Vasa Vasorum Vasculitis Research Articles

Vasculitis of Vasa Vasorum and Aneurysm Formation in Kawasaki Disease: Predilection for Coronary Arteries Lesions

<i>Backgrounds</i>. The mechanism causing coronary artery lesions in Kawasaki disease (KD) has not yet been fully clarified. <i>Objective</i>. We hypothesized that the main coronary artery (MCA) segment perfused by the vasa vasorum (VV) arose from the atrial and ventricular branches of peripheral coronary arteries in the myocardium (Type 1 VV externa) is more prone to aneurysm formation than that perfused by Type 2 VV originated from the ostium. <i>Methods and Results</i>. We reviewed the coronary angiography and two-dimensional echocardiogram (2DE) data of KD patients in our hospital and measured the distances from the left coronary ostium to the proximal point of the aneurysm in the left MCA (D1) and to the MCA bifurcation (D2). We found that the ratio of the distances (D1/D2) was negatively correlated with the patients’ age of KD onset, indicating that longitudinal extension of the left MCA aneurysms coincided with the development of Type 1 VV externa. We performed a literature review of KD cases with extracardiac aneurysms and found that 15 patients also had giant aneurysms in the MCA. Also, 8 of 9 extracardiac aneurysm cases whose clear 2DE images were available in the reports, the giant MCA aneurysms seemed to have developed at positions immediately adjacent to the ostium. We assume that the giant coronary aneurysms might be a consequence of the coincidence of aneurysms in the MCA segments perfused by Type 1 and 2 VV externas and reflect a severe inflammation where Type 2 VV externa which is less susceptible to blood flow reduction than Type 1 VV externa is affected. <i>Conclusions</i>. Vasculitis in VV externa with the unique structure originating from and distributing most richly across coronary arteries might induce a vicious circle of hypoperfusion of VV externa and reduced coronary blood flow.

Difference in the expression of IL-9 and IL-17 correlates with different histological pattern of vascular wall injury in giant cell arteritis.

GCA is a large- and medium-vessel arteritis characterized by a range of histological patterns of vascular wall injury. The aim of this study was to immunologically characterize the various histological patterns of GCA. Thirty-five consecutive patients with biopsy-proven GCA and 15 normal controls were studied. IL-8, IL-9, IL-9R, IL-17, IL-4, TGF-β and thymic stromal lymphopoietin expression was evaluated by RT-PCR and immunohistochemistry on artery biopsy specimens. Confocal microscopy was used to characterize the phenotypes of IL-9-producing and IL-9R-expressing cells. Five additional patients who had received prednisone when the temporal artery biopsy was performed were also enrolled to evaluate the effect of glucocorticoids on IL-9 and IL-17 expression. IL-17 overexpression was observed mainly in arteries with transmural inflammation and vasa vasorum vasculitis. IL-9 overexpression and Th9 polarization predominated in arteries with transmural inflammation and small-vessel vasculitis. The tissue expression of both IL-9 and IL-17 was correlated with the intensity of the systemic inflammatory response. IL-4, TGF-β and thymic stromal lymphopoietin, which are involved in the differentiation of Th9 cells, were overexpressed in arteries with transmural inflammation and small-vessel vasculitis. IL-9R was also overexpressed in GCA arteries with transmural inflammation and was accompanied by increased expression of IL-8. Herein we provide the first evidence that distinct populations of potentially autoreactive T cells, expressing different cytokines (Th17 vs Th9), characterize patients with particular histological subsets of GCA and may thus contribute to the heterogeneity of tissue lesions observed in these patients.

Inflamed temporal artery: histologic findings in 354 biopsies, with clinical correlations.

We reviewed 888 temporal artery biopsies (TAB) performed in 871 patients in a single institution from January 1986 to December 2013. Forty-four biopsies (4.9%) were inadequate, 490 (55.2%) were devoid of inflammation and were considered negative, and 354 (39.9%) showed inflammation and were considered positive. On the basis of the localization of the inflammation, positive TABs were further classified into 4 categories: small vessel vasculitis (SVV), in which inflammation was limited to small periadventitial vessels devoid of muscular coat, with sparing of the temporal artery (32 cases, 9% of the positive biopsies); vasa vasorum vasculitis (VVV), in which inflammation was limited to the adventitial vasa vasorum (23 cases, 6.5% of the positive biopsies); inflammation limited to adventitia (ILA), in which inflammation extended from a strictly perivascular localization to the surrounding adventitia, without medial involvement (25 cases, 7% of the positive biopsies); and transmural inflammation (TMI), in which inflammation crossed the external elastic lamina and extended to the media (274 cases, 77.5% of the positive biopsies). In TMI, inflammation was generally more prominent between media and adventitia and mostly consisted of T lymphocytes and macrophages, with occasionally a significant number of plasma cells. Numerous eosinophils or neutrophils (with or without leucocytoclasia and suppurative necrosis), fibrinoid necrosis (limited to small branches of the temporal artery), and acute thrombosis were unusual, being present in 8%, 1.8%, 0.7%, and 9.5% of our biopsies with TMI, respectively. Giant cells, laminar necrosis, and calcifications prevailed along the internal elastic lamina and were present in 74.8%, 25.2%, and 20% of the biopsies with TMI, respectively. Among the 322 patients with positive TAB on whom we obtained clinical information, 317 had giant cell arteritis and 5 had a different disease: 3 (with SVV at histology) had ANCA-associated vasculitis, 1 (with SVV with amyloid deposits) had primary systemic amyloidosis, and 1 (with TMI limited to a small branch) had polyarteritis nodosa. In none of these cases the biopsy showed fibrinoid necrosis or significant numbers of eosinophils or neutrophils. Considering the 317 patients with giant cell arteritis, those with SVV and VVV compared with those with TMI had a significantly lower frequency of cranial manifestation (including headache, jaw claudication, and abnormalities of temporal arteries), lower serum levels of acute-phase reactants, and a reduced frequency of prednisone therapy at the time of TAB, of the "halo sign" at color duplex sonography of temporal arteries, and of systemic symptoms (for VVV). Polymyalgia rheumatica and blindness were equally represented in all patients groups, whereas there was a higher frequency of male sex and peripheral arthritis in patients with SVV. Patients with ILA were more similar to those with TMI, having a lower frequency of headache, of abnormalities of temporal arteries, and of a positive "halo sign" at color duplex sonography of temporal arteries. In conclusion, the histologic spectrum of inflammatory lesions that can be found in TAB is broad, and the differences have clinical implications.

Is colour duplex sonography-guided temporal artery biopsy useful in the diagnosis of giant cell arteritis? A randomized study.

The aim of this study was to assess the usefulness of colour duplex sonography (CDS)-guided temporal artery biopsy (TAB) for the diagnosis of GCA in patients with suspected GCA. From September 2009 through December 2012, 112 consecutive patients with suspected GCA were randomized to undergo CDS-guided TAB or standard TAB. All patients underwent temporal artery physical examination and temporal artery CDS prior to TAB. CDS of the temporal artery was performed by the same ultrasonographer, who was unaware of the patient's clinical data, and all TABs were evaluated by the same pathologist. Seven patients in whom biopsy failed to sample temporal artery tissue were excluded from the analysis. Fifty patients were randomized to undergo CDS-guided TAB and 55 patients to standard TAB. Except for a younger age in patients who underwent standard TAB (P = 0.026), no significant differences were observed between the two groups. There were no significant differences in the frequencies of positive TAB for classic transmural inflammation (28% vs 18.2%) or for periadventitial small vessel vasculitis and/or vasa vasorum vasculitis (6% vs 14.5%) between the two groups. No significant differences in the frequency of positive TAB in the two groups were observed when we excluded the patients treated with glucocorticoids and when we stratified the patients of the two groups for the presence or absence of the halo sign. Our study showed that CDS-guided TAB did not improve the sensitivity of TAB for diagnosing GCA.

FRI0472 Correlations between Different Histological Subsets of GIANT Cell Arteritis and Clinical Manifestations in A Large Monocentric Cohort of Biopsy Positive GCA Patients

BackgroundTemporal artery biopsy (TAB) showing transmural inflammation is considered the gold standard for the diagnosis of giant cell arteritis (GCA). In some cases of GCA, inflammation is confined to the...

SAT0268 Comparison of Histopathological Findings with Clinical Manifestations in A Large Single Center Cohort of Patients with Biopsy-Proven GIANT Cell Arteritis

BackgroundGiant cell arteritis (GCA) is a vasculitis that involves large and medium sized arteries in patients older than 50 years. Temporal artery biopsy (TAB) is the gold standard for the...

Comparison between colour duplex sonography findings and different histological patterns of temporal artery

To assess the findings of temporal artery colour duplex sonography (CDS) in GCA characterized by a histological pattern of periadventitial small vessel vasculitis (SVV) and/or vasa vasorum vasculitis (VVV) and compare it with those observed in classic GCA with transmural vasculitis. We studied 30 patients with SVV and/or VVV, 63 patients with classic GCA and 67 biopsy-negative patients identified over a 9-year period. CDS of the temporal arteries was performed in all patients by one ultrasonographer. Temporal artery biopsy was used as the reference standard. Sensitivities, specificities and likelihood ratios (LRs) were calculated. The frequency of the halo sign on CDS was significantly lower in the patients with SVV and/or VVV compared with those with classic GCA (20% vs 82.5%, P = 0.0001). The halo sign had a sensitivity of only 20% (95% CI 8.4, 39.1%) and a specificity of 80.6% (95% CI 68.7, 88.9%) for the diagnosis of SVV and/or VVV. The negative LR was 0.992 (CI 0.824, 1.195), and the positive LR was 1.030 (CI 0.433, 2.451). The halo sign for the diagnosis of biopsy-proven classic GCA had a higher sensitivity of 82.5% (CI 70.5, 90.5%), the same specificity of 80.6% (CI 68.7, 88.9%) and a higher positive LR (4.253; CI 2.577, 7.021). The halo sign is infrequently found in GCA characterized by a histological pattern of SVV and/or VVV. This limits the sensitivity of CDS in correctly identifying patients with GCA.

Small‐vessel vasculitis surrounding an uninflamed temporal artery and isolated vasa vasorum vasculitis of the temporal artery: Two subsets of giant cell arteritis

To evaluate the frequency and clinical characteristics of periadventitial small-vessel vasculitis (SVV) and isolated vasa vasorum vasculitis (VVV). We identified 455 temporal artery biopsies performed in residents of Reggio Emilia, Italy between 1986 and 2003. Slides of temporal artery biopsy specimens were reviewed by a pathologist who was blinded with regard to clinical data. SVV was defined as inflammation of the small vessels external to the temporal artery adventitia, and VVV was defined as isolated inflammation of temporal artery vasa vasorum. Medical records of patients with SVV and/or VVV were reviewed, and demographic, clinical, laboratory, and followup data were collected. For comparison purposes, we collected the same data from an equal number of randomly selected patients with evidence of classic giant cell arteritis (GCA). Sixteen patients had SVV, 18 had isolated VVV, and 5 had both SVV and VVV. Compared with patients with classic GCA, the frequencies of headache, scalp tenderness, abnormalities of temporal arteries, jaw claudication, anorexia, and weight loss, the levels of acute-phase reactant at diagnosis, and the initial and cumulative doses prednisone were significantly lower and the frequency of peripheral synovitis was higher in the patients with SVV, and the frequency of cranial ischemic events was similar in the 2 groups. In contrast, the clinical characteristics and erythrocyte sedimentation rate at diagnosis of patients with isolated VVV were similar to those of patients with classic GCA. Our findings indicate that isolated VVV and SVV should be considered part of the histopathologic spectrum of GCA.

Chronic periaortitis: a large-vessel vasculitis?

Chronic periaortitis is characterized by a fibro-inflammatory process spreading from the abdominal aorta and the iliac arteries. Originally, chronic periaortitis was considered a localized inflammatory response to severe aortic atherosclerosis. However, subsequent studies have shown that chronic periaortitis may also involve other arteries and present with features of auto-immune diseases. This article reviews the issue of large-vessel involvement in chronic periaortitis and its implications in the pathogenesis and nosography of the disease. In many reports, chronic periaortitis has been shown to involve not only the aorto-iliac axis but also other vascular segments such as the thoracic aorta, the proximal epiaortic arteries, the coronary, renal, and mesenteric arteries. Thoracic aorta involvement may manifest as thoracic periaortitis with or without aneurysmal dilatation, or simply as thoracic aorta aneurysm. Thoracic periaortitis can also be a feature of the so-called IgG4-related systemic disease, with which chronic periaortitis may sometimes be associated. Histopathologic studies of chronic periaortitis show adventitial inflammation and fibrosis, vasculitis of vasa vasorum, and adventitial lymphoid follicles with germinal centers, suggesting that chronic periaortitis could be a primary aortitis. Genetic studies have demonstrated an association with HLA-DRB1*03, a marker of auto-immunity, and with the CCR5Δ32 polymorphism, which has been mapped to a Th2 response. Taken together, these findings support the notion of a primary inflammatory or immune-mediated disorder. Chronic periaortitis is an inflammatory or immune-mediated disorder characterized histopathologically by adventitial inflammation and clinically by variable involvement of different arteries, mainly of large caliber. These findings raise the issue of whether chronic periaortitis should be considered a large-vessel vasculitis.

Association of low-grade urinary albumin excretion with left ventricular hypertrophy in the general population: a reply

cases of retroperitoneal fibrosis are secondary to specific causes, namely: drugs, infection, retroperitoneal haemorrhage and malignancy, while the other two-thirds of cases are considered idiopathic, as no specific causes can be identified. The histological lesions of retroperitoneal fibrosis in patients with and without inflammatory aneurysm are not different and the suggested pathogenesis for the disease does not differentiate between the two forms. In fact, inflammation and autoimmunity have been advocated as the pathogenetic processes leading to idiopathic retroperitoneal fibrosis. Inflammation is well documented by the rise of inflammatory tests and by the presence of inflammatory cells sometimes associated with frank vasculitic lesions in the fibrotic tissue. The reported association of the disease with other autoimmune disorders suggests that idiopathic retroperitoneal fibrosis could be an immunemediated disorder with marked inflammatory vascular traits. Parums et al. [1] postulated that the disease may be due to an immune reaction to some components of atherosclerothic plaques, i.e. ceroids, which are a complex of proteins and oxidized LDL. This hypothesis has been partially confirmed by the finding of antibodies directed against ceroid in the sera of patients with retroperitoneal fibrosis. However, the same antibodies have also been detected in the sera of healthy elderly subjects and in patients with atherosclerosis [1]. In fact, no clear differences in the severity of atherosclerosis have been demonstrated between patients with chronic periaortitis and controls [2] and this theory would not explain retroperitoneal fibrosis occurring in children and young people, who have no atheromatous arterial disease. Another possible pathogenetic hypothesis for chronic periaortitis suggests that vasa vasorum vasculitis of the aortic adventitia could be the ‘primum movens’ of chronic periaortitis, as demonstrated for other inflammatory aorta disorders and its main branches such as Takayasu arteritis, Behcet’s disease and aortitis associated with spondyloarthropaties [3]. As hypothesized by Numano et al .[ 4], regarding the above-mentioned diseases, vasa vasorum vasculitis of the aortic adventitia may trigger the recruitment of inflammatory cells in the aortic adventitia and in the retroperitoneum. The inflammatory process may progress from the adventitia to the media and the intima with consequent infiltration of lipids, blood cells and other blood material causing intimal changes similar to typical atherosclerotic lesions or inflammatory aneurysms. Our recent demonstration, that patients with active retroperitoneal fibrosis had a significantly increased number of circulating endothelial cells of microvascular origin with an activated phenotype (as evidenced by the surface expression of E-selectin), in comparison to healthy subjects and patients with diffuse atherosclerosis, would indicate that endothelial injury, as a part of immune-mediated inflammatory vascular damage, may play a key role in the pathogenesis of chronic periaortitis [5] and may support the above-mentioned pathogenetic hypothesis. In conclusion, in our opinion, the retroperitoneal fibrosis observed in patients with and without inflammatory aneurysm could however be considered idiopathic.

132 Increased arterial stiffness is associated with left ventricular diastolic dysfunction in patients with Adamantiades-Behcet's disease

Adamantiades-Behcet’s disease (ABD) is multisystem disorder characterized by vasculitis leading to arterial aneurysm formation, stroke and arterial or venous occlusive disease. We investigated whether arterial stiffness is related with left ventricular (LV) dysfunction in patients with ABD. Methods: We studied 73 patients with ABD (age 3911 years) by 2D and Doppler echocardiography for assessment of thoracic and abdominal Ao (ABAO) diameters (mm/BSA), LV diastolic function [E/A ratio, deceleration (DT-ms) and isovolumic relaxation time (IVRT-ms)] and radial artery tonometry with pulse wave analysis (Sphygmocor) for estimation of arterial stiffness [central augmentation index (CAI%), reflection time index,(RTI-%))] Results: All patients had normal systolic LV function. Abnormal CAI and RTI were related to increased ABAO diameters (r=0.36 and r=-0.28, P 125 ms (n=36) or RTI 14 (table). CAI >125 would predict an IVRT >95 with 72% sensitivity and 61% specificity (ROC curve area:71% (CI:57-83)). CAI DT IVRT ABAO RTI DT IVRT ABAO >125 (n=36) 210±40 92±16 11±1.8 14(n=34) 189±36 83±15 9.9±1.7 p <0.01 <0.01 <0.01 p <0.01 <0.01 <0.01 Conclusion: Patients with ABD present increased aortic diameters, associated with significant arterial stiffness possibly due to vasa vasorum vasculitis. Increased arterial stiffness may reduce coronary blood flow or increase LV afterload and thus, cause significant LV diastolic dysfunction in these patients.