1. Autoinflammatory diseases Gilles Grateau Service de médecine interne Centre de référence des amyloses d’origine inflammatoire et de la fièvre méditerranéenne familiale Paris

2. Autoinflammatory diseases No consensus definition

3. Autoinflammatory diseases No consensus definition Disease of the innate immune system and no autoimmune abnormality

4. 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

5. 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

6. Familial Mediterranean fever A prototypic auto-inflammatory disease

7. Familial Mediterranean Fever (FMF)

8. Age at Onset 0-20 years 82 % over 40 years 1%

9. 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

10. Peritonitis in 96% of the cases. presenting feature in 80%. resembles “surgical abdomen”. about 30% undergo appendectomy. Zissin R et al

11. Pleuritis In 25-80% of the cases: (Armenians>Jews) Severe pleuritic pain May mimic pulmonary embolism Sometimes with effusion Benchetrit E

12. Pericarditis relatively rare <1% constrictive pericarditis in very few cases Benchetrit E

13. 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

14. Skin Involvement In 7-40% of the cases Erysipelas-like erythema May be an only feature in children Benchetrit E

15. TNF receptor associated periodic syndrome TRAPS

16. TRAPS attack fever 100% myalgias80% abdominal pain88% pleuritic pain40% arthralgias 52% headache68% conjonctivitis44% or orbital edema skin involvement88% Toro, 2000Drenth JP, 2001

17. Inflammatory monocytic fasciitis of the thigh in a patient with TRAPS Hull et al, 2002

18. TRAPS Mc Dermott E, 1997 Hull K, 2002

19. 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)

20. Cryopyrinopathies Urticaria Cold sensitivity in FCU Nerve deafness in MW Early onset in CINCA with severe CNS manifestations Clinical continuum

21. Cryopyrinopathies FCAS CINCA

22. Cryopyrinopathies Joint involvement

23. Mevalonate kinase deficiency associated periodic syndrome MKD or MAPS Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) Mevalonic aciduria (MA)

24. HIDS-attack Drenth JP, 2001 Clinical features fever100% lymphadenopathy 94% skin lesions 82% diarrhea 82% arthralgia 80% chills 76% abdominal pain 72% arthritis 64% vomiting 56% splenomegaly 48% Drenth JP, 1994 Precipitating factors Immunization, viral infection

25. HIDS Drenth JP

26. A watershed in our knowledge of inflammatory diseases Cryopyrin/NLRP3 the protein involved in « cryopyrinopathies » Is involved in the IL-1  processing

27. NLRP/NALP family 14 members

28. The concept of inflammasome Multiproteic Complex Cytoplasmic localisation Activation of pro-inflammatory caspase : caspase-1 Main features Martinon 2009

29. Secretion / activity IL-1  : a controlled process 1. Transcription / traduction of IL-1  ADN ARN 1 pro-IL-1  immatur e 1 Control steps

30. Secretion / activity IL-1  : a controlled process ADN ARN 1 2 pro-IL-1  IL-1  immature mature Caspase-1 1 1.Transcription / traduction of IL-1  2.Cleavage of pro-IL1  to mature IL-1  through inflammasome Control steps

31. Secretion / activity IL-1  : a controlled process ADN ARN 1 2 pro-IL-1  IL-1  immaturemature Caspase-1 1 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

32. Secretion / activity IL-1  : a controlled process ADN ARN 1 2 pro-IL-1  IL-1  immaturemature Caspase-1 1 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-1  4 signal transduction IL-1RI IL-1R-AcP IL-1Ra

33. Secretion / activity IL-1  : a controlled process ADN ARN 1 2 pro-IL-1  IL-1  immaturemature Caspase-1 1 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-1  4 signal transduction IL-1RI IL-1R-AcP IL-1Ra IL-1RII 5 no transduction IL-1sRI IL-1sRII

34. 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

35. DIRA Aksentijevich NEJM 2009

36. 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

37. Classification of auto-inflammatory disorders Hereditary recurrent fever syndromes

38. Classification of auto-inflammatory disorders Mendelian diseases of the innate immune system Hereditary recurrent fever syndromes Blau Majeed PAPA

39. Classification of auto-inflammatory disorders Diseases of the innate immune system Mendelian diseases of the innate immune system Hereditary recurrent fever syndromes Blau Majeed PAPA JIA Adult onset Still’s disease gout

40. Classification of auto-inflammatory disorders Diseases of the innate immune system Mendelian diseases of the innate immune system Hereditary recurrent fever syndromes Blau Majeed PAPA JIA Adult onset Still’s disease Atherosclerosis ? gout

41. Hôpital Cochin Inserm U567 Marc Delpech Catherine Dodé Laurence Cuisset Hôpital Trousseau Inserm U933 Serge Amselem Isabelle Jéru Marie Legendre Philippe Duquesnoy Thanks Hôpital Tenon Katia Stankovic