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