Background 11/8/2011. Disclosure. Hereditary Periodic Fever Syndromes Mutations in Idiopathic Acute Recurrent Pericarditis.

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1 Mutations in Idiopathic Acute Recurrent Pericarditis Disclosure I have no relevant financial relationships to disclose Guillaume Geri, Pierre Hausfater, Catherine Dodé, Zahir Amoura, Jean-Charles Piette, Nathalie Costedoat-Chalumeau, Patrice Cacoub Internal Medicine Department, CNRS UMR 7087, Pierre & Marie Curie University National Reference Center for Autoimmune Diseases La Pitié-Salpêtrière Hospital, Paris, FRANCE References Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari F, et al. Colchicinee in addition to conventional therapy for acute pericarditis: results of the Colchicine for acute PEricarditis (COPE) trial. Circulation 2005;112(13): Background Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M, et al. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet 2000;92(4): Dode C, Papo T, Fieschi C, Pecheux C, Dion E, Picard F, et al. A novel missense mutation (C30S) in the gene encoding tumor necrosis factor receptor 1 linked to autosomal-dominant recurrent fever with localized myositis in a French family. Arthritis Rheum 2000;43(7): Acute Pericarditis Chest pain, fever, brief course, benign Isolated or part of a more systemic disease Numerous causes Infectious diseases (6-8%)» Tuberculosis (4%)» Pyogenic infection (2%)» Fungal and parasitic infections (rare) Auto-immune diseases (3-5%) Cardiac surgery or myocardial infarction (5-10%) Malignant diseases (5-10%) Idiopathic 70-90% Determined etiology Acute Pericarditis Idiopathic Natural History of Acute Pericarditis Short-term Right Heart Failure <2% Complete recovery Mid-term Chronic pericardial effusion Long-term Recurrence 20-40% Constrictive Pericarditis <2% Lange RA, New Engl J Med 2005 Troughton RW, Lancet 2004 Geri G, Rev Med Int

2 Recurrences of fever lasting from a few days to a few weeks Symptom-free intervals of variable duration Diagnosis should be discussed if : Attacks with a predictable course and a similar set of symptoms Family history Imazio M, 2007 Familial Mediterranean Fever (FMF) The most prevalent periodic fever syndrome Predominantly affects people from the Mediterranean basin Short attacks of serositis (peritonitis, pleuritis, arthritis) & fever Autosomal recessive disease Treatment: colchicine TNF receptor-associated periodic syndrome (TRAPS) Recurrent attacks of fever, myalgia & painful skin erythema Autosomal dominant inheritance Response to high doses prednisone... and TNF alpha-blockers Others HPFS Hyper IgD syndrome Familial cold urticaria and Muckle-Wells syndrome Idiopathic Recurrent Acute Pericarditis (IRAP) Periodic recurrences Symptom-free intervals Family history No auto-immune process Great efficacy of colchicine Hereditary Periodic Fever Syndromes (HPFS) Drenth JPH, New Engl J Med 2001 Idiopathic Recurrent Pericarditis and Hereditary Periodic Fever Syndromes - Litterature data Pericarditis may be the sole manifestation of FMF 2 cases (Tauber T, 1995) Idiopathic recurrent acute pericarditis : FMF in a cohort of Caucasian patients. 0/23 Italian patients with mutation (Brucato A, 2005) Idiopathic recurrent pericarditis refractory to colchicine treatment may reveal TRAPS syndrome 4/30 (13.3%) patients with mutation (Cantarini L, 2009) Imazio M et al. Ann Intern Med

3 Aims Idiopathic Recurrent Pericarditis and Aims 1. To search for the presence of HPFS gene in a large cohort of patients presenting with recurrent pericarditis 2. To analyze the impact of HPFS gene in patients with IRAP on: Sentivitity to treatments, i.e. NSAIDs, colchicine Mid- and long-term outcome, i.e. pericarditis relapses Treatment withdrawal, i.e. steroids Methods Retrospective study: Pitié Salpêtrière Hospital (tertiary university) Recurrent pericarditis Systematic check-up Methods Acute Pericarditis Chest pain and fever Increased inflammatory biomarkers Blood cultures ± pericardial effusion Mycobacteriological searching Recurrent Acute pericarditis HIV serology 2 acute events ANA, dsdna Ab, ANCA, RF, C3 & C4 complement Body CT-scan Pericardial fluid analysis Methods Epidemiologic and clinical features Inflammatory biomarkers C-reactive protein (+ if > 20mg/L) Fibrinogen (+ if > 5g/L) Treatment Aspirin and non steroidal anti-inflammatory drugs Corticosteroids & immunosuppressants Colchicine Outcome : pericarditis relapse Delay, number Methods Gene Mutations of Hereditary Periodic Fever Syndrome Genomic DNA isolated from patients peripheral blood leucocytes Mutations: MFEV gene M680I, M694V, M694I, V726A, E148Q TNFRSF1A gene 3

4 Results Hereditary Periodic Fever Syndrome Mutations in Idiopathic Recurrent Pericarditis The presence of one HPFS gene mutation was found in 14/53 (26.4%) recurrent pericarditis. MFEV gene mutation in 7/53 (13.2%) IRAP patients TNRFS1A gene mutation in 7/53 (13.2%) IRAP patients Hereditary Periodic Fever Syndrome Mutations in Idiopathic Recurrent Pericarditis Hereditary Periodic Fever Syndrome Mutations in Idiopathic Recurrent Pericarditis HPFS gene mutation 14/53 (26.4%) in IRAP MFEV gene (13.2%) Heterozygous M694V: 2 patients Heterozygous M694I: 2 patients Heterozygous E148Q: 3 patients TNRFS1A gene (13.2%) Heterozygous R92Q: 4 patients Homozygous R92Q: 1 patient Heterozygous P46L: 2 patients HPFS gene mutation 14/53 (26.4%) in IRAP MFEV gene (13.2%) vs. < 1% in healthy controls Heterozygous M694V: 2 patients Heterozygous M694I: 2 patients Heterozygous E148Q: 3 patients TNRFS1A gene (13.2%) vs. 1-4% in healthy controls Heterozygous R92Q: 4 patients Homozygous R92Q: 1 patient Heterozygous P46L: 2 patients Epidemiologic Features All patients N= 53 Median age, 36.5 (Q1,Q3),y (24,53) Gender, M/F (%) 32/21 (60.4) HPFS N= (24,57.8) No HPFS N= (23,52.3) P /5 (64.3) 23/16 (59.0) 1 Ethnic origin European 41 (87.2) 11 (78.6) 30 (83.3) - North Africa 5 (10.6) 2 (14.3) 3 (8.3) - Others 1 (2.1) 1 (7.1) 0 (0) - NA HPFS: hereditary periodic fever syndrome Clinical Features All patients N= 53 HPFS N= 14 No HPFS N= 39 Extracardiac features 36 (67.9) 10 (71.4) 26 (66.7) 1 - Pleural effusion 9 (16.9) 2 (14.3) 7 (17.9) - Arthralgia 7 (13.2) 1 (7.1) 6 (15.4) Time between 2 events, months 3 (1-6) 2.5 (1.8-4) 5 (2-12) 0.19 Increased inflammatory biomarkers, n (%) 36 (67.9) 11 (78.6) 25 (64.1) 0.51 HPFS: hereditary periodic fever syndrome P 4

5 Treatment of Recurrent Pericarditis & HPFS Mutation Pericarditis Relapse according to HPFS Mutation All patients N= 53 HPFS N= 14 No HPFS N= 39 P Median follow-up, y 2 (1-4) 4 (1-6.5) 2 (1-4) NS Corticosteroids withdrawal 5 out of 7 patients 3/4 with HPFS mutation 2/3 w/o HPFS mutation Relapses under colchicine, n (%) Median time before relapse, months Relapse at colchicine withdrawal, n (%) 18 (34.0) 4 (28.6) No 14 HPFS (36.0) mutation NS HPFS mutation ( ) 6 (4-27) 9 (1-12) NS 8 (15.1) 4 (28.6) 4 (10.3) 0.19 HPFS: Hereditary Periodic Fever Syndrome HPFS: hereditary periodic fever syndrome Conclusion Mutations of hereditary periodic fever syndromes are frequently found in patients with idiopathic recurrent pericarditis (26.4%). Such should be searched for in patients presenting with IRAP. The impact of the presence of HPFS gene mutation on more specific therapeutic strategy in IRAP patients will need further studies. Evolution of Recurrent Acute Pericarditis Lotrionte. Am J Cardiol N=84 patients, fu 24 months 5

6 Imazio M et al. Ann Intern Med