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Familial Mediterranean Fever
(FMF)
Definition
An autosomal recessive disease, characterized
by recurrent febrile episodes with serositis
involving the peritoneum, pleura and synovium.
Ethnic distribution
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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
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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
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Type I: - 95%
Short attack: 3-7 days.
Abrupt onset.
Peak 24-48 hours.
Large effusion.
Complete resolution
(Usually).
Arthritis (Cont.)
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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
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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)
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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.
The Pyrin Domain Defines a Family of
Inflammatory/Apoptotic Proteins
Pyrin
PYD
NALP1
(DEFCAP, CARD7)
PYD
NBS
LRR
NALP2
PYD
NBS
LRR
NALP3
(Cryopyrin)
PYD
NBS
LRR
NALP4
PYD
NBS
LRR
ASC
PYD
B
C-C
B30.2
CARD
PYD
B
POP1
C-C
PYD
B30.2
AIM2
PYD
MNDA
PYD
HIN-200
HIN-200
PYD
HIN-200
B-box zinc finger
Coiled-coil domain
B30.2 domain
NBS
Nucleotide-binding site
domain
LRR
Leucine-rich repeat
domain
Caspase activation and
recruitment domain
CARD
IFI16
Pyrin domain
CARD
HIN-200
HIN-200
Hematopoietic IFNinducible nuclear protein
ASC Can Act as a Link between Pyrin
and Inflammatory Pathways
Pyrin
Pyrin
ASC
Pyrin CARD
CARD
Pro-Caspase-1
NF-kB,
(IL-1 Converting
Enzyme, ICE)
IL-1
activation
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.)
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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
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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
O
O
O
O
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OO
O
O
Silk Road
Spreading FMF in ancient
time
Spreading FMF in recent
years
O
O
Phenotype-Genotype Correlation
• M694V is associated with more severe
disease:
• Earlier onset
• More arthritis
• Higher dose of colchicine
• Amyloidosis
Treatment
Colchicine - is the drug of choice since
1972.
Goldfinger, NEJM
Ozkan, 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 Interaction
Representative substrates and inhibitors
of CYP 3A4
• Substrates
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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
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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).
Can amyloidosis affect male fertility ?
In some cases of azoospermia biopsies from the
testes disclosed amyloidosis
Testicular Biopsy
Long-term colchicine treatment in
childbearing age
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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
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Colchicine and male fertility
Colchicine and pregnancy
Colchicine and breast feeding
Colchicine and child growth
Long-term colchicine treatment in
childbearing age
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Colchicine and male fertility
Colchicine and pregnancy
Colchicine and breast feeding
Colchicine and child growth
Colchicine and pregnancy
(Studied in FMF)
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Does not increase abortion rate
Normal pregnancy length
Normal birth weight
Normal outcome
• Amniocentesis ? No need
E Ben-Chetrit et al. AC&R 2011