Assessment of propositions
The proposition specific search was then undertaken and the results were merged with the results from the general search to form the basis of evidence for the evaluation of each proposition or modalities within each proposition. The following propositions are grouped by topic (clinical, urate crystals, biochemical, radiographic, and risk factors/co‐morbidities) with no weighting according to order.
1. In acute attacks the rapid development of severe pain, swelling, and tenderness that reaches its maximum within just 6–12 hours, especially with overlying erythema, is highly suggestive of crystal inflammation though not specific for gout.
Strength of recommendation: 88 (95% CI, 80 to 96)
One multicentre case–control study was undertaken in Europe—including Manchester, Paris, Moscow, Heinola, Piestanny, and Sofia—through a WHO fellowship programme.11
Fifty nine patients with gout and 761 patients with other musculoskeletal diseases were recruited from rheumatology outpatient settings. The gold standard diagnosis was established on the basis of the clinician's opinion. Composite diagnostic criteria of painful joint, swelling, attacks with abrupt onset of severe pain, and remission within two weeks were examined. This composite had very high sensitivity (0.98 (95% CI, 0.95 to 1.02)) but very low specificity (0.23 (0.10 to 0.35)). LR was 1.27 (1.08 to 1.50), suggesting only limited diagnostic value of this criteria set for the presence of gout. It was less specific than classic podagra and the presence of tophus (table 4). (NB: Although “podagra”, as in this document, is commonly used to describe acute attacks affecting the first metatarsophalangeal joint, podagra literally means “seizing the foot”.) Erythema has been investigated as a diagnostic criterion in another similarly sized case–control study in the USA (table 4).12
The diagnostic value of erythema was slightly higher than the composite of pain and swelling (fig 3). It is recognised that rapid onset, severely painful, self limiting attacks of synovitis with erythema may be produced by other crystal associated synovitis syndromes (for example, calcium pyrophosphate dihydrate crystal or pseudogout) and by septic or reactive arthritis, although involvement of the first metatarsophalangeal joint and tophi are both more specific for gout. However, as the gold standard of these studies was not urate crystal presence the results have yet to be confirmed.
Table 4Evidence of diagnostic test: sensitivity, specificity, and likelihood ratio
Figure 3Likelihood ratio (LR) and 95% confidence interval (CI) for various features in the diagnosis of gout. MSU, monosodium urate
In conclusion, rapid onset of severe pain, swelling, and erythema that is self limiting, while indicative of crystal associated synovitis, appears to have limited diagnostic value specifically for gout (level IIb evidence). Further evidence using urate crystal presence as the gold standard for diagnosis is still required.
2. For typical presentations of gout (such as recurrent podagra with hyperuricaemia) a clinical diagnosis alone is reasonably accurate but not definitive without crystal confirmation.
Strength of recommendation: 95 (95% CI, 91 to 98)
Unlike pain, swelling, and erythema, podagra has very high sensitivity (0.96 (95% CI, 0.91 to 1.01) and specificity (0.97 (0.96 to 0.98)).11,12
An LR of 30.64 (20.51 to 45.77) confirms that this presentation has excellent diagnostic value for gout (table 4; fig 3). Other conditions, such as calcific periarthritis cause by apatite crystal deposition, may produce “pseudo‐podagra”, but these are relatively rare. There are no data for both podagra and hyperuricaemia, but the LR of this combination is likely to be higher than for podagra alone.
In conclusion, classic podagra is an excellent clinical marker for an acute attack of gout (level Ib evidence). However, the results are based on clinically diagnosed gout and further evidence using urate crystal presence as the gold standard is still required.
3. Demonstration of MSU crystals in synovial fluid or tophus aspirates permits a definitive diagnosis of gout
Strength of recommendation: 96 (95% CI, 93 to 100)
Two systematic reviews have examined the value of synovial fluid analysis in the diagnosis of joint disease.18,19
Of the 200 studies included in the latest review, six relate to MSU crystal identification.19
The gold standards for these studies were crystal samples predefined by expert investigators. The studies aimed to compare results between different observers or between laboratories. Sensitivity ranged from 0.63 to 0.78 and specificity from 0.93 to 1.00; the inter‐observer reliability (κ) ranged from 0.35 to 0.63. Therefore, although training and quality control relating to crystal identification is clearly an important issue, identification of MSU crystals is a reliable investigation when undertaken by experienced operators.
A multicentre case–control study was undertaken in the USA to examine various clinical features and investigations, including MSU crystal identification, in the diagnosis of acute gout.12
The study compared the features of patients with established gout, diagnosed by experienced rheumatologists, with features of patients diagnosed with other joint diseases such as pseudogout, rheumatoid arthritis, and septic arthritis. The results showed reasonable sensitivity (0.84 (95% CI, 0.77 to 0.92)) and extremely high specificity (1.00 (0.99 to 1.00)) and LR (566.60 (35.46 to 9053.50)) for the presence of MSU crystals during an acute attack (table 4; fig 3).
In conclusion, the detection of MSU crystals has excellent value in the diagnosis of symptomatic gout (level IIb). However, the results of this test may vary between observers and laboratories (level Ib), which has implications for training and quality control for this investigation, and its cost‐effectiveness merits further investigation.
4. A routine search for MSU crystals is recommended in all synovial fluid samples obtained from undiagnosed inflamed joints.
Strength of recommendation: 90 (95% CI, 83 to 97)
Although there are no direct comparative studies, examination of synovial fluid for MSU crystals should be an investigation undertaken for undiagnosed inflammatory arthritis as gout is a prevalent cause of joint inflammation and may present atypically (level IV evidence).
5. Identification of MSU crystals from asymptomatic joints may allow definite diagnosis in intercritical periods.
Strength of recommendation: 84 (95% CI, 78 to 91)
Several case series studies have identified MSU crystals in synovial fluid aspirated from the asymptomatic first metatarsophalangeal joint or knee of patients with proven gout during the intercritical period, even in synovial fluid from joints that had not been subject to a previous acute attack.20,21
In these studies synovial fluid urate crystal identification was positive in approximately 70% of patients. This finding was confirmed by a small case–control study in which synovial fluid urate crystals were identified in asymptomatic joints aspirated during intercritical periods from 16 of 23 patients (70%) with known crystal proven gout, but in none of 10 asymptomatic joints of normouricaemic controls with other types of arthritis, giving a sensitivity of 0.70 (95% CI, 0.50 to 0.87), a specificity of 0.95 (0.83 to 1.08), and an LR of 15.13 (0.99 to 229.95).13
In addition, urate crystals can be identified in a small proportion of hyperuricaemic subjects who have never experienced gout (one of 19 healthy people with asymptomatic hyperuricaemia and two of nine hyperuricaemic patients with renal failure13
), thus confirming gout in its preclinical phase. Conversely, detection of MSU crystals from asymptomatic joints of patients with confirmed gout can become negative with time if appropriate urate lowering treatment has been instituted.22
In conclusion, MSU crystals can be detected during the intercritical period (level IIb evidence) and are highly likely to confirm the diagnosis if previously inflamed joints of untreated patients are examined. In treated patients with normal or low SUA levels, the detection rate depends on the duration and effectiveness of urate lowering treatment.
6. Gout and sepsis may coexist, so when septic arthritis is suspected Gram staining and culture of synovial fluid should still be performed, even if MSU crystals are identified.
Strength of recommendation: 93 (95% CI, 87 to 99)
There are reported cases of patients with coexistent sepsis and gout occurring in the same joint. Among 30 such cases reported by Yu et al
all fulfilled American Rheumatism Association criteria for acute gout,12
19 had positive MSU crystal identification, and 25 had subcutaneous tophi; one patient required above‐knee amputation and two died. Organisms were identified in synovial fluid culture in 73% of these patients. This is similar to the 76% positive culture rate in the septic arthritis patient group included in the study by Wallace et al
to test diagnostic criteria for gout12
; in that study, 4% of patients with septic arthritis had coexistent gout (tophi but not MSU crystal identification).12
The discriminative value of synovial fluid culture between septic arthritis and gout is quite high (sensitivity 0.76 (95% CI, 0.68 to 0.84); specificity 0.96 (0.90 to 1.01); LR
18.61 (4.77 to 72.63)). This is an important clinical message as septic arthritis is a treatable cause of rapid joint destruction that carries significant associated morbidity and mortality. Therefore in clinical situations where sepsis is suspected full investigation for sepsis, including synovial fluid Gram stain and culture, should be undertaken, even if the more rapidly performed test of MSU crystal identification has confirmed gout as a diagnosis (level IIb evidence).
7. While being the most important risk factor for gout, serum uric acid levels do not confirm or exclude gout, as many people with hyperuricaemia do not develop gout, and during acute attacks serum levels may be normal.
Strength of recommendation: 95 (95% CI, 92 to 99)
Two population based cohort studies, one of New Zealand Maoris24
and one of North Americans,25
have examined whether higher SUA levels associate with a higher incidence of gout. During the 11 year follow up period of the first study,20
the age standardised incidence of gout was over four times higher in men (RR
4.57 (95% CI, 1.11 to 18.84)) and 17 times higher in women (RR
16.90 (95% CI, 2.21 to 129.07)) who had SUA
6 mg/dl (360 μmol/l) compared with those with SUA below this level.24
This finding was supported by the US Normative Aging Study which followed for 15 years 2046 healthy subjects who were free of gout at baseline.25
Levels of SUA were categorised as <6, 6–, 7–, 8–, 9– and 10– mg/dl. The RR per level increase was 2.33 (95% CI, 2.00 to 2.71), adjusted by age, body mass index (BMI), serum lipid and glucose levels, hypertension, alcohol intake, and socioeconomic status using the Cox regression model.
Such data have encouraged the use of an SUA level of 6 mg/dl (360 μmol/l)—which is below the theoretical saturation point for MSU crystals—as a convenient cut off point for a risk factor for gout. Five case–control studies with sufficient data for calculation of sensitivity and specificity have been identified.11,14,15,16,26
The results show that the cut off level of 6 mg/dl (360 μmol/l) has moderate sensitivity (0.67 (95% CI, 0.47 to 0.87)) and specificity (0.78 (0.51 to 1.05)). Not surprisingly, a higher cut off index (>7 mg/dl or 420 μmol/l) has reduced sensitivity (0.57 (0.44 to 0.70)) but increased specificity (0.92 0.93 to 0.94)). Nevertheless, when using different criteria for men and women, the LR increases substantially, from 3.00 (95% CI, 0.85 to 10.57)) to 7.61 (5.31 to 10.91)), indicating an overall improvement (table 4). These results are supported by a cohort study where the level of 6 mg/dl (360 μmol/l) was less appropriate for men (LR
1.32 (95% CI, 1.14 to 1.52)) than for women (LR
2.47 (1.96 to 3.12)), as men have higher mean levels of SUA than women.24
In practice most laboratories calculate their own cut off level for hyperuricaemia as the mean plus two standard deviations from their local healthy population (calculated separately for men and women). This may further increase LR up to 9.74 (7.45 to 12.72), as shown by Wallace and colleagues12
Nevertheless, although a raised SUA level is a major risk factor for gout, many people with high SUA levels do not have gout. Conversely, individual patients who present with MSU crystal proven gout may have normal SUA levels at the time of investigation.27
One reason for this could be that SUA behaves as a negative acute phase reactant, being temporarily lowered during episodes of acute inflammation and stress.28
Two studies of patients with gout have reported lower SUA levels, even within the normal range, when measured during acute attacks, compared with raised SUA levels when measured in intercritical periods.29,30
An increase in renal excretion of uric acid during acute episodes is also suggested as the mechanism.28
In some patients the prior risk factors for hyperuricaemia may have been modified or removed at the time of presentation with gout (for example, cessation of diuretic, reduction of obesity or beer intake). Thus SUA has limited diagnostic value, especially during an acute attack of gout.
In conclusion, hyperuricaemia is one of the risk factors for gout (level IIa evidence). The definition of hyperuricaemia varies between populations, and men usually have higher levels of SUA than women. Therefore different diagnostic levels based on the normal range of SUA for the local population may be more valuable if SUA is to be used for diagnostic purposes (level Ib evidence). However, care must be taken as some individuals may develop gout without raised SUA, or may have a normal SUA during an acute attack.
8. Renal uric acid excretion should be determined in selected gout patients, especially those with a family history of young onset gout, onset of gout under age 25, or with renal calculi.
Strength of recommendation: 72 (95% CI, 62 to 81)
Three case–control studies met the inclusion/exclusion criteria for this proposition. All were hospital based studies comparing the 24 hour urinary uric acid/creatinine ratio (Uur/Ucr) between subjects with gout and those without.31,32,33
Gout was diagnosed on the basis of either the American Rheumatism Association criteria12
or the presence of synovial fluid MSU crystals. In addition, subjects with gout were categorised into three groups, according to urine uric acid excretion, as overexcreters, normoexcreters, and underexcreters. Overexcretion of uric acid was defined by a 24 hour urinary uric acid excretion of
1000 mg/day with regular diet, while underexcretion was defined by a uric acid clearance of <6 ml/min.31
The results showed no differences of Uur/Ucr ratio between gout and non‐gout patients (p>0.05). However, within the gout patients, a graded Uur/Ucr ratio was observed, with the highest ratio in uric acid overexcreters, followed by normoexcreters and underexcreters (p<0.05). In addition, patients treated with allopurinol had a lower Uur/Ucr ratio than those without (p<0.05).32
One study also examined a spot urine test for this ratio.31
Unfortunately, the ratio was similar in all group comparisons, including overexcreters versus normoexcreters. However, using mean plus two standard deviations in subjects with normal uric acid excretion as a cut off value to define overexcretion, the early morning spot urine sample and the 24 hour sample had similar sensitivity (0.25) but the 24 hour test had greater specificity than the spot test (24 hour, 0.99; spot, 0.96).
In conclusion, tests for urinary excretion status such as the uric acid to creatinine ratio may be useful to identify overexcretion of uric acid for treatment purpose (level IIb evidence). This may be undertaken by collecting a 24 hour urine sample or an early morning spot urine sample, but the robustness of the latter and its cost‐effectiveness need further evaluation.
9. Although radiographs may be useful for differential diagnosis and may show typical features in chronic gout, they are not useful in confirming the diagnosis of early or acute gout.
Strength of recommendation: 86 (95% CI, 79 to 94)
Although radiographs of joints affected by gout are frequently normal (apart from non‐specific soft tissue swelling), non‐comparative case series analyses have identified radiographic changes in all stages of gout, even in clinically silent cases.34,35
A multicentre case–control study suggested that the radiographic evidence of asymmetrical swelling and subcortical cysts without erosion may be useful (LR 4.13 and 6.39, respectively) to differentiate chronic gout from other joint conditions (fig 3) (level IIb). A further case–control study matched by age, sex, and disease duration showed that radiographs had some value in detecting the severity of tophi.17
Patients with intradermal tophi were more likely to have severe radiographic changes, supporting the clinical impression that the more specific radiographic features for gout tend to occur late in the evolution of the disease (table 4) (level IIb). Thus radiographs play only a minor role in diagnosis in most patients with gout, though in late or severe disease characteristic radiographic features may be present.
10. Risk factors for gout and associated co‐morbidity should be assessed, including features of the metabolic syndrome (obesity, hyperglycaemia, hyperlipidaemia, hypertension).
Strength of recommendation: 93 (95% CI, 88 to 98)
Various epidemiological studies have examined the risk factors and associations of gout, including one cohort study and four case–control studies relevant to this proposition. The cohort study compared the incident rates of gout between 2295 hypertensive individuals and 2280 normotensive controls in an eight year follow up period.36
The incidence of gout in men was fourfold higher in hypertensive subjects than in controls (RR
3.93 (95% CI, 1.6 to 9.7)), adjusted for the use of diuretics. The four case–control studies included two population based studies (the UK General Practice Research Database (GPRD) study and the Taiwan study) and two hospital based studies.2,37,38,39
The UK GPRD study investigated the relation between gout and co‐morbidities such as coronary heart disease (OR
1.75 (95% CI, 1.70 to 1.79)), hypertension (OR
1.52 (1.48 to 1.56)), diabetes mellitus (OR
1.11 (1.06 to 1.16)), and chronic renal failure (OR
4.95 (4.28 to 5.72)).2
The Taiwan study examined the association between gout and obesity (OR
3.81 (1.22 to 11.84)).37
The two hospital based studies showed that triglyceride and apo‐lipoprotein B were higher (p<0.05) but high density lipoprotein was lower (p<0.05) in gout patients than in control subjects.38,39
In addition, other factors including sex,2
have been well documented as risk factors for gout (table 5). Three cohort studies investigated gout as a risk factor in the development of coronary heart disease.42,43,44
Only one study found significant risk (RR
1.6 (95% CI, 1.1 to 2.2)) after adjustment for other risk factors for coronary heart disease such as hypertension, obesity, and diabetes mellitus.42
The pooled RR from these three cohort studies was 1.24 (0.92 to 1.67), suggesting that although cardiovascular risk factors may play a role in the development of gout,2
gout itself may make no contribution to the development of coronary heart disease.
Table 5Selected risk factors and co‐morbidities associated with gout
In conclusion, a number of common risk factors and co‐morbidities have been identified for gout (level IIa or IIb evidence). Because of their prevalence, impact on gout development and requirement for treatment in their own right, these factors should be considered when treating a patient who present with gout.