Takayasu Arteritis and Other Vasculitides

Definition and Classification

TA is classified under predominately large-vessel vasculitis in the proposed Pediatric Rheumatology European Society/European League Against Rheumatism (PReS/EULAR) classification of vasculitis. The classification criteria for TA are detailed in Box 37.1 and include imaging abnormalities of the large arteries as a mandatory criterion with at least one of five additional criteria, four of which are physical examination findings and one laboratory criterion. ^, A limitation of these criteria is that the validation was performed by comparison to children with other types of inflammatory vasculitis, thus not including patients with noninflammatory anatomical mimics of vasculitis (see subsection Diagnosis). Thus the specificity of these criteria for diagnosis are likely lower than reported for classification.

Epidemiology

TA is rare, with estimates of the annual incidence in adults ranging from 0.26 to 0.64 per 100,000 in the United States and Sweden to 4.2 per 100,000 in Japan. Accurate pediatric incidence data are not widely available. In the National Institutes of Health (NIH) cohort of patients with TA, 32% of patients presented younger than 20 years old. In an eastern China tertiary medical center, 23 children were diagnosed with TA over a 14-year period, and 1% of all children were seen with vasculitis. Cattalini et al. estimated the prevalence of TA at 2.6 per 1 million children. A comprehensive study in the southernmost county of Sweden found an annual incidence of 0.4 (95% confidence interval, 0 to 1.1) per 1 million children. However, this was based on one patient with TA over 10 years of observation.

TA occurs more frequently in adolescence than in childhood but can occur in very young children, including the first year of life ^, and the neonatal or even prenatal period. In the PReS classification study, which included 87 patients with TA from 97 centers in 36 countries, the mean age of onset was 10.4 years. TA is more common in females than in males (∼2:1), but to a lesser degree than the female predominance among adults. ^{, ,} Familial occurrences have been reported; in one case, five siblings from one family were affected. Although it was first described in Japan and is relatively common in the Far East, TA can occur in all ethnicities. In the international PReS series, 58% of the patients were Caucasian, 13% Hispanic, 10% Asian, 6% African, and 13% other ethnicities. Epidemiologic data from several contemporary cohorts of children with TA are described in Table 37.1 . ^,

Etiology, Genetic Factors, and Pathogenesis

Clinical Manifestations

Patterns of blood vessel involvement and stage of disease (acute, stenotic, fibrotic) determine the clinical manifestations. The frequencies of symptoms described in this section are summarized from pediatric or mixed cohorts and comprehensive reviews ( Table 37.1 ). ^{, , ,} The most common presentation of TA in children is the triad of constitutional features, hypertension, and elevated acute phase reactants. Systemic/constitutional features (fever, weight loss, malaise/fatigue) are described in 26% to 86% of patients at diagnosis. Arthritis, arthralgia, myalgia, and back pain occur in 1% to 65% of patients (dependent on the series). Rashes, including livedo reticularis, erythema nodosum, purpura, and urticaria occur in about 10% of children.

In children, supradiaphragmatic “aortic arch disease” is commonly associated with central nervous system (CNS) manifestations. These include headaches in 17% to 84% of patients, visual disturbances in up to 30%, arterial ischemic strokes in up to 18%, syncope in as many as 16%, in addition to dizziness, cognitive dysfunction, seizures, and carotidynia. Cardiac disease is common with dyspnea and is seen in as many of 54% of patients with other symptoms and features such as chest pain, palpitations, valvular disease, or cardiomyopathy, the latter leading to congestive heart failure in as many as 27% of patients. Impaired heart function, including left ventricular mechanics, hypertrophy, and arterial stiffness with impaired diastolic function are common. Rarely, patients may present with myocardial infarction. Despite frequent pulmonary artery involvement, hemoptysis or other substantial respiratory symptoms are rare. One case of portal vein hypertension in a child was reported.

Two-thirds of children with TA have both supra and infradiaphragmatic disease, the latter characterized by the “middle aortic syndrome”: hypertension, abdominal bruits, and abdominal pain. Renal artery involvement presenting as renovascular hypertension is the single most common clinical manifestation, occurring in 56% to 100% of children, dependent on the series. Gastrointestinal symptoms are seen in between 9% and 64% of patients. Mesenteric artery disease can present as bloody diarrhea and intermittent, severe ischemic/anginal abdominal pain. Gastrointestinal disease can also manifest with vomiting. Renal dysfunction is relatively uncommon; however, in the PReS international series, 21% of the patients had hematuria, proteinuria, or a decreased glomerular filtration rate. Claudication is less common in children than in adults (11% vs. 46% at the start of disease and 47% vs. 81% overall). ^,

Rare clinical associations include ^, pyoderma gangrenosum, chronic nonbacterial osteomyelitis, ^, familial Mediterranean fever (FMF), ^, ankylosing spondylitis, juvenile idiopathic arthritis (JIA), posterior reversible encephalopathy syndrome, keratouveitis, bilateral ocular ischemic syndrome, hearing loss, granulomatosis with polyangiitis, Sweet syndrome, and relapsing polychondritis. Inflammatory bowel disease appears to be a more common association and may be seen in up to 10% of patients with TA. ^{, , ,}

Physical findings are crucial in the diagnosis of TA. The most important and common findings include decreased/absent peripheral pulses (27% to 86%), discrepancies between limbs in the measurement of blood pressure (27% to 83%), bruits involving the large arteries (19% to 75%), and hypertension. Muscle atrophy and discrepancies in the size of limbs can be seen.

In general, the clinical presentation of TA is similar in children and adults. However, hypertension is more common and claudication, especially of the upper extremities, is much less common among children. Arthralgia and arthritis may be more common among adults.

Laboratory Investigations

Elevated inflammatory indices are found in the majority (33% to 100% in various series) of patients with active disease ( Table 37.1 ). No TA-specific marker has been identified, but von Willebrand factor (vWF) antigen levels, anemia, and thrombocytosis may be present. Antinuclear antibodies (ANAs) and antineutrophil cytoplasmic antibodies (ANCAs) are generally not present, although in several series ANA was detected in 22% to 36% of pediatric patients. Even among the few patients with ANCAs, specific antibodies for proteinase 3 or myeloperoxidase were not found. Antibodies reacting with endothelial cells have been reported. Disease flares are often, but not always, accompanied by raised inflammatory markers. One-third of patients have no elevation of inflammatory markers at presentation, possibly reflecting burned-out disease. Children younger than 10 years of age appear to have more anemia and thrombocytosis than older children.

Pathology

The presence of intramural multinucleated giant cells in the walls of affected large-size arteries is diagnostic, mostly in the vasa vasorum. Initially, inflammation affects the vasa vasorum and the medio-adventitial junction. There is edema with mononuclear cell infiltration (CD4 and CD8 lymphocytes, plasma cells, and macrophages) in the outer third of the media and adventitia. Eventually, the inflammatory infiltrate leads to thickening of all layers of the vessel wall. Lesions can be diffuse throughout the aorta or localized to short inflammatory segments with a length of several centimeters. Active lesions show acute cellular inflammation, granulomas, and giant cells. In the PReS international cohort, granulomatous lesions were found in 4 of 11 (36%) patients with available tissue sample. Later, laminar necrosis and fragmentation of elastic tissue may occur, the latter associated with the development of aneurysms. Loss of smooth muscle tissue also may contribute to vessel wall weakness. The inflammatory infiltrate becomes patchy and sparse with medial scarring and vascularization. At late stages, fibrosis, characterizing inactive lesions, predominates and leads to stenosis. Both active and fibrotic lesions may be present simultaneously. Active lesions may be found in clinically quiescent patients. The pathology of TA in children is reviewed by Vaideeswar and Deshpande.

Imaging Findings

Recommendations for the imaging of TA in children were published. In children, magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) is the preferred imaging modality, especially for serial follow-up ( Fig. 37.1 ). ^, Vessel wall thickness and edema can be measured in addition to anatomical changes. Gadolinium enhancement may be seen in vessel walls during the active disease. Stenosis is the most common imaging feature in pediatric TA, found in more than 90% of patients (range 71% to 100%) ( Table 37.1 , Figs. 37.2 and 37.3 ). Dilation with both fusiform and saccular aneurysms are encountered in a minority of patients (range 8% to 49%). Aneurysms are more common in patients from the Far East. Occluded vessels, often representing mural thrombosis, can be seen in about 33% (range 11% to 63%) of patients. In one series, three of 27 (11%) patients presented with dissection at diagnosis, two of the descending aorta and one of the carotid artery. Risk factors for dissection included a higher Pediatric Vasculitis Activity Score (PVAS), lower albumin, and higher neutrophil levels. Patients with dissection did not have increased blood pressure measurements compared with other patients.

Noninvasive quantification of intimal-media thickness, edema, and elastic properties of the aorta may aid in assessing aortic involvement and possibly help follow disease activity and response to therapy. Carotid intimal-medial thickness was shown to be a marker for disease activity with a sensitivity of 82% and specificity of 60%. However, edema and wall thickening are not always reversible, even in patients with clinically inactive disease, thus caution is needed in over interpreting the imaging results in regards to the effect of therapy on disease activity. MRA may overestimate the degree of stenosis. The development of new lesions is of much greater importance in following disease activity.

Conventional angiography using digital subtraction technique is the gold standard of lumen imaging in TA but is rarely employed because of its invasiveness and exposure to ionizing radiation. However, in multivessel involvement with the aorta and both subclavian arteries, it may be necessary to perform conventional angiography to measure the true central cardiac blood pressure. Computed tomography angiography (CTA) is an excellent imaging modality for TA, but its use in children is limited because of its high radiation dose. FDG-PET scans can demonstrate active inflammation in vessel walls, but its role in pediatric TA is still unclear, also considering the exposure to radiation. The use of Doppler ultrasound technique for assessing disease activity in TA has been described, especially of the renal and carotid arteries, but its role as an imaging modality in TA is limited, in part because it is difficult to image long segments of multiple blood vessels. Adult guidelines, adapted by PReS, suggest that MRI/MRA should be used as the first diagnostic imaging test. ^, CT angiogram, and/or ultrasound can be used as alternatives. In the adult guidelines, the frequency of imaging and modality for long-term follow-up are individualized for each patient.

TA is classified into six types based on the pattern of anatomical involvement ( Table 37.2 and Fig. 37.4 ). Usually the infrarenal aorta, inferior mesenteric artery, and iliac arteries are spared. The most common vessel distribution in pediatric TA are types IV and V ( Table 37.1 ), although one study found type I to be more common.

There is debate on the site and extent of vessel involvement in children as opposed to adults. Kerr et al. did not find significant differences, whereas Aeschlimann et al. found a greater proportion of aorta and renal involvement in children. A series from India found a slightly greater propensity for involvement of the descending thoracic aorta among children although the subclavian and carotid arteries were more frequently involved in adults.

Disease Assessment Tools

There are no specific disease assessment tools validated for childhood TA. However, several disease activity tools, both general vasculitis (adult and pediatric) and disease-specific tools developed for adults, have been used in several pediatric TA studies.

The nondisease specific Birmingham Vasculitis Activity Score (BVAS), developed for adults mainly for small- to medium-size vessel vasculitis, was used to describe the disease activity in a series of 22 children with TA. Cardiovascular features are underrepresented in this score. Several cohorts have used the PVAS, the pediatric adaptation of the BVAS, at baseline ^{, , ,} and follow-up. ^{, ,} These series showed that the PVAS was sensitive to change and correlated well with other disease activity tools described in the following paragraph. The nondisease-specific, and not yet validated, Pediatric Vasculitis Damage Index (PVDI) was used to demonstrate a high degree of damage (see section Outcome) in a few childhood series.

Several disease-specific disease activity and damage tools were developed for adults with TA. The first, the Disease Extent Index–Takayasu (DEI.Tak) measures only clinical (no imaging and laboratory) items over the past 6 months. The Indian Takayasu Clinical Activity Score (ITAS2010) was derived from the DEI.Tak. The ITAS2010 measures 44 items, mainly cardiovascular symptoms that have occurred or worsened over the past 4 weeks and lasted less than 3 months. ITAS2010 was used in several series of pediatric TA. ^{, ,} The ITAS-A also incorporates acute phase reactants. The Takayasu Arteritis Damage Score (TADS) was derived from the DEI.Tak and contains 42 items in seven fields, recording features that have lasted for more than 3 months. The TADS was used in several pediatric TA series. ^{, ,}

The NIH defined active disease as new onset or worsening of two of four features: (1) constitutional symptoms without other explanation, (2) elevated inflammatory indices, (3) new features of vascular ischemia (history and physical examination findings) or elevated inflammatory markers, or (4) new vascular lesions on imaging. An imaging-based ultrasound Doppler score was described earlier. A radiological damage score based on MRI or CT is under development.

Treatment

The treatment of TA includes immunosuppression for active vessel wall inflammation, antihypertensive, antiplatelet therapy (anticoagulation in some patients), and surgical or endovascular management, such as percutaneous transluminal angioplasty. Treatment efficacy should be monitored with a combination of clinical, laboratory (inflammatory markers), and imaging modalities.

Course and Prognosis

TA is usually a relapsing chronic disease. Older studies used the following to describe a triphasic disease course: early inflammatory disease characterized by constitutional nonspecific symptoms, chronic/relapsing stenotic/aneurysmal phase with symptoms related to the effect of blood vessel changes on various organs, and burned-out phase with fibrotic changes to the affected blood vessels. However, it is clear that these phases are not sequential but often occur simultaneously.

The overall 5-year survival in adults is 70% to 90%. In older series of pediatric TA, especially from developing countries, mortality was as high as 22% to 35% after 10 to 15 years of follow-up. ^{, ,} However, in 358 patients from pediatric TA cohorts reported since 2010 the mortality rate was only 5.3% (range 0% to 27%) ( Table 37.1 ), although the median time of follow-up was quite short (≤3 years in almost all the series). Causes of death include aortic dissection, cardiomyopathy, heart failure, hypertensive crises, myocardial infarction, stroke, and renal failure. In one series, risk factors for mortality were younger age at onset and higher damage score but not a delayed time to diagnosis, cardiac involvement, nor the need for surgical intervention.

The disease is monophasic in 20% to 25% of patients. In pediatric TA series published since 2010, 55% (range 38% to 78%) of patients attained remission, and flares (clinical and/or imaging) were reported in 32% (range 14% to 50%). In the cohort with the longest time of follow-up (median 5.4 years), the mortality, remission, and flare rates were 8%, 54% (39% off medication), and 31%, respectively. The average duration of remission and frequency of flare in the pediatric population is unknown. In the NIH cohort, more children attained remission (60% vs. 40% in adults) in a shorter time from the start of treatment (11 months vs. 33 months). However, a study from Brazil reported a lower rate of remission among children than adults (24% vs. 56). It appears that flare-free remission in more frequently attained by children treated with biologics.

Disease and/or treatment-related morbidity is common and usually reflects complications caused by stenotic vessels. Patients often accrue irreversible damage early in the disease course. Relatively high damage scores on the nondisease-specific PVDI and the disease-specific TADS were accrued in contemporary series in patients even with a median follow-up of less than 3 years. ^{, ,} Eleftheriou et al. reported a median PVDI score of 5.5 (range 3 to 19, 72 maximal score), whereas Aeschlimann and Sahin et al. reported a median score of 4 (range 1 to 7). The latter also reported a median TADS of 4 (range 1 to 7). Misra reported a median TADS of 8 (range 6.3 to 9.8) after a median of only 2.4 years of follow-up. Aeschlimann et al. reported strokes in 26% of patients and seizures in 11% within 2 years of disease onset. Fan et al. found that low body mass index, prior stroke, revascularization procedures, and renal artery involvement were poor prognostic factors for long-term remission and complications.

Etiology and Pathogenesis

The etiology is unknown. However, similarities to syphilitic keratitis have led to searches for infectious etiologies. Studies from the NIH found serological evidence for infection by Chlamydia trachomatis in many patients, but this has not been replicated by other investigators. Other investigated organisms included additional species of Chlamydia and Borrelia burgdorferi. The Mayo Clinic series found that smoking rates among patients were twice that of the general population.

The pathogenesis is considered to be autoimmune. Usually relatively protected from the immune system, the eye and inner ear may develop an immune response to various undetermined insults, resulting in T- and B-lymphocyte activation and the formation of autoantibodies. However, most studies in adults did not find evidence of autoantibody formation to antigens of the inner ear, including to 68 kDa, frequently found in idiopathic progressive bilateral sensorineural hearing loss. ^, Other studies in adults found antibodies to the density-enhanced protein tyrosine phosphatase 1 (DEP-1) in some patients with Cogan syndrome. These are expressed on endothelial cells, which have a peptide with partial homology to the SSA antigen and to connexin 26 expressed in inner ear cells. Antibodies to heat shock protein 70 were also found in patients with classic disease.

No specific pathology has been found in eye and inner ear structures, mostly because of the long time between disease onset and obtaining a histological sample; frank vasculitis is rarely found. Large-vessel vasculitis resembles that of TA and PAN.

Clinical Manifestations

Often the onset of disease is preceded by an infection, most commonly an upper respiratory infection. There do not appear to be significant differences between adult and childhood disease. The median time from onset to diagnosis is about 8 months. Table 37.3 details the proportion of children with ocular, vestibular-auditory, musculoskeletal, and systemic symptoms. Signs of large-vessel vasculitis, particularly proximal aortitis and aortic valve insufficiency, are present in 10% to 20% of children. An association with inflammatory bowel disease has been reported. In almost all cases the diagnosis of inflammatory bowel disease precedes that of Cogan syndrome with a mean lag time of 8.7 years. ^,

More than 50% of the children have multisystem disease with approximately 25% of cases involving two systems, whereas in approximately 20%, only one system is involved. The interval between development of ocular and vestibular-auditory symptoms is generally less than 2 years. However, several children were already deaf by the time ocular symptoms started.

Investigations

Acute phase reactants are usually elevated but can be normal in patients with isolated ocular and vestibular-auditory disease. Autoantibodies are usually negative but antiphospholipid antibodies and ANCAs are found in a few patients, the latter in a perinuclear pattern. Repeated audiometry testing is crucial with hearing loss noted initially in the high and low frequencies, similar to Meniere syndrome. Brainstem auditory evoked potentials are abnormal in advanced disease.

Echocardiography may demonstrate aortic valve insufficiency with thickening of the valve and proximal aortitis. Inner ear MRI with gadolinium may show cochlear enhancement. Proximal aorta MRI is useful to search for evidence of aortitis. Calcific obliteration of cochlear and vestibular structures can be found by CT.

Differential Diagnosis

The association of interstitial keratitis with vestibular-auditory inflammatory disease can be seen in many other conditions. Infections include Chlamydia, mycoplasma, Lyme disease, and congenital syphilis. Inflammatory diseases include sarcoidosis, granulomatosis with polyangiitis, relapsing polychondritis, Behçet syndrome, Sjögren syndrome, Susac syndrome, and antiphospholipid antibody syndrome. Other conditions include lymphoma, Vogt–Koyanagi–Harada syndrome, mitochondrial cytopathies, and Whipple disease.

Treatment

There are no controlled therapeutic trials in Cogan syndrome. However, early diagnosis and institution of high-dose corticosteroids (between 1 and 2 mg/kg/day) is crucial in saving hearing or preventing further loss of hearing. ^, It is often hard to wean corticosteroids, and steroid-sparing medications are often necessary and should be employed early; methotrexate being the most commonly used in children. ^{, ,} Other options used in children include mycophenolate mofetil, leflunomide, azathioprine, cyclosporine A, and cyclophosphamide (the latter mainly in cases of large-vessel vasculitis). ^{, , , ,} In adults, anti-TNF agents, especially infliximab, have been used, usually with success. Some experts advocate its early use as a corticosteroid-sparing agent and, in cases with severe disease, as first-line therapy, whereas others disagree because of lack of evidence. There are rare case reports in adults describing the beneficial use of tocilizumab, rituximab, and plasmapheresis. Ocular corticosteroid drops are commonly used. Cochlear implants are beneficial in patients with established deafness. ^{, ,}

Course and Outcome

Only about 30% of patients achieve complete, damage-free remission. Ocular outcomes are usually excellent with rare permanent damage. However, permanent partial or complete hearing loss occurs in nearly 50% of childhood cases. Use of infliximab may improve vestibular-auditory outcomes and even reverse hearing loss. Delayed diagnosis of more than 2 months was the most important factor related to a poor outcome in pediatric cases. Aortic valve damage is usually not reversible, although rarely is surgical replacement required. Only one death, from subarachnoid hemorrhage, was reported in the childhood cases. Relapses may occur in up to 30% of patients within 10 years.