1. Calcium containing crystals Major manifestations Major manifestations Acute periarthritis Acute periarthritis Destructive arthropathy Destructive arthropathy Tissue deposits mimicking tumor like masses Tissue deposits mimicking tumor like masses Types of crystals Types of crystals Calcium pyrophosphate dihydrate Calcium pyrophosphate dihydrate Basic calcium phosphate Basic calcium phosphate

2. CPPD Chondrocalcinosis Chondrocalcinosis Pyrophosphate arthropathy Pyrophosphate arthropathy

3. CPPD Precipitation of crystals of calcium pyrophosphate dihydrate (CPPD) in connective tissues Precipitation of crystals of calcium pyrophosphate dihydrate (CPPD) in connective tissues Ca2P207.2H20 Ca2P207.2H20 CPPD formation appears restricted principally to fibro- and hyaline cartilage, less commonly capsule or tendon CPPD formation appears restricted principally to fibro- and hyaline cartilage, less commonly capsule or tendon

4. EPIDEMIOLOGY Chondrocalcinosis increases with age from the 6th decade and shows female preponderance. Chondrocalcinosis increases with age from the 6th decade and shows female preponderance. The strong association with osteoarthritis (OA) and Joint trauma and aging The strong association with osteoarthritis (OA) and Joint trauma and aging

5. PREVALENCE 65 to 74 years old— 15 percent 65 to 74 years old— 15 percent 75 to 84 years old — 36 percent 75 to 84 years old — 36 percent >84 years old— almost 50 percent >84 years old— almost 50 percent

6. NTPPPH = Nucleoside triphosphate pyrophosphohydrolase NTPPPH = Nucleoside triphosphate pyrophosphohydrolase NTPase = ( one kind of NTPPPH) is a ectoenzyme NTP PPi CCPD production (ATP) NTPase NTPPPH supersaturation

7. Metabolism of PPi and formation of CPPD crystals in haemochromatosis (1) and hypomagnesaemia (2). Wright G D, Doherty M Ann Rheum Dis 1997;56:586-588 ©1997 by BMJ Publishing Group Ltd and European League Against Rheumatism

8. Crystal formation Crystal formation may reflect elevated levels of either calcium or pyrophosphate (PPi), matrix changes that enhance local CaPPi supersaturation, NTPPPH overactivity or a combination of these factors. Crystal formation may reflect elevated levels of either calcium or pyrophosphate (PPi), matrix changes that enhance local CaPPi supersaturation, NTPPPH overactivity or a combination of these factors. A close association is reported with hypertrophic or metaplastic chondrocytes, the surrounding matrix often being proteoglycan depleted and degenerative. A close association is reported with hypertrophic or metaplastic chondrocytes, the surrounding matrix often being proteoglycan depleted and degenerative.

9. Site of crystal formation CPPD crystals form in peri-cellular sites,in the mid-zone of fibro- and hyaline cartilage CPPD crystals form in peri-cellular sites,in the mid-zone of fibro- and hyaline cartilage

11. Inhibitor of CPPD deposition Local Mg Local Mg Proteoglycan Proteoglycan Alkalinphosphatase Alkalinphosphatase 5´ nucleotidase 5´ nucleotidase

12. Promoting factor for crystal formation Iron Iron Calcium Calcium Phospholipid Phospholipid Copper Copper PTH promotion of PP synthtesis PTH promotion of PP synthtesis Other crystals Other crystals

13. Metabolic diseases predisposing to CPPD Definite Definite Hyperparathyroidism Hyperparathyroidism Haemochromatosis Haemochromatosis Hypophosphatasia Hypophosphatasia Hypomagnesaemia Hypomagnesaemia Wilson's disease Wilson's disease Hypothyroidism Hypothyroidism Probable Probable Gout Gout Ochronosis Ochronosis joint injection of hyaluronate joint injection of hyaluronate X-linked hypophosphatemic rickets X-linked hypophosphatemic rickets familial hypocalciuric hypercalcemia familial hypocalciuric hypercalcemia

15. Clinical manifestations Acute pseudo-gout Acute pseudo-gout May rarely present as May rarely present as Pseudo-rheumatoid Pseudo-rheumatoid Pseudo-ankylosing spondylitis Pseudo-ankylosing spondylitis Pseudo-neuropathic arthropathy Pseudo-neuropathic arthropathy Secondary osteoarthritis Secondary osteoarthritis Chondrocalcinosis Chondrocalcinosis Tenosynovitis Tenosynovitis

16. Acute peudogout CPPD crystal induced synovitis – clinically resembles gout CPPD crystal induced synovitis – clinically resembles gout Precipitated by trauma, surgery or severe medical illness Precipitated by trauma, surgery or severe medical illness Acute attacks are usually self-limiting and resolve within one to three weeks Acute attacks are usually self-limiting and resolve within one to three weeks Fever is common, mildly confused Fever is common, mildly confused Knee – most common joint Knee – most common joint Coexistence of urate and CPPD crystals in a single inflammatory effusion is not uncommon Coexistence of urate and CPPD crystals in a single inflammatory effusion is not uncommon

17. Acute CPPD

18. Acute pseudogout

19. CPPD crystals Detected by compensated polarized light microscopy Detected by compensated polarized light microscopy Positively (but weakly) birefringent Positively (but weakly) birefringent Rhomboid shaped Rhomboid shaped More difficult to detect More difficult to detect Smaller and more polymorphic Smaller and more polymorphic

20. A faintly yellow, positively birefringent, rhomboidal, intracellular crystal characteristic of calcium pyrophosphate dihydrate (CPPD) is seen in the synovial fluid of a patient with pseudogout, when viewed with compensated, polarized microscopy.

22. CPPD crystal

23. triggers of acute pseudogout Trauma Trauma Intercurrent medical illness Intercurrent medical illness Surgery Surgery Blood transfusion/parenteral fluid administration Blood transfusion/parenteral fluid administration

24. Autoremission Phagocytosis and dissolution of crystals may play a role. Phagocytosis and dissolution of crystals may play a role. Adhesion of components of extracellular fluid or plasma to crystals may decrease their inflammatory potential. Adhesion of components of extracellular fluid or plasma to crystals may decrease their inflammatory potential.

25. Familial Chondrocalcinosis Autosomal dominant disease Autosomal dominant disease Clinical disease occurs early in life Clinical disease occurs early in life Associated with ANKH gene mutation Associated with ANKH gene mutation Transmembrane protein involved in pyrophosphate transport Transmembrane protein involved in pyrophosphate transport

26. Chronic pyrophosphate arthropathy elderly and female. elderly and female. Asymptomatic radiographic finding of calcification of articular or fibrocartilage. Asymptomatic radiographic finding of calcification of articular or fibrocartilage.

27. Charactristic site of CPPD deposition ¤ Lateral & medial meninscus in knee joint ( most common ) ( most common ) ¤ Acetabular labrum in hip ¤ Fibrocartilageinous Symphysis pubis ¤ articular disc of wrist ¤ Anulus fibrous of intervertebral discs

28. X Ray finding

33. Normal wrist

37. Axial presentations 'pseudo-ankylosing spondylitis' 'pseudo-ankylosing spondylitis' acute self-limiting meningitic episodes may relate to CPPD deposition in degenerative ligamenta flava and cervical discs acute self-limiting meningitic episodes may relate to CPPD deposition in degenerative ligamenta flava and cervical discs

38. Spine

39. Crowned dens syndrome

40. Odontoid erosion

41. Pseudo - osteoarthritis Consider CPPD disease when O.A occurs in joints not commonly affected in primary O.A Consider CPPD disease when O.A occurs in joints not commonly affected in primary O.A Wrist, MCP joints, shoulders and elbows

43. CPPD

44. CPPD

45. Chronic pyrophosphate arthropathy DD with OA the site of predominant involvement (wrists, shoulders, ankles and elbows are uncommonly affected in OA) the site of predominant involvement (wrists, shoulders, ankles and elbows are uncommonly affected in OA) the often marked inflammatory component the often marked inflammatory component superimposition of acute attacks superimposition of acute attacks

46. CPPD disease treatment Acute pseudo-gout Acute pseudo-gout NSAIDs, colchicine, I.A steroid injection NSAIDs, colchicine, I.A steroid injection Prophylaxis with colchicine 0.6mg P.O bid Prophylaxis with colchicine 0.6mg P.O bid Chronic and progressive CPPD crystal deposition Chronic and progressive CPPD crystal deposition No effective treatment No effective treatment Probenecid is being investigated Probenecid is being investigated

47. Basic calcium phosphate crystals Types of crytals Types of crytals Hydroxyapatite Hydroxyapatite Tricalcium phosphate Tricalcium phosphate Octacalcium phosphate Octacalcium phosphate Identification of crystals Identification of crystals Very difficult to detect secondary to small size Very difficult to detect secondary to small size Non-birefringent chunks Non-birefringent chunks Stain positive with Alizarin red stain Stain positive with Alizarin red stain

48. BCP crystal deposition disease Acute calcific periarthritis Acute calcific periarthritis Destructive arthropathy Destructive arthropathy Osteoarthritis Osteoarthritis Soft tissue calcification Soft tissue calcification

49. Acute calcific periarthritis

50. Hydroxyapatite

51. Hydroxyapatite

52. Hydroxyapatite

53. Hydroxyapatite

54. Destructive arthropathy Milwaukee shoulder syndrome Milwaukee shoulder syndrome BCP crystal associated joint degeneration BCP crystal associated joint degeneration Massive joint effusions – usually bloody Massive joint effusions – usually bloody May effect other joints – knees, hips and elbows May effect other joints – knees, hips and elbows

55. Milwaukee shoulder

56. BCP crystals and OA Calcium crystals are very common in O.A joints ( in contrast rarely found in R.A ) Calcium crystals are very common in O.A joints ( in contrast rarely found in R.A ) Data support a causative role Data support a causative role Presence correlates strongly with severity of radiographic O.A Presence correlates strongly with severity of radiographic O.A

57. BCP crystal deposition in other disease Atherosclerosis Atherosclerosis Hydroxyapatite is the major constituent Hydroxyapatite is the major constituent Positive correlation between coronary artery calcification and cardiovascular events Positive correlation between coronary artery calcification and cardiovascular events Breast cancer Breast cancer Mammary microcalcifications is a diagnostic marker of breast cancer Mammary microcalcifications is a diagnostic marker of breast cancer BCP crystals augment mitogenesis in breast cancer cell lines BCP crystals augment mitogenesis in breast cancer cell lines

58. Potential treatment options Phosphocitrate Phosphocitrate Inhibits BCP and CPPD crystal formation Inhibits BCP and CPPD crystal formation Blocks degeneration promoting effects of crystals Blocks degeneration promoting effects of crystals Bisphosphonate Bisphosphonate High dose etidronate High dose etidronate