Takayasu Arteritis (TAK) is the most common large vessel vasculitis in children. It is characterized by granulomatous inflammation of the aorta, its major branches and the pulmonary arteries that may result in segmental stenosis, occlusion, dilatation and/or aneurysms. Systemic inflammation, local inflammatory processes and organ dysfunction secondary to ischemia lead to a highly variable clinical presentation and significant morbidity if untreated. Therapy is often extrapolated from adult studies given the very low prevalence of the disease in children. Better understanding of pathophysiologic mechanisms has resulted in the use of cytokine targeting therapies. Although early recognition and therapy seem to improve outcome in childhood-onset TAK, long-term follow-up data are lacking and prognosis remains guarded. This article reviews recent publications on epidemiology, pathogenesis, clinical presentation, laboratory biomarkers, imaging, treatment, and outcomes with a focus on the pediatric literature.

The incidence and prevalence of TAK are much higher in adults compared to children. A recent systematic review and meta-analysis found an incidence rate of 1.11 per million person-years (95% CI 0.70, 1.76) with considerable variation across different populations (1). Indeed, the described incidence rates of TAK range from 0.3 to 3.3 per million per year and the prevalence from 0.9 to 360 cases per million depending on the population and geographic region studied, with higher rates observed particularly in Asia (2).

Epidemiological data in childhood-onset TAK are scarce. The annual incidence rate reported in a Swedish study was 0.4 (95% CI 0, 1.1) per million for childhood-onset TAK (3). The prevalence estimated from a National Health Insurance database in South Korea varied between 0.04 (95% CI 0.00, 0.08) for children 0 to 4 years old and 0.63 (95% CI 0.36, 0.91) per 100,000 for those 15–19 years old, with an increase of the age-standardized prevalence of TAK over the years (4).

Takayasu Arteritis most commonly affects young women with a peak incidence between 20 and 40 years of age. It is unknown why TAK occurs predominantly in women. In children, female preponderance is lower than in adult-onset TAK and estimated around 2.5:1–3:1 (5). Mean age at disease onset in the pediatric population is 12 years, but TAK has been described across all ages and even in infants (6–9).

While there are still major gaps in our understanding, the etiology of TAK has begun to be elucidated. Current knowledge of pathophysiology is mostly extrapolated from adult studies and animal models of large vessel vasculitis (10). Both, the innate and adaptive immune systems have been implicated in the pathophysiology of TAK (11). Histologically, the inflammatory process usually predominates in the adventitia and the outer part of the media, but may affect all three blood vessel layers. The consequences are vessel wall damage with laminar necrosis and elastic fiber fragmentation, and eventually fibrosis and arterial remodeling (12). Inflammatory cell infiltrates of the arterial wall consist of macrophages and lymphoid cells (αß CD4+ and CD8+ cells, γδ T-cells, natural killer cells, and B cells) (13).

Multiple proinflammatory cytokines have been implicated in the pathogenesis of TAK (14). Increased levels of tumor necrosis factor (TNF)α, interferon (IFN)α, IFNγ, interleukin (IL)-6, IL-8, IL-12, IL-17, and IL-18 have been observed in the peripheral blood of patients with TAK compared to healthy controls. Serum IL-6 and IL-18 levels have been shown to correlate with disease activity (15–18). Novel insights in disease pathways and identification of key pro-inflammatory cytokines have led to the use of cytokine targeting agents such as TNFα- or IL- 6-, and more recently janus kinase (JAK)-inhibitors.

T cells, and particularly Th1 and Th17 responses seem to play an important role in driving the systemic and vascular manifestations in TAK, as demonstrated by increased expression of Th1 and Th17-related cytokines in patients with TAK that correlate with disease activity (17).

Furthermore, recent data indicate the implication of the mammalian target of rapamycin (mTOR) pathway in T cell activation and the development of vascular lesions in TAK. mTOR is a kinase that drives different signaling pathways to regulate cell differentiation, proliferation and metabolism (19), as well as vascular remodeling (20, 21). In addition, mTOR Complex 1 (mTORC1) has been involved in the differentiation of Th1 and Th17 cells (22). In patients with TAK, mTORC1 pathway is hyperactivated in CD4+ T cells and correlates with disease progression (23). This hyperactivity of mTORC1 has been identified as a critical mechanism underlying the altered differentiation of Th1 and Th17 cells (23). In vitro and mouse model studies show, that blockade of mTORC1 by sirolimus, a specific mTOR inhibitor, or by genetic knockdown, successfully suppresses the hyperactivation of the mTOR pathway, altered differentiation of CD4+ T cells and arterial inflammation (23, 24). Thus, targeting the mTORC1 pathway may represent an interesting novel therapeutic strategy in patients with TAK (25).

Growing evidence supports the crucial role of the Janus Kinase/Signal Transducers and Activators of Transcription (JAK-STAT) signaling pathway in the pathophysiology of TAK. This was first shown in a large vessel vasculitis mouse-model, in which the JAK1/3 inhibitor tofacitinib significantly reduced vessel wall infiltrates and expression of IFNγ, IL-17, and IL-21, and further diminished angiogenesis and hyperplasia of the intima (26). Using transcriptome analysis, Régnier et al. found an important enrichment for pathways linked to IFN, and especially type I IFN in patients with TAK (27). The upregulation of type I specific IFN gene signature was confirmed in patients with TAK compared to healthy controls, and treatment with either ruxolitinib, a JAK1/2 inhibitor, or tofacitinib reduced T cell activation and restored T cell homeostasis in vitro (27). The same group has recently established a specific follicular helper T cell signature that characterizes TAK and highlighted the cooperation of follicular helper T cells and B cells through the JAK/STAT pathway in patients with TAK, further supporting the use of JAK-inhibitors as promising treatment strategy (28). In summary, cytokine signaling dependent on JAK/STAT is critically important in TAK and opens new therapeutic avenues, and studies are currently underway.

The involvement of humoral immune mechanisms has previously been demonstrated by the presence of circulating anti-endothelial cell antibodies (29), autoantibody-producing B cells in inflammatory vascular lesions (30), and increased numbers of plasmablasts in patients with TAK, which correlate with disease activity (31). More recently, the identification of two major endothelial autoantigens, both negative regulators of endothelial activation, and their corresponding autoantibodies further highlighted the involvement of the adaptive immune system in the pathophysiology of TAK (32). These findings supported the use of anti B cell agents in TAK (33).

Furthermore, a complex genetic predisposition may contribute, at least in parts, to the pathogenesis of TAK. Multiple susceptibility loci, including both HLA class I and II, have been identified in various studies, but only HLA-B*52 has been associated with TAK beyond ethnicity (11, 34). Genome-wide association studies established non-HLA susceptibility loci such as IL12B, IL6, RPS9/LILRB3, and FCGR2A/FCGR3A, which represent potential targets in pathophysiology and treatment of TAK (35).

More recently, monogenic causes including mutations in NOD2, STAT1 gain-of-function, and XIAP have been described in association with TAK (36–39). Clinical features associated with monogenic causes of TAK are early-onset of symptoms, associated other inflammatory and autoimmune diseases such as inflammatory bowel disease or thyroid disorder, and/or features reminding of primary immunodeficiency.

Finally, triggers of the immune response, such as the involvement of Mycobacterium tuberculosis has been suggested for a long time. Although high prevalence of tuberculosis has been described in patients with TAK (i.e., detection of active tuberculosis in up to 18% of patients with TAK, presence of mycobacterium tuberculosis DNA in aortic tissue in up to 70% of cases), particularly in regions with a high prevalence of tuberculosis infection, there is not enough evidence to establish a causal relationship (40). A possible cross-reaction between mycobacterial and arterial antigens is matter of ongoing discussion.

To summarize, almost all arms of the immune response, from cellular components of both the innate and adaptive immune systems to downstream humoral mediators and their signaling components, have been implicated in the pathogenesis of TAK, pointing to the complexity of the immune reaction. It remains to be elucidated, what is causation and what association.

The diagnosis of childhood-onset TAK is based on clinical criteria and angiographic abnormalities, and is supported by laboratory findings. It requires a high index of suspicion, especially in children, because (1) onset is often insidious with non-specific symptoms mimicking many inflammatory conditions, (2) the clinical presentation greatly varies due to variable localization and extent of the vessels involved, and (3) the occurrence is rare.

Different sets of classification criteria have been proposed for childhood-onset TAK. The initial 1990 American College of Rheumatology (ACR) classification criteria for TAK were based on data from adult patients with TAK (41). In 2005, the vasculitis working group of the European League against Rheumatism/Pediatric Rheumatology European Society (EULAR/PReS) proposed new classification criteria for childhood-onset TAK (42). These were subsequently endorsed by EULAR, the Pediatric Rheumatology International Trial Organization (PRINTO), and PReS (EULAR/PRINTO/PReS) (43). They optimized the 1990 ACR classification criteria by including the mandatory criterion of angiographic abnormalities (not only conventional angiography, but also more recent imaging modalities such as CT or MRI), as well as the extra criteria arterial hypertension and elevated acute phase reactants. The latter was added to help differentiate TAK from non-inflammatory conditions [e.g., fibromuscular dysplasia (FMD)]. The EULAR/PRINTO/PReS classification criteria for childhood-onset TAK, presented in Table 1, have a sensitivity and specificity of 100 and 99.9%, respectively (43). Of note, these are classification criteria, that are not required to be met to make a diagnosis of TAK and initiate treatment.

Disease often presents with non-specific constitutional symptoms, including fever and systemic inflammation (pre-pulseless stage), and evolves to vascular symptoms attributable to occlusive arteritis. Up to 25% of children are diagnosed during the late inactive, “burnt-out” phase of the disease, where symptoms result from irreversible vascular damage rather than active vasculitis lesions (44–46). TAK may be associated with other inflammatory diseases, such as inflammatory bowel disease, spondyloarthritis or sarcoidosis (47–50). A child with TAK, pyoderma gangrenosum and chronic recurrent multifocal osteomyelitis has also been described (51).

In children, the aorta (arch, thoracic or abdominal) is most commonly affected, followed by the renal, subclavian, carotid, and splanchnic arteries (5, 52; Figure 1). Stenotic lesions predominate, but occlusion, concentric vessel wall thickening and aneurysms may also be observed. Lesions are characteristically located close to the origin of the aortic branches, with an often segmental and patchy distribution (53).

Table 2 summarizes childhood-onset TAK cohorts published during the last decade (6, 7, 44–46, 52, 54–62). Children may present with non-specific symptoms such as fever, dyspnea, headaches, weight loss or abdominal pain. Unlike adults, musculoskeletal symptoms including arthritis are infrequent (5), although they are more commonly described in pediatric TAK cohorts from South America (54, 56, 63). Cutaneous involvement (erythema nodosum, pyoderma gangrenosum) (51, 64) and ocular disease such as retinal vasculitis (47, 65) are rare in children. Presentation may be dramatic and life-threatening when acute hypertensive crisis, heart failure or arterial dissection develop (66–69).

Organ-specific manifestations result from ischemia secondary to vascular stenosis. Arterial hypertension is the main presenting feature (56–100% of children depending on ethnicity, with higher prevalence in Asians) and is primarily related to renal artery stenosis and subsequent renovascular hypertension (44, 58). Arterial hypertension and other clinical signs of hypoperfusion such as blood pressure discrepancy between limbs, decreased peripheral pulses and bruits over large arteries are found in over 60% of children at diagnosis and highlight the necessity of a rigorous physical exam, especially in a child with unexplained systemic inflammation. Claudication of extremities, secondary to decreased blood supply, is reported in a third of children at presentation. Abdominal pain, often related to vasculitis of the abdominal aorta or the mesenteric arteries may occur. Prevalence of cardiovascular complications such as cardiomyopathy, ischemic heart disease, heart failure and valvular disease is estimated between 5 and 27% (6, 45), but coronary artery involvement is reported in only about 11% of children with TAK (44). Neurologic involvement including headache, dizziness, seizures, transitory ischemic attacks, and stroke may be observed. In adults, stroke is more often ischemic than hemorrhagic. While ischemic strokes are more commonly a consequence of steno-occlusive lesions in the carotid and vertebrobasilar vessels, hemorrhagic strokes usually occur as a result of steno-occlusive lesions in the abdominal aorta and renal arteries (70).

More recently, several groups have been directly comparing pediatric and adult TAK cohorts (5, 52, 54, 60–62). Childhood-onset TAK has a lower female predominance (5, 52, 54) and a shorter diagnostic delay, possibly due to a more pro-inflammatory presentation (5, 62). Children have more commonly arterial hypertension, less claudication of the upper extremities, and less carotidynia. This reflects the vascular disease pattern, which more often affects the aorta and the infra-diaphragmatic renal and mesenteric arteries in children, but more frequently the aortic arch in adults (5, 52, 61, 62). Higher disease activity scores such as the Indian TAK Clinical Activity Score (ITAS 2010) at diagnosis have been reported in the pediatric compared to the adult population, but this does not seem to be associated with accrued damage over time (52, 54, 62).

Duration of symptoms before treatment initiation has been positively associated with disease extent and damage (52). Disease course is most commonly relapsing-remitting, especially when untreated, but monophasic evolution may be observed.

Although various biomarkers have been explored for monitoring disease activity in TAK, none has yet been identified for reliable use in clinical practice. In children, elevation of acute phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) is commonly observed (45, 55), but their sensitivity to reflect disease activity is uncertain, and they also lack specificity (71). In addition, they rapidly normalize and are masked under IL-6 blockade, adding further challenges to disease activity assessment in tocilizumab-treated patients (72). Anemia and thrombocytosis may be associated with chronic inflammation, particularly in children.

Among inflammatory molecules, IL-6, a pro-inflammatory cytokine that drives CRP synthesis and thrombocytosis and increases ESR seems promising as a biomarker and a treatment target. In tocilizumab-treated patients with TAK, longitudinal IL-6 monitoring might be useful for assessing disease activity and for detecting infections. While infections seem to trigger a significant, but short-term peak in serum IL-6, persistent IL-6 elevation may indicate subclinical disease activity or relapse (73, 74).

Further, IL-6 independent inflammatory biomarkers, such as S100 proteins or pentraxin-3 are being investigated (75). Pentraxin-3, for example, an acute phase protein synthetized locally at sites of inflammation, has been reported to correlate with disease activity in adults with TAK and may help to predict subclinical vascular inflammation (76). As mentioned previously, anti-endothelial antibodies have recently been identified in patients with TAK (32), but like many other serological biomarkers, they have limited availability and are not used in clinical practice; as a result, their clinical value yet remains to be defined. Studies searching for novel laboratory biomarkers are ongoing.

Vascular imaging aims at depicting morphologic anomalies of the aorta and its branches suggestive of arteritis, and at distinguishing active inflammation from chronic inactive disease. Thus, imaging is crucial for diagnosis, assessment of disease extent and follow-up management of TAK. Imaging modalities include conventional angiography, magnetic resonance (MR) angiography, computer tomography (CT) angiography, Doppler ultrasound (US), and fluorodeoxyglucose positron emission tomography (PET) (¹⁸F-FDG-PET). Although listed in the EULAR/PRINTO/PReS classification criteria for childhood-onset TAK, conventional angiography is nowadays rarely used and restricted to very few, specific indications such as angiographic imaging prior to revascularization procedures (77).

In childhood-onset TAK, contrast-enhanced MR angiography is the most popular imaging modality (Figure 2). It is proposed as the first imaging for suspected TAK by the EULAR recommendations on imaging of large vessel vasculitis (77), and is particularly appealing for repeated evaluations in the pediatric population due to lack of invasiveness and of radiation (78). However, recent research evidenced accumulation of gadolinium in the brain and other human tissues with repeated exposure. This raises concerns about potential toxicity particularly in the pediatric population and underlines the importance to carefully consider the indications for each MRI (79). Similar to MR imaging, CT angiography provides information on anatomical changes of the vascular lumen and wall, and the extent of arterial lesions with good spatial resolution. However, radiation exposure remains an important concern, especially in children and with repeated exposure. Doppler US is non-invasive and non-radiating, it visualizes the arterial wall and lumen, as well as altered blood flow characteristics. Challenges with its use include the lack of pediatric radiologists with expertise in vasculitis imaging, as well as acoustic technical limits, restricting the accessibility of certain vessels such as the descending aorta, especially in children (80).

More recently, ¹⁸F-FDG-PET has been suggested to support radiologic assessment of disease activity (81). In children though, ¹⁸F-FDG-PET plays a minor role for routine imaging monitoring of disease activity, mainly due to the high radiation dose.

While these imaging modalities (MR angiography, CT angiography, Doppler ultrasound, and ¹⁸F-FDG-PET) reliably detect signs suggestive of vascular inflammation and allow diagnosis of TAK even in the early pre-stenotic phase, their role for follow-up monitoring is less evident. As an example, vascular changes such as vessel wall thickening or ¹⁸F-FDG uptake are not specific to active TAK, but may also be induced by healing processes or fibrotic remodeling. This causes difficulties for interpretation of imaging as there is no clear correlation of imaging results with disease activity during the course of disease. Hence, it is crucial to combine clinical, laboratory and imaging evaluation for disease management.

The interested reader is referred to a recent extensive review on imaging in adult and childhood-onset TAK for more information (82).

Efforts to describe angiographic patterns of vascular involvement in TAK have resulted in the identification of different patterns with distinct clinical presentation in various ethnicities (53, 83). Most recently, three distinct clusters with distinct clinical symptoms and outcomes were identified in a large cohort of 806 adults with TAK of Indian and North American origins (84). Yet, these angiography-based disease classifications require validation regarding prognostic prediction.

Given the variable clinical presentation with often non-specific symptoms, differential diagnosis of childhood-onset TAK is broad and also depends on disease presentation. For example, differential diagnoses of fever of unknown origin have to be considered during the early disease phase, when non-specific systemic inflammatory symptoms predominate. Infections including tuberculosis and syphilis may cause aortitis, bacterial infections such as staphylococcus aureus, streptococcus, salmonella, or brucella should be considered in children with more acute clinical presentations (85, 86).

Differential diagnosis also includes other primary vasculitides (Behçet disease, Kawasaki disease, polyarteritis nodosa) and vasculitides secondary to systemic lupus erythematosus, spondylarthritis or sarcoidosis. Non-inflammatory diseases such as aortic coarctation, Williams syndrome, Marfan or Ehlers-Danlos syndrome, and fibromuscular dysplasia (FMD) may mimic childhood-onset TAK. In contrast to TAK, FMD is not an inflammatory disease; but it may be difficult to differentiate from TAK during the “burned-out” disease phase as–unlike in adults–the characteristic angiographic “string of beads” pattern is rarely observed in childhood-onset FMD (87).

Assessment of disease activity is often difficult in clinical practice because an outcome measure that reliably reflects vascular inflammation does not exist. The current tools insufficiently reflect disease activity in pediatric large vessel vasculitis, although the Pediatric Vasculitis Activity Score (PVAS) has been validated in children. Other disease activity measurement tools such as the ITAS 2010 and ITAS-A, which additionally includes acute phase reactants, have been developed specifically for TAK, but are only validated in adults.

The US National Institute of Health (NIH) criteria, commonly used to assess disease activity in TAK, define active disease as the presence of constitutional symptoms, new bruits, increased acute phase reactants or new angiographic findings (133).

Although tools for assessment of disease damage exist for adults with TAK, none has been validated in children. These scores may help to assess accumulated damage over time, but discrimination between disease and treatment-related damage may be difficult (134).

Children with TAK present with more systemic inflammation and more widespread vascular disease than adults. However, relapses and accrued damage are high and equally frequent in both groups and seem to be associated with longer duration of symptoms (44, 52, 61).

Recent advances in disease recognition and therapeutic strategies have decreased morbidity and mortality in TAK. Several recent studies have reported the benefit of biologic therapies such as TNFα-inhibitors or Tocilizumab in adults, with up to 80% of patients achieving complete remission at 6 months (92, 112). In children, data are scarce. A retrospective cohort study demonstrated significantly higher 2-year flare-free survival rates and higher rates of inactive disease at last follow-up in children treated with biologic agents, compared with those on non-biologic therapies (44).

Young age and high CRP at disease onset, stroke, lower BMI, longer duration of symptoms and high accrued damage scores have been associated with poor outcomes including increased mortality in childhood-onset TAK (45, 46, 52). In the recent pediatric cohorts, mortality rate varied between 0 and 27% (6, 7, 44–46, 54–59). Despite growing literature, more data are needed, particularly in children, to better describe the long-term outcome of new therapeutic strategies and to identify factors predicting treatment response and relapses.

Timely diagnosis of childhood-onset TAK is important because the disease is associated with a significant morbidity and mortality. Despite persisting gaps in the knowledge of the pathophysiology of TAK, critical inflammatory pathways contributing to the disease begin to be elucidated and provide avenues for new treatment approaches. Treatment recommendations are mostly based on adult TAK studies with level of evidence two or three, although few randomized controlled trials have been published with biologic agents. Corticosteroids remain the mainstay for induction of remission, but biologic agents such as TNFα- or IL-6- and JAK-inhibitors are increasingly used, particularly in severe, relapsing or DMARD-refractory cases. Whether upfront use of biologic agents improve long-term outcome, yet needs to be investigated.

Large international collaborative efforts are required to conduct well-designed studies to determine efficacy of current therapeutic regimens, to identify reliable biomarkers that help to assess disease activity and guide treatment choice, and to better define the long-term outcome of pediatric TAK using validated pediatric outcome measures. One of the main goals is thereby finding therapeutic strategies to reduce cumulative corticosteroid use and to achieve the best possible efficiency-tolerance balance with minimal cumulative damage.

FA reviewed the literature and drafted the manuscript. RY and RL reviewed the literature and revised the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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