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Familial Mediterranean Fever (FMF)

Familial Mediterranean Fever (FMF). Definition. An autosomal recessive disease, characterized by recurrent febrile episodes with serositis involving the peritoneum, pleura and synovium. Ethnic distribution. Turks Armenian Arabs and Druzes Non-Ashkenazi Jews.

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Familial Mediterranean Fever (FMF)

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  1. Familial Mediterranean Fever(FMF)

  2. Definition An autosomal recessive disease, characterized by recurrent febrile episodes with serositis involving the peritoneum, pleura and synovium.

  3. Ethnic distribution • Turks • Armenian • Arabs and Druzes • Non-Ashkenazi Jews. • Sporadic cases - all over the world.

  4. Age of Onset 0-10 years 53% 11-20 years 29% 21-30 years 14% 31-40 years 3% Over 40 years 1%

  5. Attack Duration and Frequency • Lasts 24-96 hours • Peak intensity –12 hours • Vary • Once –twice a week to once a year

  6. Fever • In most of the cases (99%). • Temp. 37.5 to 40 C. • Rarely can be the only feature.

  7. Peritonitis - In 96 % of the cases. - Presenting feature in 80%. - Resembles “surgical Abdomen”. - About 30% undergo Appendectomy.

  8. Pleuritis • In 25-80% of the cases: (Armenians>Jews) • Severe pleuritic pain. • May mimic P.E. • Sometimes with effusion. • No fibrosis.

  9. Pericarditis - Relatively rare <1%. - Constrictive pericarditis in very few cases.

  10. Arthritis (Synovitis)Two Types • Type I: - 95% • Short attack: 3-7 days. • Abrupt onset. • Peak 24-48 hours. • Large effusion. • Complete resolution (Usually).

  11. Arthritis (Cont.) • Type II: • Chronic destructive arthritis. • Commonly affects the hips and knees. • Sometimes – sacroiliitis-HLA B27 negative.

  12. Skin Involvement • In 7-40% of the cases. • Erysipelas-like erythema. • Medial or lateral aspect of the ankles or dorsum of the foot. • D.D with cellulitis or arthritis. • May be an only feature in children.

  13. Myalgia • Three types (mainly in children) - 25%. • Spontaneous pattern (8%):appearing during attacks, affecting legs and arms. • Exercised induced (81%) - may occur between attacks. • Protracted febrile myalgia (11%) -vasculitis? Steroid responsive.

  14. Involvement of Other Organs • Acute orchitis. • Splenomegaly with no amyloidosis. • Meningitis?? (Mollaret’s).

  15. Precipitating Factors • Physical activity. • Emotional stress. • Inter-current infections. • Cold exposure. • Menstruation. • Fatty meal ??

  16. Amyloidosis • Type I: Following many years of typical FMF attacks. ( with no treatment). • Type II (?): Appearance of nephrotic syndrome without previous classic FMF attacks.

  17. Etiology and Pathogenesis-(hypotheses) • Autoimmune disease (vasculitis) ?. • Etiocholanolone fever ?. • Disturbed metabolism of cathecholamines ?. • Deficiency of complement components ?. • HLA-related ?.

  18. In 1992 the FMF gene was located to the short arm of chromosome 16. E Pras et al. NEJM

  19. In 1997 the MEFV gene was isolated independently by two consortia:The International FMF consortium The French consortium.

  20. Marenostrin/Pyrin (1997-2000) • A new cytosolic protein with unknown function. • 781 amino acids. • Expressed mainly in mature neutrophils. • Is not expressed by synovial or peritoneal cells.

  21. LRR LRR LRR LRR NBS NBS NBS NBS NBS LRR The Pyrin Domain Defines a Family of Inflammatory/Apoptotic Proteins Pyrin PYD B C-C B30.2 NALP1 (DEFCAP, CARD7) PYD CARD NALP2 PYD NALP3 (Cryopyrin) PYD NALP4 PYD Pyrin domain PYD ASC PYD CARD B B-box zinc finger POP1 PYD C-C Coiled-coil domain B30.2 B30.2 domain AIM2 PYD HIN-200 Nucleotide-binding site domain Leucine-rich repeat domain MNDA PYD HIN-200 Caspase activation and recruitment domain CARD IFI16 PYD HIN-200 HIN-200 Hematopoietic IFN- inducible nuclear protein HIN-200

  22. Pyrin Pyrin ASC Pyrin CARD CARD ASC Can Act as a Link between Pyrin and Inflammatory Pathways Pro-Caspase-1 (IL-1 Converting Enzyme, ICE) NF-kB, IL-1 activation

  23. FMF - Diagnosis • Typical clinical manifestations. • Family history. • Routine laboratory tests are not specific or contributory.

  24. FMF Diagnosis (Cont.) In atypical cases: • Mutations detected by PCR is an additional tool for FMF diagnosis, especially in atypical cases.

  25. Genetics of FMF • FMF occurs in members of one generation – suggesting autosomal recessive heredity. • High consanguinity rate may lead to its occurrence in successive generations – pseudo-dominant trait. • Several studies described autosomal dominant transmission in patients with mutations of deletion (M694del).

  26. Genetics (Cont.) • Carrier rate varies among ethnic groups: • Iraqi Jews - 1:3 • North-African Jews - 1:5 • Ashkenazi Jews - 1:10 • Israeli Arabs - 1:10 • Armenians - 1:7 • Turkish - 1:5

  27. Mutations Distribution • In Israel • North-African Jews - M694V, E148Q • Iraqui Jews-V726A, M694V, E148Q,M680I • Ashkenazi Jews – E148Q,V726A, • Arabs -V726A,M680I,M694V,M694I,E148Q • Turks – M694V, M680I, V726A, E148Q

  28. O O O O O O O O O O O Silk Road Spreading FMF in ancient time Spreading FMF in recent years O O O

  29. Phenotype-Genotype Correlation • M694V is associated with more severe disease: • Earlier onset • More arthritis • Higher dose of colchicine • Amyloidosis

  30. Treatment Colchicine - is the drug of choice since 1972. Goldfinger, NEJM Ozkan, Medical Bulletin of Istanbul

  31. Mechanism of Action Colchicine Inhibits leukocytes chemotaxis • It may interfere microtubules function. • It may affect the function of adhesion molecules on the surface of leukocytes and endothelial cells.

  32. Substrates Colchicine Lovastatin Estrogen Midazolam Steroids Quinidine Dapsone Terfenadine Diltiazem Testosterone Erythromycin Nifedipine Lidocaine Verapamil Cyclosporine Inhibitors Diltiazem Gestodene Ketoconazole Toleandomycin Erythromycin FK-506 Grapefruit Juice Drug – drug InteractionRepresentative substrates and inhibitors of CYP 3A4

  33. Long-term colchicine treatment in childbearing age • Colchicine and male fertility • Colchicine and pregnancy • Colchicine and breast feeding • Colchicine and child growth

  34. Colchicine and male fertility Colchicine may cause oligo or azoospermia (very rarely in FMF and Gout, but relatively more frequently in Behcet’s syndrome).

  35. In some cases of azoospermia biopsies from the testes disclosed amyloidosis • Can amyloidosis affect male fertility ?

  36. Testicular Biopsy

  37. Long-term colchicine treatment in childbearing age • Colchicine and male fertility • Colchicine and pregnancy • Colchicine and breast feeding • Colchicine and child growth

  38. Conclusion:Breast feeding is safe under colchicine treatment

  39. Long-term colchicine treatment in childbearing age • Colchicine and male fertility • Colchicine and pregnancy • Colchicine and breast feeding • Colchicine and child growth

  40. Long-term colchicine treatment in childbearing age • Colchicine and male fertility • Colchicine and pregnancy • Colchicine and breast feeding • Colchicine and child growth

  41. Colchicine and pregnancy(Studied in FMF) • Does not increase abortion rate • Normal pregnancy length • Normal birth weight • Normal outcome • Amniocentesis ? No need E Ben-Chetrit et al. AC&R 2011

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