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.

14. 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.

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

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

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

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

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

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

22. 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.

23. C-C PYDBB30.2 PYD CARD PYD HIN-200 PYDHIN-200 PYDHIN-200 CARD NBSLRR PYD NBSLRR PYD NBS LRR PYD NBS LRR Pyrin NALP1 (DEFCAP, CARD7) NALP2 NALP3 (Cryopyrin) NALP4 ASC POP1 AIM2 MNDA IFI16 The Pyrin Domain Defines a Family of Inflammatory/Apoptotic Proteins PYD B C-C B30.2 NBS LRR CARD HIN-200 Pyrin domain B-box zinc finger Coiled-coil domain B30.2 domain Nucleotide-binding site domain Leucine-rich repeat domain Caspase activation and recruitment domain Hematopoietic IFN- inducible nuclear protein

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

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

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

29. 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).

30. 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

31. 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

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

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

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

36. 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.

38. Drug – drug Interaction Representative substrates and inhibitors of CYP 3A4 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

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

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

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

42. Testicular Biopsy

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

45. Conclusion: Breast feeding is safe under colchicine treatment

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

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

49. 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