**2. Takayasu arteritis: review in pediatrics**

Takayasu arteritis (TA) is classified as a large-vessel vasculitis. It affects the aorta and major branches by causing stenosis, occlusion, and/or aneurysms of the vessel; it is an inflammatory disease with unknown etiology. Predominantly presented in females.

Takayasu arteritis was first described by Doctor Mikito Takayasu, a Japanese ophthalmologist, after a case of changes in the retinal vessels of a 22 year old female in 1908. Since then, there have been many case reports that matched Dr. Takayasu's patient and the disease received many names like pulseless disease, aortic arch syndrome, or obstructive productive arteritis. It was until 1990 when the American College of Rheumatology published and described the disease named "Takayasu arteritis" publishing with it classification criteria for its diagnosis [1].

### **2.1 Epidemiology**

TA is a rare disease and its frequency seems to be influenced by ethnicity. It is generally known to be presented in females under 40 years of age, but it can be seen in older patients as well as children. There is not a statistical value that is acceptable for the general population since the prevalence can vary a lot by ethnicity. TA is known to be a more popular vasculitis in Asia, and their countries have the highest prevalence. In Japan, the prevalence is higher than 4/million. In the United Kingdom, they have an incidence of 0.8/million. North America has an incidence of 2.6/million [2, 3].

Ethnicity does not only affect the incidence and prevalence of the disease, it can also affect the characteristics of presentation, the intensity of symptoms, and the prognosis of the patient. A French retrospective study compared black, white, and North African patients with TA and found that North African patients had lower survival rates in 5 and 10 years than the other two ethnicities, all because North African patients had more ischemic relapses; also white patients seem to have a prolonged diagnosis, according to the mean age of diagnosis, being 10 years later than North African and black patients [4].

The manifestation of TA can also vary, for example, Japanese patients seem to have the aortic arch and branches affected and Indian patients have abdominal aorta and branches more frequently affected [5].

#### *2.1.1 Epidemiology in children*

In children, it is very rare to see TA, and because of that there is not a lot of data, there is an estimated incidence of TA in children that is 2.6/ million of all ages. A very limited study of 21 patients in the United States found that it continues to be more common in females, having 71% of their population being females, and having a very large age gap for symptoms on set, from 1.5 months to 17 years, having a median age of 13 years old [6].

#### **2.2 Pathogenesis**

The pathogenesis of TA remains unclear, although the involvement of immune mechanisms mediated by cells that secrete proinflammatory cytokines is known to play an important role, so this leads to the use of cytokine-targeting agents, such as TNF or IL-6 inhibitors as treatment [7, 8].

*Takayasu Arteritis: Review in Pediatrics DOI: http://dx.doi.org/10.5772/intechopen.105907*

Inflammatory infiltrates of the arterial wall consist of macrophages and lymphoid cells. Th1 and Th17 responses seem to play an important role as demonstrated by an increased expression of Th1 and Th17 immunity in TA, such inflammation that correlates with disease activity [8].

A possible genetic association, a polymorphism of tumor necrosis factor (TNF) has been studied and both human leukocyte antigen (HLA) classes I and II have been associated with TA, and most notably, the HLA-B52 allele has been reported across multiple ethnicities. The genetic contribution to disease pathogenesis is supported by the identification of multiple susceptibility loci in various studies. This disease was also associated with IL-6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 [7, 8].

Both the innate and adaptive immune systems seem to be involved in the pathogenesis of TA. The inflammatory process usually involves the vasa vasorum, the adventitia, and the outer part of the media and results in vessel wall damage with laminar necrosis and elastic fiber fragmentation, which is eventually replaced by fibrosis and arterial remodeling [8].

The involvement of humoral immune mechanisms is evidenced by the presence of circulating antiendothelial cell antibodies and autoantibody-producing B cells in inflammatory TA lesions that may cause vascular dysfunction. Also, TA patients have also been shown to generate a significantly large number of plasmablasts. These results lend support to the use of anti-B-cell agents in the treatment of TA [8].

#### **2.3 Clinical presentation**

TA clinical onset and clinical characteristics can be very hard to describe or identify since it is a compile of nonspecific inflammatory symptoms. We can divide TAK clinical presentation into two phases:


The active phase can be very nonspecific and have different intensity of symptoms, and it seems that the active phase can be more intense in pediatric patients and have different symptoms than in adults (**Table 1**) [9].

#### **2.4 Diagnostic criteria**

The diagnosis of TA is made with specific criteria. The initial criteria created by the American College of Rheumatology (ACR) in 1990 has a sensitivity of 91% and a specificity of 98%. The diagnosis is made when the patient has three of the six diagnostic criteria. In 2009, the European Alliance of Associations for Rheumatology (EULAR) published a guide for large-vessel vasculitis, including TA, with an update in 2018. The new guides have greater sensitivity (100%) because they include a diagnostic criteria that is necessary for the diagnosis, which is an angiographic abnormality in any kind of imaging study, with greater accessibility to imaging studies nowadays the EULAR criteria is the go to criteria (**Tables 2** and **3**) [10].


#### **Table 1.**

*Comparison of onset symptoms in children with Takayasu arteritis (cTAK) and adults with Takayasu arteritis (aTAK) [9].*


#### **Table 2.**

*ACR diagnosis criteria for Takayasu arteritis.*

#### *2.4.1 Imaging diagnosis*

There are multiple imaging tools that are useful in these patients. Some are specific to make our diagnosis and others provide a complete evaluation of our patients.

The gold standard in image study is the digital subtraction arteriography since it provides a very specific view of the arteries where the caliber is measurable with more precision, as well as compares the difference in width all along the aorta and branches. Since digital subtraction arteriography is not available in every clinical center, other image studies can help with the diagnosis.

Magnetic resonance imaging (MRI) or computed angiotomography is usually more available and can also be very helpful in assessing the caliber of vessels. A contrast-enhanced MRI will allow to detect vascular abnormalities.


#### **Table 3.**

*EULAR diagnosis criteria for Takayasu arteritis.*

In patients with TA, an echocardiogram can be done to completely evaluate the cardiovascular health in our patient evaluating the ventricular function, hypertrophy, aortic valve, and aortic and coronary arteries (**Figures 1** and **2**) [11].

In the image studies, there are multiple patterns of altered anatomy in the vessel, the four principal patterns are: [13]


Angiographic classification of TA classifies the image findings into five types depending on the part of the aorta that is affected: [11].

I: Branches of the aortic arch.

IIa: Ascending aorta, aortic arch, and its branches.

IIb: Ascending aorta, aortic arch, and its branches, thoracic and descending aorta.

III: Thoracic, descending aorta, abdominal aorta, and/or renal arteries.

IV: Abdominal aorta and/or renal arteries.

V: Combined features of types IIb and IV.

#### *2.4.2 Laboratory findings*

Anemia, generally hypochromic normocytic anemia, leukocytosis, and thrombocytosis have been reported in patients in an active phase of the disease or secondary to chronic inflammation [8, 14].

In pediatric cohorts, biologic inflammation is commonly reflected by the elevation of acute phase reactants, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). However, their sensitivity to reflect active disease remains uncertain, and in addition, they lack specificity as well [8].

C-reactive protein (CRP), more accurately reflects the burden of systemic inflammation and is increasingly measured as a disease activity marker, otherwise, high CRP levels have also been found to be associated with a higher risk of thrombotic complications [2, 3].

**Figure 1.** *Vascular abnormalities in computed tomography, such as dilation of the abdominal aorta and stenosis of the renal artery [12].*

Erythrocyte sedimentation rate (ESR) increased is common in the acute phases of the disease but without clinical awareness and suspicion. ESR is more sensitive than C-reactive protein in the mentioned phases but both still have poor sensitivity and specificity, the ESR may continue to be elevated in disease remission, but actually, there are cases with active vasculitis without elevation of ESR and/or CRP [3, 7, 11].

Biomarker pentraxin-3 (PTX-3), is a protein rapidly produced in response to an inflammatory reaction, especially by endothelial cells. Levels higher than 1 ng/ml are more accurate than normal thresholds of C-reactive protein or ESR to distinguish active from inactive disease, although we need more reliable biomarkers that reflect vascular wall inflammation. PTX-3 may identify vascular progression only in a subgroup of TA patients not receiving anticytokine treatments. However, in other patients with TA, including those receiving anticytokine treatments, even plasma PTX-3 levels were shown to be normal despite ongoing smoldering vascular inflammation [2, 11].

CD8 cells with reversal of T-cell CD4:CD8 ratio increased is a marker of disease activity [11].

Some authors have suggested new biomarkers correlated with disease activity, such as matrix metalloproteinase (MMP)-2, −3, and − 9, IL-6, IFNg, vascular cell adhesion molecules (VCAM), and pentraxin-3 (PTX-3), but to date, a specific biomarker for TAK does not exist and none of them have yet been validated or implemented as a routine in clinical practice [7, 8].

*Takayasu Arteritis: Review in Pediatrics DOI: http://dx.doi.org/10.5772/intechopen.105907*

#### **Figure 2.**

*Vascular abnormalities are shown in magnetic resonance angiography, such as stenosis in the thoracic aorta, iliac artery, and renal artery [12].*

#### *2.4.3 Histopathology*

A lymphomonocyte infiltrate is observed, and occasionally giant cells with the presence of granulomas, which initially affect the adventitia, but progress toward the arterial lumen, in the form of panarteritis. Over time, there is a reduction in lumen due to thickening, due to fibrosis of the intima and media, thrombotic phenomena appear, and progressively, stenosis, dilation, and aneurysms [7].

A pediatric series from the United Kingdom observed lymphocytic infiltration with incipient neovascularization and the absence of granulomas. This finding contrasts with that observed in adults, in which the presence of granulomas predominates (**Table 4**) [7].


#### **Table 4.**

*Similarities and differences of some differential diagnosis in comparison with Takayasu arteritis.*

#### **2.5 Differential diagnosis**

Differential diagnosis are shown in **Table 4**.

#### **2.6 Treatment options**

The primary objective of treatment is inducing and maintaining remission of the disease, so early treatment is crucial to resolve or alleviate the inflammation and prevent complications and disease progression. Patient and parent's education, and cooperation between doctor and the patient (including family) are important for compliance and progression [2, 11].

The base of the treatment, at the beginning, is glucocorticoid pulses combined with immunosuppressive drugs (cyclophosphamide) to induce remission, and the use of low doses of corticosteroids and background immunosuppression as maintenance therapy (methotrexate) [7].
