Autoinflammatory diseases and cardiovascular manifestations

Figures & data

Table I. Major features of familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS).

Disease	FMF	TRAPS
Gene (protein)	MEFV (pyrin, also known as marenostrin)	TNFRSF1A (tumour necrosis factor receptor type 1)
Chromosomal locus	16p13.3	12p13
Transmission	Autosomal recessive	Autosomal dominant
Age at onset	All paediatric ages	From late infancy to adulthood
Ethnic diffusion	Sephardic Jewish, Armenian, Arab, Turkish, and Italian populations	North-European populations, though described all over the world
Main clinical features	Recurrent fevers, arthralgia or arthritis, serosal inflammation (mostly sterile peritonitis)	Recurrent fevers, arthralgia or arthritis, abdominal or muscular pain, fasciitis, migratory centrifugal rash, conjunctivitis, serosal inflammation
Duration of febrile attacks	From 1 to 3 days	From 1 to 4 weeks
Distinctive features	Erysipeloid erythema of lower extremities	Periorbital oedema, corticosteroid responsiveness
Amyloidosis	In colchicine-resistant or untreated patients	In 15% of cases
Mainly reported cardiovascular manifestations	Pericarditis, predisposition to vasculitis, rheumatic carditis, and myocardial infarction	Pericarditis, myocarditis
Treatment	Colchicine, anakinra	Corticosteroids, etanercept, anakinra

Figure 1. Mechanism of pyrin action in the pathogenesis of familial Mediterranean fever (FMF). Pyrin is known to play a key role in NLRP3 inflammasome inhibition by a competitive binding either of ASC or procaspase-1/caspase-1. FMF-associated pyrin mutations, which lead to inflammasome activation by decreased interaction of pyrin with the specific substrates, result in abnormal interleukin-1β production.

Figure 2. Mechanism of TNFRSF1A action in the pathogenesis of tumour necrosis factor receptor-associated periodic syndrome (TRAPS). TNFRSF1A receptor is known to play an important role in the regulation of the inflammatory response through tumour necrosis factor (TNF)-α binding. TNF-α binding activates several signalling pathways responsible for the survival and/or apoptosis. Following TNFRSF1A activation the extracellular portion of the receptor is shed by a metalloprotease from the cell surface and released in the extracellular compartment. TRAPS-associated TNFRSF1A mutations result in impaired i) TNFRSF1A trafficking to the cell surface; ii) TNF-α binding; iii) activation-induced shedding; iv) TNF-α induced activation of transcription factors or apoptosis; v) accumulation of mutated TNFRSF1A in the endoplasmic reticulum (ER) with unbalanced reactive oxygen species (ROS) production and unfolded protein response (UPR).

Table II. List of the cardiovascular manifestations described in the medical literature referring to familial Mediterranean fever and tumour necrosis factor receptor-associated periodic syndrome.

Familial Mediterranean fever
Authors	Year of publication	Cardiovascular abnormalities	Number of patients reported
Eliakim M, Ehrenfold EN (10)	1961	Pericarditis	3 out of 30
Dabestani A et al. (11)	1982	Pericarditis	8 out of 30
Zimaud S et al. (12)	1993	Massive cardiac tamponade	1
Kees S et al. (13)	1997	Pericarditis	27 out of 1553
Tunca M et al. (14)	2005	Pericarditis	60 out of 2468
Tutar E et al. (15)	2003	Pericardial effusion	2 out of 42
Okutur K et al. (16)	2008	Idiopathic recurrent pericarditis	1
Tutar HE et al. (17)	2001	Isolated recurrent exudative pericarditis	1
Tekin M et al. (19)	1999	Increased prevalence of rheumatic heart disease	3 out of 162
Tutar E et al. (20)	2002	Rheumatic carditis	7 MEFV mutations found on 27 patients with no FMF symptom
Grimaldi MP et al. (21)	2006	Coronary heart disease	30 carriers of the M694V mutation out of 121 patients with acute myocardial infarction
Akcay A et al. (22)	2009	Abnormal cardiovascular reactivity (greater QT dispersion and transmural dispersion of repolarization)	50 (in comparison with 50 healthy controls)
Tumour necrosis factor receptor-associated periodic syndrome
Authors	Year of publication	Cardiovascular abnormalities	Number of patients reported
Dodé et al. (26)	2002	Recurrent pericarditis	2
Cantarini L et al. (29)	2009	Recurrent pericarditis as first manifestation	4
Cantarini L et al. (30)	2010	Recurrent pericarditis as first manifestation	2
Cantarini L et al. (31)	2010	Recurrent pericarditis as first manifestation	1
Trost S et al. (32)	2005	Myocarditis with acute dilated cardiomyopathy	1
Roubille F et al. (33)	2009	Myocarditis	1
Stojanov S et al. (34)	2008	Myocardial infarction	1 (carrier of the V173D mutation)
Stojanov S et al. (34)	2008	Arterial thrombosis	1 (carrier of the V173D mutation)

Eliakim M, Ehrenfeld EN. Electrocardiographic changes in recurrent polyserositis (‘periodic disease’). Am J Cardiol. 1961; 7:517–20.

 PubMedGoogle Scholar

Dabestani A, Noble LM, Child JS, Krivokapich J, Schwabe AD. Pericardial disease in familial Mediterranean fever: an echocardiographic study. Chest. 1982;81:592–5.

 PubMed Web of Science ®Google Scholar

Zimaud S, Tauber T, Hegesch T, Aladjen M. Familial Mediterranean fever presenting with massive cardiac tamponade. Clin Exp Rheumatol. 1994;12:67–9.

 PubMedGoogle Scholar

Kees S, Langevitz P, Zemer D, Padeh S, Pras M, Livneh A. Attacks of pericarditis as a manifestation of familial Mediterranean fever (FMF). QJM. 1997;90:643–7.

 PubMed Web of Science ®Google Scholar

Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, . Turkish FMF Study Group. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine. 2005;84:1–11.

 PubMed Web of Science ®Google Scholar

Tutar E, Yalçinkaya F, Özcaya N, Ekim M, Atalay S. Incidence of pericardial effusion during attacks of familial Mediterranean fever. Heart. 2003;89:1257–8.

 PubMedGoogle Scholar

Okutur K, Seber S, Oztekin E, Bes C, Borlu F. Recurrent pericarditis as the initial manifestation of familial Mediterranean fever. Med Sci Monit. 2008;14:CS139–41.

 PubMed Web of Science ®Google Scholar

Tutar HE, Imamoglu A, Kendirli T, Akar E, Atalay S, Akar N. Isolated recurrent pericarditis in a patient with familial Mediterranean fever. Eur J Pediatr. 2001;160:264–5.

 PubMed Web of Science ®Google Scholar

Tekin M, Yalçinkaya F, Tümer N, Cakar N, Koçak H. Familial Mediterranean fever and acute rheumatic fever: a pathogenetic relationship? Clin Rheumatol. 1999;18:446–9.

 PubMedGoogle Scholar

Tutar E, Akar N, Atalay S, Yilmaz E, Akar E, Yalçinkaya F. Familial Mediterranean fever gene (MEFV) mutations in patients with rheumatic heart disease. Heart. 2002;87:568–9.

 PubMedGoogle Scholar

Grimaldi MP, Candore G, Vasto S, Caruso M, Caimi G, Hoffmann E, . Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population. J Leukoc Biol. 2006;79: 611–5.

 PubMedGoogle Scholar

Akcay A, Acar G, Sayarlioglu M, Sokmen A, Kaya H, Ispiroglu M, . QT dispersion and transmural dispersion of repolarization in patients with familial Mediterranean fever. Mod Rheumatol. 2009;19:550–5.

 PubMed Web of Science ®Google Scholar

Dodé C, André M, Bienvenu T, Hausfater P, Pêcheux C, Bienvenu J, . French Heraditary Recurrent Inflammatory Disorder Study Group. The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2002;46: 2181–8.

 PubMed Web of Science ®Google Scholar

Cantarini L, Lucherini OM, Baldari CT, Laghi Pasini F, Galeazzi M. Familial clustering of recurrent pericarditis may disclose tumour necrosis-factor receptor-associated periodic syndrome. Clin Exp Rheumatol. 2010;28:405–7.

 PubMed Web of Science ®Google Scholar

Cantarini L, Lucherini OM, Cimaz R, Baldari CT, Bellisai F, Rossi Paccani S, . Idiopathic recurrent pericarditis refractory to colchicine treatment can reveal tumor necrosis factor associated periodic syndrome. Int J Immunopathol Pharmacol. 2009;22:1051–8.

 PubMed Web of Science ®Google Scholar

Cantarini L, Lucherini OM, Cimaz R, Galeazzi M. Recurrent pericarditis caused by a rare mutation in the TNFRSF1A gene and with excellent response to anakinra treatment. Clin Exp Rheumatol. 2010;28:802.

 PubMed Web of Science ®Google Scholar

Trost S, Rosé CD. Myocarditis and sacroiliitis: 2 previously unrecognized manifestations of tumor necrosis factor receptor associated periodic syndrome. J Rheumatol. 2005;32:175–7.

 PubMed Web of Science ®Google Scholar

Roubille F, Cayla G, Gahide G, Mourad G, Macia JC. Acute myocarditis and tumor necrosis factor receptor-associated periodic (TRAP) syndrome: first case described and discussion. Eur J Int Med. 2009;20:e25–6.

 Google Scholar

Stojanov S, Dejaco C, Lohse P, Huss K, Duftner C, Belohradsky BH, . Clinical and functional characterisation of a novel TNFRSF1A c.605T > A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment. Ann Rheum Dis. 2008;67:1292–8.

 PubMedGoogle Scholar