Gout is among the most common inflammatory arthritides, characterized by deposition of monosodium urate (MSU) crystals in and around the joint and soft tissue (1–3). Persistent hyperuricemia is an important factor in the development of gout, but not all hyperuricemic patients develop gouty arthritis (4). The risk of supersaturation and crystal formation increases with increasing urate concentration. Alteration in various factors including pH and temperature also aggravates crystal formation and deposition in joints such as the first metatarsophalangeal (MTP) joint, a normally lower-temperature joint (5). The release of these preformed crystals initiates an intense inflammatory response in the synovium causing acute gouty arthritis (6).

Worldwide prevalence of gout ranges from 0.1 to 10%, with an incidence of 0.3 to 6 cases per 1,000 person-years (7). However, Asian countries including India (8), Bangladesh (9) and Pakistan (10) have been reported as having low gout prevalence, with prevalence rates below 0.5% according to data published by the Community Oriented Programme for Control of Rheumatic Diseases (7).

Gout typically presents in middle-aged men as severe pain and/or swelling with redness around joints, which may last from hours to days. Acute gouty arthritis usually has monoarticular presentation with a predisposition to develop in joints of lower extremities, particularly the first MTP joint. Other joints including the ankle and wrist may also be affected. Oligo- or polyarticular presentation may also occur, albeit rarely, typically in conditions such as chronic untreated gout or in postmenopausal women (11).

The gold standard test for the diagnosis of gout remains to be identification of MSU crystals in the synovial fluid (SF) by polarizing microscopy (12–14), which has previously been reported to have a sensitivity of at least 84.4% (15) and specificity of 97.2% (16). This technique requires specialized equipment and training, and is not available freely in countries with limited resources. Although hyperuricemia is a feature of gout, serum uric acid (UA) level may be within normal range during an acute attack (11). Such normouricemia at the time of an acute attack may be attributed to release of interleukin 6 (IL-6) during the acute inflammatory process (17). UA levels may be efficiently measured in the SF by colorimetric and enzymatic methods. The enzymatic method of UA measurement results from oxidation of UA by the uricase enzyme (18). The present study used the latter method with the aim of evaluating the utility of SF to serum UA ratio (SSR) for diagnosis of gout.

SF may be considered as a dialysate of blood plasma (25). As small molecules including urate pass freely through the double barrier of the synovial membrane into SF, the concentration of most non-electrolytes and micromolecules in SF is similar to that of plasma (26,27) except for the few macromolecules that are secreted by the synovial membrane and surrounding tissues (28). Most non-electrolytes diffuse freely between serum and SF, while electrolytes follow the Gibbs-Donnan equilibrium. UA is filtered from plasma to SF, and the normal SF urate level is equal to or slightly lower than the serum levels (29). There are different hypotheses regarding the distribution of urate in serum and SF. According to Beutler et al (30), the concentration of UA in SF is identical to that in the blood. However, previous study has demonstrated that SF urate levels were higher than serum levels in patients with acute gouty attack (31). During the acute attack of gout, approximately 40% of patients may be normouricemic which may be attributed to various factors including long-term excessive alcohol intake, diuretic therapy, obesity, release of IL-6 and use of urate lowering therapy, among others (32). Thus, the current study selected the ratio of SF urate to serum urate as a measure to verify higher UA concentration in the SF of patients with gout.

In the present study, the percentage of patients with gout was higher in comparison with those of other inflammatory and non-inflammatory arthritides. This may be because of the criteria of acute onset joint pain and/or swelling. This may also explain the higher percentage of male patients. It was identified that an SSR of ≥1.01 was significantly associated with diagnosis of gout determined through MSU crystal examination by polarizing microscopy. Values <1.01 were associated with non-gout effusions including those of pseudogout or OA cases. These findings are consistent with the hypothesis that a higher level of UA in SF may in part mediate gout onset. However, there are multiple factors that may be involved in gout onset, including pH (MSU crystal solubility increases with increasing pH to a maximum at pH 7.7 at 37°C), osmolality, and serum-SF gradients of calcium, phosphorus, albumin and globulin (32).

A study in 1965 observed a similar finding of higher SF urate level in patients with gout when compared with those with knee swelling due to other causes (31). However, their data was limited to 27 patients and lacked calculation of the predictive ratio for diagnosis of gout. The present study elaborated on this by obtaining more samples, and determined the predictive value of SSR to be ≥1.01 with 89.6% sensitivity.

Consistent with the findings of the current study, Wangkaew et al (33) demonstrated that SF urate and SSR were significantly different in patients with gout compared within other types of arthritis. However, in their study, the serum UA levels were also higher in gout patients. By contrast the present data indicated that serum UA as an independent marker may not be reliable for identification of gouty arthritis.

Beutler et al (30) reported that SF urate levels tended to reflect serum levels in patients with gout and non-inflammatory arthropathies but not with inflammatory joint disorders. The results of their study did not explain the higher level of SFUA in non-inflammatory arthritis, and contradict the present data. This may be due to the small sample size in their study and selection differences of the study population. Nonetheless, the results of the current study may aid to clarify the relationship between synovial and serum UA levels in gout and non-gout populations in a larger group of patients. The results also indicate a cutoff value for SSR in predicting gout as a cause of joint pain and swelling when the gold standard test for diagnosis is not available. Notably, the higher the SSR value, the more specific it was indicated to be for identifying gout-associated effusion. An external validation of the data with larger groups is now required for confirmation of these findings.

In conclusion, though identification of MSU crystals by polarized microscopy is the gold standard method for the diagnosis of gout, some laboratories and diagnostic centers lack this facility. It also requires a qualified and experienced technician. In this context, measurement of SF urate level may be used as an alternative method, as it is inexpensive, does not require special training or equipment and may be performed in regions where technologically advanced laboratories and equipment may not be available. It may also be effective in differentiating gout effusions from others when there is diagnostic uncertainty. Thus, measurement of SF urate level may be used as an alternative test for diagnosis of gout when polarized microscopy is not available.