Gout is the clinical manifestation from the tissue deposition of monosodium urate (MSU) crystals. The disease has become more prevalent in Western populations, specifically in certain patient groups such as transplant recipients. It is one of the few medical conditions for which physicians have a nearly complete understanding of the causative and necessary factor for its development, in this case a serum urate concentration above the saturation threshold, or hyperuricemia. This understanding of the etiology and therapeutic target of the disease has not translated into adequate management for the majority of patients with gout because of a combination of factors, including incomplete knowledge of the basic therapeutic principles of the disease and the growing complexity of patients with gout, driven by multiple comorbidities or polypharmacy. Until recently, a scarcity of therapeutic options for gout added to these challenges, but that panorama has started to change.

Gout is a chronic disease that, if untreated, typically progresses over four phases: (a) asymptomatic hyperuricemia, (b) gout flares, (c) intercritical periods, and (d) chronic, usually tophaceous gout. This progression is illustrated in Figure 20.2. Typically, gout flares present as warmth, swelling, erythema, and pain of abrupt onset in the involved joint, with symptoms peaking over 8 to 12 hours. Patients usually describe the pain as excruciating, and even the slightest physical contact with the affected area (like that produced by a bedsheet) can induce marked suffering. Nighttime onset of symptoms is frequent. Fever, chills, and malaise are commonly part of the presentation in patients with polyarticular flares. In the elderly, atypical presentations that include delirium are frequent. Commonly, the involved joints are in the feet (with the first metatarsophalangeal being eventually involved in more than 90% of cases), ankles, knees, elbows, wrists, and fingers. The predilection for the lower extremities is because of lower temperatures in these joints that favor the precipitation of MSU crystals. Extra-articular sites are also involved, including the bursas (mainly the olecranon and prepatellar bursas) and tendons. The first attack is usually monoarticular, and locates at the first metatarsophalangeal joint in 50% of the cases. Precipitants of gout flares include acute illness (trauma, sepsis, surgery), alcohol intake, starvation, excessive intake of certain food groups (mainly purines), and medications. Drugs such as allopurinol, thiazides, and cyclosporine—which affect serum urate levels or cause body fluid shifts—have been associated with gout flares. Untreated attacks frequently resolve over 3 to 10 days, sometimes with exfoliation of the overlying skin.

The clinical course of gout is characterized by an amelioration or complete disappearance of symptoms during the intercritical period. However, if the disease progresses into chronic gout, the length of these intercritical periods shortens and chronic joint pain persists even during these intercritical periods (Fig. 20.2). It is not infrequent to recover MSU crystals from aspirates of a previously affected joint during the intercritical period.

Chronic gout is characterized by the unremitting nature of the symptoms, destructive arthritis, and the identifiable deposition of solid uric acid in tissues
(tophi). At this stage the involved joints remain persistently uncomfortable, stiff, and swollen. The condition may mimic other inflammatory arthritides, such as rheumatoid arthritis. Superimposed acute flares, which are usually polyarticular and additive, still occur. Tophi appear as a function of the degree and duration of untreated hyperuricemia, usually over extensor surfaces (forearms and the Achilles tendon) and pressure points, typically in the fingers, wrists, knees, and olecranon bursas.

The diagnosis of gout is strongly supported by the combination of a classical clinical presentation (monoarthritis and tophi) along with evidence of hyperuricemia and clinical response to colchicine, NSAIDs, or glucocorticoids. However, it is very important to emphasize that each one of these diagnostic considerations are imperfect and that the diagnosis can only be reliably established by the identification of negatively birefringent needle-shaped MSU crystals from an affected joint or tissue.

The most common way of identifying MSU crystals in patients suspected of having a gout flare is through synovial fluid aspiration from an affected joint. The fluid obtained from joints affected by gout is usually turbid with a yellow tinge, but in extreme cases, it is thick and chalky, with a white coloration. The cell counts are usually in the inflammatory range from 3,000/mm³ up to greater than 50,000/mm³, more than 90% of these cells being polymorphonuclear. Often, needle-shaped MSU crystals can be identified under standard light microscopy. However, the optimal way to visualize MSU is through polarized light microscopy, in which needle-shaped MSU crystals will appear with a bright-yellow or blue coloration (depending on if the axis of the polarizer is parallel or perpendicular to the crystal) against a purple background (Fig. 20.1). Many times the MSU crystals are found inside a leukocyte that is attempting phagocytosis. Despite being the standard way of determining the presence of a gout flare, synovial fluid analysis with crystal identification has some drawbacks. For example, patients with gout and hyperuricemia that are not having a gout flare could have MSU crystals in their joint synovial fluid (usually in the context of a noninflammatory cell count). Also, the aspiration of small joints could be technically challenging and the procedure could be difficult to perform for untrained practitioners. Another potential issue is that synovial fluid has to be promptly analyzed as cells counts decline and crystals degenerate when sample processing is delayed. Finally, the identification of MSU crystals in partially treated patients or those in which the gout flare is resolving can be challenging and requires lots of patience on part of the examiner. Bursal fluid, tophi aspirates, and tissue samples can also be analyzed with the purpose of identifying MSU crystals.

Measurement of serum urate is an unreliable predictor of gout flares and should not be used with diagnostic purposes as up to 40% of cases of acute gout occur in the setting of normouricemia. On the other hand, hyperuricemia is frequent in the general population and could be present in the setting of an acute arthritis secondary to rheumatoid disease, psoriasis, infection, and so on. Other ancillary investigations such as the measurement of urine urate excretion and plain radiographs have a limited role in diagnostic and management decisions.

The American College of Rheumatology (formerly American Rheumatism Association) proposed preliminary criteria for the diagnosis of acute gouty arthritis in 1977 (Table 20.2; 4). Despite their widely adopted use and citation, those were never validated, and important limitations in their performance have been recognized. More recently, the European League Against Rheumatism has proposed recommendations for the diagnosis of gout that translate
into a diagnostic rule (5). In addition, a Dutch primary care group developed a diagnostic rule for identification of gout in patients with monoarthritis without the need of an arthrocentesis that could be of great usefulness to clinicians in communities without access to prompt synovial fluid analysis (Table 20.2; 6).