Non-infectious aortitis is more frequently encountered than infectious aortitis: inflammation is secondary to an autoimmune reaction in most of the non-infectious diseases, idiopathic in a minority of cases. The association between autoimmune (“rheumatic”) diseases and aortic involvement is well known, but the prevalence of aortic involvement in the different rheumatic diseases is quite variable: in some of them, namely large-vessel vasculitides, aortic involvement is, by definition, part of the canonical clinical picture (e.g. Takayasu arteritis, giant cell arteritis); in others (e.g. spondyloarthropathies or anti-neutrophil cytoplasmic antibody-related diseases) an arterial inflammation, possibly but not regularly involving also the aorta, can be observed as a part of a systemic or multiorgan involvement. In fact, according to the 2012 Chapel Hill Consensus Conference Nomenclature [2], vasculitides that affect large arteries more often than the others are named “large-vessel vasculitis”, those affecting predominantly medium caliber arteries are referred to as “medium-vessel vasculitis” and those affecting predominantly small size vessels are named “small-vessel vasculitis” (Table 2.1). Consistently, in 2006 a review on aortic involvement in rheumatic disorders listed Takayasu arteritis and giant cell arteritis among those most frequently affecting the aorta (>10 % patients), along with long-standing ankylosing spondylitis and Cogan syndrome; rheumatic diseases in which aortic involvement is an uncommon (<10 %) but well-documented complication include rheumatoid arthritis, seronegative spondyloarthropathies, Behçet disease and relapsing polychondritis; rheumatic diseases with isolated case reports of aortic involvement or uncertain involvement include sarcoidosis, antineutrophil cytoplasmic antibody-associated aortitis (Wegener granulomatosis and polyarteritis nodosa), and systemic lupus eryhematosus [3].

Giant-cell arteritis (GCA), also known as Horton’s (temporal) arteritis, is a chronic inflammatory large- and medium-vessel vasculitis that affects persons older than 50 years of age (reported male to female ratio ranges 1:2 to 2:3). GCA is much more common than Takayasu arteritis in the general population, with an estimated incidence of about 19 cases/million/year among patients over 50 years of age [4]. Although there is a markedly increased incidence of GCA in northern Europe and in populations with similar ethnic background [5], the disease can occur in all populations. The rate of aortic involvement in GCA is classically reported around 15–18 % (with a predominance of the ascending aorta, but possible involvement of the abdominal), however subclinical inflammation of the aorta may be present in a notably larger proportion of GCA patients. Branches most commonly involved are those arising from the external carotid artery, especially the superficial temporal artery, but ophthalmic, vertebral, coronary, and mesenteric arteries may also be involved.

The etiology of GCA is not well established. Polymorphisms of genes such as tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), intercellular adhesion molecule (ICAM)-1, IL-6, and others appear to be more frequent in patients with GCA, although their pathogenetic role is still to be determined. It has been also postulated that a still unknown infectious pathogen may trigger the aberrant immune response [6].

The characteristic pathology feature of GCA is the presence of granulomatous inflammatory reaction in the vessel wall, with mostly macrophages, CD4⁺ T-cells and giant multinucleated cells constituting the granulomas, particularly located at the intima-media border, but also B-cells. Giant cells can actually be absent in 30–40 % cases. The CD4⁺ lymphocytes differentiate into T-helpers and produce interferon-gamma (IFN-γ), which activates macrophages, in turn producing reactive oxygen species and proteolytic enzymes, including matrix metalloproteases, the effectors of arterial wall elastic matrix degradation [7]. Lymphocytes and macrophages’ products, including TNF-α and IL-6, also enter the blood and are responsible for the systemic clinical syndrome in GCA (see next section). Alternatively or adjunctively, a systemic inflammatory response may stimulate pattern recognition receptors at vascular level thereby activating vascular dendritic cells, in turn initiating T-cell response. The intima may be thickened and the medial elastic laminae fragmented, whereas in the late stages intimal changes may be minimal and medial changes are largely constituted by fibrosis.

Also known as pulseless disease or Martorell syndrome, Takayasu arteritis (TKA) is a necrotizing and obliterative segmental, large-vessel panarteritis of unknown cause with a predilection for young women (>80 % of cases). Epidemiology varies in the different geographic areas: in the United States, incidence estimates from Olmstead County, Minnesota, are 2.6 cases/million/year, whereas in Sweden and Germany they are 1–1.2 cases/million/year [8] Autopsy studies in Japan document a much higher prevalence, with evidence of TKA in 1 every 3,000 individuals. Also, the age of disease onset differs: it is earlier (15–25 years) in Asians compared to European women (40 years) [9]. Involvement of the aorta is frequent, reported between 80 and >90 %. The most commonly affected aortic segment is the abdominal aorta, however ascending aorta involvement has been described as more typical in Japanese women [3].

Although the exact etiology of TKA is not well known, a prior tubercular or streptococcal infection, genetic factors, and autoimmune mechanisms (possible association with rheumatoid arthritis) have been implicated as etiological factors [9]. The pathogenetic mechanisms are unknown as well, although it is considered to be antigen-driven cell-mediated autoimmune processes, although the specific antigenic stimuli have not been identified [10]. Vessel injury occurs as a result of invasion by leukocytes (including T-lymphocytes, NK-cells, B-lymphocytes, macrophages and others) deriving from the vasa vasorum, migrating to the intimal layer and producing a number of cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), B-cell activating factor (BAFF) and others. Myointimal proliferation most commonly results, leading to stenosis of the vessel (most commonly the abdominal aorta) or its branches (especially supra-aortic vessels, iliac arteries and renal arteries), however medial smooth muscle cell necrosis and derangement of the extracellular matrix is another possible evolution, leading to aneurysm formation in 45 % cases (more common at the aortic root and ascending tract) [8]. Aside from the presence of granulomas, possibly including giant cells, in the aortic wall (particularly in the adventitia) and of perivascular cuffing of the vasa vasorum, histopathology usually reveals lymphoplasmacytic infiltrate of adventitia and media (Fig. 2.1), a non-specific finding present in a number of rheumatic disorders, such as relapsing polychondritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, as well as in aortitis of infectious or toxic etiology. At late stages (at least >5 years of disease), unspecific wall calcification is observed, especially in the case of stenotic evolution.

Indeed, the pathology pictures of the different forms of aortitis show substantial overlap, and contribute to make differential diagnosis quite challenging. In this perspective, the stenotic lesions, with thickened intima and media, have been reported as pathognomonic of TKA [8].

Ankylosing Spondylitis (AS) is an HLA-B27 disease classified as a seronegative spondyloarthritis, since it is not characterized by circulating rheumatoid factor. Risk of aortic involvement (predominantly aortic valve, root, ascending aorta) increases with disease duration. Pathology studies of the sacroiliac joints in patients with AS have shown a prominent role of synovitis and subchondral myxoid bone marrow changes, processes mediated by activated T-lymphocyte-derived TNF-α and TGF-β, in initiating intra-articular joint destruction; a Klebsiella pneumoniae infection may participate in providing an antigen that reaches the synovia and initiates T-cell responses in genetically susceptible individuals [11]. Similar mechanisms could induce the typical fibrosis changes of AS-associated valvulitis and aortitis: in particular at the level of the proximal aorta, vasa vasorum narrowing, fibrotic changes in the adventitia, medial matrix disruption and fibrosis and myointimal proliferation ensue [12].

Cogan’s syndrome (CS) is a rare disease of young adults, with a mean age of 29 years at disease onset, defined by the presence of both ocular (keratitis) and inner ear inflammation [13]. Aortitis with valvulitis and aortic insufficiency has been documented as occurring from 2 weeks to 12 years after the initial diagnosis of the syndrome and has an estimated prevalence of up to 10 % [1, 3]. Etiopathogenesis is unknown: formerly believed to derive from a Clamydia spp. infection, today, after the finding of autoantibodies and lymphocyte activation against corneal and endothelial antigens, it is considered an autoimmune disorder [14]. Histologic analysis of the aortic wall reveals inflammation with prominent lymphocytic infiltration, destruction of medial elastic tissue, fibrosis, and neovascularization, which finally result in aneurysm formation [15].

Behçet disease (BD) is a rare, multisystemic, and chronic inflammatory disease of unknown etiology, characterized by mucocutaneous manifestations (aphtous ulcers), especially including genital and oral ulcers and often-severe sight-threatening inflammatory eye disease. It can be associated (up to 30–40 % cases) with vasculitic manifestations in arteries and veins of variable size [2]. The frequency of aortic involvement in BD varies according to different studies, ranging from 50 % of patients in reports from Turkey and Italy [16], to <1 % in other studies including only clinically significant aortic aneurysms [17]. Macroscopically, saccular aneurysms affecting the abdominal and/or thoracic aorta and their branches are typical of BD. Histopathology of the involved aorta shows lymphocytic infiltration mixed with histiocytes and eosinophils with giant cells around vasa vasorum of media and adventitia. Destruction of media leads to aneurysm formation and may proceed to pseudoaneurysm formation and rupture [18]. Aortitis derives not from direct large-vessel inflammation but rather due to vasculitis of the vasa vasorum that supply the vessel wall.

Apart from AS, other HLA-27-associated seronegative spondyloarthropathies can present with vascular involvement and potentially, but more rarely compared to the other abovementioned syndromes, with aortitis. These include Reiter’s syndrome, an arthritic disease of the lower limbs associated with typical cutaneous lesions and relapsing polychondritis, affecting proteoglycan rich tissues, such as cartilages and vessels. Less frequently, some of the anti-neutrophil cytoplasmic antibody- (ANCA-) related diseases, namely Wegener’s granulomatosis, microscopic polyangiitis and polyarteritis nodosa, which more typically involve small-size vessels, can be associated with large-vessel involvement and therefore aortitis. Whether aortitis in such cases is initiated by vasa vasorum involvement or by primitive inflammation of the intimal layer (“intimitis”) has not been clarified yet [19].

Following the 2012 Chapell Hill Consensus Conference Nomenclature [2], isolated idiopathic aortitis (more frequently observed at the abdominal level) should be classified within the group of “single organ” vasculitides. Idiopathic aortitis is characterized by aortic wall inflammation in absence of any systemic disease or infection, and it usually involves the ascending aorta and arch. This condition affects women more often than men (3:2 ratio) and is asymptomatic until it is discovered incidentally or by post-surgical histological analysis [20]. In those latter cases, macroscopic appearance can already suggest inflammatory etiology, i.e. by the typical diffuse irregular scarring of the intima, referred to as “tree-barking” sign [1]. Histology can vary, however overlapping with the spectrum of lesions already mentioned above for specific etiologies. Infiltrates can include macrophages, T-cells, B-cells and also giant multinuclear cells. Idiopathic inflammatory aneurysms of the abdominal aorta, constituting 5–25 % of all abdominal aneurysms [21], are characterized by thickening of the aortic wall, associated with a considerable peri-aortic reaction and dense adhesions. They are more frequently observed in young males with familiar history of aneurysm, and use of tobacco smoke. Retroperitoneal fibrosis is characterized by a chronic inflammation with fibrous tissue deposition in the retroperitoneum surrounding the aorta, the stem of its main abdominal branches and the ureters. Complications include hydronephrosis, aortic-enteric fistula, and secondary bacterial infections [1].

It has been recently discovered that some cases of idiopathic aortitis, idiopathic aneurysm and retroperitoneal fibrosis are actually secondary to a so-called “IgG4-related systemic disease”, in which multiple organs are involved by inflammatory infiltrates constituted by IgG4-expressing plasmacells, and abnormally high levels of IgG4 are found in the serum. This syndrome was first described in patients with autoimmune forms of pancreatitis, but other glands (e.g. salivary glands and thyroid) can be involved, as well as lungs, kidneys, heart, retroperitoneum, mediastinum and aorta [22].

Infectious aortitis is an infectious and inflammatory process of the aortic wall directly induced by micro-organisms. In the preantibiotic era, it was most likely a complication of bacterial endocarditis secondary to Streptococcus pyogenes, Streptococcus pneumoniae, and Staphylococcus. Nowadays, the most common pathogens, which account for almost 40 % of infections, include Staphylococcus aureus and Salmonella spp. Other pathogens involved include Treponema pallidum, Mycobacterium tuberculosis (less common today in developed countries), and other bacteria such as Listeria, Bacteroides fragilis, Clostridium septicum, and Campylobacter jejuni [23]. The aorta is normally very resistant to infection; however, an abnormal aortic wall, like that associated with atherosclerotic disease, preexisting aneurysm, medial degeneration, diabetes, vascular/valvular malformation, medical devices, or surgery, makes it more susceptible to infection, if a bacteriaemia occurs [24]. Mechanisms of infection include hematogenous spread (e.g. in non-typhoid Salmonella spp. Gastroenteritis), contiguous seeding from adjacent infection, septic emboli of the aortic vasa vasorum and traumatic or iatrogenic inoculation. Infected (or “mycotic”) aortic aneurysms are part of the spectrum of infectious aortitis and account for <3 % cases of aortic aneurysms. Men are affected more often than women, with most cases seen in adults after the fifth decade of life: elderly or immunocompromised patients are more susceptible to bacterial seeding at the level of preexisting aortic lesions. Both host leukocytes and responsible bacteria can induce aortic wall lesions, namely extracellular matrix degradation, by producing a variety of proteases including matrix metalloprotease-1, −2, −8 and −9 [25]. The collagenase activity may be relatively localized, leading to formation of a saccular abdominal aortic aneurysm or pseudoaneurysm in an otherwise normal appearing vessel. Collagenase activity may also be intensive, which may explain the rapid course associated with infected abdominal aortic aneurysms. Typical pathology findings include aortic atherosclerosis, acute suppurative inflammation, neutrophil infiltration, and bacterial clumps. About two-thirds of patients can show acute inflammation superimposed on severe chronic atherosclerosis; the remainder show atherosclerosis with chronic inflammation or pseudoaneurysms [25].