1. Crystal-Associated
Arthropathies
N.Movaffagh MD
Rheumatologist

2. Crystal-Associated Arthropathies
Gout
CPPD Disease
Calcium Apatite Deposition Disease
Calcium Oxalate Deposition Disease

3. Gout A metabolic disease middle-aged to elderly men
postmenopausal women

4. Gout Results from an increased body pool of urate with hyperuricemia
characterized by episodic acute arthritis or chronic arthritis caused by deposition of MSU crystals in joints and connective tissue tophi and kidneys

5. Uric acid is the biologically active end product of human purine metabolism
Hyperuricemia results from:
1. urate overproduction
2.urate under excretion
3.combination of both

6. Hyperuricemia is defined as serum urate levels > 6.8 mg/dL

7. Overproduction
Hemolytic anemia
Leukemia
Lymphoma
Underexcretion
Renal insufficiency
Dehydration/volume depletion

8. ACUTE ARTHRITIS most common early clinical manifestation of gout
Usually, only one joint is affected
MTP joint of the first toe often is involved (Podagra)
tarsal joints, ankles, and knees also are affected commonly
finger joints may be involve in (elderly patients or
advanced disease)

9. ACUTE ARTHRITIS
Inflamed Heberden’s or Bouchard’s nodes may be a first manifestation of gouty arthritis
first episode of acute gouty arthritis frequently begins at night with dramatic joint pain and swelling
Joints become warm, red, and tender
Early attacks tend to subside spontaneously within 3–10 days
most patients have intervals of varying length with no residual symptoms

10. Podagra

11. subcutaneous tophi

12. ACUTE ARTHRITIS Precipitate factors: dietary excess Trauma Surgery
excessive ethanol ingestion
hypouricemic therapy
serious medical illnesses(MI,stroke)

13. CHRONIC ARTHRITIS chronic nonsymmetric synovitis
manifest only as periarticular tophaceous deposits in the absence of synovitis

15. Women(only 5–20%)
postmenopausal and elderly women
have osteoarthritis and arterial hypertension
that causes mild renal insufficiency
usually are receiving diuretics
decreased renal urate clearance and renal insufficiency result in gout in young females

16. Laboratory Diagnosis
needle-shaped MSU crystals are intracellularly and extracellularly
In compensated polarized light negative birefringent
crystals
Synovial fluid leukocyte counts:
2000 to 60,000/μL
Effusions appear cloudy due to the increased numbers of leukocytes

17. Large amounts of crystals occasionally produce a thick pasty or chalky joint fluid
Bacterial infection can coexist with urate crystals in synovial fluid

19. DIAGNOSIS Arthrocentesis Serum uric acid levels(normal or low)
almost always elevated
Urinalysis
serum creatinine
Hemoglobin
WBC
liver function tests
serum lipids
24-h urine collection for uric acid

20. Excretion of >800 mg of uric acid per 24 h on a regular diet suggests that causes of overproduction of purine should be considered

21. Radiographic Features
advanced chronic tophaceous gout:
Cystic changes well-defined erosions with sclerotic margins (often with overhanging bony edges)
soft tissue masses

24. Ultrasound:
double contour sign overlying the articular cartilage
Dual-energy computed tomography (CT) can show
specific features establishing the presence of urate crystals

26. TREATMENT
control of body weight, low-purine diet increase in liquid intake, limitation of ethanol use, decreased use of fructose-containing foods, and avoidance of diuretics

27. TREATMENT Ice pack applications and rest of the involved joints
anti-inflammatory drugs:
NSAIDs, colchicine, or glucocorticoids
Hypouricemic therapy is considered:
after two attacks
serum uric acid levels>9.0 mg/dL
presence of uric acid stone
Presence tophi or chronic gouty arthritis

28. TREATMENT xanthine oxidase inhibitor (allopurinol)
Uricosuric agents(probenecid)
Attempts to normalize serum uric acid
to 5.0–6.0 mg/dL

29. CALCIUM PYROPHOSPHATE DEPOSITION (CPPD) DISEASE
formula, Ca2P2O7⋅H2O
Deposition of CPP crystals in articular tissues is most common in the elderly
age 65–75 years(15-10%)
age>85 year )30-50%)
In most cases, this process is asymptomatic
cause of CPPD is uncertain
likely that biochemical changes in aging or diseased cartilage

30. PATHOGENESIS
Increased production of inorganic pyrophosphate and decreased levels of pyrophosphatases in cartilage extracts

31. PATHOGENESIS Causes of increase in pyrophosphate production
1. Mutations in the ANKH gene
(gene of the membrane pyrophosphate channel)
2.enhanced activity of ATP pyrophosphohydrolase and 5′-nucleotidase
(which catalyze the reaction of ATP to adenosine
and pyrophosphate)

32. ATP ENPP PPi AMP

33. PATHOGENESIS Causes of deposition of CPP crystals:
decreased levels of cartilage glycosaminoglycans
High activities of transglutaminase enzymes

34. PATHOGENESIS Release of CPP crystals into the joint space
Phagocytosis of those crystals by monocyte-macrophages and neutrophils
releasing chemotactic and inflammatory substances
activating the inflammasome

35. Conditions Associated with CPPD
Aging
Disease-associated
Primary hyperparathyroidism
Hemochromatosis
Hypophosphatasia
Hypomagnesemia
Chronic gout
Postmeniscectomy
Gitelman’s syndrome
Epiphyseal dysplasias

36. Investigation of younger patients with CPPD should include:
Inquiry for evidence of familial aggregation
Evaluation of serum calcium, phosphorus
alkaline phosphatase, magnesium, iron, and transferrin

37. CLINICAL MANIFESTATIONS
CPPD arthropathy may be: asymptomatic acute subacute chronic
acute synovitis superimposed on chronically involved
joints

39. CLINICAL MANIFESTATIONS
association with peculiar forms of OA
radiographically mimic neuropathic arthritis
clinically similar to RA (chronic symmetric synovitis)
intervertebral disk and ligament calcification with restriction of spine mobility, spinal stenosis
periarticular tophus-like nodules (rare) Recurrent
acute inflammatory monoarticular arthritis (pseudogout)

40. A, Acute pseudogout. B, Pseudo-osteoarthritis
A, Acute pseudogout. B, Pseudo-osteoarthritis. C, Pseudorheumatoid arthritis with boutonnière deformity. D, Pseudorheumatoid arthritis showing ulnar deviation

41. knee is the joint most frequently
wrist, shoulder, ankle, elbow, and hands
temporomandibular joint be involved
Joint distribution may provide important clues suggesting CPPD disease
primary OA less often involves MCP,wrist,elbow, shoulder, or ankle joints

42. low-grade fever and, on occasion, temperatures as high as 40°C
infection in a joint with any microcrystalline deposition process can lead to crystal shedding and subsequent synovitis from both crystals
and microorganisms

43. Radiographs or ultrasound reveal:
punctate and/or linear radiodense deposits within fibrocartilaginous joint menisci or articular hyaline cartilage (chondrocalcinosis)

45. Definitive diagnosis:
typical rhomboid or rodlike crystals
(generally weakly positively birefringent or non birefringent with polarized light) in synovial fluid
In the absence of joint effusion or indications to obtain a synovial biopsy,chondrocalcinosis is presumptive of CPPD

46. One exception is chondrocalcinosis due to CaOx in some patients with chronic renal failure
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)

47. The leukocyte count in synovial fluid in acute
CPPD(several thousand cells to 100,000 cells/μL)
mean being about 24,000 cells/μL
predominant cell being the neutrophil
CPP crystals may coexist with MSU and apatite in some cases

48. CPPD

49. TREATMENT CPPD Untreated acute attacks may last a few days to a month
rest, joint aspiration, and NSAIDs or intraarticular glucocorticoid injection
daily prophylactic treatment with low doses of colchicine
short courses of glucocorticoids or, IL-1β antagonist
For severe polyarticular attacks
NSAIDS,hydroxychloroquine,methotrexate for persistent synovitis

50. CALCIUM APATITE DEPOSITION DISEASE
Ca5[PO4]3OH⋅2H2o
PATHOGENESIS
Apatite is 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)

51. In chronic renal failure,hyperphosphatemia can contribute to extensive apatite deposition
Familial aggregation is rarely

52. Conditions Associated with Apatite Deposition Disease
Aging
Osteoarthritis
Hemorrhagic shoulder effusions in the elderly (Milwaukee shoulder)
Destructive arthropathy
Tendinitis, bursitis
Tumoral calcinosis (sporadic cases)
Disease-associated
Hyperparathyroidism
Renal failure/long-term dialysis
Connective tissue diseases (e.g., systemic sclerosis, dermatomyositis, SLE)

53. Milwaukee shoulder
aggregations of Apatite are commonly present in synovial fluid in an destructive chronic arthropathy of the elderly that occurs most often in the shoulders

54. Synovial lining cell or fibroblast cultures exposed to apatite (or CPP) crystals can undergo mitosis and markedly increase the release of prostaglandin E2, various cytokines, and also collagenases and neutral proteases
Underscoring the destructive potential of abnormally stimulated synovial lining cells.

55. CLINICAL MANIFESTATIONS
acute reversible inflammation
chronic damage to the joint capsule, tendons, bursa, or articular surfaces
most common sites of apatite deposition include bursae and tendons in and/or around the knees, shoulders, hips, and fingers

56. asymptomatic radiographic abnormalities
30–50% of patients with OA have apatite microcrystals in their synovial fluid
synovial fluid leukocyte count in apatite arthritis is usually low (<2000/μL) predominance of mononuclear cells

57. DIAGNOSIS
Intra- and/or periarticular calcifications with or without erosive,destructive,or hypertrophic changes on radiographs
Definitive diagnosis of apatite arthropathy(basic calcium phosphate disease):
very small crystals with electron microscopy

59. 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
bright red with alizarin red s

60. TREATMENT Calcium Apatite Deposition Disease
Nonspecific
Acute attacks of bursitis or synovitis may be self-limiting
Aspiration of effusions
NSAIDs or oral colchicine for 2 weeks
intra- or periarticular injection of a depot glucocorticoid

61. TREATMENT
Local injection of disodium ethylenediaminetetraacetic acid (EDTA) and SC anakihnra in acute calcific tendinitis at the shoulder
calcium channel blockers, or bisphosphonates may help diffuse calcinosis
Agents to lower serum phosphate lead to resorption of deposits in renal failure that receiving hemodialysis

62. CaOx DEPOSITION DISEASE
Primary oxalosis
Secondary oxalosis

63. Primary oxalosis
Enhanced production of oxalic acid may result from at least two different enzyme defects, leading to hyperoxalemia

64. Primary oxalosis Nephrocalcinosis Renal failure
Acute and/or chronic CaOx arthritis
Periarthritis
Bone disease

65. Secondary oxalosis more common than the primary disorder
Deposition of calcium oxalate in visceral organs, blood vessels, bones, and cartilage
one of the causes of arthritis in CRF

66. CLINICAL MANIFESTATIONS
Acute synovitis
progressive articular destruction
Bone disease
Periarthritis
Deposits in fingers, wrists, elbows, knees, ankles, and feet

67. DIAGNOSIS Clinical features
Condrocalcinosis or soft tissue calcifications
in Radiography
Noninflammatory with <2000 leukocytes/μL, or mildly inflammatory in synovial effusions
Neutrophils or mononuclear cells can predominate
Bipyramidal crystals have strong birefringence
and stain with alizarin red S

69. TREATMENT NSAIDs, colchicine, intraarticular
glucocorticoids, and/or an increased frequency
of dialysis
liver transplantation in primary oxalosis