Autoinflammatory Diseases
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1 Autoinflammatory Diseases Prof.M.Seitz RIA Department of Rheumatology, Immunology and Allergology
2 Autoinflammatory disorders Crystal induced joint inflammation Hereditary periodic fever syndromes Cryopyrin-associated syndromes Schnitzler Syndrom M.Behcet? IBD (Crohn, CU)?
3 Gouty inflammation maximal plasma solubility of MSU 420mmol/l (7mg/ml)
4 The Inflammasome and gout Martinon et al., JCI 2006
5 MSU crystals CD14 TLR2/4 MYD88 Urate crystals NFkB mediated cell activation phagocytosis Pro-IL1b NALP3 Caspase 1 caspase-1 ASC IL1b monocyte IL1R endothelial activation Anakinra (Kineret ) Endothelium/leucocyte
6 The periodic fever syndromes
7 Characteristics of hereditary periodic fever syndromes Syndrom Symptomatik Gendefekt Therapie FMF Familiäres Mittelmeerfieber Fieber 1-3 Tage, Polyserositis, Arthritis,Erytheme, Splenomegalie, Amyloidose rezessiv, MEFV-Gen, 16p13 pyrin / marenostrin Colchizin NSA Anakinra HIDS Hyper IgD Syndrom Fieber 3-7 Tage Hepatosplenomegalie Bauchschmerz, Exanthem, zervik.lymphadenitis rezessiv, MVK-Gen, 12q24 Mevalonatkinase NSAID Steroide Statine (Simvastatin) Anakinra? TRAPS TNFR-assoziiertes period. Syndrom Fieber > 1 Wo. Bauchschmerzen, Myalgien, Konjunktivitis, Exanthem,Arthralgien, Amyloidose (10%) dominant, TNFRSFIA 12p13 TNFRp55 Steroide Etanercept
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10 Characteristics of hereditary periodic fever syndromes Syndrom Pathogenese Gendefekt Ethnizität/Alter FMF Familiäres Mittelmeerfieber Erhöhte IL-1b Sekretion und NF B- Aktivierung Leukozyten- Apoptose rezessiv, MEFV-Gen, 16p13 pyrin / marenostrin Juden, Armenier, Araber, Türken, Italiener 5 LJ. (50%) 20 LJ. HIDS Hyper IgD Syndrom MK-Aktivität Isoprenoide IL-1b Sekretion rezessiv, MVK-Gen, 12q24 Mevalonatkinase (MK) Holländer, Franzosen, und Nordeuropäer < 1 Jahr TRAPS TNFR-assoziiertes period. Syndrom Ektodomänen-Cleav. und intrazelluläres trafficking von TNFRp55, defekte TNF-induz. Apoptose dominant, TNFRSFIA 12p13 TNFRp55 alle ethnischen Gruppen < 10 Jahre
11 Characteristics of hereditary periodic fever syndromes Syndrom Symptomatik Gendefekt Therapie FMF Familiäres Mittelmeerfieber Fieber 1-3 Tage, Polyserositis, Arthritis,Erytheme, Splenomegalie, Amyloidose rezessiv, MEFV-Gen, 16p13 pyrin / marenostrin Colchizin NSA Anakinra HIDS Hyper IgD Syndrom Fieber 3-7 Tage Hepatosplenomegalie Bauchschmerz, Exanthem, zervik.lymphadenitis rezessiv, MVK-Gen, 12q24 Mevalonatkinase NSAID Steroide Statine (Simvastatin) Anakinra? TRAPS TNFR-assoziiertes period. Syndrom Fieber > 1 Wo. Bauchschmerzen, Myalgien, Konjunktivitis, Exanthem,Arthralgien, Amyloidose (10%) dominant, TNFRSFIA 12p13 TNFRp55 Steroide Etanercept
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13 Characteristics of hereditary periodic fever syndromes Syndrom Symptomatik Gendefekt Therapie FMF Familiäres Mittelmeerfieber Fieber 1-3 Tage, Polyserositis, Arthritis,Erytheme, Splenomegalie, Amyloidose rezessiv, MEFV-Gen, 16p13 pyrin / marenostrin Colchizin NSA Anakinra HIDS Hyper IgD Syndrom Fieber 3-7 Tage Hepatosplenomegalie Bauchschmerz, Exanthem, zervik.lymphadenitis rezessiv, MVK-Gen, 12q24 Mevalonatkinase NSAID Steroide Statine (Simvastatin) Anakinra? TRAPS TNFR-assoziiertes period. Syndrom Fieber > 1 Wo. Bauchschmerzen, Myalgien, Konjunktivitis, Exanthem,Arthralgien, Amyloidose (10%) dominant, TNFRSFIA 12p13 TNFRp55 Steroide Etanercept
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15 Characteristics of hereditary periodic fever syndromes Syndrom Pathogenese Gendefekt Ethnizität/Alter FMF Familiäres Mittelmeerfieber Erhöhte IL-1b Sekretion und NF B- Aktivierung Leukozyten- Apoptose rezessiv, MEFV-Gen, 16p13 pyrin / marenostrin Juden, Armenier, Araber, Türken, Italiener 5 LJ. (50%) 20 LJ. HIDS Hyper IgD Syndrom MK-Aktivität Isoprenoide IL-1b Sekretion rezessiv, MVK-Gen, 12q24 Mevalonatkinase (MK) Holländer, Franzosen, und Nordeuropäer < 1 Jahr TRAPS TNFR-assoziiertes period. Syndrom Ektodomänen-Cleav. und intrazelluläres trafficking von TNFRp55, defekte TNF-induz. Apoptose dominant, TNFRSFIA 12p13 TNFRp55 alle ethnischen Gruppen < 10 Jahre
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17 Characteristics of cryopyrin-associated autoinflammatory syndromes Syndrom Symptomatik Gendefekt Therapie FCAS Familiäres kälteinduziertes autoinflammat.sy. Fieber < 24h, Arthragien, Konjunktivitis, Kälteinduizierte Urtikaria dominant CIAS1/NALP3/PYAF1 1q44, Cryopyrin Kälte meiden Anakinra Steroide MWS Muckle-Wells Syndrom Fieber 1-2 Tage, Arthralgien, Arthritis, Konjunktivitis sensoneuraler Hörverlust,, Urtikaria, Amyloidose (25%) dominant CIAS1/NALP3/PYAF1 1q44 Cryopyrin Anakinra NOMID/ CINCA Fieber kontinuierlich, aseptische Meningitis, Arthritis, sensoneuraler Hörverlust, Urtikaria, dominant CIAS1/NALP3/PYAF1 1q44 Cryopyrin Anakinra
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20 Characteristics of Cryopyrin - associated autoinflammatory syndromes Syndrom Pathogenese Gendefekt Ethnizität/Alter FCAS Familiäres kälteinduziertes autoinflammat.sy. Erhöhte Aktivität des NALP3/Cryopyrin Inflammasoms mit erhöhter IL-1b Sekretion und NF B Aktivierung dominant CIAS1/NALP3/PYAF1 1q44, Cryopyrin meistens Europäer < 0.5 Jahre MWS Muckle-Wells Syndrom dito dominant CIAS1/NALP3/PYAF1 1q44 Cryopyrin vor allem Nordeuropäer Säugling - bis Schulkindalter NOMID/ CINCA dito dominant CIAS1/NALP3/PYAF1 1q44 Cryopyrin alle ethnischen Gruppen Geburt bis Ende 1.Lebensjahr
21 Key Messages Autoinflammatory Diseases Autoinflammatory syndromes may be genetically-linked diseases (hereditary periodic fever syndromes) many of which exhibit enhanced NALP3/inflammasome activity) This is also true for crystal-induced arthritis (gout) Autoinflammatory syndromes are mostly IL-1 driven and can successfully be treated with anti-il-1 strategies (i.e. IL-1 receptor antagonist, IL-1β monoclonal antibody)
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