Crystal Deposition Rheumatic Diseases

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Crystal Deposition Rheumatic Diseases
Crystal Associated Diseases
Monosodium Urate (MSU) Gout Uro-/Nephrolithiasis Acute UA Nephropathy
Calcium pyrophosphate dihydrate (CPPD) CPPD deposition disease Chondrocalcinosis
Basic calcium phosphate (BCP) Subcutaneous calcification Calcific periarthritis Arthritis
Calcium oxalate Arthritis (CRF, Oxalosis) Nephrocalcinosis
Lipid Arthritis
Microcrystalline corticosteroids Post intra-articular injection
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Uric Acid

• End product of purine metabolism
• Purine and pyrimidines are bases of nucleic acid
  that build RNA and DNA
• Main purine bases adenine guanine
• Main pyrimidine bases cytosine, thymine uracil
• Purines participate in intracellular pathways
  ATP, GTP, adenosine

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Uric Acid Metabolism
Urate is an end-product of purine metabolism
Terkeltaub D et al. Arthritis Res Ther 206,
8(Suppl 1) 1 -9
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The urate transport systems in the proximal
tubule.
The kidney excretes 70 of the daily urate
production. Urate anion transport function of
URAT1 in renal proximal tubule epithelial cells.
The organic anion transporter URAT1 exchanges
tubular lumen urate with anions inside proximal
tubular epithelial cells. URAT1 is targeted by
uricosuric and antiuricosuric agents.
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UA in Normal Physiology

• A potent antioxidant in nervous system, liver,
  lungs, and arterial walls.
• Plasma is saturated with monosodium urate (MSU)
  at a concentration of 6.8 mg/dl (415 ?mol/L) at
  37c.
• UA is more soluble in urine than in water
• pH affects UA solubility greater in alkaline
  urine

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Hyperuricemia

• Plasma ( or serum ) urate level greater than 7.0
  mg/dl (420 µmol/L)
• Urate plasma concentration above solubility
  limits of monosodium urate (MSU).
• Epidemiologically, defined as mean
• 2 S.D. of value in unselected healthy
  individuals.

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Why Hyperuricemia ?

• Uricase (urate oxidase) degrades poorly-soluble
  UA (11 mg/100 ml H2O) into more soluble product
  allantoin (147 mg/100 ml H2O).
• Uricase activity was lost in homoida during
  primate evolution, although the gene exists.
• Humans have a non-sense codon insertion into the
  gene at position 33 187, and an aberrant splice
  site
• The non-sense mutation at codon position 33
  results in loss of urate oxidase activity in
  humans.
• (Wu XW et al. J Mol Evol 1992,3478-84)

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Hyperuricemia

• Classification
• Primary
• Secondary

• Pathophysiology
• Urate overproduction
• Urate decreased excretion
• Combined

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Hyperuricemia Epidemiology

• Common 2 3.2 of ambulatory adults
• Peak age of onset Males 40-50, females gt 60
• Male female ratio 2-7 1
• In female, occurance is rare before menopause
• Associated conditions
• Obesity
• Hypertriglyceridemia (hyperlipidemia type IV)
• Insulin resistance
• Hypertension
• Syndrome X
• Unrelated to coronary heart Dx, death from
  cardiovascular Dx, or death from any cause.

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Hyperuricemia Clinical Manifestations

• Asymptomatic
• Gout arthritis
• Nephrolithiasis (urinary stones)
• Acute UA nephropathy

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Gout

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• ?????? Podagra

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Gout Arthritis

• Arthritis induced by synovial deposition of
  monosodium urate (MSU) crystals.
• General prevalence
• 8.4 per 1000 persons of all ages

The Gout, James Gilray, 1799
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Gout History

• The term gout is derived from Latin word gutta
  (drop)
• Thomas Sydenhams description of an acute gouty
  attack (1683)
• "The patient goes to bed and sleeps quietly until
  about two in the morning when he is awakened by a
  pain which usually seizes the great toe, but
  sometimes the heel, the calf of the leg or the
  ankle. The pain resembles that of a dislocated
  bone ... and this is immediately succeeded by a
  chillness, shivering and a slight fever ... the
  pain ..., which is mild in the beginning ...,
  grows gradually more violent every hour ... so
  exquisitely painful as not to endure the weight
  of the clothes nor the shaking of the room from a
  person walking briskly therein."

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Relationship of Gout and Hyperuricemia
Serum UA (mg/dl) lt7 7.0-7.9 8.0-8.9 9.0-9.9 gt10
Incidence/year () 0.1 0.5 0.8 4.9 7.0
5-Year cumulative incidence () 0.6 2.0 4.1 9.8 30.5
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Gouty Arthritis

• Clinical stages
• Asymptomatic hyperuricemia
• Acute gouty arthritis
• Intercritical gout
• Chronic tophaceous gout

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Asymptomatic Hyperuricemia

• Common
• Hyperuricemia w/o evidence of gout arthritis,
  tophi, or UA nephrolithiasis
• Most hyperuricemic individuals remain
  asymptomatic
• The risk of gout and nephrolithiasis increases
  with higher serum UA concentration.
• First clinical manifestation occurs after at
  least 20 years of persistant hyperuricemia.
• 10 40 of gouty patients suffered of renal
  colic before first attack of gout

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Hyperuricemia and Associated Diseases

• Hyperuricemia is associated with
• Hypertension
• Chronic kidney disease
• Coronary artery disease
• Congestive heart failure
• Metabolic syndrome
• Obesity
• Hyperlipidemia
• Insulin resistance
• Up-to-date, there is no evidence of a causal link
  between hyperuricemia and cardiovascular
  morbidity that justifies the use in clinical
  practice of urate-lowering drug treatment in
  asymptomatic hyperuricemia to avoid or modify the
  course of the associated diseases.
• Becker MA, Jolly M. Rheum Dis Clin N Am 2006, 32
  275 293.

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Hyperuricemia Evaluation

• Check serum creatinine, CBC.
• R/O drug-induced hyperuricemia
• Urine collection (24h.) to quantify UA and
  creatinine excretion Normal 24h. Urinary
  excretion of UA on a purine-free diet lt 600 mg/d
  (3.6 mmol/d)
• Urinary UA level gt 800 mg/d (4.2 mmol/d) (on a
  purine-free diet) hyperuricosuria
• Hyperuricemia w/ hyperuricosuria (on a
  purine-free diet) purine overproduction
• Hyperuricemia w/o hyperuricosuria (on a
  purine-free diet) decreased excretion of urate
• With renal failure, less UA is filtered through
  the glomeruli, thus a lower urinary 24h. UA
  level does not necessarily rule out urate
  overproduction
• Uricosuric drugs, corticosteroids, salicylates
  (gt2 g/d), ascorbic acid can increase urinary UA
  excretion

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Acute Gouty Arthritis

• First attack usually at age of 40-50 years.
• Onset before age of 25 suggests an underlying
  enzymatic defect or, rarely, renal disorder.
• Classically, first attack is monoarticular
  (85-90), involves 1st MTP joint (podagra)..

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Gout Presentation

• Classic gout
• Presents at any age peak in mid-40s
• Predominantly men
• Acute monoarthritis
• Asymmetric
• Usually in lower extremity, often 1st MTP joint
• Tophi rare at presentation, occur after years of
  attacks
• Can be misdiagnosed as cellulitis or infection
• Associated conditions
• Obesity
• Hyperlipidemia
• Hypertension
• Alcohol overuse

Rott KT Agudello CA. JAMA 2003, 289
2857-60 Wise CM. Clin Geriat Med 2005, 21 491 -
511
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Elderly Onset Gout

• Elderly patients over 65
• Men women
• Polyarthritis more common
• Symmetric or asymmetric
• Any joint, upper gt lower extremity
• Finger involvement more often
• Tophi common at presentation
• Chronic but can have acute flare-ups
• Chronic form can be misdiagnosed as RA, OA,
  cellulitis or infection
• Associated conditions
• Renal insufficiency
• Diuretic use, especially in women
• Alcohol use less common

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Acute Gouty ArthritisPrecipitating Factors

• Stress trauma, surgery, acute MI, stroke,
  infection
• Starvation or dehydration
• Acidosis
• Purine-rich diet
• Excessive alcohol ingestion
• ACTH and corticosteroid withdrawal
• Drugs Initiation of hypouricemic therapy
• Diuretics
• Initiation of B12 therapy in pernicius
  anemia
• Cytotoxic therapy (tumor lysis)

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Polyarticular Gouty Arthritis

• Typical gout
• Occurs after long-term attacks
• Elderly onset gout
• More common in postmenopausal women
• Predilection for involvement of interphalangeal
  joints of hand
• Co-existance with hand osteoarthritis

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Intercritical Gout

• Periods between gouty attacks
• Usually, a second attack occurs within 6 months
  to 2 years, but some patients never have a second
  attack.
• The frequency of recurrent attacks increases with
  time, have less explosive onset, become
  polyarticular, more severe and last longer.
• Few patients have a fulminate febrile course,
  which progresses directly into chronic illness
  w/o intercritical phase.

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Chronic Tophaceous Gout

• Classical gout
• Chronic polyarticular gout.
• Average time between first attack to chronic
  arthritis 11.6 years (range 3-42 years).
• Rate of tophi formation correlates w/ degree and
  duration of hyperuricemia, and also w/ severity
  of renal Dx.

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Gout Radiographic Features

• First acute attack soft tissue swelling
• Chronic tophaceous gout Martels sign
  punched-out cystic erosions w/ overhanging bony
  edges, associated w/ soft tissue calcified masses.

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Gout Advanced Disease
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Gout Diagnosis

• Aspiration of synovial fluid or tophi
• Synovial fluid analysis under compensated
  polarized microscope intracellular
  needle-shaped, negative-birefringent, MSU
  crystals
• Synovial fluid inflammatory,
• cloudy or chalky appearance, WBC- 2000-60,000/µL
  (mostly PMNs)
• Hyperuricemia almost always, but not necessary

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Intracellular MSU Crystals
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Identification of Crystals

• Compensated polarized light nicroscope
• Analysis of fresh drop of synovial fluid
• Backgroung is red
• Sign of birefringence is typical for biaxial
  crystals (2 optic axes)
• MSU negative birefringent if perpendicular to
  plane of light in compensator ? blue parallel ?
  yellow.
• CPPD weakly birefringent

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Pathogenesis of Gout Arthritis

• Hyperuricemia is necessary, but not sufficient.
• Synovial tissue and fluid MSU crystallization.
• Synovial fluid MSU crystals are found during
  acute attack, but also during intercritical
  phase.

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Gout Inflammatory Response

• Free synovial crystals induce release of
  pro-inflammatory mediators by synoviocytes, fluid
  MN cells, and chondrocytes ? ? IL-1,6,8, TNF?,
  NO.
• Release of complement peptides (C3a, C5a),
  bradykinin, kallikrein ? joint pain, swelling and
  erythema.
• ? Neutrophil chemotaxis, adhesion, activation,
  and influx into synovial fluid.
• Crystal phagocytosis ? superoxide anion and
  lysosomal proteases release, ? chemokines release
  
• inflammation amplification

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Treatment Asymptomatic Hyperuricemia

• Because most hyperuricemic patients are
  asymptomatic, and hypouricemic drugs entail
  inconvenience, cost, and toxicity No indication
  to treat asymptomatic hyperuricemic patients.
• Evaluation and follow up
• Correct precipitating factors
• Low-purine diet
• Avoid excess alcohol intake

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Low-Purine Diet

• The purine content of certain foods and
  beverages.
• High purine
• Meat
• Seafood
• Yeast
• Vegetables peas, beans, lentils, asparagus,
  spinach, mushrooms
• Beverages beer alcohol

• Dietary intervation
• Caloric restriction
• Limitation of alcohol intake
• Low purine diet
• Dairy products
• Grains/cereals, bread, pasta
• Vegetables, fruits, nuts
• Sugars
• Weight reduction

Fam AG. J Rheumatol 2002,29(7)1350-5.
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Treatment Acute Gouty Arthritis

• Treat acute attack with
• NSAID / COXIB
• ACTH / corticosteroids
• Colchicine
• Do not treat hyperuricemia during acute attack
• Consider to start low-dose colchicine to prevent
  further attacks or prior to initiation of
  hypouricemic drug

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NSAID / COXIB

• Inhibit cyclooxygenase
• Drug of choice in young patients
• Rapid onset of anti-inflammatory effect
• Avoid in elderly patients, prior peptic Dx, renal
  failure, CHF, anticoagulation.
• Contraindicated in a transplant recipient treated
  with cyclosporine

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Glucocorticoid Therapy

• Intraarticular injection
• Systemic prednisone P.O. 40mg/d or I.V./I.M.
  for 3-4 days,
• ACTH Synacthen depo 1mg I.M. q12-24h for 1-3
  days
• Especially in polyarticular gout or when NSAID is
  contraindicated

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Colchicine

• Oral dose 0.5-1mg q2h up to maximal dose of 7mg
  or relief of symptoms or gastrointestinal
  toxicity occurs
• Effective early in the attack
• I.V. 1-2 mg slowly, and additional 1mg dose at
  6h intervals up to 4mg. NOT recommended d/t
  serious side-effects such as local tissue
  necrosis and fatal multiorgan failure

Colcicum Autumnale
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Colochicine Mode of Action

• Disruption of microtubules
• Inhibits neutrophil phagocytosis
• Suppresses crystal-induced tyrosine
  phosphorilation
• Suppression of phospholipase A2 activation
• Suppression of superoxide production
• Suppression of leukotriene B4 production
• Inhibits TNF? production and TNF?R expression
• Inhibits neutrophil chemotaxis
• Inhibits neutrophil-endothelial cell adhesiveness
  via modulation of endothelial E-selectin and
  ICAM-1, and neutrophil L-selectin.

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Colchicine Toxicity
Gastrointestinal (Common) Abdominal pain, nausea, vomiting, diarrhea, ileus, hepatocellular, pancreatitis
Respiratory Dyspnea, ARDS
Hematologic Leukocytosis (early), BM hypoplasia, hemolytic anemia
Cardiovascular Hypovolemia, hypotension, depressed myocardial function, peripheral vasodilatation, arrhythmias, myocarditis
Skin Rash, alopecia
Renal Proteinuria, hematuria, acute renal failure
Metabolic Metabolic acidosis, hyponatremia, hypocalcemia, hypophosphatemia, hyomagnesemia
Neuromuscular Mental status changes, coma, ascending paresis, seizures, peripheral neuropathy, rhabdomyolysis
Fertility Azoospermia, sterility
Miscellaneous Fever, hypothermia
Toxicity depends on presence of renal liver
diseases Severe toxicity occurs in overdose
usage (suicide)
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Prevention of Gout

• Do not treat asymptomatic hyperuricemia
• Do not treat hyperuricemia during acute gouty
  arthritis attack
• Low-purine diet
• Hypouricemic drugs uricosuric drugs, xanthine
  oxidase inhibitors

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Hypouricemic Drugs

• Allpurinol xanthine oxidase inhibitor
• Indications Chronic tophaceous gout
• Recurrent (gt2/year) attacks
• UA urolithiasis
• To prevent tumor lysis syndrome
• Start with low dose and gradually increase over
  weeks to months
• Aim serum UA lt 6mg/dl (or lt5 mg/dl w/ tophi)
• Use concomitant colchicine prophylaxis (1mg/d)
  for 6-12 months

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Uricosuric Drugs

• Probenecid
• Sulfinpyrazone
• Indicated when
• Normal urine UA excretion
• No history od renal calculi
• No tophi
• Normal renal function
• Able to drink at least 2 L fluid daily
• No treatment w/ low-dose aspirin

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Allopurinol

• Start with 100mg/d and gradually increase dose
  according to serum UA level (aim lt 6 mg/dl)
• Usual daily dose 300mg/d, as high as 800mg/d
• Always start with concomitant colchicine
  prophylaxis
• Do not start during or immediate following acute
  gouty arthritis attack
• Adjust dose to renal function
• 300mg / serum Cr mg
• ESRD 100 mg twice weekly
• In transplant pts. Adjust for renal function
• Reduce azathioprine dose by 25 or replace
  by mycophenolate mofetil (CellCept)

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Allopurinol Toxicity
Hypersensitivity Fever, dermatitis, hepatitis, eosinophilia, renal failure
Hematologic BM suppression, aplastic anemia, agranulocytosis
Hepatic Granulomatous hepatitis
Risk factors Renal failure, concomitant diuretics, full loading dose
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Febuxostat

• A novel, orally administered, nonpurine analogue
  inhibitor of xanthine oxidase
• Febuxostat, is more effective than allopurinol in
  lowering serum urate. Similar reductions in gout
  flares and tophus area occurred in all treatment
  groups.
• The most common adverse effects include liver
  function test abnormalities, diarrhea, headache,
  nausea, vomiting, abdominal pain, and dizziness.
• Safe in patients with renal insufficiency

Becker MA. N Engl J Med. 2005353(23)2450-61
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Recombinant Uricase

• Recombinant Aspergillus uricase highly
  antigenic, causes allergic reactions
• Recombinasnt polyethylene glycol (PEG) uricase
  from Candida utilis or Arthrobacter
• is less allergenic, has increased half-life
• May be useful and safe for the treatment of
  allopurinol-allergic gouty patients or patients
  with gout and renal failure.
• J Rheumatol 2002, 29 1942-9.
• I Clin Oncol 2001, 19 697-704.

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Gout Treatment - Summary

• Acute attack
• NSAID/COXIB drug of choice
• IA steroid injection
• IM cortictropin (ACTH) injection
• Oral colchicine (not IV)
• Prevention of recurrent attack (indicated if gt2
  attacks/year and/or tophaceous gout and/or UA
  kidney stones)
• Start colchicine 0.5mg bid with NSAID
• Continue colchicine prophylactically after attack
  resolution
• Add allopurinol 100mg/d after complete resolution
  (4-6 weeks) of recent attack, increase dose
  (adjust to creatinine clearance) until serum UA
  lt6 mg/dl
• Continue concomitant colchicine and allopurinol
  regimen for 9-12 months
• Continue allopurinol for life-time
• In patients already on allopurinol, it should be
  continued at the same dose during an acute attack
  and the attack should be treated conventionally

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Calcium Pyrophosphate Dihydrate Deposition
Disease(CPDD)
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CPDD

• Arthritis induced by CPPD crystal deposition in
  and around joints
• Chondrocalcinosis Calcification of articular
  cartilage, menisci, synovium, and periarticular
  tissues
• CPDD may be asymptomatic (chondrocalcinosis) or
  associated with acute or chronic arthropathy
• About 5 of adult population, more of the elderly
  with an average age of around 70

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CPDD Clinical Manifestations

• Asymptomatic - chondrocalcinosis
• Acute monoarthritis pseudogout
• Associated with osteoarthritis
• Severe destructive disease pseudo neuropathic
  arthritis
• Symmetric polyarthritis, pseudo- RA
• Spinal pseudo ankylosing spondylitis

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Pseudogout

• 25 of CPDD
• Knee is most frequently affected joint (gt 50)
• Men gt female
• Other joints include wrist, shoulder, ankle,
  elbow, and hand
• 2/3 of patients have polyarticular disease
• 20 have hyperuricemia, 5 have also MSU crystals
  deposition

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Chondrocalcinosis

• Most common presentation of CPDD
• Common radiographic finding in older individuals
• Prevalence
• 10 15 in age 65 75
• Over 40 in age over 80
• Often concomitant with osteoarthritis

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CPDD Associated Conditions

• Aging
• Osteoarthritis
• Familial types
• Hyperparathyroidism
• Hemochromatosis
• Hypomagnasemia
• Hypophosphatasia

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CPDD Diagnosis

• Arthrocentesis inflammatory synovial fluid,
  WBC 2000-100,000
• CPPD crystals intracellular, rhomboid crystals,
  with weak birefringence
• Chondrocalcinosis is suggestive but not
  diagnostic for pseudogout

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CPDD Treatment

• Pseudogout is usually a self-limited attack
• Management of acute attack
• Intraarticular glucocorticoid injection
• NSAID / COXIB
• Colchicine
• Prophylaxis Try colchicine P.O. 0.5 mg bid

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Calcium Hydroxyapatite Deposition Disease

• Dystrophic calcification as occurs in areas of
  tissue damage, metabolic calcification
• Metabolic calcification occurs in hypercalcemic
  states or hyperparathyroidism
• Unknown
• Hereditary
• Chronic renal failure d/t hyperphosphatemia
• Connective tissue disorders SSc, myositis, SLE
• Most commonly affects bursae and tendons

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Basic Calcium Crystals

• May be found in 30 60 of synovial fluids from
  patients with osteoarthritis
• Periarticular calcification may be associated
  with an acute inflammatory reaction calcific
  periarthritis-tendinitis-bursitis
• Shoulder is commonly involved
• Associated with
• Chronic renal failure
• Systemic autoimmune disorders
• Scleroderma
• Inflammatory myopathies
• Dermatomyositis (Juvenile)