Gout and Othercrystal-Associated Arthropathies

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Dr Budi Enoch

GOUT AND OTHERCRYSTAL-


ASSOCIATED
ARTHROPATHIES
Crystal-Associated
Arthropathies
 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 dihydrate
(CPPD), calcium apatite (apatite), and calcium
oxalate (CaOx), in inducing acute or chronic
arthritis or periarthritis
 The clinical events that result from deposition of MSU,
CPPD, apatite, and CaOx have many similarities but
also have important differences.
 Before the use of crystallographic techniques in
rheumatology, much of what was considered to be
gouty arthritis in fact was not. 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.
 A list of possible musculoskeletal manifestations of
crystal-associated arthritis is shown in Table 333-1.
 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
and 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.
 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.
Premenopausal gout is rare; it is seen mostly in
individuals with a strong family history of gout.
 Kindreds of precocious gout in young females caused by
decreased renal urate clearance and renal insufficiency
have been described.
 Most women with gouty arthritis are postmenopausal
and elderly, have osteoarthritis and arterial
hypertension that cause mild renal insufficiency, and
usually are receiving diuretics.
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 crystalline-associated
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 .
 With compensated polarized light these crystals are brightly
birefringent with negative elongation.
 Synovial fluid leukocyte counts are elevated from 2000 to
60,000/L. 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, 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
Radiographic Features

 Early in the disease radiographic studies may


only confirm clinically evident swelling.
 Cystic changes, well-defined erosions with
sclerotic margins (often with overhanging
bony edges), and soft tissue masses are
characteristic features of advanced chronic
tophaceous gout.
 Ultrasound, CT and MRI are being studied
and are likely to become more sensitive for
early changes.
Treatment
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. This
was repeated later.
 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. One useful regimen
is one 0.6-mg tablet given every 8 h with subsequent
tapering
 The drug must be stopped 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
half-life and include indomethacin, 25–50 mg tid;
naproxen, 500 mg bid; ibuprofen, 800 mg tid; and
diclofenac, 50 mg tid.
 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..
Hypouricemic Therapy
 Ultimate control of gout requires correction of the
basic underlying defect: the hyperuricemia.
 Attempts to normalize serum uric acid to <300–360
mol/L (5.0–6.0 mg/dL) to prevent recurrent gouty
attacks and eliminate tophaceous deposits entail a
commitment to long-term hypouricemic regimens
and medications that generally are required for life.
 Hypouricemic 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).
 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
must 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 maintain a serum uric acid level <360 mol/L (6
mg/dL). Probenecid is generally not effective in patients
with serum creatinine levels >177 mol/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 renal
failure.
 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, 100–300 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 6 mg/dL; however, more studies
are needed to provide exact guidance.
 Toxicity of allopurinol has been recognized increasingly in
patients who use thiazide diuretics and patients allergic to
penicillin and ampicillin. The most serious side effects
include life-threatening toxic epidermal necrolysis,
systemic vasculitis, bone marrow suppression,
granulomatous hepatitis, and renal failure
CPPD Deposition Disease
 The deposition of CPPD 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 deposition is uncertain. Because >80% of
patients are >60 years and 70% have preexisting joint
damage from other conditions, it is likely that
biochemical changes in aging or diseased cartilage
favors crystal nucleation.
 In patients with CPPD arthritis there is increased
production of inorganic pyrophosphate and decreased
levels of pyrophosphatases in cartilage extracts.
Mutations in the ANKH gene, as described in both
familial and sporadic cases, can increase elaboration
and extracellular transport of pyrophosphate
Clinical Manifestations
 CPPD arthropathy may be asymptomatic, acute, subacute,
or chronic or may cause acute synovitis superimposed on
chronically involved joints. Acute CPPD arthritis originally
was termed pseudogout by McCarty and co-workers
because of its striking similarity to gout.
 Other clinical manifestations of CPPD deposition include
(1) induction or enhancement of peculiar forms of
osteoarthritis, (2) induction of severe destructive disease
that may radiographically mimic neuropathic arthritis, (3)
production of symmetric synovitis that is clinically similar
to rheumatoid arthritis and sometimes seen in familial
forms with early onset, (4) intervertebral disk and ligament
calcification with restriction of spine mobility that mimics
ankylosing spondylitis (also seen in hereditary forms), (5)
spinal stenosis (most commonly seen in the elderly), and
(6) rarely periarticular tophus-like nodules.
 Acute attacks of CPPD arthritis may be precipitated by trauma.
 Rapid diminution of serum calcium concentration, as may occur in
severe medical illness or after surgery (especially
parathyroidectomy), can also lead to pseudogout attacks.
 In as many as 50% of cases, episodes of CPPD-induced
inflammation are associated with low-grade fever and, on occasion,
temperatures as high as 40°C (104°F). Whether or not radiographic
proof of chondrocalcinosis is evident in the involved joint(s),
synovial fluid analysis with microbial cultures is essential to rule out
the possibility of infection.
 In fact, infection in a joint with any microcrystalline deposition
process can lead to crystal shedding and subsequent synovitis from
both crystals and microorganisms. Synovial fluid in acute CPPD
disease has inflammatory characteristics. The leukocyte count can
range from several thousand cells to 100,000 cells/L, with the mean
being about 24,000 cells/L and the predominant cell being the
neutrophil. Polarized light microscopy usually reveals rhomboid,
square, or rodlike crystals with weak positive birefringence inside
tissue fragments and fibrin clots and in neutrophils (Fig. 333-2).
CPPD crystals may coexist with MSU and apatite in some cases.
Treatment: Cppd Deposition Disease
 Untreated acute attacks may last a few days to as long as a
month.
 Treatment by joint aspiration and NSAIDs or by
intraarticular glucocorticoid injection may result in return
to prior status in 10 days.
 For patients with frequent recurrent attacks of
pseudogout, daily prophylactic treatment with low doses
of colchicine may be helpful in decreasing the frequency of
the attacks. Severe polyarticular attacks usually require
short courses of glucocorticoids or, as recently reported, an
IL-1 antagonist, anakinra.
 Unfortunately, there is no effective way to remove CPPD
deposits from cartilage and synovium. Uncontrolled
studies suggest that the administration of antimalarial
agents or even methotrexate may be helpful in controlling
persistent synovitis. Patients with progressive destructive
large-joint arthropathy may require joint replacement
Calcium Apatite Deposition Disease
 Apatite is the primary mineral of normal bone and
teeth. 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 (Table 333-3).
 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.
 Joint destruction is associated with damage to cartilage and
supporting structures, leading to instability and deformity.
Progression tends to be indolent, and synovial fluid
leukocyte counts are usually <2000/L.
 Symptoms range from minimal to severe pain and disability
that may lead to joint replacement surgery. Whether
severely affected patients merely represent an extreme
synovial tissue response to the apatite crystals that are so
common in osteoarthritis is uncertain. Synovial lining cell or
fibroblast cultures exposed to apatite (or CPPD) crystals can
undergo mitosis and markedly increase the release of
prostaglandin E2 and cytokines and also collagenases and
neutral proteases, underscoring the destructive potential of
abnormally stimulated synovial lining cells.
Clinical Manifestations
 Periarticular or articular deposits may occur and may be associated
with acute reversible inflammation and/or chronic damage to the
joint capsule, tendons, bursa, or articular surfaces.
 The most common sites of apatite deposition include bursae and
tendons in and/or around the knees, shoulders, hips, and fingers.
 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/L) despite dramatic symptoms, with
predominance of mononuclear cells.
A. Radiograph showing calcification due to
apatite crystals surrounding an eroded joint.
B. An electron micrograph demonstrates dark
needle-shaped apatite crystals within a vacuole
of a synovial fluid mononuclear cell (30,000x).
 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-m shiny intra- or
extracellular nonbirefringent globules or
aggregates that stain purplish with Wright's stain
and bright red with alizarin red S.
 Tetracycline binding is under investigation as a
labeling alternative. Absolute identification
depends on electron microscopy with energy-
dispersive elemental analysis, x-ray diffraction,
infrared spectroscopy, or Raman
microspectroscopy, but they usually are not
required in clinical diagnosis.
Treatment: Calcium Apatite
Deposition Disease
 Treatment of apatite arthritis or periarthritis is nonspecific.
 Acute attacks of bursitis or synovitis may be 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) was effective in one study of calcific tendinitis
at the shoulder. Periarticular apatite deposits may be
resorbed with resolution of attacks. Agents to lower serum
phosphate levels may lead to resorption of deposits in
renal failure patients receiving hemodialysis. In patients
with underlying severe destructive articular changes,
response to medical therapy is usually less rewarding

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