1. Diagnosis of gout

2. Background
Gout is a severe inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and other tissues
Gout is the most frequent inflammatory arthritis in men
The incidence and prevalence of gout are rising in post-menopausal women
1-2% of adults are affected
The prevalence of gout increases with age
Gout is often misdiagnosed or diagnosed late in its clinical course
Gout, a disorder dating back to antiquity, is the most frequent cause of inflammatory arthropathy in men and one of the commonest in older women.
Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and other tissues. Gout may severely affect joints, inducing disability, but also other tissues or organs, and may, therefore, be considered a systemic disease.
Despite a reasonable understanding of its pathogenesis and the availability of effective treatment, gout is often misdiagnosed or diagnosed late in its clinical course; even when correctly diagnosed treatment is often suboptimal.
Lawrence RC, et al. Arthritis Rheum 1998;41:
Mikuls TR, et al. Ann Rheum Dis 2005;64: Zhang W et al, Ann Rheum Dis, 2006;65:

3. EULAR evidence based recommendations for gout
The most important scientific societies have, therefore, organised task forces of experts in gout to produce guidelines or recommendations on aspects related to the diagnosis and the management of gout. The main points of the evidence-based recommendations of the European League Against Rheumatism (EULAR) are presented here and integrated with updated information.
Zhang W, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

4. EULAR recommendations 2006 for gout: diagnosis1
In acute attacks the rapid development of severe pain,
swelling and tenderness that reaches its maximum within just hours, especially with overlying erythema, is highly diagnostic
of crystal inflammation though not specific for gout.
For typical presentations of gout (such as recurrent podagra
with hyperuricemia) a clinical diagnosis alone is reasonably accurate
but not definitive without crystal confirmation. 2
The first two EULAR recommendations are related to the clinical diagnosis of gout, stating that while some characteristic clinical features, such as a painful joint, swelling, attacks with an abrupt onset of severe pain, and remission within 2 weeks may be useful for raising the suspicion of gout, these features have a very low specificity.
Podagra, the term used to describe an acute attack of gout affecting the first metatarsophalangeal joint and literally meaning ‘‘seizing the foot’’, seems to be a more sensitive and specific sign.
There are, however, very few controlled studies on these aspects, so the strength of the evidence is limited.
Zhang, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

5. Acute gout: classical clinical picture
Acute, very painful,monoarticular inflammation usually affecting the big toe (podagra)(70%) (less frequently other foot joints, ankle, knee, finger, wrist, elbow)
Typical rapid development of severe pain, swelling and tenderness that reaches its maximum within just 6-12 hours, especially with overlying erythema
As inflammation disappears, the skin over the joint often peels
Attacks often start at night or in the early morning
Attack usually resolve within 5-10 days
The initial episode almost always involves a single peripheral joint. The joint becomes swollen, red, hot, shiny and extremely painful. Symptoms reach their maximum within just 6-12 hours. The inflammation resolves slowly over 5-10 days, often with itching and flaking of the overlying skin. In rare cases, the person never has another attack, but most patients will go on to have recurrent flares (62% within 1 year, 78% within 2 years and 89% within 5 years). Although the classical features of acute gout can be strongly indicative of gout, the diagnosis should be confirmed.
By kind permission of L. Punzi, Rheumatology Unit,
University of Padua
Wallace SL, et al. Arthritis and Rheumatism 1977;20(3):

6. Differential diagnosis of big toe gout (podagra)
Often typical gout is gout – but not always
Not rarely what does not look like gout is gout
Differential diagnosis of big toe gout (podagra)
Pseudogout (acute calcium pyrophosphate arthropathy)
Pseudogout-like (basic calcium phosphate) (pseudopodagra)
Reactive arthritis
Psoriatic arthritis
Septic arthritis
Sarcoidosis
Others
Despite apparently classical signs and symptoms of gout, some attacks of joint pain may not be due to this disease, especially in patients taking non-steroidal anti-inflammatory drugs. For example, the differential diagnosis of podagra includes acute calcium pyrophosphate-induced arthropathy, pseudogout-like (basic calcium phosphate), arthropathy (pseudopodraga), reactive arthritis, psoriatic arthritis, septic arthritis and sarcoidosis.
Zhang W, et al. Ann Rheum Dis 2006;65:
Richette P, et al. Lancet 2010;375:

7. Differential diagnosis of ankle gout
Sarcoidosis
Reactive arthritis
Psoriatic arthritis
Enteroarthritis
Septic arthritis
Other crystal-induced arthritides
acute pyrophosphate arthropathy (pseudogout)
basic calcium phosphate (pseudogout-like)
The risk of misdiagnosis of acute arthritis in other joints is increased. The differential diagnosis of gout of the ankle, probably the second most frequent localisation of this disease, includes sarcoidosis, reactive arthritis, psoriatic arthritis, enteroarthritis, septic arthritis and other crystal-induced arthritides such as acute pyrophosphate arthropathy (pseudogout) and basic calcium phosphate arthropathy (pseudogout-like).
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua
Zhang W, et al; Ann Rheum Dis 2006;65:
Richette P, et al. Lancet 2010;375:
De Leonardis F, et al. Rheumatol Int 2007;28:1-7.

8. Differential diagnosis of elbow
gout or bursitis
Septic arthritis or bursitis
Post-traumatic bursitis
Rheumatoid nodules with bursitis
Other crystal-induced arthritides or bursitis
acute pyrophosphate arthropathy (pseudogout)
basic calcium phosphate (pseudogout-like)
When considering a diagnosis of gout of the elbow, septic arthritis, in particular, should be carefully excluded, as should the other crystal-induced arthritides. Bursitis is another potential confounding condition.
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua
Ning TC, et al. Curr Opin Rheumatol 2010;22(2): .

9. Differential diagnosis
of hand-wrist gout
Algoneurodystrophy
Pitting oedema
polymyalgia rheumatica
psoriatic arthritis
Septic arthritis
Other crystal-induced arthritides or bursitis
acute pyrophosphate arthropathy (pseudogout)
In some cases the presenting appearance of gout may be difficult to interpret, such as when an acute attack occurs in a hand with concomitant panniculitis, showing features of “puffy hand”. In these cases the differential diagnosis is challenging and should include algoneurodystrophy, pitting oedema (polymyalgia rheumatica or psoriatic arthritis), septic arthritis and other crystal-induced arthritides or bursitis.
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua
Richette P, et al. Lancet 2010;375:
De Leonardis F, et al. Rheumatol Int 2007;28:1-7.
Ning TC, et al. Curr Opin Rheumatol 2010;28:

10. Chronic arthritis: gout or not gout?
Gout or psoriatic arthritis?
Gout or rheumatoid arthritis?
The initial attack is rarely polyarticular (3-14% of cases), and seldom affects the shoulders or hips. Only one episode happens in some patients, but most patients have a second attack, often within 6 months to 2 years. Subsequent attacks frequently last longer than the first attack, affect several joints, and spread to the upper limbs, especially the arms and hands.
When left untreated acute attacks of gout can lead to chronic gout, which is characterised by chronic destructive polyarticular involvement with low-grade joint inflammation, joint deformity, and tophi. Tophaceous gout develops within 5 years of the onset of gout in 30% of untreated patients.1
1. Richette P, et al. Lancet 2010;375:
Gout or osteoarthritis (Heberden’s nodes)?
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua

11. EULAR recommendations 2006 for gout: diagnosis3
Demonstration of monosodium urate (MSU) crystals in synovial fluid
or tophus aspirates permits a definitive diagnosis of gout.
A routine search for MSU crystals is recommended in all
synovial fluid samples obtained from undiagnosed inflamed joints. 4
EULAR recommendations 3 and 4 are focused on the diagnostic value of looking for and finding MSU crystals in synovial fluid or tophi.
Zhang W, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

12. The differences in the specificity and likelihood ratio (LR) of a correct diagnosis of gout based on clinical signs and symptoms or the demonstration of MSU crystals in synovial fluid or tophi are very marked. There are very few diagnostic hallmarks in medicine that have the same diagnostic specificity (100%) as MSU for. Ideally, gout should be suspected on clinical grounds and confirmed by synovial fluid analysis
Zhang W, et al. Ann Rheum Dis 2006;65(10):

13. Likelihood ratio (HR) for various features in the diagnosis of gout
The likelihood ratio (LR) of the diagnostic value of MSU crystal identification during an acute attack of joint pain is very impressive and the highest among various indices considered.
The LR is an index that summarises how many times more (or less) likely patients with gout are to test positive than patients without gout. A LR greater than 1 indicates that the test result is associated with the presence of gout, whereas a LR less than 1 indicates that the test result is associated with absence of gout. LR values above 10 or below 0.1 are considered to be strong evidence to, respectively, confirm or rule out a diagnosis of gout in most circumstances.
Zhang W, et al. Ann Rheum Dis 2006;65:

14. Ultrasonography can be useful to reveal the presence of synovial fluid in a joint, to facilitate arthrocentesis in difficult cases, and to distinguish some characteristic aspects of crystal-induced joint diseases. It is, therefore, a valuable procedure in the diagnosis of gout.
Punzi L, et al. Ann NY Acad Sci 2009;1154:
Punzi L, et al. Ann NY Acad Sci 2009;1154:

15. Ultrasound-guided arthrocentesis
High frequency ultrasonography is a quick and safe procedure that allows a useful diagnostic and therapeutic approach in patients with arthritis of small joints. Ultrasound-guided placement of the needle within the joint can be performed easily, enabling synovial fluid to be withdrawn for analysis.
Grassi W, et al. Ann Rheum Dis 1999;58:

16. MSU crystals are always found in:
Synovial fluid samples from inflamed joints
Previously inflamed joints of patients untreated with urate-lowering drugs
Material from tophi
Joints of treated patients… before they dissolve
The finding of MSU crystals has a 100% specificity for the diagnosis of gout. These crystals are always found in inflamed joints of patients with gout and in tophi. They are also found in previously inflamed joints of untreated patients. They may or may not be found in the joints of treated patients, depending on whether the arthrocentesis is performed before or after the crystals have dissolved.
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua
Zhang W, et al. Ann Rheum Dis 2006;65(10):

17. The technique for detection
Synovial fluid analysis for crystals
Steps to follow:
Steps to follow:
To detect whether there are any crystals
The technique for detection
of MSU and CPPD differs
If so: to identify what type they are
Synovial fluid should first be examined under a light microscope for the presence of fat droplets (indicative of fractures), bacteria (indicative of septic arthritis) and crystals (diagnostic of a crystal-induced arthropathy).
MSU crystals are needle-shaped and may be seen on light microscopy. They are brightly birefrigent. Calcium pyrophosphate dihydrate (CPPD) crystals, responsible for pseudogout, are more rod-shaped or rhomboid and less intensely birefringent; they may be small and difficult to see on light microscopy. Oxalate crystals are bipyramidal.
The detection of MSU crystals gives an unequivocal diagnosis of gout, since there is no other condition with MSU crystals in synovial fluid. If MSU crystals are present, the patient has gout; he might have other diseases, he might have an infection of the joint as well, but he definitely has gout.
Zhang W, et al. Ann Rheum Dis 2006;65(10):

18. Identification of MSU crystals
Monosodium Urate (MSU)
Acicular
Intense birefringence
Negative elongation
Ordinary light
Polarised light
First order red compensator
axis
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua
If joint aspiration yields at least 3 ml of synovial fluid, samples should be placed into a vacuum tube for analysis. However, even if no fluid is aspirated into the syringe, one or two drops of fluid can be found in the needle and its hub. This amount is sufficient for crystal detection (and also for culture) and should be placed on a microscope slide with a coverslip. Ordinary light microscopy is used first to detect the presence of crystals or other particular aspects. It is important to underline that this may be sometimes the best option to detect calcium pyrophosphate crystals which are frequently not birefringent. MSU crystals, in contrast, are characteristically very birefringent and shiny when observed with a polarised light. The addition of a first order compensator enables definitive identification of MSU crystals which appear yellow when parallel to the axis of the red-plate compensator, and blue when perpendicular to the axis.
Richette P, et al. Lancet 2010;375:
Pascual E, et al. Ann Rheum Dis 2009; 68: 3-7.
Sivera F, et al. Ann Rheum Dis 2008;67:

19. MSU crystals from tophi
Polarised light
First order red compensator
By kind permission of L. Punzi,
Rheumatology Unit,
University of Padua
Tophi also can be easily aspirated and the material examined by microscopy with the same technique used for synovial fluid.
Richette P, et al. Lancet 2010;375:
Pascual E , et al. Ann Rheum Dis 2009;68:3-7.
Sivera F, et al. Ann Rheum Dis 2008;67:

20. EULAR recommendations 2006
for gout: diagnosis 5
Identification of MSU crystals from asymptomatic joints may allow definite diagnosis in intercritical periods.
The fifth EULAR recommendation on the diagnosis of gout deals with the diagnostic relevance of MSU crystal identification in patients without acute joint symptoms. This is very important because patients may be referred for investigations during an acute attack of arthropathy, but be seen after the joint disorder has apparently resolved, in the so-called intercritical period.
Zhang W, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

21. MSU crystals in synovial fluid during intercritical periods
Aspiration of 101 asymptomatic gouty joints
80 knees
21 first MTP joints
All had previously been inflamed and had been free of inflammation
over two months.
MSU crystals were found in:
43/43 joints from untreated patients
34/48 (71%) joints from patients on urate-lowering drugs (p<0.001).
MSU crystals have been identified in synovial fluid aspirated from asymptomatic, but previously inflamed gouty joints, indicating that after the crystals form, they stay in the joints if serum uric acid levels are not reduced. Thus, it has been suggested that identification of crystals in synovial fluid may be used to diagnose gout during intercritical periods.
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.
In conclusion, MSU crystals can be detected during the intercritical period and are highly likely to confirm the diagnosis if previously inflamed joints of untreated patients are examined. In treated patients with normal or low serum uric acid levels, the detection rate depends on the duration and effectiveness of urate-lowering treatment.
Pascual E, et al. Ann Intern Med 1999;131:

22. EULAR recommendations 2006 for gout: diagnosis
Gout and sepsis may coexist, so when septic arthritis
is suspected gram stain and culture of synovial fluid should
still be performed even if monosodium urate crystals are identified.
The sixth EULAR recommendation emphasizes that while MSU crystal identification is diagnostic of gout, the presence of these crystals does not exclude other concomitant conditions.
Indeed, synovial fluid containing MSU crystals can coexist with other joint diseases such as psoriatic arthritis, osteoarthritis and even pyrophosphate arthropathy. The most serious occurrence is, however, the coexistence of gout and septic arthritis.
Zhang W et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

23. A possible explanation for the coexistence of these two conditions (gout and septic arthritis), which is not uncommon, is that the synovial fluid inflammation associated with septic arthritis may induce dissolution of pre-existing crystal deposits and rapid mobilisation of the crystals from these deposits.
Yu KH, et al. Rheumatol 2003;42:
Yu KH, et al. Rheumatol 2003;42:

24. There is also an association between gout and the potentially life-threatening condition of necrotising fasciitis, which is an invasive soft-tissue infection characterised by widespread, rapidly developing necrosis of the subcutaneous tissue and fascia.
The portal of entry of the infective micro-organism may be through a ruptured tophaceous wound or septic joint.
KH, et al. Rheumatol 2004;43:
Yu KH, et al. Rheumatol 2004;43:

25. EULAR recommendations 2006 for gout: diagnosis7
While being the most important risk factor for gout,
serum uric acid levels do not confirm or exclude gout since
many people with hyperuricaemia do not develop gout,
and during acute attacks serum levels may be normal
Although hyperuricaemia is a crucial prerequisite of gout, it is important to underline that only a minority of hyperuricaemic patients develop gout. On the other hand, some patients with acute gout may have normal serum levels of uric acid.
Zhang W, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

26. Follow-up of 2046 men, free of gout at the onset, over 14.9 years
Normative Aging Study
Follow-up of 2046 men, free of gout at the onset, over 14.9 years
In the Normative Aging Study, the consequences of asymptomatic hyperuricaemia on rates of a first episode of gouty arthritis were determined in a cohort of 2,046 initially healthy men followed for 14.9 years (30,147 human-years of prospective observation) with serial examinations and measurement of urate levels. Among patients with a baseline serum urate level of 9 mg/dl or more, the annual incidence rate of gouty arthritis was 4.9%, whereas it was only 0.5% for those with urate levels between 7.0 (416 mol/l) and 8.9 mg/dl (475 mol/l) and 0.1% for those with urate levels below 7.0 mg/dl (416 mol/l) . The cumulative incidence of gouty arthritis in patients with baseline urate levels of 9 mg/dl (535 mol/l) or higher reached 22% after 5 years.
Campion EW. Am J Med 1987;82:
Campion EW. Am J Med 1987;82:

27. Inflammation… effects on serum UA
During a gout attack, serum uric acid drops because of an increase of its renal excretion
For example: 50% of gouty patients have normal or low UA levels during attacks
Diseases with persistent inflammation have a negative association with hyperuricaemia and gout
For example: Rheumatoid arthritis
Serum acid uric is an inverse acute phase substance?
Patients with MSU crystal-proven gout may, however, have normal serum uric acid levels at the time of investigation. One reason for this could be that serum urate behaves as a negative acute phase reactant, being temporarily lowered during episodes of acute inflammation and stress. An increase in renal excretion of uric acid during acute episodes has also been suggested as the mechanism. In some patients the prior risk factors for hyperuricaemia may have been modified or eliminated by the time of presentation with gout (for example, cessation of diuretic, reduction of obesity or beer intake). Thus serum levels of uric acid have limited diagnostic value, especially during an acute attack of gout.
Urano W, et al. J Rheumatol 2002;29(9):
Agudelo CA, et al. Arthritis Rheum 1984;27(4):
Wu VC, et al. Am J Kidney Dis 2005;45(1):88-95.
Urano W, et al. J Rheumatol 2002;29(9):
Agudelo CA, et al. Arthritis Rheum 1984;27(4):
Wu VC, et al. Am J Kidney Dis 2005;45(1):88-95.

28. EULAR recommendations 2006 for gout: diagnosis8
Urinary 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
Over-excretion of uric acid is defined by a 24-hour urinary uric acid excretion of >1000 mg/day with regular diet, while under-excretion is defined as a uric acid clearance of <6 ml/min. Other tests of urinary excretion status such as the uric acid to creatinine ratio may be useful to identify over-excretion of uric acid for treatment purposes. Urinary uric acid excretion may also be estimated from an early morning spot urine sample, but the robustness of this method and its cost-effectiveness need further evaluation.
Zhang W, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

29. EULAR recommendations 2006 for gout: diagnosis9
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.
Although radiographs of joints affected by acute 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. Early bone erosions are better detected by the new imaging techniques, which are more sensitive. Radiography is not, therefore, useful for confirming the diagnosis of early or acute gout.
Zhang W, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65(10):

30. Likelihood ratio (HR) for radiographic features in the diagnosis of gout
The classic radiographic features of chronic gout may help to differentiate this arthritis from some other joint conditions. Radiography has some value in detecting the severity of tophi, because patients with intradermal tophi are 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. Thus radiographs play only a minor role in diagnosis in most patients with gout, although in late or severe disease characteristic radiographic features may be present.
Zhang W, et al. Ann Rheum Dis 2006;65(10):
Zhang W, et al. Ann Rheum Dis 2006;65:

31. Radiographic features of gout
DIP
PIP
Big toes
Typical plain radiographic features of chronic gout include visualisation of tophi as soft-tissue or intra-osseous masses, and the presence of a non-demineralising erosive arthropathy with erosions that are well defined with sclerotic or overhanging margins. The joint space is usually preserved until late in the disease, and other features such as peri-osteal new bone formation, extra-articular erosions, intra-osseous calcifications, joint space widening, and subchondral collapse may be present. Radiographic abnormalities are most frequently present in the feet, particularly in the first metatarsal phalangeal joint.
By kind permission of L. Punzi,
Rheumatology Unit, University of Padua

32. Risk factors and associated co-morbidity can be assessed
EULAR recommendations 2006
for gout: diagnosis 10
Risk factors and associated co-morbidity can be assessed
during the diagnosis of gout, including features of the metabolic syndrome (obesity, hyperglycaemia, hyperlipidaemia, hypertension).
A number of common risk factors and comorbidities have been identified for gout. 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 with gout, but their diagnostic value has a minor role.
Zhang W, et al. Ann Rheum Dis 2006;65:
Zhang W, et al. Ann Rheum Dis 2006;65(10):