Takayasu arteritis is a chronic granulomatous disease of the aorta and its major branches that usually affects women during the second and third decades of life, but it has been reported in young children. This review details the clinical, pathological and radiological features, differential diagnoses and management of the condition, focusing chiefly on the disease in children.
The recent definition of Takayasu arteritis is discussed. The condition should be considered in patients with unexplained arterial hypertension or unexplained inflammatory syndromes without signs of localization. Since the disease may be life-threatening and progressive, early recognition is necessary to initiate appropriate therapy.
Patients with persistent ischaemic symptoms including hypertension might benefit from revascularization procedures. The two major categories of large vessel vasculitis are temporal giant cell arteritis and Takayasu arteritis TA.
TA is an inflammatory and stenotic disease of medium- and large-sized arteries and is characterized by a predilection for the aortic arch and its branches, hence also referred to as the aortic arch syndrome. While the precise pathogenesis is unknown, intimal fibroproliferation of the aorta, great vessels, pulmonary arteries and renal arteries results in segmental stenosis, occlusion, dilatation and aneurysm formation in these vessels. An alternate term, idiopathic or non-specific aortoarteritis has been used to describe the spectrum of vascular abnormalities associated with the condition.
While an Italian pathologist, Giovanni Battista Morgagni, is credited with the first report of a patient in [ 2 ], the first detailed description was by Savory , who described a year-old woman with seizures, unilateral blindness, scalp ulcerations and pulseless vessels in the head, neck, and upper extremities.
At postmortem examination, inflammatory thickening of the aorta and major arteries was identified [ 3 ]. At the Annual Meeting of the Japanese Ophthalmology Society in , a Japanese ophthalmologist, Mikito Takayasu, described ocular arterial changes and the association of retinal arteriovenous anastomoses and absent upper extremity pulses [ 4 ]. TA is worldwide in distribution, with an incidence of 1.
The scant number of studies reporting the frequency of TA makes it difficult for one to compare incidence rates. The age of onset may vary from infancy [ 11 , 12 ] to middle age. Women with TA outnumber men by 8— A similar gender predilection has been observed in various reports for children, including those from India and South Africa, which report a female-to-male ratio of [ 13 , 14 ].
Histological specimens are seldom available, with the exception of specimens obtained during autopsy and bypass surgery. The vascular pathology in TA is characterized by segmental and patchy granulomatous inflammation of all three layers of the aorta and major branches Fig.
Types of Vasculitis
This inflammation leads to arterial stenosis, thrombosis and aneurysms. Mononuclear infiltration of the adventitia with perivascular cuffing of the vasa vasorum occurs early. Granulomatous changes may be observed in the tunica media with Langerhans cells and central necrosis of elastic fibres and smooth muscle cells. Later, fibrosis of the media and acellular thickening of the intima may compromise the vessel lumen.
The corresponding organ shows ischaemic changes, which largely determine the clinical features of the disease. TA complicated by secondary amyloidosis has been reported, with and without evidence of intercurrent tuberculosis [ 18 ].
The precise factor s responsible for the arterial damage in TA are unknown. The presence of hypergammaglobulinaemia, circulating antibodies against aorta and arteries, circulating immune complexes and a favourable response to steroids suggest the pathogenic role of autoimmunity.
It is believed that genetically linked immune responses to unidentified antigen s may incite autoimmune damage by cell-mediated or humoral pathways, resulting in the disease and its relapses [ 19 , 20 ].
Autoantibodies against aortic endothelial cells have been proposed as a key factor in the pathogenesis of TA. Immunoglobulins Igs G, M and properdin are found in lesions from pathology specimens. Chauhan et al.
Sera from AAECA-positive patients with TA were found to induce apoptosis of aortic endothelial cells, suggesting that these antibodies have a role in the pathogenesis. The association of TA with perinuclear and cytoplasmic antineutrophilic cytoplasmic antibodies ANCAs also suggests a role of these autoantibodies in the pathogenesis of the disease [ 22 ]. Case reports describing the association of TA with rheumatoid arthritis, ulcerative colitis, systemic lupus, Crohn disease, sarcoidosis and amyloidosis also emphasize the importance of immune mechanisms in the pathogenesis [ 23 , 24 ].
Although many studies have proposed that bacteria and viruses might have a causative role in primary vasculitides, no specific infectious agents have been identified [ 20 ].
This is also supported by the fact that corticosteroids are highly effective, even in the acute inflammatory phase, while, in infection-induced inflammatory diseases such as viral myocarditis, corticosteroid therapy is associated with the risk of aggravation of the inflammation.
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While previous reports have suggested the association of TA with tuberculosis, further studies have not supported this association [ 25 ]. Although TA is common in the parts of the world with high incidences of tuberculosis, exceptions such as Japan are intriguing.
These monocytes are transformed into macrophages that mediate endothelial damage and result in granuloma formation in the vessel walls. An increased incidence of skin hypersensitivity to the purified protein derivative PPD has been reported in patients with TA [ 27 ]. There is increasing evidence that HSP may be an important antigen inciting immune damage in TA [ 28 , 29 ].
The precise association of TA with tuberculosis is unclear, and the condition of patients with TA does not improve following antituberculosis therapy. Genetic susceptibility to the disease has been studied extensively. The condition has been reported in identical twins, leading to a hypothesis for a hereditary basis [ 31 ].
Kasuya et al. The clinical features of TA are divided into an early prepulseless systemic phase and a late occlusive phase.
Large Vessel Vasculitis Occurring in Rheumatoid Arthritis Patient under Anti-TNF Therapy
Approximately half of all patients show the difficult-to-diagnose early phase, characterized by nonspecific features such as low-grade fever, malaise, night sweats, weight loss, arthralgia and fatigue [ 5 ].
There is often anaemia and marked elevation of the erythrocyte sedimentation rate ESR.
In this late occlusive phase of the disease, characteristic features of TA appear, which include diminished or absent pulses, vascular bruits, hypertension as a consequence of renal artery stenosis , mesenteric angina, retinopathy, aortic regurgitation when the ascending aorta is involved and neurological symptoms secondary to hypertension or ischaemia postural dizziness, seizures, amaurosis.
Weakness of the arterial walls may give rise to localized aneurysms. A history of Raynaud phenomenon may be present [ 20 ]. Frequency of arteriographic abnormalities and potential clinical features of arterial involvement Kerr et al.
This sequential presentation is, however, likely to occur only in a minority of patients, because the disease is usually recurrent, leading to coexistence of various phases. Further, there can be activity during the chronic illness, not all patients manifest an acute phase, and some may present in chronic phase only. A variable interval months to years may separate acute from occlusive phases, during which vascular insufficiency develops. Glomerular damage in TA is manifested by microscopic haematuria and non-nephrotic-range proteinuria.
The presentation of nephrotic syndrome is uncommon, except in those with complicating amyloidosis. A review of clinical features in TA shows geographical variations based on the site of vascular involvement. Hata et al. Patients from Japan showed a high frequency of involvement of the ascending aorta, aortic arch and its branches, while involvement of the abdominal aorta and renal arteries was significantly greater in Indian patients [ 36 ].
In another series from India, in children and young adults, the abdominal aorta was the commonest vessel affected [ 13 ].
In North American children with TA, lesions of the thoracic and abdominal aorta, rather than that of the aortic arch, are common [ 9 ]. It is not known whether these variations reflect differing causes of TA. However, all patterns of vascular involvement are observed in every region.
The usual presenting symptoms are due to hypertension, heart failure or a neurological event. Claudication, bruit or a missing pulse in an asymptomatic child are uncommon presentations. TA is considered to be the commonest cause of renovascular hypertension in Asian children [ 37 ].
The largest paediatric series reported by Hong et al. In a report on 31 patients from South Africa, arterial hypertension was the chief feature, followed by cardiac failure, bruits and absent pulses [ 14 ].
In a Turkish multicentre review, TA represented 1. The majority Hypertension is not only the most common clinical presentation, but is often the sole manifestation of TA in children [ 40 , 41 ]. Summary of clinical and radiological findings in studies on Takayasu arteritis in children.
The values represent actual numbers. Dashes indicate that data were not available. The diagnosis of TA is often delayed because of non-specific clinical symptoms. The Ishikawa criteria [ 42 ], widely used for diagnosis, are based on observations in Japanese patients and consist of obligatory, major and minor criteria.
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The major criteria are involvement of the right or left mid-subclavian artery, and the minor criteria include raised ESR, carotid artery tenderness, hypertension, aortic regurgitation, pulmonary artery lesions and involvement of the common carotid, brachiocephalic, descending thoracic aorta or abdominal aorta. In addition to the obligatory criterion, the presence of two major criteria, or one major and two or more minor criteria, or four minor criteria, suggests a high probability of the presence of TA [ 42 ].
These criteria have greater sensitivity for patients with active disease than for those with inactive disease. Geographic variations in the pattern of arterial involvement may reduce the sensitivity of these criteria. The presence of two major criteria, or one major and two minor criteria, or four minor criteria, suggests a high probability of TA [ 43 ].
Large vessel vasculitis
When applied to Indian and 79 Japanese patients with angiographically proven TA, the above criteria had a sensitivity and specificity that were greater than those of the Ishikawa and American College of Rheumatology ACR criteria [ 43 ].
Adoption of these criteria is expected to prevent the possibility of under-diagnosis of TA. American College of Rheumatology criteria for the classification of Takayasu arteritis [ 6 ]. Takayasu arteritis is classified if at least three of the six criteria are present.
The presence of three or more criteria yields a sensitivity of In a consensus conference on childhood vasculitis, under the auspices of the EULAR and the PRES, proposed diagnostic criteria for various vasculitides that differ in some respects from the ACR classification criteria.
A prospective validation of the proposed classification criteria was recently reported on 87 children with TA enrolled from 97 centres in 36 countries. Takayasu arteritis is diagnosed if at least one of the five criteria is present, together with the mandatory criterion.
Giant cell arteritis (Temporal arteritis)
No specific serum markers for TA have been identified. Concentrations of acute phase reactants, including C-reactive protein and the ESR, correlate poorly with disease activity. Some patients show elevated transaminase levels, hypoalbuminaemia and hypergammaglobulinaemia [ 10 ].
The concentration of von Willebrand factor-related antigen may be elevated. Anti-endothelial cell antibodies are often present, and anti-nuclear antibody is usually negative. Conventional or digital subtraction angiography is considered to be necessary for the diagnosis of TA and its complications.
Angiography shows luminal irregularity, vessel stenosis, occlusion, dilatation or aneurysms in the aorta or its primary branches Figs. The Takayasu Conference proposed a classification based on angiographic abnormalities [ 13 ]:.