Takayasu arteritis affects more commonly young females and it involves large vessels, typically the aortic arch and proximal branches of the aorta as well as the pulmonary arteries. The course of disease is usually chronic, with cutaneous, neurologic, gastrointestinal, and constitutional symptoms. Angina pectoris may occur following coronary artery ostial stenosis from aortitis or coronary arteritis in 10–45% of the cases and may have severe clinical sequelae, even though regression upon immunosuppression is possible [19]. In these cases, coronary artery stenosis is caused by the diffusion of the inflammatory process and intimal proliferation form the wall of the ascending aorta [6]. The pathogenesis is unclear, but cell-mediated mechanisms (particularly cytotoxic lymphocytes, especially gamma delta T lymphocytes releasing the cytolytic protein perforin) are thought to be involved [20]. The presence of a (yet unknown) specific antigen in the aorta might explain the selective localization of the disease [21]. At histology, mononuclear cells—predominantly lymphocytes, histiocytes, macrophages, and plasma cells—are present, and giant cells and granulomatous inflammation are found in the arterial media. The expansion of these inflammatory processes may lead on one side to destruction of the elastic lamina, causing the aneurysmal dilation of the affected vessel, or to narrowing of the lumen. Systemic inflammatory markers are often elevated. Systemic therapy consists of corticosteroids and immunosuppression, but anti-IL6 therapy with Tocilizumab has also been associated with a reduction in the markers of inflammation and, importantly, also the number of coronary artery lesions [22]. Takayasu is a progressive chronic disease with remissions and relapses and an 80–90% survival at five years [23].

This condition shares several similarities with Takaysu’s arteritis, and the differential diagnostic is based on a rather artificial criterium of age (older than 50 in giant cell arteritis and younger than 40 in Takayasu) and vascular district involvement (more frequent involvement of supraaortic vessels in giant cell arteritis) [24]. Both giant cell arteritis and Takayasu involve the aorta and its major branches and are indistinguishable histopathologically. Although the prevalence of coronary artery involvement in giant cell arteritis is thought to be lower [8], large cohort studies report that the incidence of acute myocardial infarctions is twice as high as that in patients without giant cell arteritis, particularly early after diagnosis (Hazard Ratio for AMI: 11.9 [2.4–59.0]) [25]. Therapy with tocilizumab, an anti-IL6 antibody, is recommended in addition to corticosteroids, but its efficacy specifically on coronary vasculitis has not been investigated. The disease does not compromise life expectancy except for those patients in whom aortic dissection is present [8].

Polyarteritis nodosa is a systemic necrotizing vasculitis which predominantly involves medium-sized arteries, more rarely small muscular arteries in middle-aged adults. Unlike microscopic polyarteritis, granulomatosis with polyangiitis, polyarteritis nodosa is antineutrophil cytoplasmic antibodies (ANCA)-negative [2]. It may affect virtually any organ in the body (kidneys, skin, joints, muscles, nerves, and gastrointestinal tract), usually in combination, but usually does not involve the lungs. Coronary involvement is considered to be rare but may be severe, including aggressive three-vessel disease with infaust outcome (Figure 1) [26]. Clinical sequelae of this involvement include congestive heart failure, hypertension, pericarditis, and arrhythmias.

Coronary involvement may manifest in the form of stenosis, occlusion, aneurysm, or dissection. In a recent review of cases, a total of 34 patients with an average age of 41 years were identified from 32 publications. Male sex is more frequent, coronary disease was the first manifestation of polyarteritis nodosa in ¾. The clinical course of the disease was in general very severe, with cases of death from cardiac arrest, pulmonary edema with alveolar hemorrhage or multiple intracranial hemorrhages after thrombolytic therapy [27]. The formation of immune complexes as the result of a virus infection (hepatitis B or C virus) and hairy cell leukemia is thought to mediate the inflammatory reaction, which most often lead to media thickening and stenosis rather than aneurysm formation. Medical therapy includes cyclophosphamide in addition to corticosteroids and/or azathiprine, even though the long-term effectiveness of this approach appears to be limited. Five-year survival reaches 80%.

Also known as mucocutaneous lymph node syndrome, Kawasaki disease is an acute, self-limited small and medium vessel systemic vasculitis with a frequent involvement of coronary arteries (right more often than left) affecting children <5 years of age with rare cases in older children [28]. Although Kawasaki disease generally has a self-limiting febrile course, given the decreasing incidence of rheumatic disease, it represents the most common cause of acquired heart disease in childhood in developed countries [29] and it accounts for as many as 5% of the cases of acute coronary syndrome in patients younger than 40 years. Clinically, it presents as polymorphous rash, mucosal changes (including dry, cracked lips and strawberry tongue), extremity changes (including palmar and/or plantar erythema, swelling, and desquamation), bilateral nonpurulent conjunctivitis, and cervical lymphadenopathy (≥1.5 cm diameter), usually unilateral. Although a genetic influence has also been hypothesized, like for Behçet, the pathogenesis of Kawasaki is not clear and may be related to a wind-borne or water-borne pathogen. The most commonly affected age group are children under five years of age, but cases in adults are also common. For instance, a case of adult-onset Kawasaki Disease Shock Syndrome complicated by coronary aneurysms in a 20-year old man of East Asian ancestry has been recently reported [30]. Like for Behçet, the prevalence is higher, and the prognosis worse, in males affected by Kawasaki [12]. In the current hypothesis, it is believed that the activation of an immune reaction involving in the first phase neutrophils and then lymphocytes, cytokines, and proteinases; tumor necrosis factor alpha (TNF-a); Interleukin 1, 4, and 6 and matrix metalloproteinases (MMP3 and MMP9) triggered by exposure to an airborne virus may subtend Kawasaki. CD8+T cells, plasma cells, and monocytes cause release of pro-inflammatory cytokines IL-1β and TNFα. These processes may evolve for months to years resulting in a chronic arteritis. Oligoclonal IgA plasma cells appear to be central in the cascade leading to coronary arteritis. Clinical manifestations may include myocarditis and arteritis resulting in fibrinoid necrosis of the internal elastic lamina and subsequent formation of coronary aneurysms in up to one-third of untreated patients. Cerebral aneurysms are less frequent at 1–2% of patients. Monocytes, neutrophils and macrophages appear to be involved in the pathogenesis of these vascular lesions. Resulting from these inflammatory processes, an inappropriate healing response may also cause coronary stenosis. Otherwise, typical complications associated with the presence of the aneurysms include thrombus formation causing embolism and peripheral occlusion and rupture. Cases of regression of small coronary aneurysms upon inflammatory therapy have also been reported [31]. In the acute phase of Kawasaki disease, therapy with intravenous Immunoglobulin, corticosteroids, and aspirin monotherapy is encouraged [32]. Therapy with immunoglobulins and corticosteroids is associated with a reduction in the incidence of coronary events (odds ratio: 0.3 [0.2–0.5]) [33], but the presence of signs compatible with coronary vasculitis is a negative predictor for the responsiveness to immunoglobulins. The prognosis is variable and depends on the size of the aneurysms. Regular follow-up is therefore important.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides compose a family of conditions involving severe, systemic, small-vessel vasculitis featuring autoantibodies directed against the neutrophil proteins leukocyte proteinase 3 or myeloperoxidase. Their clinical presentation and therapies have been recently reviewed [34]. Within this group of diseases, eosinophilic granulomatosis with polyangiitis most commonly involves coronary vessels. This condition (which is not necessarily mediated by ANCA) has an incidence of ~0.5–2 cases per million per year, its time of onset is typically in the middle or older age and is equally frequent in males and females. Histologically, it is characterized by eosinophil-rich and necrotizing granulomatous inflammation predominantly affecting small-to-medium vessels; eosinophilia is the typical marker and pulmonary involvement and asthma are often associated. Connected, but not overlapping, with this condition, the first case of a novel medium-sized arteritis with eosinophilic inflammation limited to the adventitia and periadventitial soft tissue of epicardial coronary arteries was reported in 1989. Eosinophilic coronary periarteritis is not systemic and differs from poliarteritis nodosa and Churg–Strauss Syndrome in that it does not involve other arterial layers and it does not show fibrinoid necrosis. This form of coronary artery vasculitis has an adult onset and it has been associated with cases of spontaneous coronary artery dissection or coronary spasm [35,36]. Eosinophilic arteritis without dissection is more frequent in men than women, while a spontaneous dissection—prevalently of the left anterior descending coronary—is more frequent in females. Although the etiology and pathogenesis of this condition remain uncertain, it is possible that this disease may play a role in several cases of spontaneous dissection that remain etiologically undiagnosed. Churg–Strauss syndrome is a related disease that is diagnosed in the presence of the following six criteria: severe asthma, fleeting pulmonary infiltrates on chest radiographs, eosinophilia, paranasal sinus abnormalities, eosinophilic infiltration on biopsy, and neurologic manifestations. The highest incidence is in the fourth-fifth decade of life and is higher in females. Cardiac involvement may manifest as pericarditis, restrictive or dilated cardiomyopathy, myocarditis, arrhythmias, and sudden cardiac death. The prognosis of these diseases is markedly improved by the use of corticosteroids, and the mortality is in the range of 30% at 5 years [37].

Behçet disease is a severe disease most frequent in the eastern Mediterranean and the east, where it reaches an incidence of 0.03% of the population. The incidence in males, most commonly in the fourth and fifth decade of life, is three times higher than in females. The most common manifestations include signs of inflammatory activation such as fever and constitutional symptoms. Clinical features of this disease include oral and/or genital ulcerations, ocular disease, and arthritis. Behçet´s disease has an unknown cause even though a genetic predisposition is suspected; its pathophysiology is based on autoinflammatory mechanisms, endothelial damage/dysfunction, and impaired fibrinolysis involving the activation of T-lymphocytes, including T helper 17 cells, immune complex formation, neutrophil activation, and the secretion of inflammatory cytokines. From the histologic perspective, Behçet is associated with perivasculitis with neutrophil infiltration, fibrinoid necrosis and endothelial swelling [15,16]. Anti-lymphocyte and anti-cardiolipin antibodies are a feature of this condition and allow its diagnosis. Arterial involvement in Behçet disease manifest itself as aneurysms of the medium- and large-sized arteries. The vascular manifestations of Behçet vary between 10 and 30% of the cases and may involve both arteries and, approximately 4 times more frequently, veins [14]. Vascular involvement portends a negative prognosis, particularly in younger males without traditional coronary artery disease risk factors (except for smoking). Although native coronary disease is most commonly described, cases of in-stent restenosis have also been reported [14]. Therapy may include colchicine and general immunosuppressive therapy with corticosteroids, azathioprine, cyclosporine A, and cyclophosphamide). The prognosis is good, although the incidence of relapses is very high.

Erdheim–Chester disease is a rare non-Langerhans histiocytosis and is essentially a malignancy of myeloid progenitor cells caused by a somatic mutation of signaling molecule genes, which explains the increased expression of inflammatory cytokines (IL-6, interferon alpha, MCP-1). Fewer than 1000 cases of this disease have been reported, most commonly under the form of multifocal sclerotic lesions of the bones. Bone pain, neurologic symptoms, and cardiac symptoms are the most common manifestations. It may result in multisystem involvement including vasculitis-like phenomena of large and medium-sized arteries, particularly of the aorta (around 60% in a recent case series) [17]. Coronary artery involvement is rather common (55%), leading to about one-third of deaths [38]. The most common presentation includes infiltration, particularly at the level of the right atrium; periarterial fibrosis, thickening and pleural effusion are also common. Its histologic hallmark is perinephric fibrosis. The treatment may include a BRAF inhibitor (vemurafenib), a MEK inhibitor, interferon alfa, or immunosuprression with corticosteroids or cytotoxic therapies. Five-year survival reaches 70%.

Immunoglobulin G4-related disease is a rare fibroinflammatory condition with multiorgan lymphoplasmacytic infiltration that affects more comonly males. Every organ may be affected and extracardiac involvement may manifest as sialadenitis, thyroiditis, nephritis, lymphadenopathy, and lung disease. The pathogenesis of this disease appears to depend on an immune response mediated by Th1 and Th2 cells, while the role of IgG4 antibodies remains unclear. Cardiovascular manifestations of IgG4-RD may include aortitis, medium-sized vessel arteritis, pulmonary vascular disease, phlebitis, valvulopathy, pericarditis, and antineutrophilic cytoplasmic antibody-associated vasculitis and more frequently involve the abdominal vasculature, even though cardiac cases have also been reported [39,40]. Therapy with glucocorticoids leads to a remission in 98% of the cases, but a spontaneous remission without therapy is also often observed. Cases that are refractory to steroids and require immunosuppression, however, also exist.