[Rheumatology] Clinical diagnosis of gout vs. ddx? (in progress)

[Category] Topic; 1. Workup; 2. Management; 3. Tip and Teaching point; 4. References;

Uptodate:

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 [79,80].

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 [81]. 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 [82,83] (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) [82]. 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 [84] and is based upon statistically refined characterization of the variables [82,83].

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 computed tomography (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 [83]. 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, 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 early gout was best established in patient subsets with more advanced disease, crystal deposition can be demonstrated by this approach 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.)

We limit the use of DECT examination for gout diagnosis to patients in whom, despite more chronic arthropathy or deformity, 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 alternative imaging modalities, including magnetic resonance imaging (MRI). (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 [58,85,86]. 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 [87].

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 [88]. 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 League Against Rheumatism (EULAR) and are based upon studies of patients representing a broad array of ethnicities and geographic sites [89,90].

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 [89,90]. 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 [82,83,91] and classification [79,80,92,93] criteria when considering the development of robust and accurate schemes for diagnosing, treating, and studying any disease [94]. 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 DIAGNOSISA wide variety of conditions may result in acute monoarthritis or polyarthritis (see "Overview of monoarthritis in adults" 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 [80,95]. 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 [96] (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 [97]. 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. 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 [54]. 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 computed tomography (DECT) and magnetic resonance imaging (MRI). (See "Osteomyelitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)


WHEN ARE YOU ORDER DECT?
Dual-energy computed tomography – Dual-energy computed tomography (DECT) examination can specifically identify urate deposits in articular and periarticular locations and can distinguish urate from calcium deposition [53,65,74-76]. There are potential artifacts with DECT, and ways to minimize them and avoid false-positive interpretations have been described [77]. In addition, studies are needed to determine the frequency of identifiable deposits in early disease and the clinical utility of this approach, which may be of future benefit to patients in whom the diagnosis remains uncertain despite standard clinical evaluation [69,76,78]. Tophus size can be quantified by DECT [74], but the clinical usefulness of this information for gout diagnosis is uncertain.
HELP DDX. OM vs GOUT vs CELLULITS ?!