gout. Note the dilated vessels, representing the throbbing, hot erythematous joint, and the large numbers of neutrophils.
In some patients, the deposited monosodium urate crystals will be released into the joint space and cause the dramatic acute inflammatory response of acute gouty arthritis. Crystals are believed to be released either by some metabolic change, such as an increase or decrease in serum urate level, or by mechanical trauma. In the joint space, synovial lining cells appear to be the first to phagocytize the crystals.6 This sets into motion the formation of a complex called the inflammasome, which releases IL-1 beta, one of the most important mediators of the acute attack.7 It stimulates the release of chemokines, other cytokines, prostaglandins, and a variety of other proinflammatory molecules.8 The chemokines attract neutrophils into the synovial tissue and the synovial fluid. Neutrophil influx into the joint is a key feature of an acute attack of gout (Figure 1).

Gout flares may resolve spontaneously

Clinicians should be aware that gout attacks initially subside spontaneously.9 Because acute attacks of gout typically resolve with or without treatment, especially early in the course of the disease,10 it can be difficult to evaluate which treatments actually are effective against acute attacks.

A number of factors have been identified to explain how inflammation in acute attacks can be spontaneously suppressed. Crystals may dissolve or become sequestered in the tissue. Monocytes mature into macrophages, changing their responsiveness to urate crystals, and can begin to produce anti-inflammatory cytokines. In addition, some proteins that exude into the joint space with the attack, such as apolipoprotein B, can coat the crystals and reduce their inflammatory properties.11

Crystals persist during intercritical periods

Figure 2. The synovium between acute gout attacks, viewed under polarized light. Two small micro-tophi and mononuclear cells are apparent, but there is no acute inflammatory response.
Following an acute attack, the symptoms of gouty arthritis may be gone, but the crystals are still present in the joint. Therefore, the patient remains at risk for continued flares and progressive disease.12 The crystals that remain in the joint are often associated with a low-grade persistent inflammation.13 It is not known why these crystals that remain in the joint fluid between attacks, some of which are phagocytized by white cells, do not initiate the whole cascade of inflammation. The reason may be related to the number of crystals present, their protein coating, or the nature of the resident synovial cells. Crystals may also persist as micro-tophi in the synovium (Figure 2). The key point is that low-grade inflammation persists and crystals remain in the joint, which can lead to progressive disease.14

ADVANCED GOUT

Figure 3. Large, cystic joint erosions producing an overhanging edge (circled area) characteristic of chronic gouty arthritis.
Clinicians treating patients with gout need to prevent the development of chronic, destructive arthritis and the overt, large tophaceous deposits of advanced gout. Over time, even in the absence of flares, deposited crystals and inflammation can lead to the development of clinically evident joint damage and erosions that can be seen on radiographs (Figure 3) or magnetic resonance imaging.15

INTERVENTIONS MUST NORMALIZE URATE LEVEL

Acute gout attacks can be treated with anti-inflammatory drugs, but the disease can and often will continue to progress unless the serum urate level is normalized. Two studies of patients whose serum urate levels were successfully reduced to less than 6 mg/dL showed that crystals began to be depleted from the patients’ joint fluid, which should ultimately prevent the risk of progressive gouty arthritis.12,16 Perez-Ruiz and colleagues have shown that tophi can be dissolved by decreasing the serum urate level.17 When tophi are present, aiming for even lower levels of serum urate, such as 4 to 5 mg/dL, may help to promote more rapid dissolution of crystals.17

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