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.• Sporadic cases - all over the world.

Age of Onset

0-10 years 53% 11-20 years 29% 21-30 years 14% 31-40 years 3% Over 40 years 1%

Attack Duration and Frequency

• Lasts 24-96 hours• Peak intensity –12 hours• Vary• Once –twice a week to once a year

Fever

• In most of the cases (99%).

• Temp. 37.5 to 40 C.• Rarely can be the

only feature.

Peritonitis

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

Pleuritis

• In 25-80% of the cases: (Armenians>Jews)

• Severe pleuritic pain.• May mimic P.E.• Sometimes with

effusion.• No fibrosis.

Pericarditis

- Relatively rare <1%.- Constrictive pericarditis in

very few cases.

Arthritis (Synovitis)Two Types

• Type I: - 95%• Short attack: 3-7

days.• Abrupt onset.• Peak 24-48 hours.• Large effusion.• Complete resolution

(Usually).

Arthritis (Cont.)

• Type II:• Chronic destructive arthritis.• Commonly affects the hips and knees.• Sometimes – sacroiliitis-HLA B27

negative.

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.

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.

Involvement of Other Organs

• Acute orchitis.• Splenomegaly with no amyloidosis.• Meningitis?? (Mollaret’s).

Precipitating Factors

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

Amyloidosis

• Type I: Following many years of typical FMF attacks. ( with no treatment).

• Type II (?): Appearance of nephrotic syndrome without previous classic FMF attacks.

Etiology and Pathogenesis-(hypotheses)

• Autoimmune disease (vasculitis) ?.• Etiocholanolone fever ?.• Disturbed metabolism of

cathecholamines ?.• Deficiency of complement

components ?.• HLA-related ?.

In 1992 the FMF gene was located to

the short arm of chromosome 16.

E Pras et al. NEJM

In 1997 the MEFV gene was isolated independently by two

consortia:The International FMF consortium The French

consortium.

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.

C-CPYD B B30.2

PYD

PYD CARD

PYD

HIN-200

PYD HIN-200

PYD HIN-200HIN-200

CARDNBS LRRPYD

PYD NBS LRR

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

Pyrin

Pyrin

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)

FMF - Diagnosis

• Typical clinical manifestations.• Family history.• Routine laboratory tests are not specific

or contributory.

FMF Diagnosis (Cont.)

In atypical cases:• Mutations detected by PCR is an

additional tool for FMF diagnosis, especially in atypical cases.

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).

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

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

O

OO

O O

O

OO

O

O

OSilk Road Spreading FMF in ancient time

Spreading FMF in recent years

O

Phenotype-Genotype Correlation

• M694V is associated with more severe disease:

• Earlier onset• More arthritis• Higher dose of colchicine• Amyloidosis

TreatmentColchicine - is the drug of choice

since 1972.

Goldfinger, NEJMOzkan, Medical Bulletin of Istanbul

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.

Drug – drug InteractionRepresentative 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

Long-term colchicine treatment in childbearing

age

• Colchicine and male fertility• Colchicine and pregnancy• Colchicine and breast feeding• Colchicine and child growth

Colchicine and male fertility

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

In some cases of azoospermia biopsies from

the testes disclosed amyloidosis

Can amyloidosis affect male fertility ?

Testicular Biopsy

Long-term colchicine treatment in childbearing

age

• Colchicine and male fertility• Colchicine and pregnancy• Colchicine and breast feeding• Colchicine and child growth

Conclusion:

Breast feeding is safe under colchicine treatment

Long-term colchicine treatment in childbearing

age

• Colchicine and male fertility• Colchicine and pregnancy• Colchicine and breast feeding• Colchicine and child growth

Long-term colchicine treatment in childbearing

age

• Colchicine and male fertility• Colchicine and pregnancy• Colchicine and breast feeding• Colchicine and child growth

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