GOUT

Definition

Gout is a crystal deposition disease characterized by the supersaturation and precipitation of MSU crystals in tissues resulting in inflammation and, consequently, tissue damage. Gout is characterized by acute or subacute attacks of joint or soft tissue inflammation resulting from MSU crystal deposition. The clinical course of gout can be summarized into the stages of acute intermittent gout and chronic tophaceous gout.

Hyperuricemia is the underlying metabolic aberrancy in gout and is defined as the serum urate level, in body fluids, above which urate precipitates into monosodium urate crystals. A urate level greater than 6.8 mg/dL is considered hyperuricemia.

Prevalence

Gout is a fairly common disease, more common in men than women, and rare in premenopausal women. There have been few studies on the incidence or prevalence of gout and even fewer on CPPD arthropathy. In a population of medical students with a median age of 22 years, the cumulative incidence of gout was reported as 8.6%.¹ In this same study, body mass index (relative risk [RR], 1.12), excessive weight gain (RR, 2.07), and hypertension (RR, 3.26) were identified as risk factors for developing gout.¹

Overall, the prevalence of gout in the U.S. population increased between 1990 and 1999,² and factors such as lifestyle habits, obesity, diet, alcohol intake, comorbid diseases such as hypertension, and the use of diuretics were identified as potential contributing factors.³ A study done in the United Kingdom, examining the epidemiology of gout, reported the prevalence of gout to be 1.4% in 1999 and as high as 7% in men older than 65 years.⁴ Reviews have found that epidemiologic investigations suggest that incidence of gout is on the rise worldwide.⁵

The annual incidence of gouty arthritis is about 5% at serum urate levels of 9.0 mg/dL or higher and less than 1% at urate levels of 7 mg/dL and lower.⁶

Pathophysiology

Gout is an inflammatory crystal arthropathy that results from the pathogenic effect of MSU crystals in the joints and soft tissue. Uric acid in body fluid, at pH 7.4, exists in the urate form. Thus, when referring to uric acid in physiologic fluid it is preferable to use the term urate.

Uric acid comes from the metabolism of purine nucleotides. Purine metabolism leads to inosine then hypoxanthine. Hypoxanthine is metabolized to xanthine and xanthine to uric acid. These two last steps are catalyzed by the enzyme xanthine oxidase, which is the major site for pharmacologic intervention by allopurinol. Uric acid, in humans, is the final product. Human beings lack the ability to degrade urate further.⁷

Minimal amounts of urate are eliminated through the urinary and intestinal tracts. Therefore, when the human body is unable to eliminate large burdens of urate, hyperuricemia develops. As urate levels increase and saturate the synovial fluid or soft tissues, crystals precipitate, leading to tissue damage and the development of tophi. After urate crystals deposit in soft tissues and joints, monocytes and macrophages are activated in an attempt to clear the crystals by phagocytosis. This then leads to the release of proinflammatory cytokines and chemokines into the surrounding area, triggering a cascade of acute inflammatory reaction and influx of neutrophils into the joint, for example.^7,⁸

The mechanism leading to the self-limited inflammatory process is not fully unveiled. The innate anti-inflammatory processes, mediated by anti-inflammatory cytokines, possibly are called into action and interrupt the inflammatory process.⁸ Thus, the natural course of gout is one that would resolve spontaneously in 1 to 2 weeks on average.⁷

An additional proposed mechanism has been elucidated in research work indicating the role of an inflammasome and interleukin 1 (IL-1) in the pathogenesis of inflammation induced by monosodium urate (the crystal in gout) and calcium pyrophosphate dehydrate (the crystal in pseudogout). Cryopyrin inflammasome detects MSU and CPPD crystals, resulting in an inflammatory cascade by activation of IL-1.⁹ These IL-1–mediated inflammatory effects of MSU crystals could potentially be blocked by IL-1 inhibitors, such as anakinra. This presents opportunities for the management of patients with gouty arthritis who are otherwise intolerant of or inadequate responders to standard anti-inflammatory therapies. Large randomized, controlled trials are required to assess the benefit and safety of blocking IL-1 in the management of polyarticular gouty arthritis.

Clinical Manifestations

The cascade of pathologic events leads to acute inflammation of the joint or soft tissue. The clinical manifestations of gout include arthritis, direct soft tissue damage, and accumulation of MSU crystals, known as tophi, in soft tissue and bones. Hyperuricemia can also result in uric acid nephrolithiasis and possible nephropathy if uric acid accumulates in the renal interstitium and tubules.

The arthritis in acute gout usually manifests as asymmetric monoarticular or oligoarticular inflammation, lasts 3 to 10 days, and resolves spontaneously. Eventually the attacks occur more frequently, last longer, and do not resolve completely, leading to chronic gouty arthropathy. Gouty arthropathy can lead to erosions and joint destruction, but it is distinguished from rheumatoid arthritis by the absence of joint space narrowing and absence of periarticular osteopenia.

In general, joints involved in gout include the lower extremity joints as well as those of the upper extremities. Inflammation in joints such as the first metatarsophalangeal (MTP) joints is termed podagra and is highly suggestive of gout. Any joint in the feet, ankles, knees, hands, wrists, or elbows may be involved. Acute gout can occur in bursae, such as the olecranon or prepatellar bursae, causing bursitis.

Occasionally, a gout attack triggers a systemic inflammatory response manifesting with fevers, leukocytosis, elevated sedimentation rates, and elevated C-reactive protein (CRP).

Acute attacks can be precipitated by several factors, such as increased alcohol consumption (especially beer), trauma, use of diuretics, dehydration, cyclosporine, diet (organ meat, shellfish), and any drug that can lead to sudden changes (increase or decrease) in urate levels, such as hypouricemic agents.^10,¹¹

When urate accumulates in a supersaturated medium, it can deposit in soft tissue or bones and form a tophus. Tophi can be present over the helices of the ears, extensor areas of the limbs, pressure areas such as the finger pads, and over the Achilles tendons. Occasionally, they are not seen on physical examination but are noted on x-ray films as cystic or masslike lesions. In general, a tophus on radiographic films is radiolucent, but when it occurs over a calcified nodule it may be seen as radioopaque.¹²

Diagnosis

Analysis of Synovial Fluid

Synovial fluid analysis is the gold standard for diagnosis, and one should attempt a synovial aspiration for microscopic analysis whenever feasible.

Synovial fluid analysis offers a valuable diagnostic tool for evaluating patients with gout or pseudogout. Once the fluid is aspirated, it can be examined grossly for color and turbidity. In general, transparent synovial fluid in the syringe is more suggestive of a noninflammatory condition, whereas fluid that appears turbid or purulent is more suggestive of inflammation or infection (e.g., rheumatoid arthritis, gout, septic arthritis). However, gross appearance alone is by no means diagnostic.

To confirm or rule out infection, the fluid needs to be processed for Gram stain and culture. It is possible to have concomitant gout and septic arthritis at the same time. On microscopic examination, the number of white blood cells (WBCs) per high-power field can be estimated. The WBC count may be a useful adjunct in estimating the degree of inflammation present.¹³ With gout, synovial fluid analysis reveals leukocytosis, a nonspecific finding of inflammatory arthritis including infectious and crystalline causes.

Crystal analysis is done with compensated polarized light. An accurate diagnosis can be made by a trained observer by detecting and identifying MSU crystals or CPPD crystals.¹⁴

MSU crystals are birefringent, with strong negative elongation when viewed under compensated polarized light. CPPD crystals are weakly birefringent and rhomboid or rod shaped. CPPD crystals might not be as evident and thus possibly missed, especially if the analysis is not done by a trained examiner.¹³^–¹⁵ In addition to shape and birefringence, MSU and CPPD differ in color depending on the axis of orientation with respect to the polarizer. When the axis of the MSU crystal is parallel to the polarizer it appears yellow, and when it is perpendicular it appears blue. The CPPD crystal is the reverse of that, so when the CPPD crystal is parallel it appears blue and when perpendicular it appears yellow (Table 1).¹³

Table 1 Differences Between Monosodium Urate and Calcium Pyrophosphate Dehydrate Crystals with Synovial Analysis

Characteristic	MSU	CPPD
Birefringence	Strong	Weak
Shape	Needle-like, sharp edges	Rhomboid, rod-like
Color parallel to polarizer	Yellow	Blue
Color perpendicular to polarizer	Blue	Yellow

CPPD, calcium pyrophosphate dehydrate; MSU, monosodium urate.

Comorbid Conditions

Once the diagnosis of gout has been made, other associated medical conditions need to be considered, such as alcoholism, the metabolic syndrome, myeloproliferative disorders, and possible medication triggers (diuretics, cyclosporine). Any comorbid disease should be appropriately managed as clinically indicated.

Differential Diagnosis

Differential diagnosis of monoarticular arthritis includes infection, pseudogout, atypical rheumatoid arthritis, trauma, and fracture. The differential diagnosis should be considered based on the history and clinical presentation. Thus, the best approach starts with a good history and physical examination. If the history and clinical examination do not indicate a history of trauma or fracture, then a synovial aspiration, as discussed earlier, is performed, rather than an x-ray of the joint.

Erosive gouty arthropathy can mimic rheumatoid arthritis or CPPD arthropathy. Often, patients with advanced gouty arthropathy, especially of the hands, are mistakenly treated for rheumatoid arthritis.

Treatment

Treatment depends on the clinical presentation and findings. The aim in treating gout is to treat the acute attack, prevent future attacks, and prevent chronic joint and soft tissue mutilation from chronic tophaceous gouty arthropathy. As discussed earlier, gout is characterized by the acute or subacute attacks of joint or soft tissue inflammation resulting from deposit of MSU crystals. Hyperuricemia and gout may be divided into three stages: asymptomatic hyperuricemia, acute intermittent gout, and chronic tophaceous gout.

Asymptomatic Hyperuricemia

There are no sufficient data to support treatment of asymptomatic hyperuricemia with hypouricemic agents. In general, initiating such therapy in asymptomatic persons is not recommended, but one should consider investigating the underlying comorbid conditions and treating those conditions as clinically indicated.

Acute Intermittent Gout

The acute attack can be managed with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids (intra-articular injection or systemic). The choice of agent is dictated by the patient’s tolerance of those medications and the presence of any comorbid diseases that prevent the use of such drugs. Younger, otherwise healthy patients who can tolerate NSAIDs or colchicine may be treated with either. NSAIDs should be avoided in patients who are intolerant of such drugs or in whom such drugs are contraindicated. NSAIDs are contraindicated in renal disease, insufficiency, or failure; gastrointestinal bleeding, ulcers, or gastritis; high risk of cardiovascular disease; and history of allergy to the drug. Occasionally, in an acute gouty attack, when all of these medications are contraindicated, narcotics may be used to relieve pain until the acute attack has resolved.

Nonsteroidal Anti-inflammatory Drugs

Although indomethacin has been traditionally used for acute gout, most other NSAIDs can be used as well. NSAIDs provide rapid symptomatic relief within the first 24 hours. Indomethacin can be given at a dose of 150 mg (in three divided doses) daily for the first 3 days then 100 mg (in two divided doses) for 4 to 7 days.¹⁶

NSAIDs should be avoided in patients who are intolerant of such medications or who have other comorbid conditions contraindicating their use. Avoid NSAIDs in patients at risk for gastrointestinal (GI) bleeding, GI intolerance, or gastropathy; renal failure; hepatic failure; congestive heart failure; asthma; or hypersensitivity to NSAIDs. Avoid NSAIDs in the third trimester of pregnancy.

Adverse effects of NSAIDs should be discussed with the patient. These include potential GI intolerance, GI bleeding,¹⁷ GI ulceration or perforation, nephrotoxicity, prolonged bleeding, fluid retention, risk of cardiovascular events, Stevens-Johnson syndrome, and others.

Colchicine

Colchicine originates from the autumn crocus plant; it works as an anti-inflammatory agent.¹⁸ Early on, colchicine blocks microtubule assembly in neutrophils, which attenuates phagocytosis and the transport of MSU crystals to the lysosome.⁶ Colchicine impedes the activation of neutrophils in the vicinity of MSU crystals by blocking the release of chemotactic factors, thus diminishing recruitment of polymorphonuclear leukocytes to the inflamed joint.¹⁸

Colchicine offers the best response when initiated within the first 48 hours of acute gout. Patients usually notice improvement within 48 hours of therapy. During acute gout, oral colchicine can be started at 0.6 mg three or four times daily (taken preferably every 8 hours or in doses separated by at least 1 hour) for 2 days, then decreased to twice daily. Colchicine should not be prescribed to be taken until diarrhea develops, because this will only add more ailment to the patient already suffering from marked pain. Once symptoms resolve, colchicine may be stopped. However, colchicine may be continued at a dose of 0.6 mg every 12 hours to prevent further attacks.

Intravenous colchicine should be used only by experienced rheumatologists and reserved for hospitalized patients, if absolutely necessary, who are unable to take oral colchicine. Caution must be used with dosing, which must not exceed 3 mg per dose. Intravenous colchicine carries a high risk of myelosuppression, can be caustic, and has been associated with fatalities.

Onset of action (pain relief) is 24 hours after the first oral dose. Colchicine requires dose adjustment with decreased renal function and should not be used in dialysis patients because it is not dialyzable.

Adverse effects of colchicine include diarrhea, abdominal cramping, bone marrow suppression, axon-loss neuropathy, myopathy (especially in renal insufficiency), potential liver toxicity, arrhythmia, shock, and skin rash (uncommon). Use caution in patients with biliary obstruction, hepatic failure, or renal insufficiency or end-stage renal disease and in pregnant women, neutropenic patients, and transplant patients on cyclosporine. Concomitant use of colchicine with cyclosporine can lead to rapid-onset myopathy and increased myelosuppression.^16,¹⁸

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