Clinical manifestations and diagnosis of gout

INTRODUCTION — Gout (monosodium urate [MSU] crystal deposition disease) is characterized biochemically by extracellular fluid urate saturation, which is reflected in the blood by hyperuricemia, with serum or plasma urate concentrations exceeding 6.8 mg/dL (approximately 400 micromol/L); this level of urate is the approximate limit of urate solubility [1]. The clinical manifestations of gout may include:

●Recurrent flares of inflammatory arthritis (gout flare)

●A chronic arthropathy

●Accumulation of urate crystals in the form of tophaceous deposits

●Uric acid nephrolithiasis

●A chronic nephropathy that, in gouty patients, is most often due to comorbid states

Hyperuricemia is a necessary but not sufficient precondition for the development of urate crystal deposition disease and should be distinguished from gout, the clinical syndrome. Most hyperuricemic individuals never experience a clinical event resulting from urate crystal deposition.

The clinical manifestations and diagnosis of gout flares, chronic gouty arthritis, and tophaceous disease will be reviewed here.

Topics discussed separately include:

●Mechanisms underlying hyperuricemia and nonmodifiable and modifiable risk factors for hyperuricemia (see "Urate balance" and "Pathophysiology of gout")

●Asymptomatic hyperuricemia (see "Asymptomatic hyperuricemia")

●Treatment of gout flares (see "Treatment of gout flares")

●Prevention of recurrent gout flares (see "Nonpharmacologic strategies for the prevention and treatment of gout" and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout")

●Acute and chronic uric acid nephropathy and uric acid nephrolithiasis (see "Uric acid kidney diseases" and "Kidney stones in adults: Uric acid nephrolithiasis")

●Hyperuricemia and gout in recipients of renal transplants (see "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients")

HISTORIC PERSPECTIVE — Descriptions of the epidemiology, clinical features, and natural history of gout have evolved over more than two millennia of observations and study. The latter half of the 20^th century produced confirmation that the pathogenesis of gout involves urate crystal deposition. Pivotal in this progress was the introduction of polarized light microscopy into clinical practice, providing urate crystal identification in synovial fluid as the means to achieve rapid and definitive diagnosis and to resolve the formerly ambiguous relationship between hyperuricemia and gout [2]. Further study increased understanding of the molecular pathophysiology of gouty inflammation. (See "Pathophysiology of gout".)

In addition, the development of drugs capable of suppressing gouty inflammation and reversing hyperuricemia has provided means to prevent, and even reverse, the previously ravaging effects of acute inflammatory and chronic destructive manifestations of urate crystal deposition.

These advances have favorably influenced the course of gout in the majority of appropriately treated individuals. However, gout has less than optimal clinical outcomes in a large majority of cases, despite attempts at treatment [3,4]. This is particularly true among nonadherent or poorly instructed patients [5,6] and in patients whose demographic profiles do not fit what may have historically been considered the "classic" clinical profile of the gouty patient (ie, a 30- to 60-year-old man who is likely to be obese, hypertensive, and a frequent imbiber of alcohol).

These "non-classic" at-risk groups that are increasingly common differ from the classic profile in that they include patients of older age, an increased proportion of women [7-9], organ transplant recipients receiving diuretics and a calcineurin inhibitor such as cyclosporine or tacrolimus, and the more frequent presence of concurrent illnesses and therapies [9-11]. (See "Diuretic-induced hyperuricemia and gout" and "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients" and 'Epidemiology and risk factors' below and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Management principles and initial postdiagnostic assessment'.)

EPIDEMIOLOGY AND RISK FACTORS — Gout tends to occur earlier in life in males than females and is rare in childhood.

●Incidence and prevalence – Both the incidence [12,13] and prevalence [14-16] of the disease increased from the late 1970s to the mid-2000s in the United States, where it exceeded 3 percent in adults [17-20]. Estimates of the prevalence of gout in the United States range from less than three million [17] to eight million or more individuals [18,21,22]. Another estimate describes increasing prevalences from 2011 until 2018, with a more recent prevalence estimate of 5.1 percent and affecting approximately 12 million individuals [23].

The prevalence of gout has continued to increase steadily in the United Kingdom and worldwide [16,19,22,24].The prevalence of gout was reported to be stable in the United States in population surveys conducted from 2007 to 2016 [22], although it continued to rise subsequently [23].  

In the United States, the largest increase in prevalence of gout is among Asian American individuals [23]. From 2017 to 2018, the age and sex-adjusted prevalence of gout among Asian American individuals increased from 3.3 to 6.6 percent. Gout was more common among Asian American individuals than any other racial or ethnic group during this period.

●Impact of age – Childhood serum urate levels normally range from approximately 3 to 4 mg/dL and are similar in prepubescent males and females [25]. Thus, gout is rare in children, except in instances of marked hyperuricemia due to urate overproduction, such as inherited defects in enzymes of purine metabolism or diseases with greatly increased rates of cell proliferation (table 1), or due to severely impaired renal uric acid clearance, as in familial juvenile hyperuricemic nephropathy (table 2).

●Impact of sex - In men, adult serum urate levels of 5 to 6 mg/dL are usually reached at puberty, with little increase thereafter due to age alone [26]. The corresponding age-related course of serum urate levels differs in women, in whom serum urate concentrations average approximately 1.0 to 1.5 mg/dL lower than men of similar age; the lower levels result from higher urinary fractional excretion of urate during the childbearing period, which is mediated by estrogenic compounds [27,28]. After menopause, the urate concentrations in women rise to levels comparable to those in adult men [29]. The sex differences in age-related patterns of urate concentration appear to affect the clinical differences between males and females in the age of onset of gout [12,13]; increases in gout incidence are detectable in men by the fourth or fifth decades of life and in women by the sixth or seventh decades. These observations suggest an average period of asymptomatic hyperuricemia of at least 10 years or more in both males and females prior to the clinical expression of gout and provide at least a partial explanation for the greater prevalence of gout in men through at least the ninth decade [12-14].

●Risk factors - Increases in onset and recurrences of gout likely reflect changes in both nonmodifiable and modifiable risk factors for hyperuricemia and gout (table 3). Notable among these factors are increased longevity and age-associated cardiovascular, metabolic, and renal diseases in the population; the use of medications that alter urate balance as an unintended consequence of treatment for these chronic disorders (and to prevent organ rejection among transplant recipients); and increased dietary intake of foods and food additives (such as high-fructose corn syrup) that contribute to the development of obesity and diabetes mellitus. The epidemiology and risk factors for hyperuricemia and gout are described in more detail separately. (See "Asymptomatic hyperuricemia", section on 'Epidemiology' and "Pathophysiology of gout", section on 'Hyperuricemia and gout' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Management principles and initial postdiagnostic assessment'.)

NATURAL HISTORY — Persistent hyperuricemia is a common biochemical abnormality that results from excessive urate production and/or absolute or relative impairment of renal uric acid excretion (see "Urate balance"); all patients with gout have hyperuricemia (saturation of serum for urate) at some point in their disease. However, most hyperuricemic individuals never experience a clinical event resulting from urate crystal deposition.

The three classic clinical stages in the natural history of progressive urate crystal deposition disease (gout) are:

●Gout flares (see 'Gout flares' below)

●Intercritical gout (see 'Intercritical gout and recurrent gout flares' below)

●Chronic gouty arthritis and tophaceous gout (see 'Tophaceous gout' below)

The clinical stages of gout can be regarded as emerging sequentially (but with some overlapping), with clinical severity that often parallels the frequency of gout flares and the eventual development of chronic gouty arthropathy and tophaceous gout. In this context, treatment with antihyperuricemic (urate-lowering) agents is not curative, but it may reset the course of the individual patient and provide what is effectively a cure if subsaturating urate levels (<6 mg/dL [357 micromol/L]) are achieved and maintained.

Prior to the availability of effective urate-lowering treatment, the interval from the first gout flare to the onset of chronic gouty arthritis or detectable tophi averaged approximately 12 years, although intervals ranging from less than 5 to 40 years were noted in individual patients. During this era, duration of gout and degree of hyperuricemia were correlated with the rate and extent of tophus formation. After 20 years of untreated gout, almost 75 percent of patients were affected, with the highest prevalence of tophaceous gout in patients with the highest serum urate concentrations [30].

Urate-lowering treatment of gout with either uricosuric agents or allopurinol initially led to a dramatic reduction in chronic gouty arthritis and tophaceous gout, particularly among patients with primary gout who were adherent to treatment and among most patients with secondary gout, with a prevalence of less than 5 percent reported in some series [31]. When progression does occur, it is most often among nonadherent patients, those to whom the management scheme has not been appropriately communicated, and those in whom the diagnosis of gout has not been made.

Other patients liable to show progression of gout include those intolerant of urate-lowering agents or those treated with inadequate doses of such agents, those receiving medications (usually for comorbidities) that interfere with urate-lowering agents, and organ transplant recipients. These factors differ from those associated with the manifestations of acute hyperuricemia (primarily acute renal failure) seen in the tumor-lysis syndrome or with other causes of massive tissue breakdown. (See "Uric acid kidney diseases", section on 'Acute uric acid nephropathy'.)

As examples:

●Residual prevalences of chronic polyarticular and tophaceous gout approaching 50 percent have been reported in some series of men with gout whose major risk factors were excessive alcohol consumption, diuretic use, and, most importantly, suboptimal management with or low adherence to urate-lowering therapy [5,6].

●The triad of diuretic-induced hyperuricemia, renal insufficiency, and nodal osteoarthritis plus overrepresentation of women represents a distinctly different presentation from the classically described group of middle-aged men with tophaceous gout with longstanding disease. Patients in the former group are typically older adults and prone to develop polyarticular and tophaceous gout in osteoarthritic joints:

•In one report, 8 of 60 patients with gout were older women (mean age 82 years), all of whom were receiving diuretic therapy; most had tophi in osteoarthritic interphalangeal joints [9].

•In a second series, 17 percent of 149 patients with osteoarthritis had gout, often with low-grade inflammation, in osteoarthritic finger joints [32]. These patients were older (mean age 71 years) and were evenly distributed in sex. Over 70 percent were receiving diuretics, 60 percent had impaired renal function, and the mean serum urate concentration was 11 mg/dL (654 micromol/L).

●Organ transplant recipients treated with calcineurin inhibitors (and often diuretics as well) are at increased risk for the accelerated development of tophaceous gout [10,11]. Both renal and cardiac transplant recipients, particularly those with compromised renal function, have developed often difficult-to-manage complications of the hyperuricemic effects of cyclosporine (and, less commonly, tacrolimus [33]), which result from impaired renal urate excretion [10]. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)

●Other patients at increased risk for tophaceous gout are those who have chronic kidney disease that has been probably erroneously felt to preclude full-dose antihyperuricemic drug therapy, those who are allergic to or intolerant of urate-lowering agents, and those receiving doses of urate-lowering agents that are inadequate to achieve goal serum urate levels in a range below the limit of urate solubility (often recommended as <6 mg/dL [357 micromol/L]) [34,35].

CLINICAL MANIFESTATIONS

Gout flares — A gout flare is typically monoarticular and intensely inflammatory, occurring in the lower extremities. A variety of dietary and physical factors, comorbidities, medications, and other factors may predispose to or provoke the gout flare (see 'Factors provoking gout flares' below and 'Typical gout flare' below). Joints in other regions may also be involved, and patients may experience polyarticular flares, which are more likely to occur in patients with more longstanding disease (see 'Polyarticular gout flares' below). Patients with gout who have sustained chronic hyperuricemia may develop tissue deposits of solid urate with associated articular injury. (See 'Tophaceous gout' below.)

Factors provoking gout flares — Numerous circumstances promote or are associated with gout flares, either as incident gout or as recurrences of established disease; these sometimes work in combination and include a range of dietary and physical factors, comorbidities, medications, and other issues (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Management principles and initial postdiagnostic assessment' and "Nonpharmacologic strategies for the prevention and treatment of gout"):

●Physiologic alterations – Circumstances that promote gout flares include conditions that may provoke generalized disturbances in extracellular fluid urate concentrations or may increase the proinflammatory activities of cells interacting with monosodium urate (MSU) crystals deposited in tissues or in extracellular fluids [36]. These conditions include trauma, surgery, starvation, fatty foods and other dietary triggers, dehydration, ingestion of drugs affecting (raising or lowering) serum urate concentrations (eg, thiazide and loop diuretics and low-dose aspirin or allopurinol and uricosuric agents, respectively), and may include vaccination [37,38]. The risk of flare due to thiazide and loop diuretics appears comparable [39].

●Alcohol consumption – Alcohol consumption, including beer, spirits, and wine, is associated with a greater risk of gout flare in patients with established gout [40]. (See "Nonpharmacologic strategies for the prevention and treatment of gout".)

●Anatomic factors – Local anatomic factors may predispose individual joints to gouty inflammation; these include locally elevated urate concentrations [41] in conjunction with repeated joint microtrauma, prior degenerative change, or reduced temperature in poorly perfused distal tissues [42].

Osteoarthritic changes in interphalangeal joints (Heberden's and Bouchard's nodes) may predispose these joints to develop coexisting gout [32,43], particularly in older individuals with chronic kidney disease or in those receiving diuretic therapy. (See "Diuretic-induced hyperuricemia and gout".)

●Urate-lowering therapy – The initiation of urate-lowering therapy, although protective in the long term, can precipitate a gout flare, particularly in the early months of urate-lowering treatment [44-48]. As a result, antiinflammatory prophylaxis is usually given to prevent this complication [35]. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylaxis during initiation of urate-lowering therapy'.)

●Hospitalization – Hospitalization is a well-recognized risk factor for flares in patients with gout. A retrospective study among hospitalized patients in New Zealand described predictive factors for flare among hospitalized patients with gout including an elevated pre-admission serum urate (>6 mg/dL), presence of tophi, not being on urate-lowering therapy, presence of acute kidney injury, surgery, initiation or increase of gout flare prophylaxis, adjustment of the urate-lowering therapy while in the hospital, and use of diuretics [49].

At least several of these factors are often present together and might work in combination. As an example, lower body temperature, relative dehydration, and relatively low blood cortisol levels are present during the overnight and early morning hours during which gout flares are most likely to develop [50].

Typical gout flare — The typical gout flare, which is intensely inflammatory, includes the following clinical features:

●Severe pain, redness, warmth, swelling, and disability – Maximal severity of the flare is usually reached within 12 to 24 hours. Complete resolution of the earliest flares almost always occurs within a few days to several weeks, even in untreated individuals. Resolution of the gout flare is sometimes accompanied by desquamation of the skin overlying the affected joint. The physiologic basis of the resolution of acute gouty inflammation is complex but centers on the action of endogenous and exogenous suppressors of gouty inflammation [51]. (See "Pathophysiology of gout".)

●Onset more often at night – Gout flares are most frequent overnight and in the early morning (between midnight and 8:00 AM), when they are more than twice as likely as during the daytime [50].

●Lower-extremity involvement – At least 80 percent of initial flares involve a single joint [52], most often at the base of the great toe (first metatarsophalangeal joint, known as podagra) or the knee.

●Signs of inflammation beyond the joint – This feature may give the impression of dactylitis (sausage digit) or cellulitis or may actually be due to arthritis in several contiguous joints or tenosynovitis.

●Potential additional sites – Involvement in an ankle or instep or in a wrist, finger, or olecranon bursa, which can occur initially but is more common in a recurrent gout flare. Other potential sites of involvement include other bursas, shoulders, hips, and sternoclavicular joints.

●Uncommon involvement of axial joints – Although much less common than peripheral involvement, gout can also occur in the spine and sacroiliac joints, which may cause diagnostic confusion [53,54]. The lumbar spine region is most commonly reported as affected. Most proven cases of gout presenting as acute or chronic back pain have been associated with tophaceous involvement. There may also be neurologic signs and symptoms.

●Mild and rapidly self-limited inflammatory episodes – These appear to occur in some patients but have not been well studied.

Polyarticular gout flares — A polyarticular pattern is the initial manifestation in less than 20 percent of patients with gout but occurs with increasing frequency in later flares. Polyarticular symptoms are particularly common late in the course of untreated gout, when multiple recurrences, short or absent symptom-free intervals, and palpable tophaceous deposits are common (see "Evaluation of the adult with polyarticular pain"). Polyarticular flares are more frequent among hospitalized patients and can be accompanied by fever and mimic sepsis [55]. Oligo- and polyarticular flares have also been associated with the presence of multiple medical comorbidities, obesity, and hypertension [56].

A polyarticular initial presentation of gout may be more frequent in patients in whom hyperuricemia and gout arise secondary to a myeloproliferative or lymphoproliferative disorder [57] or in organ transplant recipients who are receiving cyclosporine or tacrolimus [10]. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)

Polyarticular gout flares may occur in a sequential (migratory) pattern or simultaneously or may involve a cluster of adjacent joints, tendons, and bursas.

Intercritical gout and recurrent gout flares — Upon resolution of a gout flare, the patient is said to have entered an intercritical (between flares) period. Even after severe and incapacitating gout flares, intercritical periods early in the course of gout are most often entirely asymptomatic. This sequence is so uncommon in arthritic disorders other than crystal deposition diseases and palindromic rheumatism that its presence is highly suggestive of the diagnosis. (See 'Diagnosis' below.)

Intervals between gout flares are of variable duration. Most untreated patients with gout will experience a second episode within two years. As an example, one large group of patients studied prior to effective antihyperuricemic (urate-lowering) therapy found that 62 percent of patients had a second flare within the first year, 78 percent within two years, and 93 percent within 10 years [58]. The risk of recurrent flares is higher in those with worse hyperuricemia at baseline [59] and with chronic kidney disease. The trend among untreated patients is toward recurrent gout flares that occur after progressively shorter asymptomatic periods and that are increasingly prolonged and disabling, polyarticular, and may be associated with fever.

Despite the intermittency of flares, continued deposition of tophaceous material may occur, causing bony erosions that can evolve into chronic gouty arthropathy.

The initial intercritical period provides an opportunity to establish the diagnosis of gout (if this has not been accomplished during the gout flare) through consideration of one or several potential sources of information, including pertinent clinical diagnostic criteria (see 'Clinical diagnosis of intercritical gout' below); analysis of the aspirate of a previously involved joint or a suspected tophus for crystals, which often persist between flares (see 'Diagnosis of intercritical or tophaceous gout' below); and the results of imaging studies of previously inflamed joints. (See 'Role of imaging in diagnosis' below.)

In addition, the intercritical period is also a time during which important patient education and counseling regarding the management of hyperuricemia and gout can take place. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Management principles and initial postdiagnostic assessment' and "Nonpharmacologic strategies for the prevention and treatment of gout".)

Tophaceous gout — Tophaceous gout is characterized by collections of solid urate accompanied by chronic inflammatory and often destructive changes in the surrounding connective tissue [60]; tophi are often visible and/or palpable and can be present on the ears or in the soft tissues, including articular structures, tendons, or bursas (picture 1). Tophi are typically not painful or tender. They may attenuate the skin, revealing a yellow or white color. On the ear, they do not transilluminate.

The chronic inflammatory process may extend beyond the confines of a single joint, producing generalized enlargement of a digit due to the presence of tophi and/or the inflammation itself. The clinical appearance may be similar to dactylitis seen in other disorders such as psoriatic arthritis, other spondyloarthritides, and sarcoidosis. The expansive and destructive changes associated with tophaceous gout may be mistaken for osteomyelitis (image 1) and have sometimes led to erroneous amputation of involved digits [61].

A characteristic chronic granulomatous inflammatory response can be seen on histologic examination of the lesions [62]; on occasion, acute inflammation, mimicking that of a gout flare, occurs adjacent to one or several tophi (picture 2). Affected areas include articular bone and cartilage, bursas, soft tissues, tendons, ligaments, and entheses [60].

While tophi may be apparent clinically or may sometimes be detected with plain radiography, other imaging techniques are more sensitive for their detection, including ultrasonography, dual-energy computed tomography (DECT), and magnetic resonance imaging (MRI). (See 'Imaging' below and 'Role of imaging in diagnosis' below.)

It is likely that many patients with gout and sustained hyperuricemia have a much larger burden of urate crystal deposits than is suspected by clinical examination alone.

In contrast to the classic presentation, a number of reports have described patients with tophaceous deposits in the absence of, or prior to, gout flare, a presentation that was previously considered a rare occurrence restricted to patients with urate overproduction due to myeloproliferative disorders or hereditary enzyme defects [59,63]. Although this situation may, in part, reflect increasing recognition that tophi can form in any area containing connective tissue (including the meninges but not the brain and spinal cord), risk factors similar to those accounting for cryptic gout in older patients may contribute to tophus formation as the first sign of gout. Such patients are more likely to be women, have predominant or exclusive involvement of the fingers, have chronic kidney disease, and be treated with a diuretic or antiinflammatory drug [63]. (See 'Natural history' above.)

Renal complications of hyperuricemia and urate crystal deposition — There are two major renal complications of chronic hyperuricemia: nephrolithiasis and chronic urate nephropathy. These conditions are discussed in detail separately. (See "Kidney stones in adults: Uric acid nephrolithiasis" and "Uric acid kidney diseases", section on 'Chronic urate nephropathy'.)

LABORATORY FINDINGS

Synovial fluid analysis — The gout flare is characterized by the presence of monosodium urate (MSU) crystals in synovial fluid obtained from joints or bursas visualized by direct examination of a sample of fluid using compensated polarized light microscopy (picture 3 and picture 4). Urate crystals may also be identified frequently by this technique in material aspirated during the intercritical period from previously affected joints and tophaceous deposits [64].

The synovial fluid is inflammatory, with white blood cell counts in joint fluid that usually range between 10,000 to 100,000 with neutrophil predominance (see "Synovial fluid analysis"). Bursal fluid white blood cell counts are usually elevated but to a much lesser degree than joint fluid, similar to findings in patients with septic bursitis. (See "Septic bursitis", section on 'Obtaining bursal samples'.)

Blood tests — During a gout flare, blood tests may show nonspecific changes consistent with inflammation; the urate level may be high, normal, or low:

●Neutrophilic leukocytosis and/or elevation of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) are common in gout flares, but their presence in other acute arthritides generally makes these findings of little diagnostic value. An exception to this may be in distinguishing gout from events such as a stress fracture, which may cause some of the above symptoms and physical findings in the absence of laboratory abnormalities and which can be confirmed by imaging studies. (See "Overview of stress fractures", section on 'Diagnosis'.)

●Serum urate levels can be difficult to interpret during a gout flare. For example, in the early months of urate-lowering drug therapy, gout flares often occur with normal or even low serum urate concentrations at the time of the acute event. Lower urate levels have also been proposed to result from effects of cytokines during flares. Overall, normal to low serum urate values have been noted in 12 to 43 percent of patients with gout flares [65-68]. In patients suspected of gout based upon clinical features, an elevated serum urate (≥6.8 mg/dL) can lend support to the diagnosis but is thus neither diagnostic nor required to establish the diagnosis. The most accurate time for assessment of serum urate (and establishment of a baseline value) is two weeks or more after a gout flare completely subsides.

IMAGING — Imaging findings consistent with various stages of gout can be seen using several different modalities:

●Plain radiography and magnetic resonance imaging – Subcortical bone cysts apparent on plain radiography or MRI examination can be suggestive of gouty tophi or erosions. Changes of these types seen in imaging procedures are not usually detectable at the time of the first gout flare. More specific gouty lesions, such as delicate "overhanging edges" of bone associated with bone erosions due to tophi, occur with more chronic disease.

The characteristics of tophi on MRI include relatively homogeneous intermediate to low signal intensity on T1-weighted images, as well as on T2-weighted images that have variable signal intensity. Either homogeneous or peripheral enhancement may occur with the addition of gadolinium [69]. These MRI findings, although sometimes supportive of gout, cannot be considered specific, and aspirate confirmation will be needed when the differential diagnosis includes infection or malignancy.

●Ultrasonography – Findings on ultrasound examination can strongly and independently support the diagnosis of gout and may be useful in the early detection and monitoring of therapy [69-71]. Important diagnostic features include a hyperechoic linear density (double contour sign [DCS]) overlying the surface of joint cartilage (image 2) or tophaceous-appearing deposits in joints or tendons, which are represented by an ovoid stippled signal (hyperechoic cloudy area [HCA]) surrounded by a hypoechoic border (image 3) [69]. (See 'Role of imaging in diagnosis' below.)

A systematic review of the diagnostic performance of ultrasonographic findings in gout found that the DCS had sensitivities and specificities of 83 and 76 percent, respectively. For HCAs consistent with tophus, the estimate was 65 and 80 percent, respectively [70]. A large, multicenter, observational study with concurrent monosodium urate (MSU) validation evaluated the performance of ultrasound features for the diagnosis of gout [72]. The overall sensitivity and specificity of the DCS were 60 and 91 percent, respectively. When comparing those with disease for more and less than two years, only the sensitivity increased meaningfully (from 51 to 63 percent). The overall sensitivity and specificity for HCA consistent with tophus was 46 and 95 percent, respectively. Similar to the DCS, only the sensitivity increased meaningfully (from 34 to 51 percent) when comparing those with disease for less and more than two years.

In patients with asymptomatic hyperuricemia in a small pilot study, both HCA and DCS were found in the joints of some patients who had never had symptoms of gout [73]. The implications of this latter study with regard to making a diagnosis of gout in patients without symptoms of the disease await further discussion and confirmation of the findings. (See "Asymptomatic hyperuricemia", section on 'Potential clinical consequences'.)

●Dual-energy computed tomography – Dual-energy CT (DECT) examination can specifically identify urate deposits in articular and periarticular locations and can distinguish urate from calcium deposition [60,69]. There are potential artifacts with DECT, and ways to minimize them and avoid false-positive interpretations have been described [74]. In a meta-analysis of 13 studies, the pooled sensitivity and specificity of DECT was reported as 89 and 91 percent, respectively [75]. Another study reported an excellent sensitivity for gout of 90 percent but emphasized that all false-negative cases happened in cases with less than six weeks of symptom duration [76]. The yield of both DECT and ultrasound is not expected to vary when a patient is having a flare, as MSU deposition conferring radiologic findings will be present.

Although typically used just for diagnosis, DECT may also be useful for determining response to therapy and prognosis. A systematic review of the literature suggested that DECT volume is associated with response to urate-lowering therapies as well as death, cardiovascular risk, and risk of future gout flares [77].

DIAGNOSIS — The preferred approach to the diagnosis of gout is based upon the identification of intracellular monosodium urate (MSU) crystals on polarizing light microscopy of an affected joint, particularly when the diagnosis has not been established or is uncertain; when this is not feasible, a diagnosis may be made based upon clinical features, including the history, examination, laboratory, and imaging studies (algorithm 1). (See 'Diagnosis of a gout flare' below and 'Diagnosis of intercritical or tophaceous gout' below and 'Role of imaging in diagnosis' below.)

A definitive diagnosis should be sought when a gout flare is suspected, both to exclude alternative explanations for the acute event and to ensure that patients with recurrent or progressive arthritis due to another cause are not treated unnecessarily with long-term, expensive, and potentially toxic urate-lowering medications. The diagnosis of gout focuses on the fundamental pathophysiologic events defining the clinical state: tissue deposition of urate crystals and the accompanying inflammatory and potentially destructive consequences.

Diagnosis of a gout flare

Urate crystal diagnosis of a gout flare — Patients with a suspected gout flare in whom the diagnosis has not been previously established or in whom the cause of acute arthritis is uncertain should undergo arthrocentesis; testing of the synovial or bursal fluid should include cell counts and differential white count, Gram stain and culture, and examination for crystals under polarizing light microscopy (algorithm 1). The diagnosis of a gout flare is most secure when supported by visualization of MSU crystals in an inflammatory synovial fluid or an aspirate of an uninflamed joint or tophus by an experienced examiner using compensated polarizing light microscopy (see 'Synovial fluid analysis' above). The sensitivity of this technique in demonstrating negatively birefringent crystals in patients with gout flares is at least 85 percent, and the specificity for gout is 100 percent [78,79].

However, gout flares may occasionally coexist with another type of joint disease, such as septic arthritis or acute calcium pyrophosphate (CPP) crystal arthritis (pseudogout). For this reason, an acute inflammatory arthritis in a patient with a previously established diagnosis of gout or the presence of urate crystals in synovial fluid aspirated from one of several inflamed joints or from a tophus does not exclude the possibility of a second, sometimes life-threatening, process (eg, systemic infection). Careful attention should thus be given to the clinical status of the patient and to clinical, laboratory, and imaging features likely to permit an accurate differential diagnosis. (See 'Differential diagnosis' below.)

The sensitivity of the joint fluid analysis can be improved by examination of the sediment in a centrifuged specimen [80]. Additional approaches to consider in the event of a negative (no urate crystals seen) study during the gout flare include aspiration of a concurrently inflamed joint or aspiration of an uninflamed but previously involved joint or of a tophus if either is present, although aspiration of an uninflamed joint or tophus is less helpful in excluding an accompanying cause for the acute event.

Clinicians who are not skilled at joint aspiration should request the assistance of an orthopedic surgeon to obtain the fluid or of a rheumatologist to perform a joint aspiration and to help with the analysis of the synovial fluid. (See "Joint aspiration or injection in adults: Technique and indications" and "Synovial fluid analysis".)

In many patients in whom crystal confirmation of the diagnosis cannot be made, an accurate diagnosis of gout can still be established on the basis of clinical data. (See 'Clinical diagnostic criteria-based diagnosis of a gout flare' below.)

Clinical diagnostic criteria-based diagnosis of a gout flare — In patients with a gout flare in whom crystal diagnosis is not achieved, confirmation of the diagnosis of gout can be made in the gout flare setting in the absence of synovial fluid or when the polarized light microscopic study of aspirated synovial fluid is negative by use of a "diagnostic rule" utilizing a set of validated clinical, historic, and laboratory criteria [81,82] (see 'Use of a clinical diagnostic rule' below). An alternative and potentially complementary approach in such patients is use of imaging techniques to demonstrate crystal deposition noninvasively; this approach also requires particular expertise in the relevant imaging techniques and their interpretation. (See 'Role of imaging in diagnosis' below.)

Use of a clinical diagnostic rule — A clinical diagnostic approach ("rule"), which can be used to estimate the likelihood of gout, has been shown to improve the accuracy of diagnosis of a gout flare made in primary care practice without joint fluid analysis (algorithm 1) [81]. The model uses seven variables (which were assigned weighted scores) that can be ascertained in primary care to distinguish three levels of risk for gout. It uses the following variables and scoring values:

●Male sex (2 points)

●Previous patient-reported arthritis flare (2 points)

●Onset within one day (0.5 points)

●Joint redness (1 point)

●First metatarsal phalangeal joint involvement (2.5 points)

●Hypertension or at least one cardiovascular disease (1.5 points)

●Serum urate level greater than 5.88 mg/dL (3.5 points)

Based upon the total score, patients can be identified as having low (≤4 points), intermediate (>4 to <8 points), or high (≥8 points) probability of gout. In addition, the authors of the rule have developed a calculator for clinical use that provides a more precise absolute calculated risk of gout for the individual patient [83] and is based upon statistically refined characterization of the variables [81,82].

The rule was based upon an analysis of 328 patients with acute monoarthritis seen initially by family practitioners in the Netherlands; the patients also underwent prompt expert synovial fluid analysis. In the study cohort, scoring for low (≤4 points), intermediate (>4 to <8 points), and high (≥8 points) probability of gout identified groups with a prevalence of gout of 2.2, 31.2, and 82.5 percent, respectively. This approach yielded substantially fewer false-positive diagnoses than those made clinically by the family practitioners (17 versus 36 percent).

Patients falling into the intermediate category would most benefit from further evaluation with synovial fluid analysis, as gout cannot be excluded or confirmed based upon an intermediate score alone. Thus, further investigation of such patients is required, including referral for joint aspiration and synovial fluid analysis and detailed clinical reassessment. Advanced imaging, such as ultrasound or dual-energy CT (DECT), may be of benefit in patients in whom a diagnosis of gout has not previously been established if appropriate expertise and technology is available. (See 'Imaging' above and 'Role of imaging in diagnosis' below.)

In patients with an intermediate score, a tentative diagnosis of gout for the purpose of clinical management may still be made in the absence of crystals based upon a preponderance of evidence otherwise favoring the diagnosis (eg, inflammatory joint fluid in a patient with evidence of or known gout in the absence of infection, especially with a score in the higher part of the intermediate range). An alternative diagnosis should be sought in patients lacking sufficient features to support a tentative diagnosis of gout.

The diagnostic rule was validated by application to another cohort of 390 patients with monoarthritis who could conceivably have had gout and were referred to rheumatologists in a regional gout research center in the Netherlands by primary care and other specialty clinicians [82]. The diagnostic rule was developed and validated in an outpatient setting so has limited applicability to hospitalized patients in whom gout is suspected.

Role of imaging in diagnosis — In cases of podagra or involvement of small joints in the hands, a plain radiograph with characteristic erosive appearance ("overhanging edge") can be very supportive of a gout diagnosis. We employ ultrasonography of affected joints selectively in patients with histories of multiple episodes of acute intermittent inflammation, especially when those episodes have involved one or a few specific joints, aspiration of synovial fluid is not feasible or not accepted by the patient, urate crystals have not been detected by prior polarized light microscopic examination, and the diagnosis of gout remains uncertain.

Even though the sensitivity and specificity of ultrasonography and DECT in the diagnosis of gout was best established in patient subsets with more advanced disease, crystal deposition can be identified using these imaging modalities in most early gout patients by practitioners with appropriate expertise. (See 'Imaging' above.)

The ready availability of ultrasonography in the clinic, the identification of abnormalities with high specificity for gout by this method, and its additional capacity to serve as the basis for directed needle aspiration of joint fluid for polarized light microscopy support this approach, which may be undertaken either in the course of an acute inflammatory episode or during an intercritical period. (See 'Imaging' above and 'Diagnosis of intercritical or tophaceous gout' below.)

The availability of DECT examination for gout diagnosis in increasing. We use DECT in cases in which a urate crystal deposition basis for the causative disorder has not been confirmed by polarized light microscopic examination of joint aspirates, pathologic analysis of tissue samples (see 'Histologic examination' below), or when a musculoskeletal radiologist trained in the specific ultrasonographic findings of gout is not available. (See 'Imaging' above.)

Diagnosis of intercritical or tophaceous gout

Crystal demonstration in aspirates of synovial fluid or tophi — Even during the asymptomatic intercritical period, urate crystals are identifiable in synovial fluid from previously affected joints in virtually all untreated gouty patients and in approximately 70 percent of those receiving urate-lowering therapy [64,84,85]. This allows late establishment of the diagnosis in the majority of patients in whom the diagnosis was not made in the acute setting.

The high prevalence of urate crystals in aspirates from joints previously affected only once supports the view that deposition of urate crystals in and about joints precedes the first clinical episode of gout by a substantial period of time in most instances.

Demonstration of urate crystals in aspirates of tophaceous deposits provides a convenient and specific means to corroborate the diagnosis in gouty individuals with tophi [86].

Histologic examination — Ideally, tissues that are being prepared for histologic examination for urate crystals should be examined as fresh or frozen sections or should be preserved in alcohol (rather than in formalin) and later stained with a nonaqueous system such as Wright-Giemsa stain. However, formalin-fixed, paraffin-embedded tissue has been reported to still occasionally have demonstrable birefringent urate crystals if stained with a nonaqueous technique using alcoholic eosin [87]. Aqueous stains, such as hematoxylin and eosin, allow urate crystals to dissolve, leaving behind a nondiagnostic eosinophilic matrix that may have foreign body giant cells.

Clinical diagnosis of intercritical gout — In the absence of the means to identify urate crystals or in the presence of a negative polarized light microscopic study, a provisional diagnosis of gout is made by a combination of clinical and historic criteria. However, non-crystal diagnostic criteria have been validated only for the gout flare setting, and their application to diagnosis of patients in intercritical period awaits validation. (See 'Use of a clinical diagnostic rule' above.)

Imaging of a previously inflamed "gouty joint" that has become persistently symptomatic may also be productive either in identifying typical features of gout (and/or intercurrent infection) or in guiding needle aspiration of the affected joint for corroboration of crystal diagnosis, intercurrent infection, or both in the joint or adjacent bone. (See 'Imaging' above and 'Role of imaging in diagnosis' above.)

Classification criteria for gout — Classification criteria for the purpose of identifying a homogeneous group of patients with gout for clinical, genetic, and epidemiologic study (but not for clinical diagnosis) have been developed by an international collaborative effort of the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) and are based upon studies of patients representing a broad array of ethnicities and geographic sites [88,89].

These 2015 criteria permit classification as having gout in patients with at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa with either the presence of MSU crystals in a symptomatic joint, bursa, or tophus or without positive synovial fluid findings (whether or not arthrocentesis has been attempted) in individuals with a sufficient number and type of a series of well-defined clinical and imaging findings. However, a negative search for MSU crystals reduces the calculated score.

Among patients with at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa, the classification criteria have a sensitivity and specificity of 92 and 89 percent, respectively [88,89]. This classification scheme, while of direct benefit to researchers, has not been evaluated for its utility in clinical practice, where joint, bursa, or tophus aspiration remains central to establishing a diagnosis of gout in the view of the investigators who developed the criteria set.

It is important to distinguish between diagnostic [81,82,90] and classification [78,79,91,92] criteria when considering the development of robust and accurate schemes for diagnosing, treating, and studying any disease [93]. Diagnostic criteria are a set of signs, symptoms, and tests developed for use in routine clinical care of individual patients and thus have treatment implications. Diagnostic criteria performance is specific to the population and clinical context in which they were developed (eg, diagnostic criteria developed in an outpatient setting might not apply to hospitalized cases). By contrast, classification criteria are standardized definitions primarily aimed at enabling clinical studies to have uniform cohorts for research and have no direct treatment implications for patients.

Classification criteria for diseases are possible to develop whether or not there is a "gold standard" diagnostic criterion, but diagnostic criteria, which require levels of specificity and sensitivity approaching 100 percent, are more problematic to achieve, except for diseases with a true gold standard, like urate crystals in gout. When a gold standard for diagnosis exists, diagnostic and classification criteria for that disease can be very similar, but the underlying aims of the processes involved will necessarily perpetuate differences in the appropriateness of applying individual criteria, even if validated for one purpose, to the other category (eg, using classification criteria for clinical diagnostic purposes).

DIFFERENTIAL DIAGNOSIS — A wide variety of conditions may result in acute monoarthritis or polyarthritis (see "Monoarthritis in adults: Etiology and evaluation" and "Evaluation of the adult with polyarticular pain"). Gout can be distinguished in most instances from other forms of acute and chronic arthritis by the identification of urate crystals in clinically affected tissues or body fluids and by the use of sets of validated clinical diagnostic criteria utilizing the clinical history, demographics, and physical examination of the patient and/or imaging modalities. (See 'Diagnosis of a gout flare' above and 'Diagnosis of intercritical or tophaceous gout' above.)

The differential diagnosis of gout can be broadly divided into conditions that may respectively mimic gout flares or tophaceous gout. (See 'Differential diagnosis of a gout flare' below and 'Differential diagnosis of tophaceous gout' below.)

Differential diagnosis of a gout flare — Several other conditions may mimic a gout flare. Aspiration of synovial fluid from the affected joint and analysis of the fluid by Gram stain, culture, and regular and polarized light microscopy (see 'Urate crystal diagnosis of a gout flare' above) permit the distinction of gout from such conditions in most patients [79,94]. These disorders include:

●Septic arthritis – Acute monoarticular gout can appear clinically indistinguishable from acute septic arthritis on history and physical examination, including fever, leukocytosis, and elevated erythrocyte sedimentation rate (ESR). On rare occasions, a gout flare and septic arthritis coexist. Extremely high white blood cell counts in synovial fluid (>100,000 cells/mL), although occasionally found in gout and pseudogout, are most supportive of a diagnosis of septic arthritis and should be approached as such until Gram stain or synovial fluid culture confirms or excludes the diagnosis [95] (see "Septic arthritis in adults"). In our experience, response to colchicine, nonsteroidal antiinflammatory drugs (NSAIDs), and systemic glucocorticoids cannot be reliably used to differentiate between crystalline and septic arthritis.

●Trauma – Gouty flares of lesser severity may be mimicked by a stress fracture or traumatic process in the bone or joint. (See "Toe fractures in adults" and "Metatarsal shaft fractures" and "Overview of stress fractures", section on 'Diagnosis'.)

●Calcium pyrophosphate crystal deposition disease – A number of features (table 4) can help to differentiate between gout and calcium pyrophosphate crystal deposition (CPPD) disease, in particular when the latter presents acutely as acute calcium pyrophosphate (CPP) crystal arthritis (pseudogout), and the crystal detected in the synovial fluid is calcium pyrophosphate dihydrate (picture 4). The presence of linear calcifications or amorphous calcium in the affected joint (chondrocalcinosis) increases the chances that an acute arthritis attack is caused by CPPD disease. In some cases, both urate and CPP crystals are identified in the synovial fluid neutrophils in patients in whom these disorders coexist. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

●Cellulitis – The extensive periarticular inflammation accompanying a gout flare (particularly involving contiguous joints) may result in a clinical picture resembling cellulitis, requiring identification and prompt treatment of the latter process. In most instances, the distribution of inflammatory signs and symptoms in cellulitis does not focus on a joint, progressively extends into nonarticular areas, and is accompanied by systemic symptoms such as fever and chills. Joint aspiration and synovial fluid analysis, sometimes aimed at distinguishing gout from cellulitis, usually shows noninflammatory joint fluid and leukocyte counts, and urate crystals are not identifiable by polarized microscopy. Arthrocentesis should not be performed through an area potentially involved by cellulitis, as this can lead to extending an infection into the joint.

●Basic calcium phosphate crystal disease – Arthritis or periarthritis due to the deposition of basic calcium phosphate (BCP) crystals usually cannot be diagnosed with certainty by polarized microscopy because the individual crystals are below the resolution of standard light microscopy and because clumps of crystal aggregates are not birefringent [96]. Radiographs may show periarticular calcifications. However, BCP or apatite crystals rarely produce highly inflammatory cell counts. Transmission electron microscopy and radiograph powder diffraction have been successfully used for research identification of these crystals but are not used in clinical practice. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

●Other – The differential diagnosis among patients with a history of recurrent flares of acute arthritis with spontaneous resolution or rapid and complete improvement with use of nonsteroidal antiinflammatory drugs [NSAIDs] includes acute CPP crystal arthritis, reactive arthritis, palindromic rheumatism, and acute rheumatic fever, as well as rare disorders such as Whipple's disease. (See "Reactive arthritis" and "Clinical manifestations of rheumatoid arthritis", section on 'Palindromic rheumatism' and "Acute rheumatic fever: Clinical manifestations and diagnosis" and "Whipple's disease".)

Differential diagnosis of tophaceous gout — The clinical appearance of tophaceous gout may mimic other forms of arthritis:

●Rheumatoid arthritis – The clinical presentation of tophaceous gout may be confused with other forms of chronic inflammatory polyarthritis such as rheumatoid arthritis. Occasionally, tophi may be mistaken for rheumatoid nodules (and vice versa). In these circumstances, the asymmetry and asynchrony of joint involvement in gout, the presence of urate crystals in the nodular lesions, and the distinctive radiographic features will often suffice to distinguish between these disorders. (See "Rheumatoid nodules" and "Diagnosis and differential diagnosis of rheumatoid arthritis".)

●Dactylitis – The clinical appearance of tophaceous gout may be similar to dactylitis seen in other disorders such as psoriatic arthritis, other forms of spondyloarthritis, and sarcoidosis. In the specific case of psoriatic arthritis, differentiation can be complicated by the high prevalence of hyperuricemia in psoriatic arthritis and the described coexistence of gout and psoriatic arthritis [97]. Such conditions can usually be distinguished from gout based upon the history and physical examination. (See "Clinical manifestations and diagnosis of psoriatic arthritis", section on 'Periarticular disease' and "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Dactylitis' and "Sarcoid arthropathy", section on 'Chronic arthritis' and "Reactive arthritis", section on 'Musculoskeletal signs and symptoms'.)

●Osteomyelitis – Rarely, the expansive and destructive changes associated with tophaceous gout may be mistaken for osteomyelitis (image 1) and have sometimes led to erroneous amputation of involved digits [61]. In patients with gout, the history will usually support the diagnosis, which can be confirmed by examination of a needle aspirate using polarized light microscopy for the detection of monosodium urate (MSU) crystals. In cases in which obtaining a needle aspirate is not possible, the diagnosis can be established through advanced imaging techniques such as dual-energy CT (DECT) and MRI. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gout and other crystal disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Gout (The Basics)")

●Beyond the Basics topics (see "Patient education: Gout (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Natural history and role of hyperuricemia – The three clinical stages in the natural history of progressive urate crystal deposition disease (gout) are the gout flare, intercritical (or interval) gout, and chronic gouty arthritis and tophaceous gout. Use of effective urate-lowering therapies has resulted in a reduced frequency of progression of gout to the tophaceous stage. All patients with gout have hyperuricemia (saturation of serum for urate) at some point in their disease, imparting the risk of urate crystal formation and deposition in tissues with inflammatory responses, resulting in the signs and symptoms of gout. Gout flares usually occur after years of asymptomatic hyperuricemia, although most hyperuricemic individuals never experience a clinical event resulting from urate crystal deposition. (See 'Natural history' above and 'Clinical manifestations' above.)

●Features of gout flares – Numerous circumstances promote or are associated with gout flares, which are typically monoarticular and intensely inflammatory, with severe pain, redness, swelling, and disability. Maximal severity of the flare is usually reached within 12 to 24 hours. Complete resolution of the earliest flares almost always occurs within a few days to several weeks, even in untreated individuals. A polyarticular pattern is the initial manifestation in less than 20 percent of patients with gout but occurs with increasing frequency in later flares. Gout sometimes occurs with normal or even low serum urate concentrations at the time of the acute event. (See 'Factors provoking gout flares' above and 'Gout flares' above and 'Typical gout flare' above and 'Polyarticular gout flares' above.)

●Intercritical gout – Upon resolution of a gout flare, the patient is said to have entered an intercritical (between flares) period, which is most often asymptomatic. This sequence is highly suggestive of the diagnosis. Without urate-lowering treatment, the trend is toward recurrent gout flares that occur after progressively shorter asymptomatic periods and that are increasingly prolonged and disabling, are polyarticular, and may be associated with fever. (See 'Intercritical gout and recurrent gout flares' above.)

●Tophaceous gout – Tophaceous gout is characterized by collections of densely packed urate crystals, which are occasionally calcified, in connective tissues and accompanied by a chronic inflammatory response. These collections can be visible and/or palpable but are usually not painful or tender; they can be present on the ears or in the soft tissues, including articular structures, tendons, bursas, or bone (picture 1). Tophi may be detected with ultrasonography, dual-energy CT (DECT), or MRI. It is likely that many patients with gout and sustained hyperuricemia have a much larger burden of urate crystal deposits than is suspected by clinical examination alone. (See 'Tophaceous gout' above and 'Imaging' above.)

●Diagnosis – A definitive diagnosis should be sought when a gout flare is suspected, both to exclude alternative explanations for the acute event and to ensure that long-term therapy is not prescribed unnecessarily (algorithm 1).

•Crystal visualization – The diagnosis is most secure when supported by visualization of urate crystals by experienced examiners in a sample of fluid aspirated from an affected joint (or bursa) (picture 3). Ultrasonography of joints and adjacent soft tissues is useful for guiding fluid aspiration and can identify specific abnormalities that are highly sensitive and specific for urate crystal deposition. DECT has been standardized and has very good diagnostic yields. (See 'Urate crystal diagnosis of a gout flare' above and 'Role of imaging in diagnosis' above.)

•Use of a "diagnostic" rule – When crystal diagnosis is not achieved, confirmation of the diagnosis of gout can be made in the gout flare setting by use of a "diagnostic rule" utilizing a set of validated clinical, historic, and laboratory criteria (algorithm 1). (See 'Clinical diagnostic criteria-based diagnosis of a gout flare' above.)

•Role of findings during intercritical period – During the asymptomatic intercritical period, extracellular urate crystals are identifiable in synovial fluid from previously affected joints in virtually all untreated gouty patients and in approximately 70 percent of those receiving urate-lowering therapy. This allows late establishment of the diagnosis in the majority of patients in whom the diagnosis was not made in the acute setting. Demonstration of urate crystals in aspirates of tophaceous deposits provides a convenient and specific means to corroborate the diagnosis in gouty individuals with clinically detectable tophi. (See 'Diagnosis of intercritical or tophaceous gout' above and 'Histologic examination' above.)

●Differential diagnosis – The differential diagnosis of the gout flare includes septic arthritis, trauma, acute calcium pyrophosphate (CPP) crystal arthritis (pseudogout), cellulitis, rheumatoid arthritis, spondyloarthritis, and other types of inflammatory arthritis. (See 'Differential diagnosis of a gout flare' above and 'Differential diagnosis of tophaceous gout' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Michael A Becker, MD, who contributed to an earlier version of this topic review.