Diagnosis of Gout




Key Points





  • The aspiration of a joint with undiagnosed arthritis, or analysis of a tissue biopsy with subsequent visualization of monosodium urate (MSU) crystals, is considered the diagnostic standard for gout.



  • Elements of the history and physical examination that have been found to be useful when making an evidence-based diagnosis of a gout flare include a rapid onset of symptoms, a first metatarsophalangeal or tarsal joint location, characteristics of the joint involvement (redness and swelling associated), and prior episodes of arthritis with similar characteristics to the one being experienced by the patient.



  • The confirmation of subcutaneous or other tissue masses found on physical examination as tophi through MSU crystal identification can establish a diagnosis of gout, although this is rarely a presenting symptom of the disease.



  • Serum urate levels should not be used to confirm or rule out the presence of acute gouty arthritis.



  • The role of conventional radiography in patients suspected of having gout is limited by the relatively late development of radiographic changes in the disease.



  • Ultrasound is a valuable tool in the assessment of patients with very early phases of gout, including initial gout attacks and even asymptomatic hyperuricemia.



  • Conditions commonly prominent in the differential diagnosis of gout attacks include septic arthritis, pseudogout, trauma, and rheumatoid arthritis. For chronic gout, the differential diagnosis usually includes rheumatoid arthritis, osteoarthritis, and calcium pyrophosphate deposition disease.



  • Classification criteria and diagnostic rules published for gout have not been properly validated and should be used with caution.





Introduction


The aspiration of a suspicious joint, or analysis of a tissue biopsy, with subsequent visualization of monosodium urate (MSU) crystals is considered the diagnostic standard for gout. Unfortunately, this deceivingly simple process is plagued with challenges for primary care providers, researchers, and even rheumatologists. Common challenges for primary care providers stem from their experience level in accessing the affected joint, as well as this provider having access to rapid identification of crystals by an experienced examiner. In addition, primary care providers and rheumatologists alike face diverse forms of presentation provided by the setting of the clinical encounter (e.g., office versus hospital) and the disease stage (gout attack versus intercritical period versus chronic gout), which add considerable heterogeneity to the diagnostic approach. For researchers trying to recruit new patients with gout or gather large numbers of existing patients for epidemiologic studies, the difficulties are multiple, as problems with clinical diagnosis of gout usually translate into large proportions of diagnostic misclassification that can jeopardize the validity of any obtained results.


Because of these challenges, alternative or complementary approaches to gout diagnosis have been used, including adding a role for serum urate, radiographs or other imaging, the use of diagnostic rules or classification criteria, and the use of administrative diagnostic codes. With the objective of providing the reader with a comprehensive view of the diagnostic approach to gout, this chapter will review the role of the clinical history and physical examination, laboratory studies, imaging, and MSU crystal examination. In addition, the value of administrative diagnostic codes, past and current diagnostic rules, and classification criteria will be analyzed.




History and Physical Examination


Diagnosis of Gout


For a complete discussion of the clinical features of gout, refer to Chapter 9 . A careful history and physical examination will be important when attempting to establish a gout diagnosis. However, different aspects of this process will acquire more relevance depending on which gout disease stage is encountered. Patients with gout can go through different stages, including (1) asymptomatic hyperuricemia, (2) gout flares, (3) intercritical periods, and (4) chronic and usually tophaceous gout. By definition, asymptomatic hyperuricemia does not have clinical manifestations related to gout (although other disease associations are described; see Chapter 19 ). On the other hand, gout attacks (“flares”), intercritical periods, and chronic gout can have clues that offer an insight into the diagnosis.


Diagnosis of Gout Flares


Even though the concept of a gout flare is familiar to both rheumatologists and primary care providers, there is a paucity of studies addressing the relevance of different clinical features when trying to make a diagnosis of gout. Preliminary classification criteria for acute gout (flares) published by the American College of Rheumatology (formerly American Rheumatism Association) (ACR) identified history and physical examination criteria, such as maximum inflammation within 1 day, monoarthritis, joint redness, first metatarsophalangeal or tarsal joint involvement, presence of tophus, and recurrent attacks of monoarthritis as relevant. The European League Against Rheumatism (EULAR) conducted a systematic review of the literature as part of its evidence-based recommendations for diagnosis, finding two elements pertaining to the history as being associated with a high strength of recommendation: these were a rapid onset of the flare (within 6 to 12 hours) and typical presentations for gout (the example of podagra in the setting of hyperuricemia is given). As part of the process of identifying response domains in acute gout (flares) and chronic gout developed by the Outcomes Measures in Rheumatology Group (OMERACT), a Delphi exercise and cognitive mapping process were performed among nine gout experts, which yielded a list of elements associated with the presence of a gout flare. Most of these elements are easy to obtain from a simple history of joint complaints (presence of swollen, tender, and warm joints), patient self-report of pain and global assessment, time to maximum pain, and complete resolution of pain. More than 80% of gout patients surveyed as part of the same study endorsed these elements as representative of a gout flare experience ( Table 8-1 ). An additional element added by the patients as representative of the gout flare experience was a similarity between the current experience and previous gout attacks.



Table 8-1

Items Selected for a Gout Flare Definition and Endorsement by a Group of 20 Gout Patients





































Item Patients Endorsing, %
Affected joint is swollen 84
Affected joint is red 84
Affected joint is extremely tender to touch 100
The pain is at its worst very quickly (4-12 hours) 95
The pain is much worse than usual 95
The affected joint is the knee, ankle, foot, or toe 95
It stops me from doing usual activities 96
I can’t walk during the attack 96
It gets better within 3-14 days 79
It was very similar to other attacks of gout 96

Data from Taylor WJ, Shewchuk R, Saag KG, et al. Toward a valid definition of gout flare: results of consensus exercises using Delphi methodology and cognitive mapping. Arthritis Rheum 2009;61(4):535-43.


As part of the process of creating a rule to aid physicians in diagnosing gout among episodes of acute monoarthritis, Dutch investigators assessed multiple history and physical examination elements for their performance in predicting gout as the cause of monoarthritis ( Table 8-2 ). Male sex, a previous attack of arthritis, involvement of the first metatarsophalangeal joint, and the presence of hypertension or other cardiovascular comorbidities were associated with gout as a diagnosis.



Table 8-2

Multivariable Analysis of Clinical Elements Significantly Associated With a Crystal-Proved Diagnosis of Gout in Patients With Acute Monoarthritis



















Variable Odds Ratio (95% Confidence Interval)
Male sex 6.7 (3.3-13.7)
Previous patient-reported arthritis attack 4.1 (2.2-7.8)
First metatarsophalangeal involvement 6.5 (3.4-12.5)
Hypertension or more than one cardiovascular disease 3.2 (1.8-5.7)

Clinical elements not associated with a diagnosis of gout after multivariable analysis included joint redness, onset within 1 day, medication use, family history of gout, body mass index, and presence of diabetes.

Data from Janssens HJ, Fransen J, van de Lisdonk EH, et al. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch Intern Med 2010;170(13):1120-6.


In conclusion, elements of the history and physical examination that have been consistently found to be useful when making an evidence-based diagnosis of a gout flare include a rapid onset of symptoms, the location (first metatarsophalangeal joint) characteristics of the joint involvement (redness and swelling more associated), and prior episodes of arthritis with similar characteristics to the one being experienced by the patient.


Diagnosis of Intercritical and Chronic Gout


The assessment of risk factors for the metabolic syndrome (obesity, hyperglycemia, hyperlipidemia, hypertension) is important to establish pretest probabilities for gout. These elements apply to patients in intercritical or chronic phases of gout, in addition to patients going through flares. Pain levels may not completely subside as patients move from the intercritical phase of the disease into chronic gouty arthritis. The confirmation of subcutaneous or other tissue masses found on physical examination as tophi through MSU crystal identification can establish a diagnosis of gout, although this is rarely a presenting symptom of the disease. In some cases, gout can cause a chronic arthritis with deformities that can mimic rheumatoid arthritis.




Laboratory Studies Relevant for Gout Diagnosis


Serum Urate in the Diagnosis of Acute Gout


Many studies have attempted to define the role of serum urate measurements in episodes of acute arthritis suspected of being a gout flare. The most common mistake is to negate the diagnosis of gout in a patient with a serum urate below the in vitro urate saturation level of 6.8 mg/dl. Investigations with groups of patients undergoing gout flares have described frequencies of normouricemia at 14% to 49%. An important caveat with these studies is the wide variability in the definition of what constitutes a normal serum urate, with ranges between 6.0 and 8.0 mg/dl. The latter threshold is usually based on a statistical definition (2 standard deviations above mean serum urate for a population) but has no physiologic basis and leads to different definitions for men and women. The threshold of 6.0 mg/dl is closer to the saturation point for urate and has been embraced as a goal for therapy by published guidelines. Regardless of the definition, it is well established that gout flares can occur while serum urate is at subsaturation levels and that serum urate during acute episodes of arthritis should not be used to rule out gout as an etiology. Physiologic explanations and clinical scenarios for this phenomenon have been postulated and include (1) that patients could have been recently initiated in urate-lowering therapy without effective gout flare prophylaxis and—having already achieved a normal serum urate—are still undergoing urate deposit removal from tissues, (2) increased urate diuresis (driven by inflammatory mediators including interleukin [IL]-6) during an acute gout flare leading to normouricemia, and (3) patients with a modifiable factor explaining the hyperuricemia (alcohol intake, obesity) could develop gout and still have flares after this factor is removed and they are normouricemic. Many of these explanations arise from the fact that serum urate is not always representative of the total body uric acid pool.


Classification and diagnostic criteria have incorporated hyperuricemia as a supportive element for the diagnosis or classification of gout. High serum urate values are elements of the Rome and ACR preliminary classification criteria. In a diagnostic rule for diagnosis of gout in patients with monoarthritis patients with a serum urate greater than 5.88 mg/dl were 9.8 times more likely to have gout against other diagnoses after multivariable adjustment. Epidemiologic data support this way of thinking, given the observation that individuals without a prior diagnosis of gout and serum urate levels greater than 9.0 mg/dl have a risk of incident gout of 20% per year. Despite these arguments, the role of hyperuricemia in the diagnosis of gout should be considered merely supportive and not confirmatory, given its high prevalence in the general population. In addition, patients with high serum urate values also tend to have comorbidities (cardiovascular and renal disease, metabolic syndrome, and diabetes) that place them at high risk for conditions in the differential diagnosis of gout, such as infectious arthritis and other crystal arthropathies.


In conclusion, serum urate levels should not be used to confirm or rule out the presence of gout flares and their role in this context should be only marginal, possibly to establish a pretest probability for gout.


Serum Urate in the Diagnosis of Chronic and Intercritical Gout


There are no studies assessing the role of serum urate in patients suspected of having gout while not having a flare. The role of serum urate in this context should be supportive, as in the case of acute flares. Hyperuricemia can support a consideration of gout in undiagnosed patients going through the chronic or tophaceous stages, but this argument must be weighted in the context of the high prevalence of hyperuricemia in the general population.


Patients in which gout is suspected but who have normal serum urate levels could, as in the case of gout flares, have had a modifiable factor associated with hyperuricemia (obesity, alcohol intake) removed or have been chronically exposed to a uricosuric agent, such as losartan, ascorbic acid, or large doses of acetylsalicylic acid. However, these factors would be unlikely to bring to a markedly high serum urate level to normal. Normal serum urate levels could support ruling out gout in suspected cases not undergoing a flare, but other considerations, like a strong clinical suspicion based on a past clinical presentation, compelling physical findings, or radiologic findings, should carry a larger diagnostic weight.


Inflammatory Markers in the Diagnosis of Gout


Serum levels of inflammatory markers, including C-reactive protein (CRP) and sedimentation rate, are elevated during gout flare episodes. Associated inflammatory cytokines, such as IL-6, have also been found to be elevated during gout flares. An elevation in inflammatory markers is correlated with an increase in renal uric acid excretion and is possibly the mechanism behind a normal serum urate in some patients undergoing gout flares.


Increases in inflammatory markers are in part a consequence of NLRP3 inflammasome-mediated mechanisms behind gout flares. Activation of the NLRP3 inflammasome leads to IL-1–mediated induction of CRP and IL-6, similar to other conditions such as certain autoinflammatory syndromes. Given the lack of specificity of inflammatory markers, these are rarely used to confirm the presence of a gout flare. Inflammatory markers could also be affected by interventions such as glucocorticoids, and the absence of an elevation in these should also be interpreted with caution.




Crystal and Synovial Fluid Analysis in the Diagnosis of Gout


Chapter 2 provides a complete description of MSU and calcium pyrophosphate dihydrate (CPPD) crystal analysis in joint fluids. Visualization of MSU in synovial fluid or tissues remains the standard practice for the diagnosis of gout. However, its performance faces many challenges in daily clinical practice, and it is performed in a minority of patients who carry the diagnosis of gout. In an epidemiologic study based on patients from the Health Professionals Study, it was found that only 118 of 730 carried a diagnosis of gout based on a crystal analysis or presence of tophi.


Despite its accepted role as the standard for the diagnosis of gout, there is a paucity of studies examining the diagnostic performance of microscopic examination for MSU crystals. As reviewed in Chapter 2 , there is considerable variability in the reported performances, with sensitivities ranging from 69% to 98% and specificities greater than 90%. Sources of variation in the diagnostic performance included the experience level of the examiner as well as heterogeneity in sample processing. The performance of the test has been reported to be consistent among well-trained and experienced examiners.


Synovial fluid analysis with crystal identification may also play an important role in the diagnosis of patients in the intercritical period of gout, as demonstrated by a study in which knees and first metatarsophalangeal (MTP) joints of patients with gout who were not going through an acute flare were aspirated and examined. All of the synovial fluid of patients who were not on urate-lowering therapy (most of whom were hyperuricemic) was positive for the identification of MSU crystals. Of the patients on urate-lowering therapy, 70% had a positive test for MSU crystals. This study demonstrated that synovial fluid analysis could be helpful for establishing diagnosis even outside the gout flare stage. In addition, it conveyed the argument that patients with an established diagnosis of gout presenting with acute arthritis of etiologies other than gout could have a false-positive test for MSU crystals. An open differential diagnosis should be maintained in patients with gout when they present with acute arthritides resembling a flare.


Other characteristics of synovial fluid in patients with gout include a translucent to cloudy appearance, low viscosity, cells counts ranging from 200 to 50,000/mm 2 , and proportions of polymorphonuclear leukocytes among the nucleated cells of greater than 90%. Unfortunately, there is a wide overlap with the fluid characteristics of pseudogout and septic arthritis, not allowing for a clear differentiation based on these additional features only.




Imaging Studies in the Diagnosis of Gout


For a complete discussion on the different radiologic and ultrasound modalities used for gout diagnosis and management, refer to Chapters 26 and 28 . Imaging studies are useful for the assessment of severity, follow-up, and outcome measure studies of gout. The role of imaging in the diagnosis of gout is complementary to that of the clinical examination and compensated polarized light microscopic examination. In addition, data describing the diagnostic performance of imaging studies are, for the most part, scarce.


Conventional Radiography


The diagnostic usefulness of plain radiography is limited by the fact that radiographic changes are relatively late features of the disease, with changes noticeable only years after onset of gout flares (5 years on average in typical patients) or when the disease has progressed to the chronic or tophaceous stages. Changes that are suggestive of gouty arthritis include an erosive arthropathy without periarticular osteopenia and with overhanging erosions or sclerotic margins, soft tissue opacifications, and marginal osteophytes. These changes are most commonly found in the feet.


A study in which radiographic findings for gout were compared with clinical diagnosis of gout and other arthropathies found that having at least one radiologic finding of gout was 31% sensitive and 93% specific ( Table 8-3 ). This was in accordance with a previous report from a large cohort that showed that 45% of patients with confirmed gout did not show any radiographic changes.



Table 8-3

Diagnostic Performance of Conventional Radiography and High-Resolution Ultrasonographic Findings in Patients With Gout





















































































Sensitivity (%) Specificity (%) Positive Predictive Value (%) Negative Predictive Value (%) Accuracy (%)
Conventional Radiology
Soft tissue opacifications 26 97
Bone erosions 20 95
Marginal osteophytes at erosions or tophi sites 5 100
Presence of any radiographic sign 31 93 89 44 63
Ultrasonography
Bright stippled foci 80 75
Hyperechoic areas 79 95
Bone erosions 24 69
Hypoechoic streaks 80 49
Hypervascularization by Doppler 94 53
Presence of any ultrasonographic findings 96 73 86 91 88

Data from Rettenbacher T, Ennemoser S, Weirich H, et al. Diagnostic imaging of gout: comparison of high-resolution US versus conventional X-ray. Eur Radiol 2008;18(3):621-30.


As a consequence, the role of conventional radiography in patients suspected of having gout and who are undergoing their initial episodes of acute arthritis is limited to support in exploring considerations in the differential diagnosis (e.g., septic or rheumatoid arthritis). For undiagnosed patients in the chronic or tophaceous stages of the disease, radiographic findings confer reasonable specificity and positive predictive value, providing valuable support for the diagnosis.


Computed Tomography


Computed tomography (CT) has been described as a useful tool for the assessment of erosions and tophi. The latter application is the one that has gained more attention, as CT has been found to be valuable in differentiating tophaceous subcutaneous nodules or intraarticular deposits as a result of other etiologies, although studies evaluating its diagnostic performance in this setting are lacking. Dual-energy CT scans offer excellent visualization of tophi deposits, but their use has been primarily limited to estimation of tophi burden, and not diagnosis.


Ultrasound


Ultrasonography is rapidly gaining wide adoption as a sensitive way of evaluating multiple musculoskeletal conditions, including soft tissue disorders and arthritides of inflammatory and degenerative nature. In addition, its usefulness in guiding invasive procedures is considerable. These characteristics, along with its relatively low cost compared with other techniques, portability, “patient-friendliness,” and absence of ionizing radiation exposure have contributed to its progressive acceptance in the rheumatology community.


Ultrasonographic findings have been described at very early stages of gout, even in patients with asymptomatic hyperuricemia. In these very early stages, small tophaceous deposits and increased power-Doppler signal could be demonstrated in at least a third of subjects in some studies, suggesting active subclinical tophus formation. In established gout, high-resolution ultrasonographic findings include a double-contour sign (deposition of urate over the hyaline cartilage), hyperechoic and bright dotted foci, erosions, hypervascularization, and visualization of tophi.


The diagnostic performance of ultrasonographic findings in patients with gout and other arthritides was evaluated in a study that described a sensitivity of 96% and a specificity of 73% for any ultrasonographic finding in patients with the disease (see Table 8-3 ). A second smaller study confirmed a superiority of ultrasound compared with conventional radiographs and clinical findings.


Ultrasound can play a valuable supportive role in the assessment of patients with very early phases of gout, including initial gout attacks and even asymptomatic hyperuricemia. It can also provide support in patients with established gout who are undiagnosed. The main challenge to ultrasonography is its marked operator-dependency, although this should improve as the technique gains more acceptance and training becomes more standardized. More studies are necessary to reevaluate its diagnostic performance in the different gout clinical stages. Its utilization in diagnostic rules for gout flares or chronic gout has not been assessed yet, but the perspective appears promising.


Magnetic Resonance Imaging


Magnetic resonance imaging (MRI) is a useful technique for early detection of tophi, bony erosions, and synovial involvement. Its performance in differentiating tophi from other soft-tissue masses has been reported as lower than CT, but performance evaluation in other scenarios related to diagnosis of gout is lacking. MRI is limited by its higher cost and limited portability, and it has not been adopted as a standard measure in the diagnostic workup of gout.




Administrative Databases in the Diagnosis of Gout


The use of administrative databases for diagnosis of medical conditions based on the International Classification of Diseases (ICD) codes pertains mainly to research and has no application in patient care. Its utilization is wide in epidemiologic and clinical research. In rheumatology, it has been applied to conditions such as osteoarthritis, spondyloarthritides, and rheumatoid arthritis. In the case of gout, two studies have been performed in the United States comparing information obtained through ICD-9 codes against investigators’ criteria and ACR, Rome, and New York criteria for gout.


The first study used administrative claims data from four large health care plans in the United States. A random sample of 200 patients yielded 121 patients with probable of definitive gout by the investigators’ consensus. When comparing the presence of two or more diagnostic codes for gout with the investigators opinion, the diagnostic codes yielded a positive predictive value of only 61%. The agreement between the diagnostic codes and accepted diagnostic criteria was poor with concordance rates (kappa) of only 0.16 to 0.20. An additional study evaluated data from the Veterans Affairs medical system in the United States. In this case, records of 281 patients with two or more diagnostic codes for gout were compared against diagnostic criteria. Depending on the specific rule applied, only 18% to 36% of patients fulfilled the standardized definition. It is important to mention that many more patients met the definition when a rheumatologist followed them.


In conclusion, current evidence reveals that the accuracy of administrative diagnoses for gout is insufficient to confidently establish a diagnosis of gout in the research setting. Additional steps should confirm these diagnoses to have a reliable representation of gout patients.

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Mar 5, 2019 | Posted by in RHEUMATOLOGY | Comments Off on Diagnosis of Gout
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