CLASSIFICATION — Persistent hyperuricemia is a common biochemical abnormality

that results from excessive urate production and/or diminished renal uric acid excretion.
(See "Uric acid balance" .)

Persistent hyperuricemia can be divided into two categories:

 Primary hyperuricemia, which usually lasts indefinitely, describes urate saturation

arising in the absence of coexisting diseases or drugs that alter uric acid
production or excretion.

 Secondary hyperuricemia refers to excessive urate production ( table 1 ) or

diminished renal clearance ( table 2 ) that is the result of another disease, drug,
dietary product, or toxin.

CLINICAL SYNDROMES — The three classic stages in the natural history of

progressive urate crystal deposition disease (gout) are:

 Acute gouty arthritis

 Intercritical (or interval) gout

 Chronic recurrent and tophaceous gout

It may be worthwhile to regard the stages of gout as emerging sequentially, with clinical
severity often paralleling the frequency of acute gout flares and, ultimately, the
development of chronic gouty arthropathy and tophaceous gout. In this context,
treatment with antihyperuricemic (urate-lowering) agents is not curative, but it may
reset the course of the individual patient and provide what is essentially a cure if therapy
is maintained.

With current effective therapies, progression of gout to the chronic tophaceous stage is
now less frequent among the majority of compliant patients with primary gout and
among most patients with secondary gout [ 18 ]. When progression does occur, it is
most often among noncompliant patients, those in whom the management scheme has
not been appropriately communicated, and those in whom the diagnosis of gout has not
been made. Other patients liable to show progression of gout include those intolerant of
or treated with inadequate doses of urate-lowering agents, those receiving medications
(usually for comorbidities) that interfere with urate-lowering agents, and organ
transplant recipients.

These considerations differ from those associated with the manifestations of acute
hyperuricemia (primarily acute renal failure) seen in the tumor-lysis syndrome or with
other causes of massive tissue breakdown. (See "Uric acid renal diseases", section on
'Acute uric acid nephropathy' .)

ACUTE GOUTY ARTHRITIS — Acute gouty arthritis usually occurs after years of
asymptomatic hyperuricemia. (See "Asymptomatic hyperuricemia" .)

Typical attack — The typical attack of acute gouty arthritis, which is intensely
inflammatory, includes the following clinical features:
  Severe pain, redness, swelling, and disability. Maximal severity of the attack is
usually reached within 12 to 24 hours. Complete resolution of the earliest attacks
almost always occurs within a few days to several weeks, even in untreated
individuals.

 Lower extremity involvement. At least 80 percent of initial attacks involve a single

joint, most often at the base of the great toe (first metatarsophalangeal joint,
known as podagra) or the knee.

 Signs of inflammation extending beyond the confines of the joint that is primarily
involved. This feature may give the impression of arthritis in several contiguous
joints or of tenosynovitis, dactylitis (sausage digit), or even cellulitis.

 Involvement in an ankle or instep or in a wrist, finger, or olecranon bursa, which

can occur initially but is more common in a recurrent episode of gouty arthritis.
Other potential sites of involvement include other bursas, shoulders, hips,
sternoclavicular joints, spine, and sacroiliac joints, which may cause diagnostic
confusion.

 More subtle inflammatory episodes, which appear to occur in some patients.

However, these have not been well-studied.

 Inconstant or nonspecific laboratory abnormalities. Neutrophilic

leukocytosis and/or elevation of the erythrocyte sedimentation rate or C-reactive
protein are common in acute gout attacks, but their presence in other acute
arthritides generally makes these findings of little diagnostic value. An exception
to this may be in distinguishing gout from events such as stress fracture, which
may cause some of the above symptoms and physical findings in the absence of
laboratory abnormalities and which can be confirmed by imaging studies.
(See "Overview of stress fractures", section on 'Diagnosis' .)

Serum uric acid (sUA) levels can be difficult to interpret during an acute gout flare. For
example, in the early months of urate-lowering drug therapy, gout attacks often occur
with normal or even low serum urate concentrations at the time of the acute event.
Lower urate levels have also been proposed to result from effects of cytokines during
flares. Overall, normal to low serum urate values have been noted in 12 to 43 percent of
patients with acute episodes of gout [ 19-22 ]. In patients suspected of gout based upon
the features noted above, an elevated sUA (≥6.8 mg/dL) can lend support to the
diagnosis but is not diagnostic. The most accurate time for assessment of sUA (and
establishment of a baseline value) is two weeks or more after complete subsidence of an
acute gout flare.

The initiation of urate-lowering therapy, although protective in the long term, can
precipitate acute gouty arthritis. As a result, prophylaxis is usually given to prevent this
complication. (See "Prevention of recurrent gout", section on 'Prophylaxis during
initiation of antihyperuricemic therapy' .)

Predisposing factors — Numerous circumstances promote or are associated with

acute attacks of gouty arthritis:

 Trauma, surgery, starvation, fatty foods and other dietary overindulgence,

dehydration, and ingestion of drugs affecting (raising or lowering) serum urate
concentrations (eg, allopurinol , uricosuric agents, thiazide, or loop diuretics) and
low-dose aspirin may all promote gouty attacks. In men, increasing alcohol
 consumption (beer and spirits, but not wine) is associated with a proportionately
greater risk of developing gout [ 23 ]. Each of these circumstances may provoke
generalized disturbances in extracellular fluid urate concentrations or may affect
crystals in the inflammatory milieu [ 24 ].

 High levels of meat and seafood consumption are associated with higher serum
urate concentrations, while increased intake of low-fat dairy products correlates
with lower urate levels [ 25 ]. The amounts of meat and seafood in the diet are
significantly associated with an increased risk of developing gouty arthritis. This
was illustrated in a prospective study of 47,150 male health professionals [ 26 ].
Those in the highest quintile of meat consumption had an adjusted hazard ratio
(HR) of 1.41 compared with the lowest quintile; those consuming the largest
amount of fish had a HR of 1.51. Neither the intake of purine-rich vegetables nor
total protein intake was associated with an increased risk of gout.

On the other hand, the highest quintile of dairy product consumption was
associated with a significant reduction in risk (HR of 0.56) [ 26 ]. In a separate
report, higher coffee consumption was also associated with a lower risk of acute
gout [ 27 ]. Coffee, but not tea, consumption reduced the risk of having
hyperuricemia, suggesting that the uric acid lowering effect is not due to caffeine
but to other, as yet unidentified, components of coffee [ 28 ].

 Locally elevated urate concentrations [ 29 ], in conjunction with repeated joint

microtrauma, prior degenerative change, or reduced temperature in poorly
perfused distal tissues [ 30 ], may predispose individual joints to gouty
inflammation.

 Osteoarthritic changes in interphalangeal joints (Heberden's and Bouchard's

nodes) may predispose these joints to develop coexisting gouty arthritis
[ 31,32 ], particularly in older individuals with chronic kidney disease or in those
receiving diuretic therapy. (See "Diuretic-induced hyperuricemia and gout" .)

Acute polyarticular gout — Polyarticular gouty arthritis is the initial manifestation in

less than 20 percent of patients with gout but occurs with increasing frequency in later
flares. Polyarticular symptoms are particularly common late in the course of untreated
gout, when multiple recurrences, short or absent symptom-free intervals, and palpable
tophaceous deposits are common. (See"Evaluation of the adult with polyarticular pain" .)

A polyarticular initial presentation of gouty arthritis may be more frequent in patients in

whom hyperuricemia and gout arise secondary to a myeloproliferative or
lymphoproliferative disorder or in organ transplant recipients who are
receiving cyclosporine A. (See "Hyperuricemia and gout in renal transplant recipients" .)

Diagnosis of acute gout — A definitive diagnosis should be sought when acute gout is
suspected, both to exclude alternative explanations for the acute event and to ensure
that long-term, expensive, and potentially toxic urate-lowering medications are not
prescribed unnecessarily if there is recurrence or progression of the arthritis.

The diagnosis of acute gout is most secure when supported by visualization of urate
crystals by experienced examiners in a sample of fluid aspirated from an affected joint
(or bursa). If crystal confirmation of the diagnosis cannot be made, a provisional
diagnosis may be made on the basis of clinical data, including history, physical
examination, appropriate laboratory tests, and, increasingly, imaging studies.
Polarizing microscopy — Synovial fluid obtained from joints or bursas (as well as
material aspirated from tophaceous deposits, if any) may be directly examined using
compensated polarized light microscopy ( picture 1A-C ).

 During an acute gouty episode, aspiration of the affected joint and polarized
compensated light microscopy of synovial fluid permit detection of intracellular
monosodium urate crystals in synovial fluid. The sensitivity of this technique in
demonstrating negatively birefringent crystals in patients with acute gouty
arthritis is at least 85 percent, and the specificity for gout is 100 percent
[ 33,34 ]. However, acute gouty arthritis may occasionally coexist with another
type of joint disease, such as septic arthritis or pseudogout.

The sensitivity of the joint fluid analysis can be improved by examination of the sediment
in a centrifuged specimen [ 35 ]. Additional approaches to consider in the event of a
negative (no urate crystals seen) study during the acute attack include aspiration of a
concurrently inflamed joint or (less helpful in ruling out an accompanying cause for the
acute event) aspiration of an uninflamed but previously involved joint or of a tophus, if
either is present.

Criteria for clinical diagnosis of gout — In the absence of the means to identify
urate crystals or in the presence of a negative polarized light microscopic study, a
tentative diagnosis of gout may be made by a combination [ 36 ] of clinical and historical
criteria [ 33,35,37,38 ]. This method of diagnosis must be regarded as provisional and
as much less specific [ 37 ]. Clinical, imaging, and laboratory criteria that may be useful
include:

 A classic history of one or more episodes of monoarticular arthritis followed by

intercritical period(s) completely free of symptoms

 Maximum inflammation (with the features described above) within 24 hours

 Unilateral first metatarsophalangeal joint attack (podagra)

 Presence of a visible or palpable lesion, which by location or appearance is likely

to be a tophus

 Hyperuricemia

 Subcortical bone cysts apparent on plain radiograph or magnetic resonance

imaging (MRI) examination identifying gouty tophi or erosions. Changes of these
types seen in imaging procedures are not usually detectable at the time of the
first acute attack of gouty arthritis.

 Dual-energy computerized tomography (CT) examination identifying urate

deposits. Several studies have shown that urates can be specifically identified in
articular and periarticular locations and can be distinguished from calcium
deposition using dual-energy CT [ 39-41 ]. Further 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 in patients in whom the
diagnosis remains uncertain despite standard clinical evaluation.

 Ultrasound examination showing either a linear density overlying the cartilage or

tophaceous appearing deposits [ 42 ]. In studies of patients with a clinical
 suspicion or proven diagnosis of gout, the ultrasound finding of hyperechoic
cloudy areas (HCA) had a sensitivity and specificity for gout of 79 and 95 percent
[ 43 ], while the double contour sign (DCS) from hyperechoic enhancement
overlying the cartilage surface had a sensitivity and specificity of 44 and 99
percent ( image 1 ) [ 44 ]. In patients with asymptomatic hyperuricemia in a
small pilot study, both HCA and DCS were found in the joints of some patients
who had never had symptoms of gouty arthritis [ 45 ]. The implications of this
latter study with regard to making a diagnosis of gout in patients without
symptoms of the disease await further discussion and confirmation of the
findings.

The accuracy of clinical diagnosis without crystal confirmation is uncertain. A study of 30

patients with crystal proven gout showed that the presence of two of three of the Rome
criteria (serum uric acid greater than 7 mg/dL; presence of tophi; or painful joint
swelling of abrupt onset and clearing within one to two weeks) had a 77 percent positive
predictive value. No clinical criteria were more than 70 percent sensitive or 89 percent
specific [ 36 ].

An appropriate clinical picture and an elevated serum urate concentration suggest the
diagnosis of acute gouty arthritis. However, as noted above, an appreciable number of
flares occur in patients who, at the time of the attack, have normal or even low serum
urate concentrations. (See 'Typical attack'above.) Conversely, patients with acute
arthritis due to causes other than gout may have coincidental hyperuricemia.

A diagnostic approach has been proposed to improve the accuracy of diagnoses made
without joint fluid analysis, which incorporates many of the features described above.
The rule was based upon an analysis of 328 patients with monoarthritis seen initially by
family practitioners in the Netherlands; the patients also underwent prompt expert
synovial fluid analysis [ 38 ]. The model used seven variables, which were assigned
weighted scores that could be ascertained in primary care to distinguish three levels of
risk for gout. The following variables and scoring values were used:

 Male sex (2 points)

 Previous patient-reported arthritis attack (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 uric acid level greater than 5.88 mg/dL (3.5 points)

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. This rule was applied only to patients with
monoarthritis and requires external validation in another primary care setting. For ease
of use, the authors of the study have provided an online calculator that provides an
absolute calculated risk
atwww.umcn.nl/Research/Departments/eerstelijnsgeneeskunde/Pages/Jichtcalculator.as
px (accessed November 29, 2010).

Resolution — Resolution of the acute gouty attack is sometimes accompanied by

desquamation of the skin overlying the affected joint. The physiologic basis of the
resolution of acute gouty inflammation is complex but centers on attenuation of a
number of pathogenetic factors [ 46 ]. (See "Pathophysiology of gouty arthritis" .)

Differential diagnosis of acute gouty arthritis — Several other conditions may

mimic acute gouty arthritis. Aspiration of synovial fluid from the affected joint and
analysis of the fluid by Gram stain, culture, and regular and polarized light microscopy
permit the distinction of gout from the disorders below in the great majority of cases
[ 34,47 ]. (See 'Diagnosis of acute gout' above.)

The differential diagnosis of acute monoarticular gouty arthritis includes the following:

 Septic arthritis — Acute monoarticular gout can give a clinical picture

indistinguishable from acute septic arthritis, including fever, leukocytosis, and
elevated erythrocyte sedimentation rate. On rare occasions, acute gout and septic
arthritis coexist. (See "Septic arthritis in adults" .)

 Trauma — Gouty attacks of lesser severity may be mimicked by a stress fracture

or traumatic process in the bone or joint.

 Pseudogout — Features that help to differentiate between gout and pseudogout

are illustrated in the table ( table 3 ). In some cases, both urate and CPPD
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 disease" .)

 Other crystalline arthritides — Arthritis or periarthritis due to the deposition of

basic calcium phosphate crystals cannot usually 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 [ 48 ]. In this setting, transmission electron microscopy and x-ray
powder diffraction have been successfully used for research identification of these
crystals. (See "Clinical manifestations and diagnosis of calcium pyrophosphate
crystal deposition disease" .)

 Other — The differential diagnosis among patients with a history of recurrent

attacks with spontaneous resolution or rapid and complete improvement with use
of nonsteroidal antiinflammatory drugs includes reactive arthritis, palindromic
rheumatism, and acute rheumatic fever, in addition to pseudogout. (See "Clinical
features of rheumatoid arthritis", section on 'Palindromic
rheumatism' and "Clinical manifestations and diagnosis of acute rheumatic
fever" .)

While many clinicians are skilled at joint aspiration, those who are not may request the
assistance of an orthopedic surgeon to obtain the fluid or of a rheumatologist to perform
a joint tap and to help with the analysis of the synovial fluid. (See "Joint aspiration or
injection in adults: Technique and indications"and "Synovial fluid analysis and the
diagnosis of septic arthritis" .)

INTERCRITICAL GOUT AND RECURRENT GOUTY ARTHRITIS — Upon resolution of

an acute attack of gout, the patient is said to have entered an intercritical (between
attacks) period. Even after severe and incapacitating acute attacks, intercritical periods
early in the course of gout are most often entirely asymptomatic. This sequence is so
uncommon in arthritic disorders, other than crystal deposition diseases and palindromic
rheumatism, that its presence is highly suggestive of the diagnosis.

Intervals between attacks of acute gouty arthritis are of variable duration. Most
untreated patients with gout will experience a second episode within two years. As an
example, one large group of patients studied prior to effective antihyperuricemic (urate-
lowering) therapy found that 62 percent of patients had a second attack within the first
year, 78 percent within two years, and 93 percent within 10 years [49 ]. The trend
among untreated patients is toward recurrent acute attacks that occur after
progressively shorter asymptomatic periods and that are increasingly prolonged and
disabling, polyarticular, and associated with fever.

Polyarticular flares of gouty arthritis may occur in a sequential (migratory) pattern or

simultaneously or may involve a cluster of adjacent joints, tendons, and bursae. Bony
erosions and deformities can develop (chronic gouty arthropathy), resulting in the
disappearance of intercritical periods.

This stage of chronic gouty arthropathy is often accompanied by tophaceous deposits

that contribute to deformity and disability. (See 'Chronic tophaceous gout' below.)

Evaluation — The availability of effective means to control hyperuricemia has led to

substantial reductions in the rates of recurrence of gouty arthritis and of tophi in patients
adherent to long-term urate-lowering therapy [ 18 ]. The initial intercritical period
provides an excellent opportunity to do the following:

 Establish the diagnosis of gout if this has not been accomplished during the acute
attack (see'Diagnosis of intercritical or chronic tophaceous gout' below)

 Identify and relieve reversible causes of hyperuricemia, potentially obviating the

need for long term urate-lowering therapy

 Classify the patient with regard to the mechanism underlying hyperuricemia and
gout, including the causes of secondary hyperuricemia due to overproduction or
underexcretion ( table 1 andtable 2 ) (see 'Classification' above
and "Asymptomatic hyperuricemia" )

 Institute prophylactic antiinflammatory and urate-lowering therapy, if indicated.

The prevention of recurrent gout is discussed separately. (See "Prevention of
recurrent gout" .)

 Evaluate the patient for and, if appropriate, initiate management of comorbidities

common in gout patients (such as hypertension, chronic renal functional
impairment, cardiovascular disease, and the components of the metabolic
syndrome) [ 50 ]. In the context of these comorbidities, as well as for the aim of
some degree of serum urate reduction, lifestyle changes should be reviewed with
the patient [ 23,25,26 ]. These might include changes in dietary intake and
composition, reduction of alcohol intake, reduction to ideal body weight, and
 dietary supplementation, such as with vitamin C. (See "Prevention of recurrent
gout" .)

CHRONIC TOPHACEOUS GOUT — Tophaceous gout is characterized by collections of

solid urate in connective tissues (which may occasionally be calcified). While these
collections may be apparent clinically or may be detected with plain radiography, dual
energy computerized tomography (CT), ultrasonography, or magnetic resonance (MR)
imaging, it is likely that many patients with gout and sustained hyperuricemia have a
much larger burden of clinically inapparent urate crystal deposits than is suspected.

Clinical appearance — Tophi are visible and/or palpable and can be present on the
ears or in the soft tissues including articular structures or bursae ( picture 2 ). Tophi are
typically not painful or tender. They may attenuate the skin, revealing a yellow or white
color. On the ear, they do not transilluminate. A chronic granulomatous inflammatory
response is identifiable on histological examination of the lesions, and, on occasion,
acute inflammation, mimicking that of gouty arthritis, occurs adjacent to one or several
tophi ( picture 3 ).

The inflammation may extend beyond the confines of a single joint, producing
generalized enlargement of a digit due to the presence of tophi and/or the inflammation
itself. The appearance may be similar to dactylitis seen in other disorders, such as
psoriatic arthritis, other spondyloarthropathies, and sarcoidosis. The expansive and
destructive changes associated with tophaceous gout may be mistaken for osteomyelitis
( image 2 ) and have sometimes led to erroneous amputation of involved digits [ 51 ].

The clinical picture of chronic tophaceous gout may be confused with other forms of
chronic inflammatory polyarthritis such as rheumatoid arthritis (particularly if tophi are
mistaken for rheumatoid nodules). 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.

Imaging — Bone erosions due to tophi may have characteristic delicate "overhanging"
edges. The characteristics of tophi on magnetic resonance (MR) images include relatively
homogeneous intermediate to low signal on T1-weighted images, as well as T2-weighted
images that have variable signal intensity [ 52 ]. Either homogeneous or peripheral
enhancement may occur with the addition of gadolinium. Tophus size can be estimated
on MR imaging [ 53 ] or quantified by dual energy CT [ 39 ], but the clinical usefulness
of such information is uncertain.

Ultrasound examination directed to joints or soft tissue deposits is an increasingly

promising modality for the early detection and monitoring of therapy for gout [ 42 ].
Characteristic lines overlying the surface of joint cartilage can be very suggestive
( image 1 ). (See 'Criteria for clinical diagnosis of gout'above.)

Course — Prior to the availability of effective urate-lowering treatment, the interval

from the first gouty attack to the onset of chronic arthritis or detectable tophi averaged
about 12 years, although intervals ranging from less than 5 years to 40 years were
noted in individual patients.

In the era preceding the availability of effective urate-lowering treatment, duration of

gout and degree of hyperuricemia were correlated with the rate and extent of tophus
formation. After 20 years of untreated gout, almost 75 percent of patients were affected,
with the highest prevalence in patients with the highest serum urate concentrations
[ 54 ].

In contrast to the classic presentation, a number of reports have described patients with
tophaceous deposits in the absence of, or prior to, gouty arthritis, a presentation that
was previously considered a rare occurrence restricted to patients with uric acid
overproduction due to myeloproliferative disorders or hereditary enzyme defects
[ 55,56 ]. Although this situation may, in part, reflect increasing recognition that tophi
can form in any area containing connective tissue (including the meninges but not the
brain and spinal cord), risk factors similar to those accounting for cryptic gout in older
patients may contribute to tophus formation as the first sign of gout. Such patients are
more likely to be women, to have predominant or exclusive involvement of the fingers,
to have chronic kidney disease, and to be treated with a diuretic or antiinflammatory
drug [ 56 ].

Urate-lowering treatment of gout with uricosuric agents and allopurinol initially led to a
dramatic reduction in chronic gouty arthritis and tophaceous gout, with a prevalence of
less than 5 percent reported in some series [ 18 ]. However, these progressive forms of
gout are being seen more frequently once again in certain subgroups of patients:

 Residual prevalences of chronic polyarticular and tophaceous gout approaching 50

percent have been reported in some series of men with gout whose major risk
factors were excessive alcohol consumption, diuretic use, and, most important,
suboptimal management or poor patient compliance [ 4,5 ].

 A more compliant group of older patients (most often women) is prone to develop
polyarticular and tophaceous gout in osteoarthritic joints as illustrated by the
following observations:

 In one report, 8 of 60 patients with gout were older women (mean age 82 years),
all of whom were receiving diuretic therapy; most had tophi in osteoarthritic
interphalangeal joints [ 8 ].

 In a second series, 17 percent of 149 patients with osteoarthritis had gout, often
with low-grade inflammation, in osteoarthritic finger joints [ 32 ]. These patients
were older (mean age 71 years) and were evenly distributed in gender. Over 70
percent were receiving diuretics, 60 percent had impaired renal function, and the
mean serum urate concentration was 11 mg/dL (654micromol/L).

The triad of diuretic-induced hyperuricemia, renal insufficiency, and nodal osteoarthritis

plus overrepresentation of women represents a distinctly different presentation from the
classically described group of middle aged men with tophaceous gout who have a higher
incidence of hypertension, obesity, and ethanol abuse.

 Organ transplant recipients treated with cyclosporine (and often diuretics as well)
are at increased risk for the accelerated development of chronic tophaceous gout
[ 9,10 ]. Both renal and cardiac transplant recipients, particularly those with
compromised renal function, have developed severe and often difficult to manage
complications of the hyperuricemic effect of cyclosporine, which is due to
impaired urate excretion [ 9 ]. (See "Hyperuricemia and gout in renal transplant
recipients" .)
  Other patients at increased risk for chronic tophaceous gout are those who have
chronic kidney disease that has been felt to preclude full-dose antihyperuricemic
drug therapy, those who are allergic to or intolerant of urate-lowering agents,
and those receiving doses of urate-lowering agents that are inadequate to
achieve goal serum urate levels in a range below the limit of urate solubility
(often recommended as <6 mg/dL [357 micromol/L]) [ 57 ].

RENAL COMPLICATIONS OF CHRONIC HYPERURICEMIA — There are two major

renal complications of chronic hyperuricemia: nephrolithiasis and chronic urate
nephropathy.

Nephrolithiasis — Uric acid stones are a component of the morbidity suffered by

patients with gout. Pure uric acid stones account for only 5 to 10 percent of all urinary
tract stones in the United States and Europe but comprise 40 percent or more of stones
in areas with hot, arid climates in which the tendency to a low urine volume and acid
urine pH promote uric acid precipitation. (See "Uric acid nephrolithiasis" .)

The prevalence of uric acid stones among patients with gout prior to effective
antihyperuricemic treatment was about 20 percent, several hundred-fold greater than
that in the adult non-gouty population. Although many urinary tract calculi in patients
with gout are composed entirely of uric acid, many more contain calcium oxalate or
calcium phosphate surrounding a central nidus of uric acid.

There are three major risk factors for uric acid nephrolithiasis:

 Increased uric acid excretion

 Reduced urine volume

 Low urine pH, a setting in which most of the uric acid exists as the un-ionized,
more insoluble uric acid form rather than as the dissociated, more soluble urate
anion form

Chronic urate nephropathy — Renal impairment is common among patients with gout
but usually reflects the coexistence of other disorders such as hypertension, diabetes
mellitus, obesity, atherosclerosis [ 50,58,59 ], or, in some instances, lead intoxication
resulting from use of unbonded whiskey (moonshine) [ 60,61 ].

In addition, urate crystals can deposit in the renal medullary interstitium, producing a
chronic inflammatory (tophaceous) reaction and varying degrees of fibrosis. The clinical
manifestations of what has been called chronic urate nephropathy are an elevated serum
creatinine, a bland urine sediment, and hyperuricemia out of proportion to the degree of
renal insufficiency [ 62 ]. (See "Uric acid renal diseases", section on 'Chronic urate
nephropathy' .)

DIAGNOSIS OF INTERCRITICAL OR CHRONIC TOPHACEOUS GOUT — 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 uric acid-lowering therapy [ 63-65 ]. 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 noted above that, in most instances, deposition of urate crystals
in and about joints precedes the first clinical episode of gout by a substantial period of
time.

Demonstration of urate crystals in aspirates of tophaceous deposits provides a

convenient and specific means to corroborate the diagnosis in the small proportion of
gouty individuals with tophi [ 66 ].

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 [ 67 ]. 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.

Pathophysiology of gouty arthritis

HYPERURICEMIA AND GOUT — Hyperuricemia can be caused by impaired renal

excretion or overproduction of uric acid and/or by overconsumption of purine-rich foods
that are metabolized to urate. Detailed discussions of the causes of hyperuricemia and of
the normal mechanisms of urate handling are presented separately. (See "Asymptomatic
hyperuricemia" and "Uric acid balance" .)

A causative relationship among hyperuricemia, deposition of urate crystals, and gout

was proposed by Garrod in 1859 and later [ 1 ]. However, injection of solutions of uric
acid into blood or joints failed to reproduce the clinical features of the disease, casting
doubt on the association. Freudweiler noted in 1899 that injection of tophaceous
material caused inflammation [ 2,3 ].

The identification of MSU crystals within phagocytes when synovial fluid was examined
using compensated polarized microscopy was an important advance in understanding the
pathogenesis of gout [ 4 ]. This was followed by the observation that injection of MSU
crystals into normal joints produced acute gout attacks, reestablishing the connection
between urate crystals and gout [ 5,6 ]. The outline of the pathophysiology of gout is as
follows: a period of hyperuricemia leads to MSU crystal deposition, reaction to which can
result in acute and/or chronic inflammation.

Risk factors that have been associated with the development of gout appear to mediate
their effects, at least in part, through increased extracellular urate levels, reflected by
hyperuricemia. Non-modifiable risk factors include male gender, advanced age, and
ethnicity (eg, Pacific Islanders). Modifiable risk factors include obesity; diets rich in meat
and seafood content; alcohol-containing beverages (especially beer and distilled spirits);
sodas and fruit juices high in fructose content; hypertension; thiazide or loop diuretic
use; postmenopausal and organ transplant recipient status; use of certain medications
(eg,cyclosporine A or low-dose aspirin , although cardioprotective aspirin doses of only
81 to 325 mg/daygenerally do not increase attack frequency to a significant degree and
do not warrant discontinuation); and toxic exposures (eg, lead).
Lead toxicity has been associated with gout since the 1700s, but the mechanism has
been a matter of debate [ 7 ]. Some evidence has suggested that blood lead levels
widely considered to be within an acceptable range may be associated with an increased
prevalence of gout [ 8 ]; in population-based data from the National Health and Nutrition
Examination Survey (NHANES) for 2005 to 2008 in the United States, individuals in the
highest blood lead level quartile (mean of 0.19 mmol/L [3.95 mcg/dL])had a significantly
higher risk for gout and for hyperuricemia compared with those in the lowest quartile for
blood lead levels (mean of 0.04 mmol/L [0.89 mcg/dL]) (odds ratios for gout of 3.6,
95% CI 2.1-6.3, and for hyperuricemia of 1.9, 95% CI 1.3-2.6). These findings need
confirmation, and it is unknown whether interventions to lower such levels will reduce
risk.

All genetic mutations or polymorphisms associated with gout are also associated with
hyperuricemia [ 9]. However, although hyperuricemia is a necessary predisposing factor,
its presence does not always lead to the development of gout. Indeed, the majority of
hyperuricemic patients never develop gout [10-12 ]. Individual differences in the
formation of crystals or in inflammatory responses to those crystals (or both) may play a
role in determining whether a person with hyperuricemia will develop gout. Favoring an
unexplained increase in crystal formation in those with gout is the observation that
crystals are frequently found in synovial fluid from uninflamed joints [ 13 ], but it is
unusual to find them in joint fluid from non-gouty hyperuricemic people [ 14 ]. Higher
levels of uric acid in the blood clearly bring a greater risk for developing gout [ 11,12 ],
although not necessarily more severe gout. Obesity and ethanol ingestion further
increase the risk for gout at any given level of hyperuricemia [15 ]. Among people with
an established history of gout, consumption of alcohol or intermittent use of diuretics,
which may result in abrupt changes in extracellular fluid urate levels, appear to acutely
increase the risk of an attack [ 16,17 ].

Unfortunately, there have not been completely satisfactory explanations for some of the
fascinating clinical aspects of acute gout, including [ 18-21 ]:

 Precipitation of acute attacks by trauma or surgery

 Predilection for the first metatarsal-phalangeal (MTP) joint

 Spontaneous resolution of attacks

Plausible though unproven explanations for the frequent involvement of the first MTP
include relative coolness of the feet (reducing the solubility of MSU); the repeated
microtrauma to which the MTP joint is subjected [ 22 ]; and differential reabsorption into
the joint of exuded solvent (joint fluid) and solute (urate) from the periarticular area
when weightbearing is replaced by recumbency [ 23 ].

In addition, the initiation of antihyperuricemic therapy, although protective in the long

term, can initially precipitate acute gouty arthritis. Prophylaxis is usually given to
prevent this complication. (See"Prevention of recurrent gout", section on 'Prophylaxis
during initiation of antihyperuricemic therapy' .)

CRYSTALS — The solubility of MSU in physiologic saline at 37ºC, about

7 mg/dL (416 mmol/L), is approximately the same concentration above which patients
are at risk of developing gout [ 10,11 ]. Measurements of MSU solubility in plasma and
serum have varied more widely than those in saline, although the average value is
similar.

Temperature — The solubility of MSU falls rapidly with decreasing temperature [ 24 ].

Noninflamed synovial fluid is significantly cooler than serum, being 90 to 91ºF (32ºC) in
the knee [ 25 ], so the key value for urate solubility in a tissue of a given joint could be
considerably less than 7 mg/dL (416mmol/L).

Nucleation and growth — Solubility is a thermodynamic parameter determined when

a fluid is in equilibrium with a solid phase. Supersaturation may persist if nucleation and
growth of MSU crystals do not occur. Indeed, MSU has been noted to remain in solution
indefinitely at a concentration of 84mg/dL (5 mmol/L) [ 26 ]. Data are conflicting on
whether particular components of cartilage or joint fluid promote or inhibit the critical
nucleation step [ 27 ]. Amid this uncertainty, immunoglobulin (Ig) stands out as a likely
promoter of nucleation, although whether by nonspecific or by MSU-specific binding is
unclear [ 27-29 ]. MSU crystals from tophi and synovial fluid during acute gout are
coated with Ig [ 30,31 ].

Both nucleation rates and subsequent growth rates of MSU crystals are directly
proportional to the degree of MSU supersaturation [ 32 ]. Together, these data provide
an explanation for, but not a detailed mechanism of, the observations that
hyperuricemia is necessary but not sufficient for the development of gout and that risk
increases with increasing concentration of uric acid.

INFLAMMATION — The phagocytosis of MSU crystals by neutrophils plays a central

role in an acute attack of gout. In an experimental animal model, depletion of
neutrophils with vinblastine prior to injection of MSU crystals prevented inflammation
[ 33 ]. Such treatment could also affect other cell types. Synovial cells, monocytes, and
endothelial cells have all been shown to phagocytose MSU and to release various
mediators of inflammation [ 34-36 ]. Phagocytosis of MSU crystals by synovial lining
cells (some of which are macrophage-like) precedes influx of neutrophils in vivo
[ 37,38 ].

Macrophage phagocytosis of MSU crystals and subsequent cytokine release may require
the presence of cell surface receptors of the innate immune system. In some murine
model systems, the absence of the toll-like receptors, TLR-2 or TLR-4; of the TLR
adapter protein; of myeloid differentiation factor 88 (MyD88); or of an adapter protein
shared by TLR-2 and TLR-4 (CD14) is associated with blunted production of
proinflammatory cytokines in vitro and in vivo [ 39,40 ]. However, in another murine
model, although MyD88 signaling was critically important, toll-like receptors did not
appear to play a role in the inflammatory response to intraperitoneally injected MSU
crystals [ 41 ].

Monocytes and synoviocytes release interleukin–1 (IL-1), IL-6, IL-8, and tumor necrosis
factor (TNF) in response to MSU crystals in vitro [ 35,42-44 ]. Increased levels of IL-6,
IL-8, and TNF occur in gouty tissues in vivo [ 42-44 ]. Blockade of IL-8 or of TNF activity
prevents MSU-induced inflammation in animal models [ 45,46 ]. The ability of crystals of
MSU to cause increased production of cytokines and chemokines involves effects on gene
transcription and stabilization of mRNA [ 47 ].

MSU crystal-induced release of IL-1, IL-6, and TNF from the monocytes of patients with
end-stage renal disease (ESRD) is reduced [ 48 ]. The decrease in production of selected
cytokines is present whether or not such patients are on hemodialysis. This phenomenon
may partially explain the observation that patients with ESRD develop gout relatively
infrequently despite the presence of severe hyperuricemia [48 ]. However, it is unknown
if either azotemia or dialytic therapy affects MSU crystal nucleation or growth.

Recruitment and activation of neutrophils appears to be dependent upon locally

produced cytokines [49,50 ]. Interleukin 1 is probably an important factor; rodents
deficient in IL-1 receptors do not mount as vigorous an inflammatory response as wild-
type animals do to injected MSU crystals [ 41,51 ], and clinical trials of IL-1 antagonists
support a central role for IL-1 in human gout [ 52,53 ].

It appears that resident tissue cells rather than bone marrow-derived cells utilize the IL-
1 signaling pathway, as irradiated chimeric animals transplanted with bone marrow cells
lacking IL-1 receptors are able to mount a neutrophil response [ 41 ]. Crystals of MSU
activate the particular inflammasome that contains cryopyrin (also referred to as the
NALP3 or PYPAF1 protein), thereby generating IL-1 beta [ 54]. Neutrophils respond to
MSU crystals with a respiratory burst and release of lysosomal enzymes, superoxide
anion, leukotriene B4, and IL-1 [ 49,55-59 ].

The cellular biology and intracellular signaling mechanisms involved in neutrophil

chemotaxis and activation in response to crystals have been intensively investigated and
are quite complex [ 60,61 ]. Tyrosine kinases, phospholipases, chemoattractants, and
adhesion molecules such as E-selectin may all play important roles in gout and are
potential targets for therapeutic interventions [ 62-65 ].

Colchicine , long used for the treatment and prophylaxis of gout, inhibits tyrosine
phosphorylation in neutrophils in response to crystals (MSU or calcium pyrophosphate)
but does not inhibit this pathway when bacterial products are the stimulus [ 62 ].
Colchicine blocks activation of the NALP3 inflammasome in monocytes by MSU crystals
[ 54 ]. At low doses, colchicine interferes with microtubule function and inhibits the
activity of relevant adhesion molecules on neutrophils and on endothelial cells; these
effects may inhibit neutrophil migration [ 66,67 ].

Proteins attached to MSU crystals have important modulating effects on the

inflammatory response. Depending upon the type of protein, the result may be
proinflammatory or antiinflammatory. As an example of proinflammatory effects, MSU
crystals derived from tophi produce more inflammation than synthetic ones, a difference
that is eliminated by protease treatment of tophi [ 68 ]. Binding of IgG to MSU crystals
results in an increased release of superoxide and lysosomal enzymes from human
neutrophils in vitro when compared with protein-free crystal-induced release of these
substances [58,69,70 ].

The inflammatory potential of MSU crystals is reduced when lipoproteins, particularly

those containing apolipoprotein B (ApoB), are allowed to bind to them before injection in
animal models [ 71 ]. Effects of these lipoproteins are likely to play a role in the self-
limited nature of acute gout. (See 'Spontaneous resolution' below.)

The role of the kinin and complement systems in acute gout is unclear. MSU crystals can
activate Hageman factor, and kinins can be detected in inflamed joints. However, acute
inflammation still occurs in experimental models where these mediators are absent
[ 72,73 ]. MSU crystals can activate complement by both the classical and alternative
pathways and by a mechanism dependent upon the presence of either IgG or C-reactive
protein [ 74,75 ]. However, depletion or deficiency of complement results in incomplete
inhibition of inflammation in experimental models [ 76-78 ]. Total hemolytic complement
is elevated, rather than depleted, in synovial fluid during acute inflammation [ 79 ]. The
dispensability of the kinin and complement systems in gouty attacks does not mean that
they do not participate at all. Antiinflammatory synergy did not occur with blockade of
both systems, but an additive effect was present [ 76 ].

SPONTANEOUS RESOLUTION — Even without treatment, a typical attack of acute

gout resolves within a few weeks. There are many feedback mechanisms that tend to
limit inflammatory states, such as the inactivation of inflammatory mediators; death,
deactivation, or differentiation of inflammatory cells; and upregulation of
antiinflammatory mediators, such as transforming growth factor-beta (TGF-beta), IL-1
receptor antagonist (IL-1ra), and peroxisome proliferator-activated receptor gamma
(PPAR gamma) [ 80,81 ]. These are likely to play a role in limiting the duration of an
acute attack of gout [ 82]. (See "Role of cytokines in rheumatic diseases" .)

The different responses to MSU crystals of cells of the monocyte-macrophage lineage

obtained from sites of early and late inflammation are illustrative. Leukocytes, when
recovered 16 hours after an experimentally-induced blistering skin lesion, predominantly
secrete proinflammatory cytokines (eg, TNF) when exposed to MSU in vitro; leukocytes
recovered from blister fluid at 40 hours after injury produce the antiinflammatory
cytokine TGF-beta [ 80 ].

Dissolution of urate crystals by products of phagocytes, including superoxide, could also

serve to turn off inflammation [ 83 ]. However, resolution of an acute attack of gout
occurs even in the ongoing presence of crystals. The physical properties of crystals may
change with inflammation. Indeed, neutrophil products remove IgG from MSU crystals
thereby making them less inflammatory [ 84 ]. Perhaps more importantly, increasing
amounts of antiinflammatory ApoB bind to MSU crystals during the course of an attack
[ 85 ].

THE TOPHUS — Tophi are deposits of MSU crystals surrounded by granulomatous

inflammation. They are most often found in joints, bone, cartilage, and skin but may
(uncommonly) be found in parenchymal organs as well. The tissue reaction to a tophus
is generally chronic inflammatory in type; both innate immunity and adaptive immunity
participate. Although clinical signs of acute inflammation sometimes occur in tophi, this
is unusual; swelling accompanying a tophus is most often due to the mass of crystals
itself.

Surgically obtained tophi from 12 established gout patients were analyzed by

quantitative immunohistochemistry [ 86 ]. The coronal zones of the tophi (relative to the
surrounding fibrovascular zones) contained substantial numbers of CD68+ mononuclear
macrophages, multinucleated CD68+ cells (to a lesser extent), and plasma cells but
contained very few neutrophils. CD20+ B cells, present in small numbers, were found in
the fibrovascular zone, and both mast cells and T cells were found in modest numbers in
both sites. Of note, IL-1 beta was frequently expressed by CD68+ cells in the corona,
and the number of mononuclear cells expressing IL-1 beta correlated with number
expressing antiinflammatory TGF-beta1.

These findings indicate that the tophus is a complex but organized chronic inflammatory
response to urate crystal deposition, in which both innate immunity and adaptive
immunity participate. It seems likely that correlated expression of both pro- and
antiinflammatory factors in these lesions is reflected by the cyclic processes of tophus
inflammation and resolution and of tissue remodeling.

Visible or palpable tophi are usually noted only among those patients who have had
repeated attacks of acute gout, often over many years. However, microscopic
examination of synovium from those with acute gout, but without macroscopic tophi, can
show micro-tophi, which are surrounded by only a thin rim of fibrocytes [ 87 ]. Although
unsubstantiated, the initiation of an acute gout attack may begin with the release of MSU
crystals from micro-tophi into the synovial fluid or may actually begin in the tissue. The
latter mechanism is consistent with the clinical observation that joint fluid obtained
shortly after the onset of symptoms is sometimes free of crystals, while a repeat
aspiration a day or more later is floridly positive [ 88 ]. It is particularly tempting to
ascribe post-traumatic acute gout to this mechanism.

Crystals of MSU from tophi are associated with IgG and other proteins [ 30 ]. Their
biology is probably complex, as evidenced by conflicting data on their inflammatory
properties [ 68,89 ]. The pathologic effects of tophi, particularly their ability to cause
erosion of bone, cartilage, and soft tissues, are poorly understood.

Treatment
NSAIDS/COX-2 INHIBITORS — There are no high-quality randomized, placebo-
controlled trials of nonsteroidal antiinflammatory drugs (NSAIDs) for acute gouty
arthritis [ 2 ]. Nevertheless, they are first-line therapy for most patients with this
disorder.

Complete or nearly complete resolution of pain and disability typically occurs within
several days to one week. Aspirin is usually avoided because of the paradoxical effects of
salicylates on serum urate, resulting from renal uric acid retention at low doses (<2 to
3 g/day) and uricosuria at higher doses.

A number of randomized trials have compared different NSAIDs with each other, without
any apparent differences in efficacy [ 2-7 ]. In the two largest trials, indomethacin and
the selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib had comparable efficacy
[ 3,4 ]. Significant pain relief was noted at the initial assessment four hours after the
first dose [ 3 ].

Caution is necessary in patients with known cardiovascular disease or with multiple risk
factors for atherosclerotic coronary disease, since an increased risk of myocardial
infarction, stroke, and heart failure have been associated with use of both selective COX-
2 inhibitors and, perhaps to a lesser degree, nonselective NSAIDs. (See "COX-2 selective
inhibitors: Adverse cardiovascular effects" and"Nonselective NSAIDs: Adverse
cardiovascular effects" .)

Unless contraindicated (eg, by gastrointestinal, cardiovascular, or renal disease, or

allergy), we suggest administration of a potent oral nonselective NSAID (such
as naproxen or indomethacin ) for reduction of acute gouty inflammation, especially if
treatment is initiated within 24 hours of the onset of symptoms ( algorithm 1 ). A typical
starting dose for naproxen is 500 mg twice daily and for indomethacin 150 mg/day given
in three divided doses.
In view of the frequent gastrointestinal intolerance associated with NSAIDs, the dose
should be reduced by one-half as soon as objective and subjective improvement is
noted, often within three days. Further dose reductions and withdrawal over several
more days is safe and practical. Most patients are on NSAIDs until the attack has
completely resolved; this may be a total of seven to ten days.

In an attack of several days duration a longer course of treatment may be necessary and
an antiinflammatory agent with fewer gastroduodenal side effects (such
as nabumetone or a selective COX-2 inhibitor) may be preferred. In patients at high risk
of gastric ulcer or gastrointestinal bleeding addition of an antiulcer medication to a
nonselective NSAID may be helpful. (See "NSAIDs (including aspirin): Primary
prevention of gastroduodenal toxicity" .)

COLCHICINE — Many patients report that incipient attacks can be aborted with
oral colchicine taken at the first symptom. Whether, however, colchicine therapy offers
more rapid or complete relief of gout flares than alternative antiinflammatory agents is
not clearly established and awaits head-to-head comparisons of colchicine with NSAIDs,
glucocorticoids, and IL-1 inhibitors.

Despite centuries of use of colchicine -containing products for treatment of the

symptoms and signs of gout, oral colchicine (uncombined with another active ingredient)
was approved for the first time by the US FDA in 2009 [ 8 ].

Oral — Oral colchicine can be effective for the treatment of acute gouty arthritis, and
side effects are less likely when a low-dose regimen is used at the onset of symptoms of
flare [ 9 ]. The regimen recommended by the FDA for administration of this agent (in the
absence of concurrent use of interacting drugs or of end-stage
renal disease/renal dialysis) is a low-dose course consisting of 1.2 mg (2 tablets) at the
first dose followed one hour later by 0.6 mg (1 tablet), to give a total dose of 1.8 mg on
the first day of colchicine treatment [ 8,10 ].

Traditional regimen — The traditional regimen of 0.6 mg (one tablet) per hour or
every two hours until there was either relief of gouty pain and inflammation, a total dose
of 4 to 6 mg was reached, or GI symptoms occurred, was limited by adverse
gastrointestinal effects (diarrhea, abdominal cramping, nausea, vomiting). As an
example, in a placebo-controlled trial demonstrating efficacy of oral colchicine, 43
hospitalized patients with acute gout flares were randomized to receive colchicine (1 mg
followed by 0.5 mg every two hours as tolerated or until complete response) or placebo
at a mean of 38 hours after the onset of symptoms [ 11 ]. About two-thirds (73 percent)
of colchicine-treated patients improved (≥50 percent pain relief on a pain VAS) at 36 to
48 hours from treatment initiation, compared with about one-third (32 to 36 percent) of
the placebo group. However, all patients taking colchicine (mean total dose 6.7 mg)
developed diarrhea and/or vomiting at a median time of 24 hours and, in the majority of
patients, GI symptoms occurred before or concomitant to pain relief.

Lower dose regimens — The unfavorable therapeutic index for traditional (higher
dose) oralcolchicine treatment led to interest in lower-dose oral colchicine treatment. As
an example, an alternative regimen was recommended by a task force of the European
League Against Rheumatism (EULAR) Standing Committee for International Clinical
Studies (2006) which was based on a consensus of expert opinion [ 12 ]. The EULAR
guideline recommended colchicine 0.5 mg three times daily. And, as noted above
(see 'Oral' above), the US FDA approved a lower dose regimen for treatment of acute
gout that consists of 1.2 mg at the first dose followed one hour later by 0.6 mg, for a
total dose of 1.8 mg.

 Efficacy – Low-dose colchicine may have similar efficacy to that of a higher dose
regimen. This was the conclusion of the AGREE trial in which 575 patients with
recurrent gout enrolled [ 9 ]. Of these, 184 patients with a validated flare of gout,
who had been randomly assigned to low-dose, higher dose, or placebo groups
received one of the following regimens:

 Low-dose oral colchicine – A total dose of 1.8 mg over one hour, followed by
placebo hourly for five more hours, or

 Higher dose – An initial dose of 1.8 mg over one hour followed by colchicine 0.6
mg for five additional hours (maximum total dose 4.8 mg)

 Placebo – The placebo group received placebo at all time points.

The primary comparison was the proportion of subjects in the high dose group versus
those in the placebo group who achieved a ≥50 percent pain reduction by 24 hours from
treatment initiation (without the use of rescue medication) versus placebo. Comparison
of the proportion of low-dose-treated subjects reaching endpoint versus placebo was an
additional endpoint.

Both the low- and higher-dose colchicine treatments had greater efficacy at 24 hours of
treatment than placebo; 38 percent, 33 percent, and 16 percent. Pain reduction at 32
hours and exceeding two units at 24 and 32 hours were also significant for both
colchicine-treated groups when compared with placebo.

In all efficacy measurements, low-dose treatment appeared to have efficacy similar to

higher-dose treatment. In fact, a smaller proportion of low-dose-treated subjects (but
not higher-dose-treated subjects) took rescue medication than placebo-treated subjects,
and pain reduction of all degrees was achieved by a higher proportion of low-dose than
higher-dose- or placebo-treated subjects.

 Adverse effects – In the AGREE trial (see above), differences in adverse GI events
between the treatment groups were striking [ 9 ]. Subjects in the low-dose
treatment group experienced diarrhea (23 percent) or other GI symptoms no
more often than placebo-treated subjects (16 percent diarrhea) during the trial,
but diarrhea occurred in 77 percent of higher-dose-treated subjects (odds ratio
21.3; CI 8-57). Diarrhea was graded as severe in 19 percent of high-dose
treatment subjects versus 0 percent in the low-dose group, and vomiting was
seen in 17 percent in the high-dose group but 0 percent in the other groups.

Although oral colchicine in both low- and higher-dose regimens has efficacy in the
treatment of pain in acute gout flare, the GI toxicity of the high-dose regimen
substantially reduces the benefit to risk ratio of treatment. In contrast, toxicity of low-
dose treatment was not discernibly different from that of placebo, supporting
recommendations for low-dose colchicine treatment in acute gout [ 8-10,12 ] rather than
higher-dose treatment.

In patients on ongoing colchicine prophylaxis therapy who have an acute flare, a course
of low-dose colchicine could be followed by return to the preceding prophylaxis dose on
the day after low-dose flare treatment. (See "Prevention of recurrent gout" .)
When low-dose first day oral colchicine treatment of acute flare is beneficial but the
response is incomplete in a patient not receiving ongoing colchicine prophylaxis therapy,
the guidelines for use of colchicine prophylaxis can be applied on subsequent days until
resolution of the acute flare [ 10 ]. (See"Prevention of recurrent gout" .)

Finally, when low-dose colchicine therapy is ineffective or minimally effective in

suppressing acute gout in timely fashion, alternative antiinflammatory agents, including
an intraarticular glucocorticoids, should be considered. (See 'Glucocorticoids' below.)

Intravenous — Because of the potential for life-threatening adverse effects, the United
States Food and Drug Administration in February 2008 asked that intravenous
preparations containing colchicine no longer be manufactured or shipped in the USA
[ 13 ]. Although existing intravenous preparations were not recalled, this cessation of
supply severely limits, and effectively ends, the use of colchicine by the intravenous
route in the USA.

Intravenous colchicine is a consideration in hospitalized patients who are unable to take

oral medications. However, as mentioned above, its use is limited by serious systemic
reactions, including bone marrow suppression, hepatic necrosis, acute renal failure,
disseminated intravascular coagulation, seizures, and even death. Severe sclerotic tissue
reactions can occur in the event of colchicine extravasation, so secure intravenous
access is essential.

Precautions for the use of intravenous colchicine have been published in an effort to
reduce adverse events [ 14 ]. In 20 reported deaths attributed to the use of intravenous
colchicine, each patient received a cumulative dose that exceeded the recommended
maximum [ 15 ].

Absolute contraindications to intravenous colchicine therapy for acute gout include

combined renal and hepatic disease, creatinine clearance below 10 mL/min, and
extrahepatic biliary obstruction.

An initial dose of 1 to 2 mg of colchicine is typically given and, if necessary, another 1

mg dose is administered 6 to 12 hours later. The total intravenous dose should in no
instance exceed 4 to 5 mg during any 24-hour period or during any attack [ 14 ].

With the availability of multiple alternative approaches, we have had little occasion to
use intravenouscolchicine in recent years. Although intravenous colchicine can reduce
the inflammation of pseudogout, the potential dangers of this approach have led to
withdrawal of approval in the United States for the distribution of colchicine for
administration by the intravenous route.

Where the intravenous preparation is still available, it should be considered only in

hospitalized patients with polyarticular gout, or those unable to tolerate NSAIDs or take
oral medications. Administration should be supervised by physicians experienced in
intravenous use. Adherence to the precautions cited above is essential to avoid
potentially life-threatening toxicity [ 14-17 ].

Drug interactions — Drug-drug interactions of colchicine may occur. These occur

largely with agents that interfere with the functions of the membrane P-glycoprotein
multiple drug resistance transporter (P-gp) and/or the cytochrome P450 system
component CYP3A4 [ 10 ].
Both P-gp and CYP3A4 are involved in colchicine metabolism and, when colchicine
treatment is given along with agents inhibiting or utilizing these systems, there is the
risk for severe or fatal outcomes. Use of colchicine with P-gp inhibitors
(eg, cyclosporine , tacrolimus , amiodarone , quinidine , azole antifungals, some calcium
channel blockers, vinca alkyloids, erythromycin , etc. [ 18 ]) or strong CYP3A4 inhibitors
(eg, protease inhibitors, macrolide antibiotics, azole antifungals, etc. [ 19 ]) is
contraindicated. Care should be taken in combining use of colchicine with the wider array
of less strong CYP3A4 inhibitors, including statin and other lipid-lowering drugs ( table
1 ).

GLUCOCORTICOIDS — Glucocorticoid therapy can be injected into the affected joint(s)

or given systemically, either orally or parenterally.

Intraarticular — Intraarticular (depot) glucocorticoids are a reasonable option in

patients with only one or two actively inflamed joints, although evidence of their benefit
has been limited to small, open label trials [ 20 ]. We consider this option preferable to
systemic glucocorticoids in patients who cannot take NSAIDs or colchicine .

The diagnosis of acute gouty arthritis should be secure and infection must be ruled out
before injection is considered. We typically use triamcinolone acetonide 40 mg for knee
joints and lower doses for smaller joints. Equivalent doses of
depo- methylprednisolone may also be used.

Systemic — Systemic glucocorticoids may be administered orally in patients who

cannot take NSAIDs or colchicine and who are not candidates for intraarticular
glucocorticoid injection because of polyarticular disease.

While the data on efficacy of oral glucocorticoids are limited, they support clinical
experience that suggests that prednisone or prednisolone in doses of 30 to
50 mg/day (or other equivalent glucocorticoid) for one to two days, then tapered over
seven to ten days, effectively reduces acute symptoms to a similar extent as do NSAIDS
[ 21 ]. However, rebound attacks are relatively common once glucocorticoids are
withdrawn, especially in patients who have previously suffered a number of prior attacks
and whose intercritical periods have progressively shortened.

In patients who cannot take oral medications, intravenous glucocorticoids or

subcutaneous adrenocorticotropic hormone (ACTH) are options. Guidelines for the use of
glucocorticoids in this setting are similar to those for oral therapy, but we generally do
not favor their use in the treatment of acute gout unless intravenous access is already in
place.

In addition to stimulating release of corticosteroids, ACTH may act on melanocortin type

3 receptors on cells involved in gouty inflammation [ 22 ]. Data on the efficacy of ACTH
are limited. In one retrospective report, virtually all acute attacks resolved within 5.5
days of ACTH administration with few significant adverse effects [ 23 ]. More than one
injection may be required.

Various ACTH dosing regimens have been advocated. We have used 40 to 80 USP units,
administered twice daily for two days and then once daily for several succeeding days as
needed. Others have studied 40 units as a single injection, with reinjection as needed
[ 24 ], or 25 units as a single injection when treating acute small joint monoarticular
gout [ 25 ]. Use of ACTH may be limited by availability and to avoid delay in
administration, the hospital pharmacy, or formulary should be consulted before ordering.
Interleukin-1 inhibition (investigational) — Interleukin-1 (IL-1) is an important
mediator of inflammation and therapeutic target in acute gout. Monosodium urate
crystals induce the release of proinflammatory cytokines from leukocytes, an action
likely to contribute significantly to the symptoms of the acute gout flare. Among the
cytokines involved is interleukin-1 beta (IL-1), which is released by monocytes and
synovial mononuclear cells through innate immune mechanisms that include the toll like
receptors TLR-2 and TLR-4 [ 26 ] and the inflammasome complex [ 27 ].
(See "Pathophysiology of gouty arthritis" .)

Inhibition of the interleukin-1 (IL-1) pathway by use of targeted biologic agents has been
effective in patients with acute gout:

 Anakinra — IL-1 inhibition prevented peritoneal neutrophil accumulation in

response to intraperitoneal injection of urate crystals in mice; the encouraging
findings in this animal model led to an open label pilot study of the recombinant
IL-1 receptor antagonist, anakinra, in the treatment of acute gouty arthritis
[ 28 ]. Ten subjects who had either failed or could not tolerate alternative
antiinflammatory treatment received anakinra (100 mg) subcutaneously for three
days, and were evaluated by tender and swollen joint counts and by subjective
estimations of pain relief after three days and 30 days. In all 10 subjects, the
acute inflammatory arthritis responded favorably (pain improvement 50 to 100
percent; clinical evaluation concordant) within 24 to 48 hours. No adverse effects
were reported.

 Canakinumab — Canakinumab (ACZ2885), a fully humanized monoclonal

antibody that blocks IL-1β signaling, was effective for the treatment of acute gout
in patients with a history of multiple flares and either refractoriness or
contraindication to acute flare treatment with NSAIDs orcolchicine [ 29 ]. In this
phase 2 randomized trial a series of single subcutaneous doses of canakinumab
were compared with intramuscularly administered triamcinolone acetonide (TA)
for efficacy and safety in treatment of acute gout flare pain, levels of acute phase
reactants, and flare recurrence over a period of 60 days from onset of treatment.

All five doses of canakinumab used (range 10 to 150 mg) resulted in numerically
greater pain reduction compared with TA (40 mg); thus, the dose of canakinumab
resulting in pain reduction equivalent to that achieved with TA could not be
identified. However, a dose-dependent response was observed for canakinumab.
Significant pain relief at 72 hours was shown for the 150 mg dose of the IL-1β
inhibitor; at this dose, pain relief was more prompt than with TA. Both CRP and
SAA levels also decreased promptly in patients receiving the IL-1β inhibitor. The
relative risk of flare recurrence over the 60 days following 150 mg canakinumab
injection was reduced by 94 percent compared with that following TA
administration. No significant safety signals emerged in this trial.

Treatment of acute gout (or gout flare prophylaxis) with IL-1 inhibition remains off-label
and cannot currently be recommended. Further studies are required.

SPECIAL CIRCUMSTANCES

Chronic tophaceous gout — Acute attacks of gout are treated in the same way for
patients with and without clinically apparent tophi. Long-term management to prevent
chronic gouty arthropathy is discussed separately. (See "Prevention of recurrent gout" .)
Hospitalized patients — A relatively common problem is the development of acute
gouty arthritis in hospitalized (often postoperative) patients receiving no oral feedings.
Treatment options in this setting include:

 Intraarticular glucocorticoids

 Intravenous glucocorticoids

 Intramuscular or subcutaneous ACTH

 Intravenous colchicine (in rare circumstances)

These therapies are described in more detail above.

End-stage renal disease — Although renal insufficiency predisposes to hyperuricemia

and gout, patients with advanced chronic kidney disease or end-stage renal disease
requiring maintenance dialysis may be at lesser risk of symptomatic disease [ 30 ]. Such
patients can be safely treated with intraarticular or oral glucocorticoids as described
above. Colchicine is generally avoided and, in patients not yet on dialysis, there is
concern about worsening renal function with an NSAID. (See "NSAIDs: Acute kidney
injury (acute renal failure) and nephrotic syndrome" .)

Renal transplant — Gout can be a particular problem in patients who have undergone
renal transplantation due to both reduced uric acid excretion and the use
of cyclosporine . Treatment of gout in this setting is challenging, in part due to complex
and potentially serious drug interactions. As a result, gout in organ transplant recipients
should only be managed by physicians experienced with these clinical problems.
(See "Hyperuricemia and gout in renal transplant recipients" .)

PATIENTS TAKING ANTIHYPERURICEMIC THERAPY — In patients who have had

recurrent attacks of acute gouty arthritis, antihyperuricemic therapy
(eg, allopurinol , febuxostat , probenecid ,pegloticase ) is used for long-term prophylaxis
but has no role in the treatment of active gouty inflammation. However, once treatment
with an antihyperuricemic agent has been initiated, most authorities believe that it
should not be interrupted during an acute attack. (See "Prevention of recurrent gout" .)

Failure to appreciate the distinction between antiinflammatory therapy and

antihyperuricemic therapy is frequently responsible for prolongation of the symptomatic
state in patients whose gout should be readily controlled. Such patients should be
treated for the acute attack the same way as patients who are not taking
antihyperuricemic drugs.

The use of polarizing light microscopy during synovial fluid analysis in 1961 by McCarty
and Hollander and the subsequent application of other crystallographic techniques, such as
electron microscopy, energy-dispersive elemental analysis, and x-ray diffraction, have
allowed investigators to identify the roles of different microcrystals, including monosodium
urate (MSU), calcium pyrophosphate (CPP), calcium apatite (apatite), and calcium oxalate
(CaOx), in inducing acute or chronic arthritis or periarthritis. The clinical events that result
from deposition of MSU, CPP, apatite, and CaOx have many similarities but also have
important differences. Because of often similar clinical presentations, the need to perform
synovial fluid analysis to distinguish the type of crystal involved must be emphasized.
Polarized light microscopy alone can identify most typical crystals; apatite, however, is an
exception. Aspiration and analysis of effusions are also important to assess the possibility of
infection. Apart from the identification of specific microcrystalline materials or organisms,
synovial fluid characteristics in crystal-associated diseases are nonspecific, and synovial fluid
can be inflammatory or noninflammatory. Without crystal identification, these diseases can
be confused with rheumatoid or other types of arthritis.

GOUT
Gout is a metabolic disease that most often affects middle-aged to elderly men and
postmenopausal women. It results from an increased body pool of urate with hyperuricemia.
It typically is characterized by episodic acute arthritis or chronic arthritis caused by
deposition of MSU crystals in joints and connective tissue tophi and the risk for deposition in
kidney interstitium or uric acid nephrolithiasis

ACUTE AND CHRONIC ARTHRITIS

Acute arthritis is the most common early clinical manifestation of gout. Usually, only one
joint is affected initially, but polyarticular acute gout can occur in subsequent episodes. The
metatarsophalangeal joint of the first toe often is involved, but tarsal joints, ankles, and knees
also are affected commonly. Especially in elderly patients or in advanced disease, finger
joints may be involved. Inflamed Heberden’s or Bouchard’s nodes may be a first
manifestation of gouty arthritis. The first episode of acute gouty arthritis frequently begins at
night with dramatic joint pain and swelling. Joints rapidly become warm, red, and tender,
with a clinical appearance that often mimics that of cellulitis. Early attacks tend to subside
spontaneously within 3–10 days, and most patients have intervals of varying length with no
residual symptoms until the next episode. Several events may precipitate acute gouty
arthritis: dietary excess, trauma, surgery, excessive ethanol ingestion, hypouricemic therapy,
and serious medical illnesses such as myocardial infarction and stroke.

After many acute mono- or oligoarticular attacks, a proportion of gouty patients may present
with a chronic nonsymmetric synovitis, causing potential confusion with rheumatoid arthritis
(Chap. 380). Less commonly, chronic gouty arthritis will be the only manifestation, and,
more rarely, the disease will manifest only as periarticular tophaceous deposits in the absence
of synovitis. Women represent only 5–20% of all patients with gout. Most women with gouty
arthritis are postmenopausal and elderly, have osteoarthritis and arterial hypertension that
causes mild renal insufficiency, and usually are receiving diuretics. Premenopausal gout is
rare. Kindreds of precocious gout in young females caused by decreased renal urate clearance
and renal insufficiency have been described.

Laboratory Diagnosis Even if the clinical appearance strongly suggests gout, the presumptive
diagnosis ideally should be confirmed by needle aspiration of acutely or chronically involved
joints or tophaceous deposits. Acute septic arthritis, several of the other crystallineassociated
arthropathies, palindromic rheumatism, and psoriatic arthritis may present with similar
clinical features. During acute gouty attacks, needle-shaped MSU crystals typically are seen
both intracellularly and extracellularly (Fig. 395-1). With compensated polarized light, these
crystals are brightly birefringent with negative elongation. Synovial fluid leukocyte counts
are elevated from 2000 to 60,000/μL. Effusions appear cloudy due to the increased numbers
of leukocytes. Large amounts of crystals occasionally produce a thick pasty or chalky joint
fluid. Bacterial infection can coexist with urate crystals in synovial fluid; if there is any
suspicion of septic arthritis, joint fluid must be cultured.

MSU crystals also can often be demonstrated in the first metatarsophalangeal joint and in
knees not acutely involved with gout. Arthrocentesis of these joints is a useful technique to
establish the diagnosis of gout between attacks.

Serum uric acid levels can be normal or low at the time of an acute attack, as inflammatory
cytokines can be uricosuric and effective initiation of hypouricemic therapy can precipitate
attacks. This limits the value of serum uric acid determinations for the diagnosis of gout.
Nevertheless, serum urate levels are almost always elevated at some time and are important
to use to follow the course of hypouricemic therapy. A 24-h urine collection for uric acid can,
in some cases, be useful in assessing the risk of stones, elucidating overproduction or
underexcretion of uric acid, and deciding whether it may be appropriate to use a uricosuric
therapy (Chap. 431e). Excretion of >800 mg of uric acid per 24 h on a regular diet suggests
that causes of overproduction of purine should be considered. Urinalysis, serum creatinine,
hemoglobin, white blood cell (WBC) count, liver function tests, and serum lipids should be
obtained because of possible pathologic sequelae of gout and other associated diseases
requiring treatment and as baselines because of possible adverse effects of gout treatment.

Radiographic Features Cystic changes, well-defined erosions with sclerotic margins (often
with overhanging bony edges), and soft tissue masses are characteristic radiographic features
of advanced chronic tophaceous gout. Ultrasound may aid earlier diagnosis by showing a
double contour sign overlying the articular cartilage. Dual-energy computed tomography
(CT) can show specific features establishing the presence of urate crystals.

TREAT MENT Gout

ACUTE GOUTY ARTHRITIS

The mainstay of treatment during an acute attack is the administration of anti-inflammatory
drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids.
NSAIDs are used most often in individuals without complicating comorbid conditions. Both
colchicine and NSAIDs may be poorly tolerated and dangerous in the elderly and in the
presence of renal insufficiency and gastrointestinal disorders. Ice pack applications and rest
of the involved joints can be helpful. Colchicine given orally is a traditional and effective
treatment if used early in an attack. Useful regimens are one 0.6-mg tablet given every 8 h
with subsequent tapering or 1.2 mg followed by 0.6 mg in 1h with subsequent day dosing
depending on response. This is generally better tolerated than the formerly advised higher
dose regimens. The drug must be at least temporarily discontinued promptly at the first sign
of loose stools, and symptomatic treatment must be given for the diarrhea. Intravenous
colchicine has been taken off the market. NSAIDs given in full anti-inflammatory doses are
effective in ∼90% of patients, and the resolution of signs and symptoms usually occurs in 5–
8 days. The most effective drugs are any of those with a short halflife and include
indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid; diclofenac, 50 mg
tid; and celecoxib 800 mg followed by 400 mg 12 h later, then 400 mg bid.

Glucocorticoids given IM or orally, for example, prednisone, 30–50 mg/d as the initial dose
and gradually tapered with the resolution of the attack, can be effective in polyarticular gout.
For a single joint or a few involved joints, intraarticular triamcinolone acetonide, 20–40 mg,
or methylprednisolone, 25–50 mg, have been effective and well tolerated. Based on recent
evidence on the essential role of the inflammasome and interleukin 1β (IL-1β) in acute gout,
anakinra has been used, and other inhibitors of IL-1β, including canakinumab and rilonacept,
are under investigation.

HYPOURICEMIC THERAPY

Ultimate control of gout requires correction of the basic underlying defect: the
hyperuricemia. Attempts to normalize serum uric acid to <300–360 μmol/L (5.0–6.0 mg/dL)
to prevent recurrent gouty attacks and eliminate tophaceous deposits are critical and entail a
commitment to hypouricemic regimens and medications that generally are required for life.
Hypouricemic drug therapy should be considered when, as in most patients, the
hyperuricemia cannot be corrected by simple means (control of body weight, low-purine diet,
increase in liquid intake, limitation of ethanol use, decreased use of fructose-containing foods
and beverages, and avoidance of diuretics). The decision to initiate hypouricemic therapy
usually is made taking into consideration the number of acute attacks (urate lowering may be
cost-effective after two attacks), serum uric acid levels (progression is more rapid in patients
with serum uric acid >535 μmol/L [>9.0 mg/dL]), the patient’s willingness to commit to
lifelon therapy, or the presence of uric acid stones. Urate-lowering therapy should be
initiated in any patient who already has tophi or chronic gouty arthritis. Uricosuric agents
such as probenecid can be used in patients with good renal function who underexcrete uric
acid, with <600 mg in a 24-h urine sample. Urine volume should be maintained by ingestion
of 1500 mL of water every day. Probenecid can be started at a dose of 250 mg twice daily and
increased gradually as needed up to 3 g per day to achieve and maintain a serum uric acid
level of less than 6 mg/dL. Probenecid is generally not effective in patients with serum
creatinine levels >177 μmol/L (2 mg/dL). These patients may require allopurinol or
benzbromarone (not available in the United States). Benzbromarone is another uricosuric
drug that is more effective in patients with chronic kidney disease. Some agents used to treat
common comorbidities, including losartan, fenofibrate, and amlodipine, have some mild
uricosuric effects.

The xanthine oxidase inhibitor allopurinol is by far the most commonly used hypouricemic
agent and is the best drug to lower serum urate in overproducers, urate stone formers, and
patients with renal disease. It can be given in a single morning dose, usually 100 mg initially
and increasing up to 800 mg if needed. In patients with chronic renal disease, the initial
allopurinol dose should be lower and adjusted depending on the serum creatinine
concentration; for example, with a creatinine clearance of 10 mL/min, one generally would
use 100 mg every other day. Doses can be increased gradually to reach the target urate level
of less than 6 mg/dL. Toxicity of allopurinol has been recognized increasingly in patients who
use thiazide diuretics, in patients allergic to penicillin and ampicillin, and in Asians
expressing HLA-B*5801. The most serious side effects 2235 include life threatening toxic
epidermal necrolysis, systemic vasculitis, bone marrow suppression, granulomatous hepatitis,
and renal failure. Patients with mild cutaneous reactions to allopurinol can reconsider the use
of a uricosuric agent, undergo an attempt at desensitization to allopurinol, or take febuxostat,
a new, chemically unrelated specific xanthine oxidase inhibitor. Febuxostat is approved in the
United States at 40 or 80 mg once a day and does not require dose adjustment in mild to
moderate renal disease. Pegloticase is a pegylated uricase, now available for patients who do
not tolerate or fail full doses of other treatments. It is given intravenously usually at 8 mg
every 2 weeks and can dramatically lower serum uric acid in up to 50% of such patients. New
uricosurics are also undergoing investigation.
Urate-lowering drugs are generally not initiated during acute attacks but after the patient is
stable and low-dose colchicine has been initiated to decrease the risk of the flares that often
occur with urate lowering. Colchicine anti-inflammatory prophylaxis in doses of 0.6 mg one
to two times daily should be given along with the hypouricemic therapy until the patient is
normouricemic and without gouty attacks for 6 months or as long as tophi are present.
Colchicine should not be used in dialysis patients and is given in lower doses in patients with
renal disease or with P glycoprotein or CYP3A4 inhibitors such as clarithromycin that can
increase toxicity of colchicine.