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Thoracic Aortic Aneurysm—Guilt by Association Chapter | 10 117
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Prepregnancy counseling is advised in patients with increased risk of aneurysm, such as those with Marfan syndrome
or BAVs. For those with particularly high risk—as those with Marfan syndrome and/or a TAA greater than 4 cm in diameter—pregnancy should be avoided until after surgical correction [63].
REFERENCES
[1] Elefteriades JA, Sang A, Kuzmik G, Hornick M. Guilt by association: paradigm for detecting a silent killer (thoracic aortic aneurysm). Open Heart
2015;2:e000169.
[2] Ziganshin BA, Elefteriades JA. Guilt by association: a paradigm for detection of silent aortic disease. Ann Cardiothorac Surg 2016;5:174–87.
[3] Chaer RA, Vasoncelos R, Marone LK, et al. Synchronous and metachronous thoracic aneurysms in patients with abdominal aortic aneurysms. J Vasc
Surg 2012;56:1261–5.
[4] Kim SC, Singh M, Huang J, et al. Matrix metalloproteinase-9 in cerebral aneurysms. Neurosurgery 1997;41:642–66. Discussion 646–647.
[5] Koullias GJ, Ravichandran P, Korkolis DP, Rimm DL, Elefteriades JA. Increased tissue microarray matrix metalloproteinase expression favors
proteolysis in thoracic aortic aneurysms and dissections. Ann Thorac Surg 2004;78:2106–10. Discussion 2110–2101.
[6] Zhang X, Shen YH, LeMaire SA. Thoracic aortic dissection: are matrix metalloproteinases involved? Vascular 2009;17:147–57.
[7] Schievink WI. Intracranial aneurysms. N Engl J Med 1997;336:28–40.
[8] Schievink WI. Cerebrovascular involvement in Ehlers-Danlos syndrome. Curr Treat Options Cardiovasc Med 2004;6:231–6.
[9] Cannon Albright LA, Camp NJ, Farnham JM, MacDonald J, Abtin K, Rowe KG. A genealogical assessment of heritable predisposition to aneu-
rysms. J Neurosurg 2003;99:637–43.
[10] Kuzmik GA, Feldman M, Tranquilli M, Rizzo JA, Johnson M, Elefteriades JA. Concurrent intracranial and thoracic aortic aneurysms. Am J Cardiol
2010;105:417–20.
[11] Kuzmik G, Gunel M, Bulsara K, Tranquilli M, Elefteraides JA. Intracranial aneurysm patients may harbor thoracic aortic aneurysms. In: American
association of thoracic surgery aortic symposium 2012. 2012. New York (NY).
[12] Kuzmik G.A., Correlations between intracranial aneurysms and thoracic aortic aneurysms. In:1 Online resource 2013;(59 pp.).
[13] Regalado E, Medrek S, Tran-Fadulu V, et al. Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and
intracranial saccular aneurysms. Am J Med Genet a 2011;155A:2125–30.
[14] Dumfarth J, Chou AS, Ziganshin BA, et al. Atypical aortic arch branching variants: a novel marker for thoracic aortic disease. J Thorac Cardiovasc
Surg 2015;149:1586–92.
[15] Hornick M, Moomiaie R, Mojibian H, et al. ‘Bovine’ aortic arch – a marker for thoracic aortic disease. Cardiology 2012;123:116–24.
[16] Malone CD, Urbania TH, Crook SE, Hope MD. Bovine aortic arch: a novel association with thoracic aortic dilation. Clin Radiol 2012;67:28–31.
[17] Keyte A, Hutson MR. The neural crest in cardiac congenital anomalies. Differentiation 2012;84:25–40.
[18] Moorehead PA, Kim AH, Miller CP, Kashyap TV, Kendrick DE, Kashyap VS. Prevalence of bovine aortic arch configuration in adult patients with
and without thoracic aortic pathology. Ann Vasc Surg 2016;30:132–7.
[19] Kirby ML, Waldo KL. Role of neural crest in congenital heart disease. Circulation 1990;82:332–40.
[20] Diwan A, Sarkar R, Stanley JC, Zelenock GB, Wakefield TW. Incidence of femoral and popliteal artery aneurysms in patients with abdominal aortic
aneurysms. J Vasc Surg 2000;31:863–9.
[21] Albornoz G, Coady MA, Roberts M, et al. Familial thoracic aortic aneurysms and dissections–incidence, modes of inheritance, and phenotypic pat-
terns. Ann Thorac Surg 2006;82:1400–5.
[22] Hultgren R, Larsson E, Wahlgren CM, Swedenborg J. Female and elderly abdominal aortic aneurysm patients more commonly have concurrent
thoracic aortic aneurysm. Ann Vasc Surg 2012;26:918–23.
[23] Larsson E, Vishnevskaya L, Kalin B, Granath F, Swedenborg J, Hultgren R. High frequency of thoracic aneurysms in patients with abdominal aortic
aneurysms. Ann Surg 2011;253:180–4.
[24] Ruddy JM, Jones JA, Ikonomidis JS. Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin.
Prog Cardiovasc Dis 2013;56:68–73.
[25] Verma S, Siu SC. Aortic dilatation in patients with bicuspid aortic valve. N Engl J Med 2014;370:1920–9.
[26] Roberts WC. The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol 1970;26:72–83.
[27] Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002;39:1890–900.
[28] Fedak PW, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation
2002;106:900–4.
[29] Davies RR, Kaple RK, Mandapati D, et al. Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve. Ann
Thorac Surg 2007;83:1338–44.
[30] Oladokun D, Patterson BO, Sobocinski J, et al. Systematic review of the growth rates and influencing factors in thoracic aortic aneurysms. Eur J Vasc
Endovasc Surg 2016;51:674–81.
[31] Wojnarski CM, Svensson LG, Roselli EE, et al. Aortic dissection in patients with bicuspid aortic valve-associated aneurysms. Ann Thorac Surg
2015;100:1666–74.
[32] Friedman T, Mani A, Elefteriades JA. Bicuspid aortic valve: clinical approach and scientific review of a common clinical entity. Expert Rev
Cardiovasc Ther 2008;6:235–48.
118 PART | I Overview
https://t.me/med1917
[33] Biner S, Rafique AM, Ray I, Cuk O, Siegel RJ, Tolstrup K. Aortopathy is prevalent in relatives of bicuspid aortic valve patients. J Am Coll Cardiol
2009;53:2288–95.
[34] Ikonomidis JS, Ruddy JM, Benton Jr SM, et al. Aortic dilatation with bicuspid aortic valves: cusp fusion correlates to matrix metalloproteinases and
inhibitors. Ann Thorac Surg 2012;93:457–63.
[35] Hope MD, Hope TA, Meadows AK, et al. Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns.
Radiology 2010;255:53–61.
[36] Barker AJ, Markl M, Burk J, et al. Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta. Circ Cardiovasc Imaging
2012;5:457–66.
[37] Michelena HI, Desjardins VA, Avierinos JF, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional
bicuspid aortic valve in the community. Circulation 2008;117:2776–84.
[38] Tobin Jr JR, Bay EB, Humphreys EM. Marfan’s syndrome in the adult dissecting aneurysm of the aorta associated with arachnodactyly. Arch Intern
Med (Chic) 1947;80:475–90.
[39] Halushka MK. Single gene disorders of the aortic wall. Cardiovasc Pathol 2012;21:240–4.
[40] Falk RH. Images in clinical medicine. The “thumb sign” in Marfan’s syndrome. N Engl J Med 1995;333:430.
[41] Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476–85.
[42] Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010;55:841–57.
[43] Coady MA, Davies RR, Roberts M, et al. Familial patterns of thoracic aortic aneurysms. Arch Surg 1999;134:361–7.
[44] Biddinger A, Rocklin M, Coselli J, Milewicz DM. Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg 1997;25:506–11.
[45] Erbel R, Aboyans V, Boileau C, et al. Corrigendum to: 2014 ESC guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J
2015;36:2779.
[46] Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and man-
agement of patients with thoracic aortic disease. A report of the American College of Cardiology Foundation/American heart association Task
force on practice guidelines, American association for thoracic surgery, American College of Radiology,American stroke association, Society of
Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and interventions, Society of interventional Radiology, Society of tho-
racic Surgeons,and Society for vascular medicine. J Am Coll Cardiol 2010;55:e27–129.
[47] Ziganshin BA, Bailey AE, Coons C, et al. Routine genetic testing for thoracic aortic aneurysm and dissection in a clinical setting. Ann Thorac Surg
2015;100:1604–11.
[48] Kim EK, Choi ER, Song BG, et al. Presence of simple renal cysts is associated with increased risk of aortic dissection: a common manifestation of
connective tissue degeneration? Heart 2011;97:55–9.
[49] Yaghoubian A, de Virgilio C, White RA, Sarkisyan G. Increased incidence of renal cysts in patients with abdominal aortic aneurysms: a common
pathogenesis? Ann Vasc Surg 2006;20:787–91.
[50] Ito T, Kawaharada N, Kurimoto Y, et al. Renal cysts as strongest association with abdominal aortic aneurysm in elderly. Ann Vasc Dis 2010;3:111–6.
[51] Harada H, Furuya M, Ishikura H, Shindo J, Koyanagi T, Yoshiki T. Expression of matrix metalloproteinase in the fluids of renal cystic lesions. J Urol
2002;168:19–22.
[52] Liu B, Li C, Liu Z, Dai Z, Tao Y. Increasing extracellular matrix collagen level and MMP activity induces cyst development in polycystic kidney
disease. BMC Nephrol 2012;13:109.
[53] Chow K, Pyeritz RE, Litt HI. Abdominal visceral findings in patients with Marfan syndrome. Genet Med 2007;9:208–12.
[54] Ikonomidis JS, Jones JA, Barbour JR, et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms
of patients with Marfan syndrome. Circulation 2006;114:I365–70.
[55] Ziganshin BA, Theodoropoulos P, Salloum MN, et al. Simple renal cysts as markers of thoracic aortic disease. J Am Heart Assoc 2016;5:e002248.
[56] Segarra M, Garcia-Martinez A, Sanchez M, et al. Gelatinase expression and proteolytic activity in giant-cell arteritis. Ann Rheum Dis
2007;66:1429–35.
[57] Rodriguez-Pla A, Bosch-Gil JA, Rossello-Urgell J, Huguet-Redecilla P, Stone JH, Vilardell-Tarres M. Metalloproteinase-2 and -9 in giant cell arte-
ritis: involvement in vascular remodeling. Circulation 2005;112:264–9.
[58] Rittner HL, Kaiser M, Brack A, Szweda LI, Goronzy JJ, Weyand CM. Tissue-destructive macrophages in giant cell arteritis. Circ Res 1999;84:1050–8.
[59] Mackie SL, Hensor EM, Morgan AW, Pease CT. Should I send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A
systematic literature review and meta-analysis. Ann Rheum Dis 2014;73:143–8.
[60] Garcia-Martinez A, Arguis P, Prieto-Gonzalez S, et al. Prospective long term follow-up of a cohort of patients with giant cell arteritis screened for
aortic structural damage (aneurysm or dilatation). Ann Rheum Dis 2014;73:1826–32.
[61] Schattner A, Gotler J. Precordial pain in a patient with rheumatoid arthritis. Mayo Clin Proc 2013;88:e103–104.
[62] Iribarren-Marin MA, Carnerero-Herrera V, Dominguez-Perez A, Gonzalez-Martin R. Acute aortic syndrome and rheumatoid arthritis. Rev Esp
Cardiol 2011;64:246–7.
[63] Smok DA. Aortopathy in pregnancy. Semin Perinatol 2014;38:295–303.
[64] Thornburg KL, Jacobson SL, Giraud GD, Morton MJ. Hemodynamic changes in pregnancy. Semin Perinatol 2000;24:11–4.
[65] Campisi D, Bivona A, Paterna S, Valenza M, Albiero R. Oestrogen binding sites in fresh human aortic tissue. Int J Tissue React 1987;9:393–8.
[66] Manalo-Estrella P, Barker AE. Histopathologic findings in human aortic media associated with pregnancy. Arch Pathol 1967;83:336–41.
[67] Elefteriades JA. Thoracic aortic aneurysm: reading the enemy’s playbook. Curr Probl Cardiol 2008;33:203–77.
Chapter 11
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Inflammatory Diseases (Takayasu, Giant
Cell Arteritis, Behçet Disease)
Cătălina Arsenescu-Georgescu
1
“Prof. Dr. George I.M. Georgescu” Institute of Cardiovascular Diseases, Iasi, Romania; 2“Grigore T. Popa” University of Medicine and Pharmacy,
Iasi, Romania
Chapter Outline
Vascular Inflammation—Central Role in the Pathogenesis of
Takayasu’s Arteritis, Giant Cell Arteritis, and Behçet Disease 119
Biomarkers in Inflammatory Vasculitis 120
Diagnostic Imaging and Assessment of Aortic Inflammation 121
Pleiotropic Therapy of Inflammatory Vasculitis 122
1, 2
, Liviu Macovei
1, 2
Corticosteroids and Cytotoxic Agents 122
Future Therapies 124
B Cell Depletion 125
References 125
VASCULAR INFLAMMATION—CENTRAL ROLE IN THE PATHOGENESIS OF TAKAYASU’S
ARTERITIS, GIANT CELL ARTERITIS, AND BEHÇET DISEASE
Takayasu’s arteritis (TAK) is a large-vessel panarteritis with a chronic, indolent course affecting the aorta and its main
branches and the pulmonary arteries, with intimal proliferation [1]. Segmental stenosis, occlusion, dilatation, or aneurysm
formation may occur in the vessel wall during the course of the disease [2].
The underlying pathologic process in TAK is inflammatory, with several etiologic factors having been proposed, including spirochetes, Mycobacterium tuberculosis, streptococcal organisms, and circulating antibodies due to an autoimmune
process. Acute lesions contain mononuclear cell infiltrates that appear to have entered the vessel wall through the vasa
vasorum and subsequently migrate to the arterial intima. These cells are predominantly macrophages and T cells (gammadelta, cytotoxic, and natural killer). The presence of various cytokines, including interleukin-6 (IL-6) and tumor necrosis
factor (TNF) in these granulomatous lesions, has prompted various therapeutic approaches using cytokine-targeted biologic
agents [3].
Genetic factors may play a role in the pathogenesis. An antigen may stimulate aortic tissue, leading to the expression of
heat shock protein-65, which, in turn, induces major histocompatibility complex (MHC) class I–related chain A (MICA)
[4]. Natural killer cells and gamma-delta T cells expressing NKG2D (natural killer group 2D) receptors may infiltrate
and recognize MICA on vascular smooth muscle cells, leading to acute inflammation. Proinflammatory cytokines are
also released from the natural killer and T cells, inducing the production of matrix metalloproteinases and amplifying the
inflammatory response. This, in turn, would induce more MHC antigen and stimulate molecule expression on vascular
cells, recruiting more mononuclear cells. Histocompatibility complexes are activated through toll-like receptors. Th1 lymphocytes, through interferon-gamma, activate macrophages, which, in turn, release vascular endothelial growth factor. This
ultimately results in smooth muscle migration and intimal proliferation [4].
Giant cell arteritis (GCA) is also a chronic autoimmune vasculitis whose major hallmark is the inflammatory damage of
medium size and large blood vessels, mainly the aorta and external carotid arteries and their corresponding branches. GCA
affects predominantly women and people generally >50 years of age, being the most common form of systemic vasculitis
in adults [5].
The cause of GCA remains unknown but it is primarily a disease of cell-mediated immunity, which is thought to arise as
a maladaptive response to endothelial injury. The vasa vasorum furnishes the conduit for the mononuclear cells (dendritic
New Approaches to Aortic Diseases from Valve to Abdominal Bifurcation. http://dx.doi.org/10.1016/B978-0-12-809979-7.00011-0
Copyright © 2018 Elsevier Inc. All rights reserved.
119
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cells, macrophages, and Th1-type lymphocytes) that mediate vascular injury. Dendritic cells participate in the process by
presenting to lymphocytes the putative antigen that is believed to promote the development of GCA. Vascular lesions initially overexpress proinflammatory cytokines such as IL-1, IL-6, TNF, and interferon-γ (IFN-γ) [6]. The primary inflammatory response involves the internal elastic lamina within the media of the arterial wall. The subsequent release of cytokines
within the arterial vessel wall can attract macrophages and multinucleated giant cells. In turn, activated CD4+ T helper cells
respond to an antigen presented by macrophages, which gives diseased vessels their characteristic histology [7].
In later stages, growth factors such as platelet-derived growth factor and fibroblast growth factor participate in stimulating myointimal proliferation, leading to vessel stenosis [8].
Actinic damage to the temporal artery from chronic sun exposure has been proposed as one source of the injury. The
adventitia is the likely site of initial immunologic injury and is considered the immunological center of the disorder,
whereas the intima and media are the histological center [9].
Behçet disease (BD) is a chronic relapsing multisystemic inflammatory disease of an unknown etiology characterized by repeated oral and genital ulcerations, ocular lesions, skin manifestations, arthritis, vasculitis, and gastrointestinal
involvement [10].
The underlying pathology is an inflammatory response in the arteries and veins, and lymphocytes play an important
role in its pathogenesis. Viral, bacterial, genetic, environmental, toxic, and immune factors all have been proposed to play
roles in its pathogenesis [11].
The basic histopathological sign of BD is vasculitis in large, medium, and small veins. Lymphocytes, monocytes,
and dense neutrophil infiltrations are evident in the lesions. Today, the most accepted view about BD pathogenesis is an
increased response of the innate and acquired immune systems against environmental antigens and autoantigens in addition
to a genetic predisposition. The presence of antilymphocyte and anticardiolipin antibodies has been reported in BD, and
they are used in the diagnosis of the disease [12].
BIOMARKERS IN INFLAMMATORY VASCULITIS
Because there are no reliable criteria available to measure the progression of inflammatory vasculitis; it is, therefore, crucial
to identify appropriate markers to monitor disease activity (Table 11.1).
Histologic findings of inflammatory cell infiltration of the arterial vascular cells strongly suggest that cell-mediated immunity plays an important role in the pathogenetic sequence leading to development of atherosclerotic lesions.
T cells and macrophages are critical players in the vasculitic process sustaining granulomatous inflammation in the
arteries. High levels of Th1 and Th17 cytokines are associated with disease activity. These Th1 and Th17 T cell responses
are reminiscent of those observed in GCA. The cytokine production pattern observed in vasculitic lesions is essentially
identical to that detected in circulating monocytes, except for the weak expression of IL-17A in inflamed vessels [13].
TABLE 11.1 Biomarkers in Inflammatory Vasculitis
Biomarker Takayasu’s Arteritis Giant Cell Arteritis Behçet Disease
IL-6 [3,5,6,22] + + +
TNF [5,6,12] + + +
IFN-γ [6,12,21,24] + + +
IL-23 [21] − − +
IL-12 [24] − − +
IL-17 [15,21,24] − − +
IL-4 [6,12,22] − + −
IL-8 [6,12,22] + − −
IL-10 [6,12] − + −
IL-18 [12,22] + + −
IL, interleukin; TNF, tumor necrosis factor.
Inflammatory Diseases (Takayasu, Giant Cell Arteritis, Behçet Disease) Chapter | 11 121
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In TAK, inflammatory cell infiltration tends to be localized in the adventitia and outer part of the media involving the
vasa vasorum. Infiltrating cells consist mainly of T lymphocytes, natural killer cells, macrophages, cytotoxic T lymphocytes, and T helper cells [14]. In animal models, mice deficient in IFN regulatory factor 4 (IRF-4)–binding protein, a protein
that inhibits IL-17A production by controlling the activity of IRF-4 transcription factor, rapidly developed a large-vessel
vasculitis due to inappropriate synthesis of IL-17A [15]. Few studies have documented quantitative and qualitative alterations in cytokine production in TAK [14,16].
In a recent study, Saadoun et al. made important insights into the pathogenic events leading to TAK. They observed an
expansion of Th1 and Th17 cell pathways that appears to have an important role in driving TAK-related inflammation, both
systemically and in blood vessels [16].
In BD, it seems to be a dominance of Th1 cytokines [17]. A recent study observed the infiltration of CD4+ and CD8+
T cells in intestinal lesions of BD, along with the expression of messenger RNAs of proinflammatory and T helper type 1
(Th1) cytokines/chemokines [18]. Th17 cells produce a number of proinflammatory cytokines, including IL-17, IL-17F,
IL-21, and IL-22. In human Th17 development, IL-1b and IL-23 are required, but the role of transforming growth factor-b
is controversial [18,19]. These cytokines induce the expression of RAR (retinoic acid receptor)-related orphan receptor C
(RORC), which is the master transcription factor of Th17 cells. An increase of IL-17 production in inflammatory bowel
disease and multiple sclerosis suggests that Th17 cell dysregulation may be involved in the pathogenesis of certain human
autoimmune diseases [19]. A recent study has identified IL-23R/IL-12RB genes as the disease-susceptible genes in BD
[20]. They suggest that both the Th17/IL-23 pathway and the Th1/IL-12 pathway may be dysregulated in patients with BD.
Another study suggested that IL-23R gene conferred susceptibility to BD [21].
Serum autoantibodies such as antiaorta or antiendothelial antibodies and serum biomarkers such as IL-6, IL-8, and
IL-18 [12,22] have been suggested to be related to active disease in TAK; however, these data require confirmatory studies.
Among biomarkers to assess clinical activity, pentraxin-3 is perhaps the most promising, but its validity and superiority
against acute-phase reactants in clinical practice need to be demonstrated [23].
Elevated levels of TNF have been detected in GCA patients with a strong systemic inflammatory response, and a high
production of this cytokine was associated with longer corticosteroid requirements for these patients. High expression
of IFN-γ is also related to the pathogenic mechanisms affecting the arterial walls in GCA patients. In this regard, GCA
is considered a typical Th1 disease, and IFN-γ-producing CD4+ T cells have been described as one of the dominant cell
populations in the arterial infiltrates. It has been observed that IFN-γ is released in the vasculitic lesions even after months
of corticosteroid therapy [24]. Other cytokines that are implicated in the pathogenesis of GCA are IL-4, IL-6, IL-10, and
IL-18 [6].
DIAGNOSTIC IMAGING AND ASSESSMENT OF AORTIC INFLAMMATION
In TAK, the diagnosis is largely based on the combination of clinical information, laboratory evaluation, and diagnostic
imaging. Digital subtraction angiography was the traditional procedure of choice, with findings ranging from mild vessel
stenosis to frank occlusion (Fig. 11.1).
Modern noninvasive diagnostic modalities including ultrasonography, positron emission tomography (PET) scan, computed tomography scanning and magnetic resonance angiography have progressively replaced conventional angiography
for diagnosis of large vessel involvement because of their reduced risks and the ability to provide information not only
about the lumen but also about the vessel wall (Table 11.2).
Aortic wall thickening, which has been described as a “double ring” appearance at contrast-enhanced computed tomography (CT), is the typical finding in the early stage, with a poorly enhanced internal ring (the swollen intima) and an
enhancing outer ring (the inflamed media and adventitia) (Fig. 11.2) [11].
Specific magnetic resonance imaging (MRI) sequences such as delayed contrast-enhanced MRI may allow the detection
of edema and arterial wall thickening at a reversible stage, before luminal narrowing occurs. MRI allows early detection of
subtle changes in the aortic wall as well as disease activity, avoiding the risks associated with arterial puncture, iodinated
contrast load, and radiation exposure. Currently, conventional angiography is basically used to guide endovascular intervention procedures or to combine imaging with the detection of central blood pressure in patients with significant limb artery
stenosis [25].
In GCA, diagnosis is usually obtained by temporal artery biopsy. CT and in particular MR angiography are able to
demonstrate vessel wall edema, which reflects activity of the disease, as well as smooth tapering proximal and distal to
the lesion (Fig. 11.3). Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been shown to be sensitive for
extracranial vasculitis but not for intracranial vasculitis on account of its poor spatial resolution [11].
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(A)(B)
(C)(D)
FIGURE 11.1 Arteriography and aortography: multiple and diffuse arterial calcifications specific for Takayasu’s arteritis in a 49-year-old woman.
PLEIOTROPIC THERAPY OF INFLAMMATORY VASCULITIS
Medical management of inflammatory vasculitis depends on the disease activity and the complications that develop. Some
patients have only mild forms of the disease; others deteriorate considerably (Table 11.3). One of the most important
aspects of treatment is controlling the inflammatory process.
Corticosteroids and Cytotoxic Agents
Corticosteroid treatment continues to be the most effective therapy for inflammatory vasculitis. Almost all patients with
TAK improve when treated with high doses of a corticosteroid (e.g., prednisone, 1 mg/kg daily or divided twice daily
and tapered over weeks to months as symptoms subside); relapses are common with tapering of corticosteroid therapy.
Corticosteroid-resistant or relapsing patients may respond to the addition to daily therapy of cyclophosphamide (approximately 2 mg/kg) or weekly therapy with methotrexate (approximately 20 mg). Approximately 40% of patients who receive
a cytotoxic agent and corticosteroids will achieve remission but, over time, about half of these patients will also relapse,
leading to the need for chronic immunosuppressive therapy in many patients [26].
Corticosteroid treatment is one of the most effective therapy also for GCA. Prednisone (≈0.7–1 mg/kg/day) will reduce
symptoms within 1–2 days and often eliminate symptoms within 1 week. Approximately 2–4 weeks after clinical and laboratory measurement, particularly of the erythrocyte sedimentation rate (ESR), normalized tapering of corticosteroids can
begin. Unfortunately, the ESR does not always normalize, even with disease control, and so it should not be relied on as the
only measure of disease activity. Occasional patients may either not achieve complete remission or not tolerate weaning of
TABLE 11.2 Imaging Techniques Applied to Assess Large-Vessel Vasculitis
(A) (B)
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Technique Findings Advantages Disadvantages
Color duplex
ultrasound
MRI Wall thickening
CTA Wall thickening
FDG-PET FDG uptake by metabolically
Angiography Lumen patency assessment Therapeutic procedures (angioplasty)
Wall thickening
Hipoechoic halo
Reduced pulsation
Stenosis/occlusions/dilatations
Contrast enhancement
Stenosis/occlusions/dilatations
Lumen patency assessment
Contrast enhancement
Stenosis/occlusions/dilatations
Lumen patency assessment
active cells such as inflammatory
infiltrate
Inexpensive
Repeatable
No radiation
No IV contrast needed
Good resolution for small arteries
Repeatable
No radiation
Rapid and available
Inexpensive
Repeatable
Repeatable
Whole body assessment
High resolution for small vessels
Central blood pressure detection
Not suitable for structures below
air or bone
Expensive
Not suitable for patients with
claustrophobia
Not feasible with metal devices
Limited resolution for small vessels
Contraindicated if renal insufficiency or iodine allergy
Radiation exposure
Expensive
Not widely available
No lumen patency assessment
No resolution for vessels <4 mm
Not suitable for cranial arteries
Invasive
Radiation
Contraindicated if renal insufficiency or iodine allergy
CTA , computed tomography angiography; FDG-PET, fluorodeoxyglucose-positron emission tomography; IL, interleukin; MRI, magnetic resonance imaging.
From Garcia-Martinez A, Prieto-Gonzalez S, Arguis Gimenez P, et al., Aortitis and aortic aneurysm in systemic vasculitis. In: Grundmann R, editor. Etiology,
pathogenesis and pathophysiology of aortic aneurysms and aneurysm rupture. In Tech; 2011. ISBN:978-953-307-523-5.
(C) (D)
FIGURE 11.2 Computed tomography scan: subocclusion of the main left coronary artery (A) and right coronary artery (B) before and after percutaneous transluminal coronary angioplasty with stent in a 49-year-old woman with Takayasu’s arteritis; important calcifications of aorta (C and D).
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FIGURE 11.3 Cross-sectional view of a computed tomography angiography of a patient with newly diagnosed giant cell arteritis displaying a marked
circumferential thickening of the aortic wall. From Garcia-Martinez A, Prieto-Gonzalez S, Arguis Gimenez P, et al., Aortitis and aortic aneurysm in
systemic vasculitis. In: Grundmann R, editor. Etiology, pathogenesis and pathophysiology of aortic aneurysms and aneurysm rupture. In Tech; 2011.
ISBN:978-953-307-523-5.
TABLE 11.3 Pleiotropic Therapy of Inflammatory Vasculitis
Vasculitis Therapy
1. Takayasu’s arteritis [26]
2. Giant cell arteritis [27,28]
3. Behçet disease [29,30]
TNF, tumor necrosis factor.
l
Glucocorticoids
l
Anti-TNF α agents
l
Interleukin-6 antibody
l
Anti-B cell therapy
l
Glucocorticoids
l
Anti-TNF α agents
l
Interleukin-6 antibody
l
Glucocorticoids
l
Anti-TNF α agents
corticosteroid therapy. Cytotoxic and other immunosuppressive agents, including anti-TNF agents, have not proved efficacious in controlled comparative trials. Two retrospective studies have demonstrated that the use of low-dose aspirin reduces
cranial ischemic events (blindness and stroke) three- to fourfold compared with patients who had not received such therapy;
in the absence of contraindications, all patients with GCA should receive low-dose aspirin [27,28].
The main goal of therapy in patients with BD is to induce and maintain remission and improve patients’ quality of life.
Selecting treatment is based on the organ involved and the assessment of the severity of the disease [10].
Although high-quality placebo-controlled trials with corticosteroids are lacking, these agents are commonly used in BD.
It is recommended an early initiation of corticosteroids for the management of severe or life-threatening manifestations,
such as ocular, vascular, gastrointestinal, or neurologic disease [29]. In such instances, pulse dose steroids (1 g intravenous
methylprednisolone infusions daily) are often used for 3 days, followed by 1 mg/kg/day prednisolone tapered slowly [30].
Colchicine is the most frequently prescribed medication for the treatment of mucocutaneous manifestations of BD.
Colchicine was shown to reduce recurrence of genital ulcers in female patients with BD, in treating arthritis, and preventing
erythema nodosum lesions in both men and women. Neither study showed beneficial effect of colchicine on oral ulcers [30].
Future Therapies
Advances in immunology have revealed that a number of molecules are important modulators in the pathophysiology of
inflammatory vasculitis. Patients with GCA, refractory to glucocorticoids, have a higher expression of proinflammatory
Inflammatory Diseases (Takayasu, Giant Cell Arteritis, Behçet Disease) Chapter | 11 125
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cytokines such as s IL-1β, TNF-α, and IL-6. Recent promise has been shown in the blockade of the soluble IL-6 receptor
with the humanized monoclonal antibody tocilizumab. This hypothesis arose with emerging evidence supporting IL-6 as
a major component in the proinflammatory process of large-vessel vasculitis, but no large randomized control trials have
confirmed this finding [25].
Th1 and Th17 cells are now thought to drive two distinct inflammatory pathways. According to Deng et al., only one of
these pathways (i.e., Th17 cells) was susceptible to glucocorticoid-mediated suppression in patients with GCA [13]. It was
previously hypothesized that Th17 immunity was “more important for acute manifestations,” whereas Th1 immunity was
associated with chronic vascular lesions [13]. In addition, only one of these pathways was susceptible to glucocorticoidmediated suppression. Glucocorticoids decreased Th1 cytokine levels but not Th17 cytokine levels in patients with TAK.
Indeed, the levels of IFN-γ, TNF-α, and IL-2 decreased following glucocorticoid therapy, whereas the levels of IL-17A,
IL-23, and IL-1R did not decrease following this therapy. Taken together, these data suggest that Th17 cytokine–targeted
intervention would be needed for optimal control of inflammatory vasculitis [17].
B Cell Depletion
Rituximab, a chimeric IgG1 antibody that binds to CD20 expressed on the surface of B cells, has shown to improve clinical
signs and symptoms of TAK. Although pathogenesis of TAK is not believed to be mediated by the humoral immune system,
it is believed that B cells have an antibody-independent effect, which may modulate regulatory T cell immune reactions
against foreign and self-antigens [26].
Anti-TNF agents have shown encouraging results in a small number of patients with relapsing TAK. In an uncontrolled series of 15 patients, adjunctive treatment with anti-TNF agents was effective in patients with active, relapsing
TAK despite treatment with steroids and multiple other immunosuppressive agents. The initial dose of etanercept was
25 mg twice weekly (7 patients); infliximab (11 patients [three were switched from etanercept to infliximab]) was
given at 3 mg/kg initially and at 2 weeks, 6 weeks, and then every 8 weeks thereafter. The preliminary results of this
study suggested that anti-TNF therapy may be a useful adjunct to corticosteroids in the treatment of patients with
TAK [16].
Over the last decade, a considerable amount of literature has been published regarding the use of TNF inhibitors also in
BD. Beneficial effects have been noted with infliximab, etanercept, and adalimumab [30].
REFERENCES
[1] Alibaz-Oner F, Aydin SZ, Direskeneli H. Advances in the diagnosis, assessment and outcome of Takayasu’s arteritis. Clin Rheumatol
2013;32(5):541–6.
[2] Direskeneli H, Aydin SZ, Merkel PA. Assessment of disease activity and progression in Takayasu’s arteritis. Clin Exp Rheumatol
2011;29(1064):S86–91.
[3] Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Takayasu’s arteritis: limitations of therapy and guarded prognosis in an American cohort.
Arthritis Rheumatol 2007;56:1000.
[4] Arnaud L, Haroche J, Mathian A, Gorochov G, Amoura Z. Pathogenesis of Takayasu’s arteritis: a 2011 update. Autoimmun Rev 2011;11(1):61–7.
[5] Youngstein T, Peters JE, Hamdulay SS, Mewar D, Price-Forbes A, Lloyd M, et al. Serial analysis of clinical and imaging indices reveals prolonged
efficacy of TNF-a and IL-6 receptor targeted therapies in refractory Takayasu arteritis. Clin Exp Rheumatol 2014;32(3 Suppl. 82):S11–8.
[6] Carmona FD, Gonzalez-Gay MA, Martin J. Genetic component of giant cell arteritis. Rheumatology 2014;53:6–18.
[7] Borchers AT, Gershwin ME. Giant cell arteritis: a review of classification, pathophysiology, geoepidemiology and treatment. Autoimmun Rev
2012;11:A544–54.
[8] Gornik HL, Creager MA. Aortitis. Circulation 2008;117(23):3039–51.
[9] Murchison AP, Gilbert ME, Bikyk JR, et al. Validity of the American college of rheumatology criteria for the diagnosis of giant cell arteritis. Am J
Ophthalmol 2012;154:617–9.
[10] Kim DH, Cheon JH. Intestinal Behçet’s disease: a true inflammatory bowel disease or merely an intestinal complication of systemic vasculitis?
Yonsei Med J 2016;57(1):22–32.
[11] Restrepo CS, Ocazionez D, Suri R, Vargas D, et al. Aortitis: imaging spectrum of the infectious and inflammatory conditions of the aorta.
Radiographics 2011;31(2):435–51.
[12] Direskeneli H. Behçet’s disease: infectious aetiology, new autoantigens, and HLA-B51. Ann Rheum Dis 2001;60:996–1002.
[13] Deng J, Younge BR, Olshen RA, Goronzy JJ, Weyand CM. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010;121:906–15.
[14] Seko Y, Sato O, Takagi A, et al. Restricted usage of T-cell receptor Va-Vb genes in infiltrating cells in aortic tissue of patients with Takayasu’s arte-
ritis. Circulation 1996;93:1788–90.
[15] Chen Q, Yang W, Gupta S, Biswas P, Smith P, Bhagat G, et al. IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by con-
trolling the activity of IRF-4 transcription factor. Immunity 2008;29:899–911.
[16] Saadoun D, Garrido M, Comarmond C, et al. Th 1 and Th17 cytokines drive inflammation in Takayasu arteritis. Arthritis Rheumatol 2015;67:1353–60.
126 PART | I Overview
https://t.me/med1917
[17] Saadoun D, Wechsler B. Behcet’s disease. Orphanet J Rare Dis 2012;7:20.
[18] Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature
2008;452:773–6.
[19] Brucklacher-Waldert V, Stuerner K, Kolster M, et al. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain
2009;132:3329–41.
[20] Mizuki N, Meguro A, Ota M, et al. Genome-wide association studies identify IL23R–IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat
Genet 2010;42:703–6.
[21] Shimizu J, Takai K, Fujiwara N, et al. Excessive CD4+ T cells co-expressing interleukin-17 and interferon-γ in patients with Behcet’s disease.
J Transl Immunol 2011;168:68–74.
[22] Nishino Y, Tamai M, Kawakami A, et al. Serum levels of BAFF for assessing the disease activity of Takayasu arteritis. Clin Exp Rheumatol
2010;28:14–7.
[23] Aydin SZ, Merkel PA, Direskeneli H. Outcome measures for Takayasu’s arteritis. Curr Opin Rheumatol 2015;27(1):32–7.
[24] Weyand CM, Younge BR, Goronzy JJ. IFN-gamma and IL-17: the two faces of T-cell pathology in giant cell arteritis. Curr Opin Rheumatol
2011;23:43–9.
[25] Garcia-Martinez A, Prieto-Gonzalez S, Arguis Gimenez P, et al. Aortitis and aortic aneurysm in systemic vasculitis. In: Grundmann R, editor.
Etiology, pathogenesis and pathophysiology of aortic aneurysms and aneurysm rupture. In Tech; 2011. ISBN:978-953-307-523-5.
[26] Alibaz-Oner F, Direskeneli H. Update on Takayasu’s arteritis. Presse Med 2015;44(6):e259–265.
[27] Nesher GN, Berkun Y, Mates M, et al. Low-dose aspirin and prevention of cranial ischemic complications in GCA. Arthritis Rheumatol 2004;50:1332.
[28] Lee MS, Smith SD, Galor A, Hoffman GS. Antiplatelet and anti-coagulant therapy in patients with giant cell arteritis. Arthritis Rheumatol
2006;54:3306.
[29] Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain A, Gul A, et al. EULAR recommendations for the management of Behçet disease. Ann
Rheum Dis 2008;67:1656–62.
[30] Saleh Z, Arayssi T. Update on the therapy of Behçet disease. Ther Adv Chronic Dis 2014;5(3):112–34.
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