Upload
tehya
View
42
Download
0
Tags:
Embed Size (px)
DESCRIPTION
Autoinflammatory diseases. Gilles Grateau Service de médecine interne Centre de référence des amyloses d’origine inflammatoire et de la fièvre méditerranéenne familiale Paris. Autoinflammatory diseases. No consensus definition. Autoinflammatory diseases. No consensus definition - PowerPoint PPT Presentation
Citation preview
Autoinflammatory diseases
Gilles GrateauService de médecine interneCentre de référence des amyloses d’origine inflammatoire et de la fièvre méditerranéenne familialeParis
Autoinflammatory diseases
No consensus definition
Autoinflammatory diseases
No consensus definition
Disease of the innate immune system and no autoimmune abnormality
Autoinflammatory diseases
No consensus definition
Disease of the innate immune system and no autoimmune abnormality
Hereditary recurrent fevers• A subgroup of Mendelian inherited disorders• Six diseases
The core of hereditary recurrent fevers
1.Beginning in infancy
2.Intermittent symptoms
3.Biological signs of inflammatory response: neutrophils C reactive protein/SAA
4.Familial character
5.Amyloidosis
Familial Mediterranean fever
A prototypic auto-inflammatory disease
Familial Mediterranean Fever(FMF)
Age at Onset
0-20 years 82 % over 40 years 1%
FMF attack
Precipitating factors• physical activity• emotional stress• inter-current infections• cold exposure• menstruation
Prodromes• pain at the attack site• constitutional symptom• unique manifestation
Drenth JP, 2001
Lidar M, 2006
Peritonitis• in 96% of the cases.• presenting feature in 80%.• resembles “surgical abdomen”.• about 30% undergo appendectomy.
Zissin R et al
Pleuritis
• In 25-80% of the cases: (Armenians>Jews)
• Severe pleuritic pain• May mimic
pulmonary embolism• Sometimes with
effusion
Benchetrit E
Pericarditis
relatively rare <1%constrictive pericarditis in very few
cases
Benchetrit E
Arthritis
Acute monoarthritis• abrupt onset• short attack: 3-7 days • peak 24-48 hours• large effusion• complete resolution
Chronic destructive arthritis• Commonly affects the hips and
knees• Sacroiliitis-HLA B27 negative
Benchetrit E
Skin Involvement
• In 7-40% of the cases• Erysipelas-like
erythema• May be an only
feature in children
Benchetrit E
TNF receptor associated periodic syndrome
TRAPS
TRAPS attack
fever 100%
myalgias 80%
abdominal pain88%
pleuritic pain 40%
arthralgias 52%
headache 68%
conjonctivitis 44%
or orbital edema
skin involvement 88%
Toro, 2000 Drenth JP, 2001
Inflammatory monocytic fasciitis of the thigh in a patient with TRAPS
Hull et al, 2002
TRAPS
Mc Dermott E, 1997Hull K, 2002
Cold induced autoinflammatory syndrome 1 (CIAS1) associated periodic syndrome
CAPS or Cryopyrinopathies
Muckle-Wells syndrome
Familial cold urticaria (FCU)/ Familial cold autoinflammatory syndrome (FCAS)
Chronic infantile neurological cutaneous articular syndrome (CINCA)/Neonatal onset multisystem inflammatory disease (NOMID)
Cryopyrinopathies
Urticaria
• Cold sensitivity in FCU• Nerve deafness in MW• Early onset in CINCA with severe CNS
manifestations
• Clinical continuum
Cryopyrinopathies
FCASCINCA
Cryopyrinopathies
Joint involvement
Mevalonate kinase deficiency associated periodic syndrome
MKD or MAPS
Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS)
Mevalonic aciduria (MA)
HIDS-attack
Drenth JP, 2001
Clinical featuresfever 100%
lymphadenopathy 94%
skin lesions 82%
diarrhea 82%
arthralgia 80%
chills 76%
abdominal pain 72%
arthritis 64%
vomiting 56%
splenomegaly 48%
Drenth JP, 1994
Precipitating factorsImmunization, viral infection
HIDS
Drenth JP
A watershed in our knowledge of inflammatory diseases
Cryopyrin/NLRP3 the protein involved in « cryopyrinopathies »
Is involved in the IL-1 processing
NLRP/NALP family
NALP6 / P¨YPAF5 892
NALP10 655
NALP2 / PYPAF2 1062
NALP1 / DEFCAP NBSPYD CARD 1473LRR
NALP3 / Cryopyrine / PYPAF1 1034
NALP4 / PYPAF4 994
NALP5 / PYPAF8 1200
NALP7 / PYPAF3 980
NALP8 1048
NALP9 991
PYPAF6 / NALP11 1033
PYPAF7 / Monarch-1 / NALP12 1061
NALP13 1043
NALP14 1093
NALP6 / P¨YPAF5 892NALP6 / P¨YPAF5 892892
NALP10 655NALP10 655655
NALP2 / PYPAF2 1062NALP2 / PYPAF2 10621062
NALP1 / DEFCAP NBSPYD CARD 1473LRRNALP1 / DEFCAP NBSPYD CARD 1473LRRNBSPYD CARDCARD 1473LRR
NALP3 / Cryopyrine / PYPAF1 1034NALP3 / Cryopyrine / PYPAF1 10341034
NALP4 / PYPAF4 994NALP4 / PYPAF4 994994
NALP5 / PYPAF8 1200NALP5 / PYPAF8 12001200
NALP7 / PYPAF3 980NALP7 / PYPAF3 980980
NALP8 1048NALP8 10481048
NALP9 991NALP9 991991
PYPAF6 / NALP11 1033PYPAF6 / NALP11 10331033
PYPAF7 / Monarch-1 / NALP12 1061PYPAF7 / Monarch-1 / NALP12 10611061
NALP13 1043NALP13 10431043
NALP14 1093NALP14 10931093
14 members
The concept of inflammasome
Multiproteic Complex
Cytoplasmic localisation
Activation of pro-inflammatory caspase : caspase-1
Main features
Martinon 2009
Secretion / activity IL-1 : a controlled process
1. Transcription / traduction of IL-1
ADN ARN1
pro-IL-1
immature
1
Control steps
Secretion / activity IL-1 : a controlled process
ADN ARN1 2pro-IL-1
IL-1
immaturemature
Caspase-11
1. Transcription / traduction of IL-1
2. Cleavage of pro-IL1 to mature IL-1 through inflammasome
Control steps
Secretion / activity IL-1 : a controlled process
ADN ARN1 2pro-IL-1
IL-1
immature mature
Caspase-11
1. Transcription / traduction of IL-1
2. Cleavage of pro-IL1 to mature IL-1 through inflammasome
3. Active secretion of IL-1 out of the cell (Ca2+)
Control steps
3
Secretion / activity IL-1 : a controlled process
ADN ARN1 2pro-IL-1
IL-1
immature mature
Caspase-11
1. Transcription / traduction of IL-1
2. Cleavage of pro-IL1 to mature IL-1 through inflammasome
3. Active secretion of IL-1 out of the cell (Ca2+)
4. Competition with a natural antagonist: IL-1Ra with a higher affinity for IL-1RI than IL-1
Control steps
3
IL-14
signal transduction
IL-1RIIL-1R-AcP
IL-1Ra
Secretion / activity IL-1 : a controlled process
ADN ARN1 2pro-IL-1
IL-1
immature mature
Caspase-11
1. Transcription / traduction of IL-1
2. Cleavage of pro-IL1 to mature IL-1 through inflammasome
3. Active secretion of IL-1 out of the cell (Ca2+)
4. Competition with a natural antagonist: IL-1Ra with a higher affinity for IL-1RI
5. Preferential Fixation of IL-1 on the inactive IL1-R-II at the membrane or soluble
Control steps
3
IL-14
signal transduction
IL-1RIIL-1R-AcP
IL-1Ra
IL-1RII
5
no transduction
IL-1sRIIL-1sRII
Hawkins PN, 2003
Serial measurements of plasma concentration of SAA protein in Two Patients with the Muckle –Wells Syndrome
Treatment with the IL1-RA anakinra
DIRA
Aksentijevich NEJM 2009
Treatment of auto-inflammatory diseases
• Cryopyrinopathies IL-1 inhibitors
• TRAPS steroids TNF inhibitors IL-1 inhibitors• MKD TNF inhibitors IL-1 inhibitors• FMF colchicine TNF inhibitors IL-1 inhibitors• DIRA IL-1 inhibitors
Classification of auto-inflammatory disorders
Hereditary recurrent fever syndromes
Classification of auto-inflammatory disorders
Mendelian diseases of the innate immune system
Hereditary recurrent fever syndromesBlau
Majeed
PAPA
Classification of auto-inflammatory disorders
Diseases of the innate immune system
Mendelian diseases of the innate immune system
Hereditary recurrent fever syndromesBlau
Majeed
PAPA
JIA
Adult onset Still’s disease
gout
Classification of auto-inflammatory disorders
Diseases of the innate immune system
Mendelian diseases of the innate immune system
Hereditary recurrent fever syndromesBlau
Majeed
PAPA
JIA
Adult onset Still’s disease
Atherosclerosis ?
gout
Hôpital Cochin
Inserm U567
Marc DelpechCatherine DodéLaurence Cuisset
Hôpital Trousseau Inserm U933
Serge AmselemIsabelle JéruMarie LegendrePhilippe Duquesnoy
Thanks
Hôpital Tenon
Katia Stankovic