GOUT AND OTHER CRYSTAL-ASSOCIATED
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ARTHROPATHIES
I. GOUT
DEFINITION
 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.
CLINICAL PRESENTATION
1. ACUTE 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.
 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,
2. CHRONIC ARTHRITIS
 Proportion of gouty patients may present with
a chronic nonsymmetric synovitis, causing
potential confusion with rheumatoid arthritis
 The disease will manifest only as periarticular
tophaceous deposits in the absence of
synovitis.
PRECIPITATING FACTORS
 Dietary excess
 Trauma and surgery
 Excessive ethanol ingestion
 Hypouricemic therapy
 Serious medical illnesses such as myocardial
infarction and stroke
LABORATORY DIAGNOSIS
 Presumptive diagnosis ideally should be
confirmed by needle aspiration of acutely or
chronically involved joints or tophaceous
deposits
 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.
 Serum uric acid levels can be normal or low at
the time of an acute attack. This limits the
value of serum uric acid determinations for the
diagnosis of gout.
 A 24-h urine collection for uric acid can 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.
 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
RADIOGRAPHIC FEATURES
 Cystic changes, well-defined erosions with
sclerotic margins with overhanging bony
edges, and soft tissue masses
 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.
TREATMENT
1. ACUTE GOUTY ARTHRITIS
 Mainstay of treatment during an acute attack is
the administration of anti-inflammatory drugs
 NSAIDs are used most often in individuals
without complicating comorbid conditions.
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 GOUT AND OTHER CRYSTAL-ASSOCIATED
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ARTHROPATHIES
 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 1 h with
subsequent day dosing depending on
response.
 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 half-life 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 as an
intramuscular injection or orally
( prednisone, 30–50 mg/d as the initial
dose and gradually tapered with the
resolution of the attack)
2. CHRONIC GOUTY ARTHRITIS
 HYPOURECEMIC THERAPY
 The decision to initiate hypouricemic
therapy usually is made taking into
consideration the number of acute
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 lifelong
therapy, or the presence of uric acid
stones.
1. URICOSURIC AGENT
o 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 <6 mg/dL.
o is generally not effective in
patients with serum creatinine
levels >177 μmol/L (2 mg/dL)
2. XANTHINE OXIDASE INHIBITOR
( ALLOPURINOL)
o 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.
II. CALCIUM PYROPHOSPHATE DEPOSITION
DISEASE
PATHOGENESIS
 Deposition of CPP crystals in articular tissues
is most common in the elderly, occurring in
10–15% of persons age 65–75 years and 30–
50% of those >85 years. In most cases, this
process is asymptomatic, and the cause of
CPPD is uncertain.
 In patients with CPPD arthritis, there is
increased production of inorganic
pyrophosphate and decreased levels of
pyrophosphatases in cartilage extracts.
 A minority of patients with CPPD arthropathy
have metabolic abnormalities or hereditary
CPP disease.Included among these conditions
are hyperparathyroidism, hemochromatosis,
hypophosphatasia, and hypomagnesemia.
CLINICAL MANIFESTATIONS
 May be asymptomatic, acute, subacute, or
chronic or may cause acute synovitis
superimposed on chronically involved joints.
 Originally was termed pseudogout because of
its striking similarity to gout.
 Other clinical manifestations of CPPD include
(1) association with or enhancement of peculiar
forms of osteoarthritis; (2) induction of severe
destructive disease that may radiographically
mimic neuropathic arthritis; (3) production of
chronic symmetric synovitis that is clinically
similar to rheumatoid arthritis; (4)
intervertebral disk and ligament calcification
with restriction of spine mobility, the crowned
dens syndrome, or spinal stenosis.
 The knee is the joint most frequently affected
in CPPD arthropathy. Other sites include the
wrist, shoulder, ankle, elbow, and hands. The
temporomandibular joint may be involved.
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 GOUT AND OTHER CRYSTAL-ASSOCIATED
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ARTHROPATHIES
DIAGNOSIS
 Definitive diagnosis requires demonstration of
typical rhomboid or rodlike crystals (generally
weakly positively birefringent or
nonbirefringent with polarized light) in
synovial fluid or articular tissue.
TREATMENT
 Treatment by rest, joint aspiration, and
NSAIDs or by intraarticular glucocorticoid
injection may result in more rapid return to
prior status.
 With frequent recurrent attacks, daily low
doses of colchicine may be helpful in
decreasing the frequency of the attacks.
 Severe polyarticular attacks require short
courses of glucocorticoids or an IL-1β
antagonist, anakinra.
 Unfortunately, there is no effective way to
remove CPP deposits from cartilage and
synovium.
 Uncontrolled studies suggest that the
administration of NSAIDS (with a gastric
protective agent if required),
hydroxychloroquine, or even methotrexate
may be helpful in controlling persistent
synovitis.
 Patients with progressive destructive large-
joint arthropathy may require joint
replacement.
III. CALCIUM APATITE DEPOSITION DISEASE
PATHOGENESIS
 Abnormal accumulation of basic calcium
phosphates, largely carbonate substituted
apatite, can occur in areas of tissue damage
(dystrophic calcification), hypercalcemic or
hyperparathyroid states (metastatic
calcification), and certain conditions of
unknown cause
 In chronic renal failure, hyperphosphatemia
can contribute to extensive apatite deposition
both in and around joints. Familial aggregation
is rarely seen; no association with ANKH
mutations has been described thus far.
 Apatite crystals are deposited primarily on
matrix vessels. Incompletely understood
alterations in matrix proteoglycans,
phosphatases, hormones, and cytokines
probably can influence crystal formation.
 Apatite aggregates are commonly present in
synovial fluid in an extremely destructive
chronic arthropathy of the elderly that occurs
most often in the shoulders (Milwaukee
shoulder) and in a similar process in hips,
knees, and erosive osteoarthritis of fingers.
CLINICAL MANIFESTATION
 Clinical manifestations include asymptomatic
radiographic abnormalities, acute synovitis,
bursitis, tendinitis, and chronic destructive
arthropathy.
 Although the true incidence of apatite arthritis
is not known, 30–50% of patients with
osteoarthritis have apatite microcrystals in their
synovial fluid. Such crystals frequently can be
identified in clinically stable osteoarthritic
joints, but they are more likely to come to
attention in persons experiencing acute or
subacute worsening of joint pain and swelling.
 The synovial fluid leukocyte count in apatite
arthritis is usually low (<2000/μL) despite
dramatic symptoms, with predominance of
mononuclear cells.
DIAGNOSIS
 Intra- and/or periarticular calcifications with or
without erosive, destructive, or hypertrophic
changes may be seen on radiographs. They
should be distinguished from the linear
calcifications typical of CPPD.
 Definitive diagnosis of apatite arthropathy,
also called basic calcium phosphate disease,
depends on identification of crystals from
synovial fluid or tissue. Individual crystals are
very small and can be seen only by electron
microscopy. Clumps of crystals may appear as
1- to 20-μm shiny intra- or extracellular
nonbirefringent globules or aggregates that
stain purplish with Wright’s stain and bright
red with alizarin red S. Tetracycline binding
and other investigative techniques are under
consideration as labeling alternatives.
 Absolute identification depends on electron
microscopy with energy-dispersive elemental
analysis, x-ray diffraction, infrared
spectroscopy, or Raman microspectroscopy,
but these techniques usually are not required in
clinical diagnosis.
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 GOUT AND OTHER CRYSTAL-ASSOCIATED
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ARTHROPATHIES
TREATMENT DIAGNOSIS

 Acute attacks of bursitis or synovitis may be  Radiographs may reveal chondrocalcinosis or

self-limiting, resolving in days to several
weeks.
 Aspiration of effusions and the use of either
NSAIDs or oral colchicine for 2 weeks or
intra- or periarticular injection of a depot
glucocorticoid appear to shorten the duration
and intensity of symptoms.
 Local injection of disodium
ethylenediaminetetraacetic acid (EDTA) and
SC anakinra have been suggested as effective
in single studies of acute calcific tendinitis at
the shoulder.S
soft tissue calcifications.
 CaOx-induced synovial effusions are usually
noninflammatory, with <2000 leukocytes/μL,
or mildly inflammatory. Neutrophils or
mononuclear cells can predominate.
 CaOx crystals have a variable shape and
variable birefringence to polarized light. The
most easily recognized forms are bipyramidal,
have strong birefringence and stain with
alizarin red S.
TREATMENT

IV. CaOx DEPOSITION DISEASE  Treatment of CaOx arthropathy with NSAIDs,

colchicine, intraarticular glucocorticoids,
PATHOGENESIS and/or an increased frequency of dialysis has
produced only slight improvement.
 Primary oxalosis is a rare hereditary  In primary oxalosis, liver transplantation has
metabolic disorder. Enhanced production of induced a significant reduction in crystal
oxalic acid may result from at least two deposits.
different enzyme defects, leading to
hyperoxalemia and deposition of CaOx crystals
in tissues. Nephrocalcinosis and renal failure
are typical results
 Secondary oxalosis is more common than the
primary disorder. In chronic renal disease,
CaOx deposits have long been recognized in
isceral organs, blood vessels, bones, and
cartilage and are now known to be one of the
causes of arthritis in chronic renal failure. Thus
far, reported patients have been dependent on
long-term hemodialysis or peritoneal dialysis,
and many had received ascorbic acid
supplements.

CLINICAL MANIFESTATION

 CaOx aggregates can be found in bone,

articular cartilage, synovium, and periarticular
tissues. From these sites, crystals may be shed,
causing acute synovitis.
 Persistent aggregates of CaOx can, like apatite
and CPP, stimulate synovial cell proliferation
and enzyme release, resulting in progressive
articular destruction. Deposits have been
documented in fingers, wrists, elbows, knees,
ankles, and feet.
 Clinical features of acute CaOx arthritis may
not be distinguishable from those due to urate,
CPP, or apatite.

PGI MIGUEL, KENNETH JAMES B. 4