Gout and Other

Crystal-Associated
Arthropathies
Agulay ● Bose
 Gout

O CALCIUM PYROPHOSPHATE
DEPOSITION (CPPD) DISEASE

utl CALCIUM APATITE DEPOSITION

(CAD) DISEASE

in CaOx DEPOSITION DISEASE

 Gout
OVERVIEW
o Metabolic disease
o Middle-aged to elderly men and postmenopausal
women
o Hallmark: Hyperuricemia
 Plasma
Stages ofand
goutextracellular
progression fluids become supersaturated with uric
• Stage 1 – Asymptomatic
acid
hyperuricemia
• Stage 2 – Acute gout
• Stage 3 – Intercritical gout
• Stage 4 – Chronic gout
 Gout
Clinical Manifestations
o Acute arthritis
 Most frequent early clinical manifestation of gout
 Frequently begins at night with dramatic pain, swelling, warmth,
and tenderness
 May be precipitated by dietary excess, trauma, surgery, excessive
ethanol ingestion, hypouricemic therapy, and serious medical
illnesses

o Chronic arthritis
 Occurs in the setting of long-standing gout

o Extraarticular tophi
o Tenosynovitis
 Gout
Clinical Manifestations
o Urate nephropathy
 Deposition of MSU crystals in renal interstitium and pyramids
 Can cause chronic renal insufficiency

o Acute uric acid nephropathy

 Reversible cause of acute renal failure
 Precipitation of urate in the tubules

o Uric acid nephrolithiasis

 Gout
Laboratory diagnosis
o Synovial fluid analysis
 Performed to confirm gout
 Gold standard: Monosodium urate crystals
 Gram stain and culture → rule out infection

o Serum uric acid

o Urine uric acid
 Excretion of >800 mg/d → overproduction of purine
 Gout
Laboratory diagnosis
o Urinalysis; serum creatinine, liver function tests,
glucose and lipids; complete blood counts
 Screening for risk factors or sequelae

o Erythrocyte HPRT and PRPP levels

o Chemical analysis of renal stones
 Gout
Radiographic Features
o Joint x-rays
 Cystic changes, erosions with sclerotic margins, and soft tissue
masses in advanced chronic arthritis

o Abdominal flat plate

 For suspected renal stones

o Ultrasound
 Double contour sign
Gout
DIFFERENTIAL DIAGNOSIS
o Septic arthritis
o Reactive arthritis
o Calcium pyrophosphate dihydrate (CPPD) deposition
disease
o Rheumatoid arthritis
Gout
ACR-EULAR CLASSIFICATION
CRITERIA
o Provides formal diagnostic criteria for gout
o Allow for a non-synovium diagnosis of gout to assist
clinicians when synovial testing is not possible
Gout
TREATMENT
o Asymptomatic hyperuricemia – treatment is not
indicated
o Acute gouty arthritis – symptomatic relief
 Ice pack application and rest Regimens
• NSAIDs – treatment • Indomethacin,
0.6-mg tablet given
25–50 every
mg tid8
 Anti-inflammatory
of choice drugs • h with subsequent
Naproxen, 500 mgtapering
bid
• NSAIDs – treatment of choice • 1.2-mg
Ibuprofen,
tablet
800followed
mg tid by 0.6
• Colchicine – effective within first 24 h of attack
• mg
Diclofenac,
in 1 h 50 with
mg subsequent
tid
• Intraarticular glucocorticoids • day dosing
Celecoxib 800depending
mg on
• Systemic glucocorticoids response
• Anakinra and other inhibitors of interleukin-1β
Gout
TREATMENT
o Hypouricemic therapy – attempts to normalize serum uric acid to <300–360 μmol/L (5.0–6.0
mg/dL)
 Xanthine oxidase inhibitors (allopurinol, febuxostat)
• Decrease uric acid synthesis
 Uricosuric drugs (probenecid, sulfinpyrazone, benzbromarone, lesinurad)
• Increase uric acid excretion
• Contraindications: age >60, renal stones, tophi, increased urinary uric acid excretion, prophylaxis during cytotoxic therapy
 Pegloticase
• Lowers uric acid by oxidizing urate to allantoin
• Used in selected pts with chronic tophaceous gout refractory to conventional therapy
CALCIUM
PYROPHOSPHATE
DEPOSITION
PATHOPHYSIOLOGY
(CPPD) DISEASE
o Unknown etiology
 ANKH gene mutations
o Deposition of CPP crystals in articular tissues
o Increased production of inorganic pyrophosphate
and decreased levels of pyrophosphatases
 Pyrophosphate combines with calcium to form CPP crystals in
matrix vesicles or on collagen fibers.
CALCIUM
PYROPHOSPHATE
DEPOSITION PATHOPHYSIOLOGY
(CPPD) DISEASE
o Decreased levels of cartilage glycosaminoglycans
→ inhibit and regulate crystal nucleation
o High activities of transglutaminase enzymes
contribute to the deposition of CPP crystals
o Release of CPP crystals into the joint space →
phago­cytosis → release of chemotactic and
inflammatory substances, and inflammasome
activation
CALCIUM
PYROPHOSPHATE
DEPOSITION
CLINICAL MANIFESTATIONS
(CPPD)
o Knee – mostDISEASE
frequently affected joint
o Asymptomatic, acute, subacute, or chronic
o Association with or enhancement of peculiar forms
of osteoarthritis
o Induction of severe destructive disease
 Radiographically mimic neuropathic arthritis
o Chronic symmetric synovitis
 Clinically similar to rheumatoid arthritis
CALCIUM
PYROPHOSPHATE
DEPOSITION
CLINICAL MANIFESTATIONS
(CPPD)
o IntervertebralDISEASE
disk and ligament calcification with
restriction of spine mobility, the crowned dens
syndrome, or spinal stenosis
o Periarticular tophus-like nodules
CALCIUM
PYROPHOSPHATE
DEPOSITION DIAGNOSIS
(CPPD)
o PresumptiveDISEASE
 Radiographs or ultrasound – punctate and/or linear radiodense
deposits within fibrocartilaginous joint menisci or articular
hyaline cartilage
o Definitive
 Compensated polarized light microscopy – rhomboid or
rodlike crystals
o Acute CPPD synovial fluid leukocyte count
 Several thousand cells to 100,000 cells/μL
 Average of 24,000 cells/μL
 Predominant cell: neutrophils
CALCIUM
PYROPHOSPHATE
DEPOSITION TREATMENT
(CPPD)
o Rest, joint DISEASE
aspiration, NSAIDs, or intraarticular
glucocorticoid injection
o Colchicine
 Frequent recurrent attacks
o Glucocorticoids and IL-1β antagonist (Anakinra)
 Severe polyarticular attacks
o Joint replacement
 Patients with progressive destructive large-joint arthropathy
 CALCIUM APATITE
DEPOSITION (CAD)
DISEASE
PATHOGENESIS
o Abnormal accumulation of carbonate substituted
apatite
 Dystrophic calcification: areas of tissue damage
 Metastatic calcification: hypercalcemic or hyperparathyroid states

o Chronic renal failure

 Hyperphosphatemia → extensive apatite deposition
o Apatite aggregates are commonly present in synovial
fluid in an extremely destructive chronic arthropathy
of the elderly
 Shoulders: Milwaukee shoulder
 Hips
 Knees
 CALCIUM APATITE
DEPOSITION (CAD)
DISEASE
PATHOGENESIS
o Abnormally stimulated synovial lining cell or
fibroblast cultures → mitosis, and markedly increase
the release of prostaglandin E2, various cytokines,
collagenases and neutral proteases → destruction
o Slow progression
 CALCIUM APATITE
DEPOSITION (CAD)
DISEASE
CLINICAL MANIFESTATIONS
o Asymptomatic radiographic abnormalities
o Acute synovitis, bursitis, tendinitis
o Chronic destructive arthropathy
o Most common sites of deposition: bursae and
tendons in and/or around the knees, shoulders, hips,
and fingers
 CALCIUM APATITE
DEPOSITION (CAD)
DISEASE
DIAGNOSIS
o Synovial fluid leukocyte count: <2000/μL
o Definitive
 Individual crystals seen on electron microscopy
o Clumps of crystals
 1- to 20-μm shiny intra- or extracellular nonbirefringent globules
 Purplish with Wright’s stain
 Bright red with alizarin red S.
 CALCIUM APATITE
DEPOSITION (CAD)
DISEASEtreatment
o Acute attacks of bursitis or synovitis may be self-
limiting, resolving in days to several weeks
o Shorten the duration and intensity of symptoms
 Aspiration of effusions
 NSAIDs
 Oral colchicine
 Intra- or periarticular injection of a depot glucocorticoid
o Acute calcific tendinitis at the shoulder
 Disodium ethylene­diaminetetraacetic acid (EDTA)
 Anakinra
 CALCIUM APATITE
DEPOSITION (CAD)
DISEASEtreatment
o Diffuse calcinosis
 IV gamma globulin
 Rituximab
 Calcium channel blockers
 Bisphosphonates
Ox DEPOSITION DISEASE
PATHOPHYSIOLOGY
o Primary oxalosis
 Rare hereditary metabolic disorder
 Enhanced production of oxalic acid → hyperoxalemia and
deposition of CaOx crystals in tissues → nephrocalcinosis and
renal failure
o Secondary oxalosis
 More common
 Seen in patients that have been dependent on long-term
hemodialysis or peritoneal dialysis, and those who receives
ascorbic acid supplements
Ox DEPOSITION DISEASE
CLINICAL MANIFESTATIONS
o Acute synovitis caused by crystal shedding
o Radiographs – chondrocalcinosis or soft tissue
calcifications
o Synovial effusions are usually noninflammatory,
with <2000 leukocytes/μL, or mildly inflammatory
o Predominant cells: neutrophils or mononuclear
cells
Ox DEPOSITION DISEASE
CLINICAL MANIFESTATIONS
o Crystals have variable shape and birefringence to
polarized light
 Bipyramidal
• Most easily recognized forms
• Strong birefringence
• Stain with alizarin red S
Ox DEPOSITION DISEASE
TREATMENT
o NSAIDs
o Colchicine
o Intraarticular glucocorticoids
o Increased frequency of dialysis
o Liver transplantation
 Primary oxalosis
Merci
Beaucoup
beaucoup
Agulay ● Bose
References
Jameson, J.L., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., & Loscalzo, J. (2018).
Harrison’s Principles of Internal Medicine (20th ed.). McGraw-Hill Education
Kasper, D.L, Fauci, A.S., Hauser, S.L., Longo, D.L., Jameson, J.L., Loscalzo, J. (2016).
Harrison’s Manual of Medicine (19th ed.). McGraw Hill Education
Vargas-Santos, A. B., Taylor, W. J., & Neogi, T. (2016). Gout classification criteria: update
and implications. Current rheumatology reports, 18(7), 46.
https://doi.org/10.1007/s11926-016-0594-8
Weisman, S. (2018). About gout: managing and preventing attacks.
https://www.bouldermedicalcenter.com/about-gout-causes-symptoms-and-treatment/