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«1. Introduction Chronic periaortitis is an idiopathic disease whose hallmark is the presence of a fibro- inflammatory tissue arising from the ...»

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Chronic Periaortitis as a Systemic

Autoimmune Disease

Chang-Hee Suh

Rheumatology, Ajou University School of Medicine


1. Introduction

Chronic periaortitis is an idiopathic disease whose hallmark is the presence of a fibro-

inflammatory tissue arising from the adventitia of the abdominal aorta and the common

iliac arteries and extending into the surrounding retroperitoneum and frequently encasing

neighboring structures such as the ureters and the inferior vena cava (Mitchinson, 1984;

Parums, 1990). It should be regarded as a generalized disease with three different pathophysiological entities, specifically idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms, and perianeurysmal retroperitoneal fibrosis (Vaglio et al., 2003; Jois et al., 2004).

Idiopathic retroperitoneal fibrosis is characterized by periaortic fibroinflammatory tissue, which often causes obstruction of the ureters and other adjacent abdominal structures by extending into the retroperitoneum (Mitchinson, 1970; Gilkeson & Allen, 1996). A dilated aorta is usually not present in idiopathic retroperitoneal fibrosis. Its initial signs and symptoms are often nonspecific, such as malaise, anorexia, weight loss, fever, and flank, back, or abdominal pain. Inflammatory abdominal aortic aneurysms characteristically develop the mass around a dilated aorta, but usually do not cause obstructions (Crawford et al., 1985; Pennell et al., 1985). It usually presents with typical symptoms and signs characterized by the triad of abdominal or back pain, a pulsatile and sometimes tender abdominal mass, and an elevated erythrocyte sedimentation rate. Perianeurysmal retroperitoneal fibrosis, which represents a link between these two diagnoses, involves an abdominal aortic aneurysms surrounded by fibroinflammatory tissue that encases other abdominal organs (Serra et al, 1980).

These definitions may be a little confusing, and it would probably be more appropriate to distinguish aneurysmal from nonaneurysmal forms of chronic periaortitis; idiopathic retroperitoneal fibrosis may be referred as non-aneurysmal chronic periaortitis, where as inflammatory abdominal aortic aneurysms and perianeurysmal retroperitoneal fibrosis as aneurysmal chronic periaortitis (Vaglio et al., 2006).

It is important to diagnose chronic periaortitis early in its course in order to attempt to prevent the severe secondary complication of renal failure due to ureteric obstruction and the potentially fatal consequence of aortic rupture (Jois et al., 2004). Although most studies have considered these entities separately, these conditions have common clinical a

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2. Epidemiology The prevalence of chronic periaortitis is not well known; the only available epidemiological data concern idiopathic retroperitoneal fibrosis and inflammatory abdominal aortic aneurysms. Reports from Duke University and the Mayo Clinic estimate that the incidence of idiopathic retroperitoneal fibrosis is less than 1 per 10,000 patients (Gilkeson & Allen 1996). A recent study conducted in Finland on idiopathic retroperitoneal fibrosis has demonstrated that its incidence and prevalence are 1/1,000,000 person-year and 1.38 cases/100,000 inhabitants (Uibu et al., 2004). On the other hand, data regarding the incidence of the aneurysmal forms of chronic periaortitis in the whole population are lacking, however they represent about 4% to 10% of all abdominal aortic aneurysms (Rasmussen et al, 1997; von Fritschen et al., 1999; Yusuf et al., 2007).

Chronic periaortitis frequently develops in middle-aged adults with a mean age of approximately 60 years, but it may also occur in children (Miller et al. 2003; Uibu et al., 2004;

Vaglio et al., 2006). Men are affected two to three times as often as women and that is even more pronounced in the inflammatory abdominal aortic aneurysms (Gilkeson & Allen 1996;

Uibu et al., 2004; Vaglio et al., 2006).

There is no evidence of a clear ethnic predisposition or familial clustering, and the disease has been reported in twins and siblings only in anecdotal cases (Duffy et al., 1984; Doolin et al. 1987). A few studies have addressed the question whether genetic factors may contribute to the development of chronic periaortitis. Recent studies have suggested that immunogenetic factors may be involved in the pathogenesis of the disease (Rasmussen et al., 1997; Martorana et al., 2006).

A case-control study evaluated the prevalence of HLA alleles in patients with inflammatory abdominal aortic aneurysms compared with healthy subjects found that in the inflammatory abdominal aortic aneurysms a genetic risk determinant mapping at the HLA-DRB1 locus (Rasmussen et al., 1997). Additionally, they identified HLA-DRB1*15 and B1*0404 as predisposing alleles.

Another recent case-control study on patients with chronic periaortitis and healthy controls in order to investigate the role of HLA in the susceptibility to chronic periaortitis revealed that the frequency of the HLA-DRB1*03 allele was markedly higher in patients with chronic periaortitis than in the controls (Martorana et al., 2006). The HLA-DRB1*03 allele is a wellknown marker of autoimmunity, since it is associated with a number of autoimmune diseases, which include systemic lupus erythematosus and autoimmune thyroid disease (Davidson and Diamond, 2001). Also, the HLA-B*08 allele was significantly associated with chronic periaortitis and it is itself linked to a wide range of immune-mediated diseases.

Furthermore, the comparison of the clinical and laboratory characteristics of HLA-DRB1*03positive and HLA-DRB1*03-negative patients showed that the HLA-DRB1*03-positive patients with chronic periaortitis have higher acute-phase reactant levels at the time of diagnosis (Martorana et al., 2006). These results could imply that the HLA system not only confers susceptibility to the development of the disease but also plays a role in the modulation of the inflammatory response.

More recently, CC chemokine receptor 5 (CCR5) gene delta 32 polymorphism has been mapped in 100 patients with chronic periaortitis (Boiardi L et al., 2011). The distribution of the CCR5 gene delta 32 genotype differed between patients with chronic periaortitis and controls (P = 0.01). The CCR5 gene delta 32 allele was more frequent in patients with chronic periaortitis [P = 0.02, odds ratio (OR) 2.8 (95% CI 1.2, 6.4)]. Furthermore, CCR5 gene delta 32 305 Chronic Periaortitis as a Systemic Autoimmune Disease allele occurred more frequently in patients with inflammatory abdominal aortic aneurysms than in patients with idiopathic retroperitoneal fibrosis [P = 0.001, OR 6.4 (95% CI 2.1, 19.1)].

The CCR5 gene delta 32 allele frequency was higher in inflammatory abdominal aortic aneurysms patients without established atherosclerotic disease compared with controls [66.7 vs 5.6%, P = 0.00001, OR 34.0 (95% CI 7.4, 156.3)].

The CC chemokine receptor 5 is expressed on many immune cells, particularly Th1 cells, and acts by binding to different chemokines, including RANTES, MIP-1 and MIP-1. The CCR5 gene delta 32 polymorphism creates a truncated, nonfunctional receptor and probably shifts the immune response toward a Th2 pattern. Interestingly, the association between the CCR5 gene delta 32 polymorphism and aneurysmal chronic periaortitis is even stronger in patients without overt atherosclerotic disease, which suggests that immune mechanisms independent of atherosclerosis play a role in the pathogenesis of chronic periaortitis (Vaglio et al., 2011).

Additionally, environmental and occupational agents have been shown to contribute to susceptibility to chronic periaortitis. In a recent study, it has been demonstrated that asbestos exposure is associated with a markedly increased risk of developing the chronic periaortitis, and smoking is also a significant risk factor (Uibu et al., 2004; Hellmann et al., 2007). Although smoking is an established risk factor for classical atherosclerotic abdominal aortic aneurysms, its frequency is even higher in patients with inflammatory abdominal aortic aneurysms (Nitecki et al., 1996; Hellmann et al., 2007).

3. Pathology Chronic periaortitis affects the aortic wall and the surrounding retroperitoneum. The classical macroscopic appearance of chronic periaortitis is grossly a whitish and hard periaortic mass which extends between the origin of the renal arteries and the bifurcation of the common iliac vessels and often distorting medially the ureters but histologically there is a continuum of lesions ranging from acute changes to chronic damage (Mitchinson, 1970).

In the early stages of chronic periaortitis, or in patients with a prominent acute-phase reaction, the tissue is highly inflammatory, with numerous lymphocytes, plasma cells, macrophages and scattered eosinophils and loose deposits of collagen matrix in thick, irregular bands (Mitchinson, 1970; Corradi et al., 2007). In late disease, these aspects evolve, either spontaneously or after glucocorticoid therapy, into a relatively acellular fibrous tissue.

Perivascular involvement of the thoracic aorta is not uncommon, while rarely atypical localizations such as peri-duodenal, peri-pancreatic and pelvic sites have also been found (Hughes & Buckley, 1993; Corradi et al., 2007).

Microscopic examination shows signs of active mononuclear cell inflammation in a framework of fibrous tissue and fibroblasts (Serra et al, 1980; Gilkeson & Allen, 1996). The background of chronic periaortitis consists of varying degrees of fibrosis, characterized by a mild-to-moderate and mitotically inactive fibroblasts and myofibroblasts, which are immuno-histochemically positive for vimentin and, in the more cellular areas, for -smooth muscle actin (Vaglio et al., 2006). The fibrous component is particularly abundant in the late stages when the tissue becomes relatively avascular and acellular; its distribution is usually diffuse, but sometimes perivascular and perineural.

The inflammatory infiltrate includes mononuclear cells such as T and B lymphocytes, macrophages and plasma cells, although scattered eosinophils can also be found 306 Autoimmune Disorders – Pathogenetic Aspects (Mitchinson, 1970). The majority of lymphocytes, macrophages and most vascular endothelial cells are HLA-DR-positive. The Ki67 and BerH2 staining is found in B cells and T-helper cells, indicating that these cells were proliferating and activated (Meier et al., 2007).

Two main inflammatory patterns are usually seen, perivascular and diffuse. The perivascular aggregates consist mainly of B lymphocytes and a smaller component of plasma cells, macrophages, and T lymphocytes, most of which are CD4+ (Corradi et al., 2007). Sometimes, these follicular aggregates show a germinal center architecture. The sclerotic component consists of thick fascicles of type-I collagen, irregularly distributed along the lesion; a pathological hallmark is the presence of a regular circumferential fibrous bundle surrounding blood vessels and nerves. On the other hand, the diffuse infiltrate has an equal percentage of T cells and B cells. Scattered eosinophils are common, whereas neutrophils are rare (Mitchinson, 1970; Vaglio et al., 2003). In cases of severe inflammation, there may be focal infiltration of the small and medium-sized retroperitoneal vessels, with frank vasculitis and fibrinoid necrosis.

The aortic wall also shows particular changes, such as atherosclerotic degeneration of the intima, medial thinning, and marked adventitial inflammation and fibrosis. The composition of the inflammatory infiltrate in the aortic wall is similar to the retroperitoneal one, with diffuse and perivascular patterns. The adventitial inflammatory infiltrate is often organized in lymphoid follicles (Sakata et al., 2008), which are examples of ectopic lymphoneogenesis and expression of a highly structured inflammatory or immune-mediated response. Adventitial vasa vasorum in aortas of chronic periaortitis show inflammatory infiltration up to frank necrotizing vasculitis, endarteritis obliterans, or obliterative phlebitis (Vaglio et al., 2003;

Sakata et al., 2008). These aortic wall changes are found in all chronic periaortitis disease entities, regardless of the presence of aneurysmal dilatation.

It is interesting to note that autopsy studies have documented the presence of adventitial inflammation in aortic sections lacking periaortic fibrosis, which may suggest that aortitis could precede the development of adventitial and periadventitial fibrosis (Mitchinson, 1970). Another autopsy studies have shown that moderate adventitial inflammation and fibrosis may not be limited to the abdominal aorta, but may also involve its thoracic aorta (Mitchinson, 1972).

Molecular analysis of aortic biopsies in patients with chronic periaortitis shows gene transcripts consistent with lymphocyte activation, such as IFN-, IL-1, IL-2 and IL-4, in keeping with the concept that chronic periaortitis is an active inflammatory aortic disease (Ramshaw et al., 1994).

4. Pathogenesis Chronic periaortitis is idiopathic in nature, and its pathogenesis remains a matter of debate.

Initially, it was postulated to represent a local inflammatory reaction to antigens such as ceroid and oxidised low-density lipoproteins (LDL), which can be found in the atherosclerotic plaques of the abdominal aorta (Parums et al., 1986; Parums et al., 1990;

Ramshaw & Parums, 1994). Since an intact media constitutes an immunoprivileged site, the capacity of lipids deposited in the intima and media to elicit an inflammatory reaction in the adventitia may depend on the thinning or breach of the media itself, with consequent transit of the lipids. These can be processed by adventitial macrophages and presented to B and T cells, thus eliciting a local inflammatory reaction which eventually leads to adventitial and peri-aortic inflammation and fibrosis.

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