Autoinflammatory diseases and cardiovascular manifestations

Abstract

A host of clinical scenarios can be depicted in hereditary autoinflammatory diseases, and the cardiovascular system can also be involved especially in familial Mediterranean fever (FMF), caused by mutations in the MEFV gene, and tumour necrosis factor receptor-associated periodic syndrome (TRAPS), caused by mutations in the TNFRSF1A gene. Pericardial diseases are the most represented cardiovascular abnormalities, though the role of MEFV and TNFRSF1A in the initiation of heart involvement has not been demonstrated formally and will be discussed herein.

Key words::

• Autoinflammatory diseases
• cardiovascular abnormalities
• familial Mediterranean fever
• tumour necrosis factor receptor-associated periodic syndrome

Key messages

• This review is focused on the cardiovascular manifestations which can be observed in the two most frequent autoinflammatory disorders: familial Mediterranean fever and tumour necrosis factor receptor-associated periodic syndrome.

• Clinicians should be aware that relapsing pericarditis might be a part of their clinical spectrum and consider mutation analysis, especially in patients of Mediterranean origin, since the lack of an appropriate treatment influences the risk of developing a secondary amyloidosis.

Introduction

Hereditary autoinflammatory diseases derive basically from an aberrant inflammatory response arising from wrong activation of pattern recognition molecules of the innate immune system: ten subtypes have been described, caused by mutations in eight different genes (1). Apart from the common phenotype of lifelong recurrent inflammatory attacks, all subtypes have distinct features and specific therapeutic options, which emphasize the need for a specific diagnosis in each case. All these disorders display inflammatory signs localized to various organs or tissues, and also the heart and the vascular tree can be sometimes involved. Genetic backgrounds promoting a proinflammatory response have been poorly studied in the cardiovascular diseases, and this is particularly distressing for the two most frequent autoinflammatory diseases, familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS). FMF is the most common recessive and TRAPS the most common dominant autosomally inherited autoinflammatory disorder: both FMF, caused by mutations in the MEFV gene, and TRAPS, caused by mutations in the TNFRSF1A gene, are characterized mainly by recurrent episodes of fever associated with abdominal or chest pain and joint and skin manifestations (2) (Table I). Furthermore both MEFV and TNFRSF1A genes are proposed to play a consistent role in controlling the leukocyte-related inflammatory responses in the body, though their role in the pathogenesis of cardiovascular manifestations of FMF and TRAPS has not been examined.

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

Familial Mediterranean fever

FMF is particularly frequent around the Mediterranean basin or in the Southern Caucasian areas, and its clinical diagnosis relies on the presence of family history, ethnic origin, and response to colchicine administration (3). This clinical work-up may be confirmed by screening the genomic MEFV coding sequence: MEFV encodes a 781-amino-acid protein, named pyrin, which has keen anti-inflammatory properties. FMF-associated mutations are thought to exert a decreased inhibition of interleukin-1 processing and secretion (4) (Figure 1). Most of the missense mutations in the MEFV gene described to date, including the M694V, are clustered in exon 10, and several studies have identified the M694V mutation in a homozygous genotype as the most deleterious (5). The frequency of FMF-related alleles can be remarkably high in non-Ashkenazi Jews, Armenians, Arabs, and Turks, with a prevalence of 1 in 500 in Israel: the presence of high carrier frequencies in geographically restricted populations suggests that people bearing MEFV mutations might have a selective advantage, possibly because of heightened resistance to pathogens, just as the sickle cell trait against malaria (6), but it has been postulated also that the low-grade inflammation in carriers, especially those carrying the M694V mutation, may worsen clinical symptoms of various immune-inflammatory diseases (7).

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.

The development of renal amyloidosis type AA is the most devastating complication of FMF and, prior to the advent of colchicine treatment, it was a major cause of morbidity and mortality among patients, even arising from severe secondary heart involvement (8). Typical febrile attacks include serosal inflammation, but although FMF is characterized by recurrent polyserositis, there is little documentation of pericardial disease among patients.

In the past Sohar did not observe a single case of pericarditis in a study of 470 FMF patients and concluded that pericardial involvement should be extremely rare (9), while Eliakim and Ehrenfold had reported that pericarditis was only an occasional feature of FMF (10). Dabestani noted that the echocardiographically revealed presence of pericarditis involved 27% of adult patients during febrile attacks (11), and Zimaud showed even the possibility of constrictive pericarditis with tamponade (12). In contrast, more recently, Kees and the Turkish FMF study group reported that pericarditis might involve respectively 0.7% and 1.4% of patients, independently from evidences of amyloidosis or congestive heart failure, and agreed that pericarditis is a rare manifestation if compared with peritonitis, pleuritis, and synovitis (13,14). Pericardial involvement in FMF usually occurs late in the course of the disease, with chest pain, orthopnoea, pericardial friction rub, increased area of cardiac dullness, transient ST-T segment changes in the ECG, transient enlargement of the cardiac shadow in chest radiograms, and echocardiographic evidence of pericardial effusion or thickening (15). In addition, idiopathic pericarditis can sometimes reveal the diagnosis of FMF (16,17).

FMF has been associated with a more frequent occurrence of vasculitic syndromes as Behçet's disease and Henoch-Schönlein purpura (18), and an increased prevalence of rheumatic heart disease, a major sequela of rheumatic fever occurring after group A β-haemolytic streptococcus pharyngitis, has been also observed (19): in particular, a four-times greater prevalence of MEFV mutations has been found in an unselected group of Turkish patients with rheumatic carditis without any sign or symptom of FMF (20). Grimaldi has found that the proinflammatory M694V mutation was significantly over-represented in a cohort of infarcted patients from Sicily than in age-matched healthy controls (21), and it may be intriguing to suggest that the mutated MEFV gene could be responsible for an increased frequency of heart ischaemic events through a decreased inhibiting effect on the migration of neutrophils and activated monocytes into the site of inflammation. Lastly, adult patients with FMF without overt cardiac involvement might have abnormal cardiovascular reactivity and occult dysautonomia, as emerged by the study of physiologic parameters during tilt-test (22).

First-choice treatment of FMF is the well known colchicine, a microtubule-depolymerizing agent, historically used to induce chromosome individualization in cells arrested at metaphase, which has a narrow therapeutic index, related to its faculty of disrupting the microtubular network: as a result, affected cells experience decreased cellular motility, culminating in multi-organ dysfunction, and even at a cardiac level it is possible to observe myocyte-interrupted cardiac conduction and disturbed contractility as colchicine side-effects (23). Ultimately, secondary heart amyloidosis in untreated FMF patients can occur as a result of the chronic myocardial deposition of the cleavage product of serum amyloid-A, which can be revealed by endomyocardial biopsy and Congo red staining: heart amyloidosis results in a restrictive cardiomyopathy, but the majority of these patients have also renal failure, revealed by variable levels of proteinuria, and can take advantage from chemotherapy or heart transplantation (24).

Tumour necrosis factor receptor-associated periodic syndrome

The clinical picture of TRAPS, due to mutations in the gene that encodes the ubiquitously expressed 55 kDa tumour necrosis factor (TNF) receptor type 1, named with the initials TNFRSF1A, was initially described in a boy of Scottish-Irish descent as ‘Hibernian fever’ and afterwards described in families of other ethnic groups (25). At a genetic level the disease is mostly related to missense mutations within TNFRSF1A exons 2, 3, and 4, affecting the first three of four extracellular cysteine-rich domains of the receptor (26). Systemic inflammation in TRAPS results from different biologic mechanisms: altered receptor expression, defective receptor trafficking, receptor misfolding and retention in the endoplasmic reticulum, impaired cleavage of the TNFRSF1A ectodomain with abnormal signal transduction, all leading to continuous cellular stimulation induced by TNF (27) (Figure 2).

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).

Clinically, TRAPS can present with recurrent fever combined with episodes of severe myalgia, muscle tenderness, arthralgia/arthritis, migratory rash, conjunctivitis, periorbital oedema and serositis; some patients might develop systemic amyloidosis, up to 15% in some series, which usually presents with nephropathy and is potentially life-threatening (28). Serosal involvement in TRAPS can occur in terms of pleuritis and pericarditis.

Recurrent pericarditis, often in the form of polyserositis, is common in TRAPS; furthermore, patients presenting with recurrent involvement of pericardium as unique clinical manifestation of the inflammatory attacks have been reported (29–31). Two reports of myocarditis have been published in patients with TRAPS, respectively with and without an acute dilated cardiomyopathy (32,33). Stojanov et al. have reported in an Austrian family the novel V173D TNFRSF1A mutation, involving the receptor cleavage site, with two members who developed respectively a myocardial infarction and an arterial thrombosis, due to a hypothetical atherogenic effect of the mutation itself (34). The influence of TNF on the development of endothelial dysfunction and atherosclerosis, probably potentiated by the prolonged inflammatory state of TRAPS, has been postulated as significantly contributive to acute cardiovascular events, and young patients presenting with heart accidents should be screened for this TNFRSF1A receptor cleavage site mutation (35). Table II summarizes all papers dealing with the cardiovascular involvement in FMF and TRAPS, which have been cited in this review.

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)

Pericardial diseases appear as the most frequent cardiovascular manifestations in FMF and TRAPS, which can sometimes present with isolated serosal involvement, especially when the onset is in adulthood. Because these patients are admitted to emergency rooms, it is possible to miss the diagnosis of FMF or TRAPS as causes of the recurrent pericardial involvement (36). Therefore, clinicians should be aware that relapsing serositis, specifically pericarditis, might be a part of the clinical spectrum of these diseases. Since the genetic diagnosis of FMF and TRAPS is now possible, we suggest that mutation analysis for these two autoinflammatory diseases should be considered in patients with idiopathic recurrent pericarditis, especially those of Mediterranean origin, because the lack of an appropriate treatment influences the risk of developing secondary amyloidosis, the most serious and dreadful long-term complication of both FMF and TRAPS.

Acknowledgements

Donato Rigante and Luca Cantarini contributed equally to the manuscript.

Declaration of interest: The authors state no conflict of interest and have received no payment in preparation of this manuscript.