?a???s?as? t?? PowerPoint

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Familial Mediterranean Fever (FMF) ?????e???
?es??e?a??? ???et?? (???)
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PFSHPF
Periodic Fever Syndromes

• S??d??µa
• ?e???d????
• ???et??

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PFS S??d??µa ?e???d???? ???et??

• Kat?????a t?? ???????µ???? a?t?f?e?µ???d??
  ??s?µ?t??.
• ?pa?a?aµßa??µe?e? ?a? a?t?pe???????µe?e?
  f?e?µ???de?? a?t?d??se??.
• ?p??s?a µ????s?? ? a?t?a??s?a?.

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PFS S??d??µa ?e???d???? ???et??

• ??s?? t?? f?s???? a??s?a????
• ???s?a?ep???e?e? ???
• ???p?p???t?? ????? ??s?µ?t??
• ? ?e?et???/pa??f?s???????? ß?s? e??a? ????st? st?
  80-85 t?? pe???d???? f?e?µ???d?? s??d??µ?? (FUO)

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PFS S??d??µa ?e???d???? ???et??
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FMF ?????e??? ?es??e?a??? ???et??

• ??t?s?µat??? ?p??e?p?µe??.
• 1997 MEFV

Nat Genet. 1997 Sep17(1)25-31. A candidate
gene for familial Mediterranean fever. The
French FMF Consortium.
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Mutations
2 mut.
Exons
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HIDS S??d??µ? ?pe?-IgD-a?µ?a?

• ??t?s?µ??? ?p??e?p?µe??.
• 1999 MVK

Nat Genet. 1999 Jun22(2)178-81 Mutations in
the gene encoding mevalonate kinase cause
hyper-IgD and periodic fever syndrome.
International Hyper-IgD Study Group.Drenth JP,
Cuisset L, Grateau G, Vasseur C, van de
Velde-Visser SD, de Jong JG, Beckmann JS, van der
Meer JW, Delpech M.
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CAPS S??d??µa s?et. ????p?????

• CIAS1

• NOD2
• Crohns Disease
• Blau Syndrome

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S??????? ?????????? ????????? ?? ????????S
???S?SF???I??S IgD (hyper-IgD)

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????????? S??????? S?????? ?? ??? TNF-????????
(TRAPS)

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?eta?? t?? pe???d???? s??d??µ?? ? ??? (FMF)
?at??e? e?????sa ??s? st? pe????? t?? ?es??e???
???? t?? s????t?t?? t??, e??a? d???t???
ep????d??? ??s?? ?a? ap?te?e? s???? s?ßa??
??????? p??ß??µa.   H ???a??? a?a?????s? ?a?
d?????s? e??a? apa?a?t?t?.
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????G??HS ??S?G?????S ??????S

• ? Ge?et??? ??s?? p?? ???????µe?ta? ??
  a?t?s?µat???? ?p??e?p?µe??? ?a?a?t??a?.
• ? ??d????eta? µe ?p?t??p?????ta ?a?
  a?t?pe???????µe?a epe?s?d?a p??et?? ?a?
  ???????t?da?
• ? pe??t???t?da
• ? pe???a?d?t?da
• ? a????t?da ?.a.
• ?a?t?????? d????s? t?? p??sßeß??µ???? ?st?? ap?
  ??dete??f??a.
• ????t??? ep????d??? ??s?? (?s??pe? epeµß?se?? ?a?
  ?e?ape?t???? ?e???sµ??, aµ???e?d?s? ?ef???,
  ?atast??f???? a????t?de? ?t?)

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• ??????? 70 ??????????S ????? ????G??F?? ???T?OS
  (http//fmf.igh.cnrs.fr/infevers)
• S???????? F???O? 1/3-1/15 (1/17 -1/70)
• S???????? ??S????O? 3-9/1000
• 40 ????? ???????GO??S ? ????S?????? ??????????S
  (??T???S ???G????)
• G?OG??F??? ????????
• ??????????F?? ??????O? ?????OS?O?
• ?G?OS??S ? ??????S ?????G???S ????S ??S ??O?????S
  (?????????S ??S F?S???S ???S??S?)

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?a? ??a a?t? µe???? ?µ?da as?e??? e?te e?a?t?a?
e???p??? ?ata??af?? t?? s??d??µ?? se µ?a
p????sµ?a?? ?µ?da, e?te µ????? ? ?t?p?? ??tas??
t?? ???????? e?d???se??, de? d?a?????s???ta?
???a??a ? ?a? ?a????? µe ap?t??esµa ?? as?e?e??
?a eµfa?????? a???µ??? ??s???t?ta ?a? ???t?t?ta.
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?F??? ??O ??? ????? S????? ?????S? ??? MEFV S???
?????? -????ST???????S? ?ST??O? ??? G????O? G??
??? ?????S?? ??S ??S?? ??? ??? G???????
????????S? (?????a d?????s??gt20 ?t?, ?a??st???s?
12 ?t?) -??????? ?????????O? ?????OS?O? ???
???????O? (?S????S ??????S??S, ????????OS?,
????S???F??? ??T?????? ???) -????????O ???G??S
??S S????????S ?O? ?G?O? F???O? S? ???F???????S
G?OG??F???S ???????S. -S????S?S G???????? ???
F????????? (?? ? R202Q/R202Q) -??????????
???G??? ??S ?????????????S ???S?S ??S ??????S
S????S? ?? ?????????? ??????
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????S ?????????O? ???T?OS
R202Q ?
(http//fmf.igh.cnrs.fr/infevers)
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22/4365, 43/hetero 40
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R202Q/R202Q, atypical phenotype, serositis (9
patients, 6), 10 UI response to
colchicine Where is the second hit? Other genes?
5UTR or 3UTR or other exons of MEFV 8/47 Booty
et al, 2009, Arthritis Rheumatism Criteria
(typical phenotype)colchicine Atypical phenotype
heterozygosity genetic screening colchicine
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Speletas et al 2009, Hum Immunol Negative
association TLR4-D299G with FMF FMF patients
display a better defense against bacterial
pathogens, providing an additional mechanism and
suggesting a positive selection advantage in the
area of the Mediterranean basin
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(No Transcript)
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• ??O?????? ??S???S ??????S
• ??T??? ??????? ???S?S ??S ??????S
• M???? t?? f?s???? a??s?a?
• ??asta?t?? t?? f?e?µ???? µ?s? ?atast???? t??
  pa?a????? IL-1ß ?a? p??a??? epa????a? t??
  ap?pt?s?? µ?s? e?e???p???s?? t?? ?d?? t??
  ?aspas?? (?asp?s? 1).

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PYRIN PROTEIN STRUCTURE
PYRIN DOMAIN Zn FINGER (RING) DOMAIN B-Box
(COILED COIL) DOMAIN B30.2 like
DOMAIN ????µ??f?p????a ?a? e?e???t???? µ??f??
µ?e????? se????
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MEFV EXON INTRON ORGANIZATION
MEFVd2
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• ? ?pe?µetaß??t?t?ta, ?a? p??????µ??f?a, ??????
  µet? ap? LPS epa????-se ep?ped? RNA-t?s? t?? full
  length ?s? ?a? t?? alternative spliced to? MEFV,
  ??e? p??sfata pe????afe? se ??tta?a (µa???f??a,
  ???ß??ste?) t?? a??????? ?µ??a
• ? ep????t?s? ?s?f??µ?? t?? MEFV, ?p?? ???eta? t?
  ?a?ß???te???? t?? µ????, ?µµesa de???e? t?
  s?µµet??? t?? st? f?e?µ???d? d?e??as?a
• Diaz et al. Nov 2004, Arthritis Rheumatism

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???????e?a Pyrin Domain (PYD)

• ???sa?µ?st??? pe????? µe a???te?t????? apa?a?t?t?
  se ?µ?t?p???? a????ep?d??se?? µeta?? s???e???
  p??te????.
• Death domains (DD)
• Death effector domains (DED)
• Caspase activation and recruitment domains
  (CARDs)
• Pyrin domains (PYD)

Structure, Vol. 11, 11991205, October, 2003.
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???????e?a Pyrin Domain (PYD)
CARD CASP PYD LRR NACHT BBOX Zn B30.2 IF120
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PYD s?et???µe?e? p??te??e?
CARD PYD LRR NACHT WD40 TIR BIR
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S?µp???µata e?e???p???s??
???sd?t?? ?p?d???a?
???sa?µ???a? ???st??
???s?
?
?
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??e???p???s? ?asp?s??-1/ICE???t??? FMF
?
??????
CIAS1
Cardinal
pro-IL1-ß
IL1-ß
ASC
ICE
IL1R
f?e?µ??? !!
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PyD and related proteinsModifiers or Stimulus
absorbers ?????
?
p????a?
??tta??p?asµa
NODS
PSTPIP
??tta???? µeµß????
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?????????

• Liliaceae
• Colchiaceae
• Colchicum autumnale

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?????????

• ??s? ???? t?? ?e?ape?t???? p??se???se?? t?? FMF
  ap? t? 1972
• ????aµß??e? ta ??e?a epe?s?d?a ?a?
• ?p?t??pe? t?? e?d???s? aµ???e?d?s??
• ??t?f?e?µ???d?? d??s?

(Goldfinger SE. Colchicine for familial
Mediterranean fever. N Engl J Med. 1972 Dec
21287(25)1302.)
S??ta?t???? t?p?? C22H25NO6 ????a?? ß????399,4
g/mol
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????????? ???a??sµ?? d??s??

• ??a??p? t?? a?t?s??a?µ?????s?? t??
  µ????s?????s???, d?µ???????ta? s?µp???µata
  t??µp??????? ??????????
• ?e??s? t?? pa?a????? TNF-a ap? ta µa???f??a ?a?
  t?? ?p?d????? t??? ap? ta e?d?????a?? ??tta?a

Vandecandelaere A et al. Biochem J. 1997 Apr
1323 ( Pt 1)189-96. Sackett DL, Varma JK.
Biochemistry. 1993 Dec 1432(49)13560-5.
Li Z et al. Immunobiology. 1996
Oct195(4-5)640-54.
Ding AH et al. J
Exp Med. 1990 Mar 1171(3)715-27.
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????????? ???a??sµ?? d??s??

• ?a??µßas? st? a????ep?d?as? ??dete??f???? ?a?
  a??e?a??? e?d???????, pa?eµßa????ta? st??
  p??sdes? t??? µe µ???a p??s?????s??
• ?-selectin
• L-selectin
• ?atast???
• e?e???p???s?? f?sf???p?s?? ?2
• ?????s?? ??s?s?µ???? e???µ??
• fa????tt???s??

Cronstein BN et al. J Clin Invest. 1995
Aug96(2)994-1002.
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????????? ??s?????a

• 1 mg ?µe??s??? st??? e?????e?
• 2 mg ?µe??s??? st??? e?????e? µe aµ???e?d?s?
• 2,5 3,0 mg ??a s??t?µ? ??????? d??st?µa (2-3
  µ??e?) ?a? epa?af???
• 0,25 mg se pa?d?? 1-2 et??, 1 mg ap? 7 ?a? p???

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????????? ???s?

• ??????? epe?s?d??? p??et?? st? 60 t?? as?e???
• ???tt?s? a???µ?? epe?s?d??? st? 20-30
• 5-10 ????? a?tap????s? st? ?e?ape?a

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????????? ?a?e????e?e?

• ????? st?? ??????
• ???????a
• ?e??s? ? ?µe??s?a d?a??es? t?? d?s??
• ?s?e?e?? µe ?pat???? ? ?ef????? ß??ße?
• ???p??e?a
• ?e???p??e?a
• ?e???pe??a
• G???µ?t?ta ?
• ?e?at???????t?ta ?

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??a??a?t???? ?e?ape?e?

• ??te?fe???? ??fa
• Se as?e?? µe FMF ?a? ?????a ?pat?t?da ?
• Ta??d?µ?d?
• S?ßa??? pa?e????e?e?
• ?a?????te? a?t?-TNF
• Infliximab (a?t?-TNFa a?t?s?µata)
• Etanercept (a?as??d. d?a??t?? ?p?d???a? ?NFa)

Calguneri M et al. Clin Exp Rheumatol. 2004
Jul-Aug22(4 Suppl 34)S41-4. Tunca M, et al.
Clin Exp Rheumatol. 2004 Jul-Aug22(4 Suppl
34)S37-40. Calguneri M, et al. Intern Med. 2004
Jul43(7)612-4. Tunca M et al. Br J Rheumatol.
1997 Sep36(9)1005-8.
Seyahi E et al. Clin Exp Rheumatol. 2002
Jul-Aug20(4 Suppl 26)S43-4. Drenth JP et al. J
Pharmacol Exp Ther. 2001 Sep298(3)1221-6.
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??a??a?t???? ?e?ape?e?

• ???s??atasta?t???
• ACTH, ste??e?d?, azathioprine, prednisone
• aµ???e?d?s? pa?e????e?e?
• ?etaµ?s?e?s? µ?e???
• ???a?a pa?at???s? ?pe?ß??? ?
• ? FMF de? ap?te?e? ?a?at?f??? as???e?a
• ?a?? ???µ???µe?? µe fa?µa?e?t??? µ?sa

Milledge J et al. Blood. 2002 Aug 1100(3)774-7.
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??e???p???s? ?asp?s??-1/ICE???t??? FMF
?
??????
CIAS1
Cardinal
pro-IL1-ß
IL1-ß
ASC
ICE
IL1R
f?e?µ??? !!
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Mitroulis et al 2008, Dec, Neth. J. Med
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??O??????????pt???? ?ate????se??

• Other periodic syndromes (FUO) ? (80uPFS)
• Genetic screening. When, Where
• Clinical follow up
• Evaluation of treatment
• Link to research centers
• Financial supporting

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??O??????????pt???? ?ate????se??

• INFLAMMASOME, NALP3
• COMPLEMENT ???, TLRs
• OTHER THAN APOPTOSIS BUT SIMILAR MECHANISMS
  (autophagy)
• TRIGGERING