Pediatric Takayasu Arteritis

Criterion

Definition

Age at disease onset less than 40 years

Development of symptoms or findings related to Takayasu arteritis at age <40 years

Claudication of limbs

Development and worsening of fatigue and discomfort in muscles of one or more limbs while in use, especially the arms

Decreased brachial arterial pulse

Decreased pulsation of one or both brachial arteries

Blood pressure difference of greater than 10 mmHg

Difference of more than 10 mmHg in systolic blood pressure between arms

Bruit over the subclavian arteries or aorta

Bruit audible on auscultation over one or both subclavian arteries or abdominal aorta

Arteriographic abnormality

Arteriographic narrowing or occlusion of the entire aorta, its primary branches,

or large arteries in the proximal limbs, not caused by arteriosclerosis,

fibromuscular dysplasia, or similar causes; changes usually focal or segmental

The presence of three or more of these six criteria demonstrates a sensitivity of 90.5 % and a specificity of 97.8 %

Angiographic classification (1994) recognizes five broad patterns of TA, with or without involvement of coronary and pulmonary arteries under each subset (Table 39.2). This is largely followed (including for pediatric patients); while of use clinically for descriptive purposes, this has not really contributed to better understanding of the pathogenesis of the disease (Table 39.1) [19].

Table 39.2

Proposed 1994 angiographic classification of Takayasu arteritis

Type	Vessel involvement
Type I	Branches from the aortic arch
Type IIa Type IIb	Ascending aorta, aortic arch, and its branches Ascending aorta, aortic arch and its branches, thoracic descending aorta
Type III	Thoracic descending aorta, abdominal aorta, and/or renal arteries
Type IV	Abdominal aorta and/or renal arteries
Type V	Combined features of types IIb and IV

According to this classification system, involvement of the coronary or pulmonary arteries should be designated as C (+) or P (+), respectively

The first attempt to classify p-TA was done in 2007 by the members of the Pediatric Rheumatology European Society (PRES) as a component of the combined classification criteria for childhood vasculitides. The EULAR-endorsed criteria for pediatric vasculitides were validated at the 2008 Ankara Consensus Conference, and the final version of classification criteria for each of the vasculitides was published in 2010 as EULAR/PRINTO/PRES criteria. This is being currently used to classify p-TA (Table 39.3). The sensitivity and specificity of the final EULAR/PRINTO/PRES classification definition were 100 % and 99.9 %, respectively [19]. It is important to emphasize however that these classification criteria are not the same as diagnostic criteria. TA classification criteria are used to differentiate TA from other forms of vasculitis of the young; there remains an urgent need for robust diagnostic criteria, in particular to differentiate TA from other vasculopathic diseases affecting large arteries (Table 39.4).

Table 39.3

p-TA EULAR/PRINTO/PRES classification of Takayasu arteritis

Criterion	Glossary
Angiographic abnormality (mandatory criterion)	Angiography (conventional, CT, or MRI) of the aorta or its main branches and pulmonary arteries showing aneurysm/dilatation, narrowing, occlusion, or thickened arterial wall not due to fibromuscular dysplasia or similar causes; changes usually focal or segmental
1. Pulse deficit or claudication	Lost/decreased/unequal peripheral artery pulse(s) Claudication: focal muscle pain induced by physical activity
2. Blood pressure (BP) discrepancy	Discrepancy of four-limb systolic BP >10 mmHg difference in any limb
3. Bruits	Audible murmurs or palpable thrills over large arteries
4. Hypertension	Systolic/diastolic BP greater than 95th centile for height
5. Acute phase reactant	Erythrocyte sedimentation rate >20 mm per first hour or CRP any value above normal (according to the local laboratory)

Mandatory criterion plus one of the five criteria is necessary to fulfill classification criteria for p-TA. These criteria should not be used as diagnostic criteria and the clinician must be ever alert to the possibility of other vasculopathies (Table 39.4)

Table 39.4

Differential diagnosis of c-TA

Infections	Septicemia or endocarditis Tuberculosis Human immunodeficiency virus Brucellosis
Inflammatory vasculitides	Kawasaki disease Polyarteritis nodosa Granulomatosis with polyangiitis (GPA, Wegener’s) Cogan’s syndrome
Autoimmune conditions	Rheumatic fever Systemic lupus erythematosus Sarcoidosis
Noninflammatory vasculopathies	Williams syndrome Congenital coarctation of the aorta Ehlers-Danlos type IV Marfan’s syndrome Neurofibromatosis – type I Fibromuscular dysplasia (and related vasculopathies)
Others	Postradiation therapy Cerebral aneurysms IgG4-related diseases Ergotism Blau’s syndrome

Modified from Table 2 in Ref. [13]

Clinical Manifestations

TA is known to have an acute inflammatory phase with a relapsing and remitting course and a late chronic phase. During acute phase, children present with nonspecific constitutional symptoms such as anorexia, fever, night sweats, weight loss, arthralgia, and skin rash. Often this phase is unrecognized during the natural history of illness in children, due to nonspecific nature of these symptoms and lack of robust screening biomarkers for the early diagnosis of p-TA. This results in significant vascular sequelae in one-third of children with advanced p-TA, presenting deceptively with apparently inactive “fibrotic-stenotic” disease. In the chronic phase, as the inflammation progresses, stenoses develop, and features secondary to arterial occlusion become clinically overt.

The spectrum of clinical features at presentation varies in pediatric patients with TA. Hypertension (82.6 %), headaches (31 %), fever (29 %), breathlessness (23 %), weight loss (22 %), and vomiting (20.1 %) are described as the more common presentations of p-TA in the west [10]. A recent study from India depicts hypertension (73 %), headache (53 %), constitutional symptoms (53 %), and fever (45 %) as the more frequent manifestations [8].

Organ-specific manifestations occur due to vascular occlusion and subsequent ischemia in the vascular territory. Pulseless disease is known to be common in p-TA. Bruit and claudication pain are uncommon in p-TA. Secondary cardiac involvement is described in 19 % of p-TA patients. Involvement of the coronary arteries in p-TA has been described in a few case reports [21, 22]. Stroke has been described in 17 % of c-TA patients. Eye involvement is rare in p-TA.

Differential Diagnoses

Due to paucity of specific tests for diagnosis of p-TA, the list of differential diagnoses is long. An association with infections like tuberculosis, in the developing countries, imparts a confounding effect on the differentials, as both Takayasu arteritis and tuberculosis are granulomatous diseases. A retrospective study from India describes strongly positive Mantoux test in one-fifth of all TA patients [23]. Whether this association represents a causal relationship or a mere coincidence is still unclear and debatable. Table 39.4 mentions the differential diagnoses that need to be considered in p-TA.

Diagnosis

Laboratory Tests

No specific laboratory markers for p-TA have been described till date. However, classical inflammatory markers, namely, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are commonly relied upon in clinical practice. Inflammatory markers are known to overall correlate poorly with disease activity, although they can be helpful for individual patients in the acute phase of the illness. Studies have described the association of high levels of CRP with higher risk of thrombotic complications in patients with TA [24].

Various other novel biomarkers have been proposed to correlate with disease activity. Matrix metalloproteinases (MMPs) 2, 3, and 9 are reported by a Japanese group to be useful in assessing disease activity and in follow-up of patients with TA [25]. Interleukin-6 (IL-6) in serum, regulated on activation, normal T expressed and secreted (RANTES), vascular cell adhesion molecules (VCAMs), and pentraxin-3 (PTX-3) are other biomarkers which have been described to correlate well with disease activity in TA [26, 27], but are not widely validated or available for routine use.

Imaging

Imaging modalities used in the diagnosis of p-TA include conventional angiography, magnetic resonance angiography (MRA), CT angiography (CTA), or Doppler ultrasound. A combination of imaging modalities may be required in special circumstances. More recently, fluorodeoxyglucose (FDG)-PET imaging (usually co-registered with CT or MRI) is being used increasingly to detect anatomical abnormality of the vessels as well as inflammatory activity of the disease. Skip lesions, without extensive calcification, and the presence of both stenotic and dilated lesions as well as pulmonary artery involvement have all been described in p-TA, similar to adult-onset TA [28]. Stenoses are reported to be the most common angiographic feature in several c-TA series.

Conventional angiography is still considered the gold standard for diagnosis of TA. The advantage of conventional angiography is the ability to visualize the flow in blood vessels and to detect the extent of collateralization. It does not, however, provide any information regarding the vessel wall, but is particularly useful in the workup for potential revascularization procedures.

In p-TA, the utility of noninvasive MRA is particularly high. MRA has been used in identifying aortic wall thickening (best demonstrated by axial T1-weighted imaging), mural thrombi, and pulmonary artery involvement. A bright T2-weighted signal is obtained in inflammatory edema of the vessel wall. Vessel wall irregularity is clearly visualized with contrast-enhanced MRA. Contrast-enhanced regular MRI alone helps in the diagnosis of focal TA activity, and it has been shown to correlate with clinical and laboratory features in few patients [29]. The advantage of multiplanar capability of MRI is useful in the assessment of the extent of the aortic lesions in a longitudinal plane. The major disadvantages of MRI include its limitation in visualizing small branch vessels and poor visualization of vascular calcification. MRA, being very sensitive, can at times falsely highlight the degree of vascular stenosis.

CTA is as useful as MRA in diagnosis and follow-up of p-TA. Concentric mural thickening of the involved arteries is the typical CT feature of TA. Calcification in the thickened wall can also be detected in CT. Multi-detector CTA is emerging as a reliable, noninvasive imaging technique to visualize both luminal and mural lesions in the aorta as well as its main branches. The main disadvantage of CT is the enormous amount of radiation exposure, an important consideration of particular relevance for children.

Ultrasound is being used extensively in the diagnosis of TA. The vessel wall appears hypoechoic due to wall edema in acute flares, in contrast with hyperechoic look in most other scenarios [30]. Pre-stenotic disease can be identified by high-resolution ultrasound machines, thus giving a window of opportunity in the management of patients with TA. The biggest disadvantage of ultrasound, however, is its dependence on investigator’s expertise for quality control, which curtails its use in regular clinical practice.

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