Pediatric Takayasu Arteritis 

Updated: Nov 03, 2015
Author: Christine Hom, MD; Chief Editor: Lawrence K Jung, MD 

Overview

Background

Takayasu arteritis is a chronic inflammatory disease of the aorta and its major branches. The disorder is a large vessel vasculitis of unknown origin that most often affects young women in the second and third decades of life (see the image below).[1] (See Pathophysiology, Etiology, and Epidemiology.) It is defined as arteritis, often granulomatous, predominantly affecting the aorta and/or its major branches. Onset usually is in patients younger than 50 years.[2]

Aortogram of a 15-year-old adolescent girl with Ta Aortogram of a 15-year-old adolescent girl with Takayasu arteritis. Note large aneurysms of descending aorta and dilatation of innominate artery.

Takayasu arteritis has been reported in pediatric patients as young as age 6 months and in adults of every age. In children, Takayasu arteritis is one of the more common etiologies of renovascular hypertension.[3] (See Pathophysiology and Epidemiology.)

The initial complaints in children are typically nonspecific constitutional signs and symptoms (eg, fever, weight loss, lethargy). Because these complaints lack specificity, the correct diagnosis may be delayed for months or years. The classic pulseless disease is more common in adults and represents later disease. (See Presentation, DDx, and Workup.)

Upon histologic examination, the aorta demonstrates evidence of granulomatous inflammation. Mixed areas of stenosis or aneurysm formation are found on angiography or magnetic resonance angiography (MRA). Vascular insufficiency related to stenosis and thrombosis of affected vessels may cause renovascular hypertension, neurologic symptoms, or lower extremity claudications. (See Workup.)

Cardiac involvement may include aortic regurgitation and congestive heart failure resulting from myocarditis or increased afterload. Aortic root dilatation contributes to the aortic regurgitation. Often, the diagnosis of Takayasu arteritis is made when a widened mediastinum is appreciated on chest radiography and a tumor is suspected. Computed tomography (CT) scanning instead reveals a widened aortic arch. The wreathlike anastomoses of the retina described by Dr. Mikito Takayasu are seen in only 16% of adults and less frequently in children.

Despite the term pulseless disease, which is a synonym for Takayasu arteritis, the predominant finding in individuals with Takayasu arteritis is asymmetrical pulse. Absent peripheral pulses occur late in the course of the disease. Although 5-year survival rates exceed 90%, the disease has a high incidence of residual morbidity. (See Prognosis, Presentation, and Workup.)

Complications

Complications of Takayasu arteritis include the following:

  • Congestive heart failure due to aortic insufficiency, myocarditis, and/or hypertension

  • Aortic aneurysms, thrombus formation, and rupture

  • Ischemic stroke

  • Myocardial infarction

  • Hypertension

  • Clinically silent progressive disease (despite normal acute phase reactants)

  • Morbidity resulting from treatment medications - Must be considered in planning long-term treatment

Patient education

Review signs of corticosteroid excess (ie, Cushing syndrome) with the patient and his or her family, refer patients for psychosocial counseling, and reinforce medication compliance.

Pathophysiology

Takayasu arteritis is characterized by granulomatous inflammation of the aorta and its major branches, leading to stenosis, thrombosis, and aneurysm formation. The lesions of Takayasu arteritis are segmental with a patchy distribution.[4]

Mononuclear infiltration of the adventitia occurs early in the course of the disease, with cuffing of the vasa vasorum. Granulomatous changes may be observed in the tunica media, with Langerhans cells and central necrosis of elastic fibers and smooth muscle cells. A panarteritis with infiltrates of both B and T lymphocytes, plasma cells, histiocytes, and giant cells is present. Later, fibrosis of the media and acellular thickening of the intima may compromise the vessel lumen. Platelet-derived growth factor (PGDF) is released, with subsequent myofibroblast proliferation, which further thickens the vessel wall. Matrix metalloproteinases weaken the arteries, allowing aneurysm formation. There is no inflammatory infiltrate of the intima; changes are thought to be reactive to inflammation in the media and adventitia. Wrinkling of the intima is visible upon gross examination.

Stenoses are the most common lesion, found in 90% of patients with Takayasu arteritis. Patients often have poststenotic dilatations and other aneurysmal areas, reported up to 45%. Stenotic arterial segments result in varied ischemic symptoms. These symptoms may range from abdominal pain after eating secondary to narrowing of the mesenteric arteries to renovascular hypertension to claudication of extremities.

In children, Takayasu arteritis is one of the more common etiologies of renovascular hypertension. Endothelial activation leads to a hypercoagulable state predisposing the patient to thrombosis. Congestive heart failure in individuals with Takayasu arteritis may occur as a result of hypertension, aortic root dilation, or myocarditis.

Transient ischemic attacks, cerebrovascular accidents, mesenteric ischemia, and carotidynia may occur. Symptoms of vascular compromise may be minimized by the development of collateral circulation, with a more insidious onset of stenosis. Vessel wall dissection may occur in areas weakened by inflammation.

One hypothesis for granulomatous vasculitis development is that antigens deposited in vascular walls activate CD4+ T cells, followed by the release of cytokines chemotactic for monocytes. These monocytes are transformed into macrophages that mediate endothelial damage and granuloma formation in the vessel wall. A mouse model supports this hypothesis. When syngeneic T cells sensitized to vascular smooth muscle cells were injected into mice, a granulomatous vasculitis of the pulmonary arterioles occurred in 20% of the mice.

Human studies suggesting endothelial cell activation have demonstrated increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in patients with Takayasu arteritis. Evidence for an autoimmune etiology is supported by circulating antiaortic antibodies and antiendothelial cell antibodies found in the sera of patients with Takayasu arteritis. Immunoglobulin G (IgG), IgM, and properdin deposits are found in lesions from pathologic specimens. Autoreactive T cells TH1 and TH17 are increased in active Takayasu arteritis, along with decreased numbers of FOXP3-positive T-reg cells.

Cytokine abnormalities include elevated tumor necrosis factor and interleukin IL–6. More recently, B cells are identified as contributing to Takayasu arteritis, with plasmablast expansion in patients with active Takayasu arteritis. This increase in B cells is not seen in inactive disease. IL-6 and B-cell activating factor (BAFF) also increase total numbers of circulating B cells; reduction in disease activity is observed with successful depletion of B cells with anti-CD20 and increase in B cells observed with relapse.[5]

Epidemiology

Occurrence in the United States

In Minnesota's Olmstead County, incidence of Takayasu arteritis was estimated at 2.6 cases per million. However, the applicability of this number to the diverse population of the United States as a whole is uncertain.

International occurrence

Takayasu arteritis is common in developing countries, where the disease is closely associated with tuberculosis. The nature of this association is unclear because most patients with Takayasu arteritis in the United States do not have tuberculosis. In contrast, many physicians in developing countries assume that tuberculosis is present in every patient with Takayasu arteritis.

In endemic areas, active tuberculosis may perpetuate Takayasu disease activity through molecular mimicry or chronic antigen stimulation. Quantitative interferon assays may be useful in identifying these patients. In a series of 66 Turkish patients with Takayasu arteritis, 37% of active patients had a positive QuantiFERON (interferon release assay) test, compared with only 17% of patients in remission. There was no difference in tuberculin skin test (TST). There is no change in activity with tuberculosis therapy.

Race-related demographics

Takayasu arteritis is more common in Asian populations but has been described in patients of all races. Japanese patients with Takayasu arteritis have a higher incidence of aortic arch involvement. In contrast, series from India report higher incidences of thoracic and abdominal involvement. In US patients with Takayasu arteritis, the most commonly involved vessels are the left subclavian, superior mesenteric, and abdominal aorta.

In US children with Takayasu arteritis, lesions of the thoracic and abdominal aorta, rather than lesions of the aortic arch, are most common. However, all patterns of vascular involvement have been observed in every country.

Sex-related demographics

In adults, females account for 80-90% of patients with Takayasu arteritis. Pediatric studies are more varied. Although sex distribution usually mirrors the 80-90% female preponderance observed in adults, series of studies of Takayasu arteritis in childhood from India and South Africa reported a 2:1 female-to-male ratio. However, these are countries in which Takayasu arteritis is associated strongly with tuberculosis, and additional etiologic and pathophysiologic factors may be present.

Age-related demographics

Takayasu arteritis is the most common large vessel vasculitis of adolescence. Takayasu arteritis is an uncommon vasculitis in children.[6] The most common are postinfectious vasculitides, Henoch-Schönlein purpura, polyarteritis nodosa, and Kawasaki disease. Most cases of Takayasu arteritis present in persons aged 10-30 years. In a series of patients with Takayasu arteritis, 20-35% were younger than 20 years at diagnosis. The youngest patient reported was aged 6 months.

Prognosis

Takayasu arteritis is a chronic, relapsing disease. More than half of patients with Takayasu arteritis achieve control on corticosteroids alone; however, their relapse rate is high and they require long periods of steroid treatment.[4]

Overall prognosis in individuals with Takayasu arteritis relates to the degree of vascular and end-organ damage, specifically retinal vasculopathy, aortic insufficiency, aortic aneurysms, and hypertension. Survival rate at 15 years is as high as 95%.

Among patients with Takayasu arteritis who are treated with glucocorticoids, 60% respond; however, as many as 40% relapse on tapering of steroids. In a Cleveland Clinic series of 75 patients, 93% achieved remission, but only 28% of patients were able to maintain 6 months of remission when steroids were tapered to 10 mg or less.[7]

Patients refractory to glucocorticoids have been offered azathioprine, methotrexate, cyclosporine, cyclophosphamide, TNF inhibition, mycophenolate mofetil, rituximab,[8] and tocilizumab,[9, 10] with varying success. These drugs can be steroid sparing and disease controlling in a subset of refractory patients, but the disease remains chronic and not cured. Patients discontinuing their medications typically flare within a few weeks.

Morbidity and mortality

Because Takayasu arteritis is rare in the United States, accurate survival data are uncertain. One study reported a survival rate of 85-95% at 15 years. In a 1994 study, only 2% of deaths were attributed directly to Takayasu arteritis. Japanese studies support 90-95% survival rates.

In contrast, in a series involving 26 Mexican children aged 3-15 years, the 5-year survival rate was only 35%.[11] Deaths resulted from rupture of aorta or aneurysms (2), stroke (2), cardiac failure (2), and peritonitis and ventricular fibrillation.

Morbidities in persons with Takayasu arteritis are related to ischemia and hypertension and include congestive heart failure, transient ischemic attacks, stroke, and visual disturbances. Pulmonary artery disease occurs in up to 50% of adult series.

Chronic, low-grade dissection of the aorta may cause recurrent chest pain for years. Upon autopsy, children with Takayasu arteritis who have died from acute rupture of the aorta have often been found to have evidence of multiple small dissections that did not progress.

An increased incidence of atherosclerotic vascular disease is independent of coronary risk factors; this is due to chronic systemic inflammation.

 

Presentation

History

Systemic symptoms in Takayasu arteritis include the following:

  • Fever, night sweats

  • Fatigue

  • Weight loss

  • Myalgia and/or arthralgia and/or arthritis

  • Skin rash (eg, erythema nodosum, pyoderma gangrenosum)

  • Headaches and/or dizziness and/or syncope

  • Congestive heart failure, palpitations, angina

  • Hypertension (may be paroxysmal)

Symptoms related to ischemia include the following:

  • Ischemic stroke and/or transient ischemic attack

  • Visual disturbances (eg, blurred vision, diplopia, amaurosis)

  • Carotidynia

  • Abdominal pain

  • Claudications (vary due to the development of collateral circulations; symptom is rare in children)

Physical Examination

The following symptoms may be observed on physical examination:

  • Blood pressure difference greater than 30 mm Hg between arms[12]

  • Asymmetrical pulses

  • Diminished or absent pulses - Midaortic lesions found in children may not affect pulses

  • Poststenotic dilatations producing what appear to be bounding pulses (often present)

  • Hypertension (may be paroxysmal) - Because this typically results from renovascular compromise, this is a high-renin hypertension

  • Bruits - Especially over subclavian arteries or the aorta

  • Skin lesions - Reported skin lesions include erythema nodosum–like lesions, pyodermagangrenosum, leukocytoclasticvasculitis, and panniculitis

Asymmetrical pulses (common) and absent pulses (rare) can be found even in the later stages of the disease (awareness of this is critical). Funduscopic examination may reveal the following:

  • Retinal hemorrhages

  • Cotton-wool exudates

  • Venous dilatation and beading

  • Microaneurysms of peripheral retina

  • Optic atrophy

  • Vitreous hemorrhage

  • Classic wreathlike, peripapillary arteriovenous anastomoses (extremely rare)

An international pediatric rheumatology consortium consisting of the European League Against Rheumatism, (EULAR), Pediatric Rheumatology International Trials Organization (PRINTO), and the Pediatric Rheumatology European Society (PReS) released the following classification criteria for Takayasu arteritis and other vasculitis syndromes in children in Ankara, Turkey in 2008[13] :

  • Angiographic evidence of vasculitis (angiography, CT scanning, or MRI) and 1 of the 5 criteria below

  • Pulse deficit or claudication

  • Bruits

  • Four-limb blood pressure discrepancy

  • Hypertension

  • Acute phase reactant levels elevated

These criteria provide a sensitivity of 100% and specificity of 99% compared with 85% sensitivity for adult Takayasu criteria.

A retrospective review emphasized that constitutional symptoms coupled with objective findings of diminished pulses, bruits, and hypertension should raise clinical suspicion for Takayasu Arteritis in pediatric patients. The study also added that pharmacologic therapy alone can be successful in controlling disease progression, however surgery was successful in minimizing symptoms when medical therapies failed.[14]

 

DDx

Diagnostic Considerations

Early diagnosis of Takayasu arteritis can be difficult due to nonspecific early symptoms; perform a thorough evaluation to eliminate other diagnoses. Conditions to consider in the differential diagnosis include the following:

  • Systemic-onset juvenile rheumatoid arthritis

  • Migraine

  • Infection

  • Malignancy

  • Cogan syndrome (associated with aortitis)

Differential Diagnoses

 

Workup

Approach Considerations

Takayasu arteritis (Takayasu arteritis) has no specific markers. However, the following results can be found in laboratory studies:

  • Complete blood count (CBC) reveals a normochromic, normocytic anemia in 50% of patients with Takayasu arteritis; acute phase reactants are elevated, with leukocytosis and thrombocytosis

  • Westergren erythrocyte sedimentation rate is elevated

  • Comprehensive metabolic profile may indicate elevated transaminases and hypoalbuminemia

  • The von Willebrand factor–related antigen (factor VIII–related antigen) may be elevated

  • Antiendothelial antibodies are present

  • Antinuclear antibody results are usually negative

  • Antineutrophil cytoplasmic antibody results are usually negative

  • Rheumatoid factor is elevated in 15% of individuals with Takayasu arteritis

  • Increased levels of immunoglobulins G, M, and A are present

Patients with normal study results can still have progressive disease in the large vessels, as demonstrated on pathology specimens. The biomarker pentraxin 3, a protein closely related to C-reactive protein, may be positive in some patients with active disease with a normal C-reactive protein.[15] It is synthesized locally, in response to innate immune signaling by Toll receptors and reflects treatment of disease and relapse. The biomarker matrix metalloproteinase (MMP)–9 is also synthesized locally and is elevated in active disease, compared with normal controls and inactive disease.[16] Whereas the white blood cell count and sedimentation rate decrease with prednisolone treatment, pentraxin 3 and MMP-9 do not.

Patients with ischemia in all 4 extremities may have falsely low peripheral blood pressures. Accurate blood pressure monitoring in such patients can be obtained reliably only by central systemic measurements.

Arteriography

Arteriography is the criterion standard for assistance in the diagnosis of Takayasu arteritis. It is performed either with invasive angiography or, more frequently, with magnetic resonance angiography (MRA). These modalities are most helpful in identifying changes in the vessel lumen. They are less successful in delineating mural disease. Drawbacks to arteriography include morbidity from the use of contrast dye in patients with renal disease and cumulative radiation exposure over time, which can be avoided by using MRA.

Arteriography often demonstrates long, smooth, tapered narrowings or occlusions. The most frequent lesions are stenotic. Stenoses occur in 90-100% of patients with Takayasu arteritis and aneurysm formation in only 27-40%. Some authors recommend arteriography of the entire aorta. Peripheral blood pressure monitoring is frequently inaccurate in persons with Takayasu arteritis; pressure readings during angiography alone may reveal aortic root hypertension.

CT Scanning and MRI

CT scanning and magnetic resonance imaging (MRI) are useful for serial examinations and diagnosis in the early phase of Takayasu arteritis. They may reveal mural thickening of the aorta and luminal narrowing.[17, 18] (See the images below.)

MRI of thorax of 15-year-old adolescent girl with MRI of thorax of 15-year-old adolescent girl with Takayasu arteritis. Note aneurysms of descending aorta.
Coronal MRI of abdomen of 15-year-old adolescent g Coronal MRI of abdomen of 15-year-old adolescent girl with Takayasu arteritis. Note thickening and tortuosity of abdominal aorta proximal to kidneys.

Use of contrast may reveal inflammatory lesions prior to the development of stenoses; these lesions may be missed by angiography. Aortic lesions, including stenosis, dilatation, wall thickening, and mural thrombi, are well visualized on MRI, which is less adequate in visualizing distal lesions of the subclavian vessels and common carotids. (See the images below.) Ultrasound can be used for monitoring in these areas. Delayed contrast techniques can demonstrate enhancement of the aortic wall, confirmed by a pathology specimen in a patient with normal inflammatory markers.[19, 20]

Gadolinium-enhanced cardiovascular MRI has also been used to demonstrate myocardial perfusion defects, which may be important in long-term prognosis.

Noncontrast, T2-weighted, short inversion imaging recovery (STIR) images may be used to monitor edema in the aortic wall, which may be a surrogate for inflammation; edema was found in 94% of patients with clinically active disease.

Large vessel edema was found in 56% of patients in clinical remission, similar to the 42-44% of patients in clinical remission who were found to have active vasculitis on pathology from bypass specimens. The prognostic significance of vessel edema is uncertain, as progression of lesions occurs in areas without edema, and progression may be absent from areas with edema on subsequent studies.

Additional Imaging Studies

Additional imaging studies include the following[21, 22] :

  • 18 F-fluorodeoxyglucose positron emission tomography (18 F-FDG PET) scanning – This technique shows FDG uptake in active lesions, as well as other areas without mural thickening. Enhancement disappears with treatment and is independent of inflammatory mediators. The ability to identify intramural lesions at the inflammatory stage, prior to morphological changes, is becoming possible.

  • Gallium-67 radionuclide scan - This scan may demonstrate increased uptake in the aorta and branches and is useful in comparison with MRI for large lesions

  • High-resolution ultrasonography - Duplex Doppler may be used to evaluate and monitor disease in the common carotids and subclavian arteries, with carotid evaluation revealing a homogenous, circumferential thickening of the vessel wall that is distinguishable from atherosclerotic thickening; this imaging study is only useful in evaluating superficial vessels. It can be used serially to follow flow and lumen.

  • Chest radiography - Chest radiography may reveal widening of the ascending aorta, an irregular descending aorta, aortic calcifications, and rib notching (late findings)

  • Echocardiography - Perform echocardiography at baseline to evaluate the aortic valve; Perform follow-up echocardiography as indicated to monitor aortic insufficiency from aortic root dilatation.

Histologic Findings

Mononuclear infiltration of the adventitia with perivascular cuffing of the vasa vasorum occurs early in the disease.

Granulomatous changes may be observed in the tunica media with Langerhans cells and central necrosis of elastic fibers and smooth muscle cells. Later, fibrosis of the media and acellular thickening of the intima may compromise the vessel lumen. Grossly, wrinkling of the intima is found.

Histologic specimens seldom are available, due to the large vessels affected, with the exception of specimens obtained during autopsy and bypass surgery. The most common infiltrates after CD4 T cells are CD19/CD20 B cells.

 

Treatment

Approach Considerations

Medical evaluation and treatment of patients with Takayasu arteritis can be performed on an outpatient basis unless the patient is acutely ill. The goals of medical therapy are to control active inflammation and to normalize clinical and laboratory parameters while preventing further vascular damage. Daily high-dose corticosteroid administration is the standard initial therapy.

Following the acute phase, patients with fibrotic changes require surgical treatment of symptomatic stenotic or occlusive disease.

Patient activity is generally self limiting, based on cardiac status. Most children participate uneventfully in school and play activities.

Consult with the following specialists as needed:

  • Pediatric rheumatologist

  • Ophthalmologist

  • Pediatric cardiologist

  • Vascular surgeon

  • Interventional radiologist

Surgical Therapy

Following the acute phase, patients with fibrotic changes require surgical treatment of symptomatic stenotic or occlusive disease. This can be achieved by percutaneous angioplasty or stenting or, in severe cases, by resection and placement of a manmade graft. Children with Takayasu arteritis rarely require bypass surgery or carotid stenting. In an adult series of 15 supraaortic stenosis treated with endovascular stenting and 24 lesions treated with carotid bypass surgery, 53% reoccluded in the stent group and 12.5% in the surgical group.[23]

Percutaneous balloon angioplasty of the aorta is reported to normalize systolic and diastolic blood pressures within 24 hours, with improvement of exercise tolerance and restoration of peripheral pulses. A high incidence of restenosis (≤78%) is observed in adults. Renovascular hypertension and congestive failure due to increased afterload are improved. Improvement has been sustained for as long as 3-5 years.

Endovascular stenting is used in patients with severe stenoses, hypertension, or ischemia during the fibrotic phase of the disease. Multiple stents have been used in children to relieve long-segment renal artery stenosis and attendant renovascular hypertension. Children with Takayasu arteritis who have received stents have lowered arterial blood pressures and decreased requirement for antihypertensives. Immunosuppressant-eluting stents could potentially deliver local treatment at sites of inflammation.

Monitoring

Monitor medications and adverse effects in patients with Takayasu arteritis. In addition, monitor acute phase reactants as a limited measure of disease activity.

Perform regular imaging of affected vasculature, as well as surveillance imaging for new lesions. Treatment may be monitored with MRI and/or MRA or CT scanning. Mural thickening is observed to decrease with corticosteroid treatment.

Recognizing that Takayasu arteritis may progress in the absence of clinical findings is important. Patients with normal erythrocyte sedimentation rates who are undergoing graft placement have been found to have active aortitis in the resected segment. Periodic imaging may identify an active disease by the appearance of new areas of stenosis, despite normal erythrocyte sedimentation rate and the absence of clinical features. The presence of active disease requires treatment with corticosteroids; however, current markers of disease activity are inadequate to identify all patients with disease flare.

Serial MRI may reveal vessel wall edema, but whether this measures actual inflammation is unclear. Structural changes visible on imaging demonstrate disease progression, but reliable indicators of vessel inflammation prior to structural damage have yet to be identified. For superficial lesions, ultrasound may be an effective way to monitor disease without radiation exposure. FDG-PET, with its coregistered CT, has significant radiation exposure but can image the thoracic aorta.

Pharmacologic Therapy

Daily high-dose corticosteroid administration is the mainstay of initial therapy. The authors have used prednisone at 1-2 mg/kg/day for 4-6 weeks. Maintain high-dose treatment until all evidence of active disease has resolved. Then taper prednisone dosage over a month to decrease morbidity from corticosteroid treatment. However, although 60% of patients respond to this treatment, 40% relapse on steroid taper.

Patients not responding to corticosteroids or who relapse during corticosteroid taper require an additional agent.

Symptoms of patients who relapse on corticosteroid taper may be controlled with weekly infusions of methylprednisolone (30 mg/kg, not to exceed 1 g/wk). However, extensive use of these infusions is associated with significant steroid-induced toxicity if continued for any significant period.

Regimens including weekly methotrexate or daily or monthly intravenous (IV) cyclophosphamide have been used in individuals with glucocorticoid-resistant Takayasu arteritis. Low-dose weekly methotrexate also has been used as a steroid-sparing agent for patients not tolerating corticosteroid taper. Ozen et al used daily oral cyclophosphamide, which was well tolerated in a small series of children.[24]

The mainstay of initial therapy is daily high-dose corticosteroid administration. Maintain high-dose treatment for several weeks, until all evidence of active disease has resolved. Among patients receiving this treatment, up to 90% respond; however, two thirds progress or relapse on steroid taper.

Patients who do not respond to glucocorticoids or who relapse during corticosteroid taper require a second agent. For patients with ongoing inflammatory disease or those dependent on moderate doses of prednisone, many immunosuppressant and anticytokine regimens have been tried. Methotrexate, infliximab, etanercept, cyclosporine, cyclophosphamide, and mycophenolate mofetil have all had some steroid-sparing effect. These medications can allow disease control and weaning from steroids. Other patients remain steroid dependent but are able to taper the steroid dose. Small numbers of patients are resistant to multiple treatments and continue to have active disease.

Mycophenolate mofetil may be useful to treat individuals with glucocorticoid-resistant disease.[25, 26] Case reports suggest disease control and steroid sparing. In a series of 21 patients,[27] the average sedimentation rate fell from 68 to 43 mm/h (P =.003) and the average prednisone dose from 36 to 19 mg/d. Cases of patients discontinuing prednisone and having no progression of disease for several months are reported.

Leflunomide has been used in glucocorticoid-resistant and methotrexate-resistant disease.[28] Tumor necrosis factor (TNF) inhibition with etanercept or infliximab has also been used in relapsing disease or glucocorticoid-dependent disease. Cyclosporine may be an alternative therapy, offering lower ovarian toxicity than cyclophosphamide. However, cyclosporine is often associated with decreased renal function and increased blood pressure, which may aggravate the damage to the heart and great vessels; it is used less frequently.

TNF inhibitors offer treatment for patients with relapses or refractory disease. Infliximab has been used in children with Takayasu arteritis.[29, 30, 31] In patients treated with TNF inhibitors, renewed disease activity has been seen on withdrawal. Patients with disease despite treatment may benefit from a change to a different TNF inhibitor, or escalating the dose, in the case of infliximab.  A retrospective case series by Stern et al found that infliximab was equivalent to cyclophosphamide with fewer adverse effects, making infliximab an alternative therapeutic option.[32]  

Response to TNF inhibitors in a small series has ranged from 74-90%; patients continuing treatment have been reported with stable disease for 24-36 months. These are patients previously with active disease, with relapse, or with progression on treatment.[33] In a series of 15 patients,[29] 14 were able to taper steroids and 10 were able to wean off steroids entirely while on infliximab. One patient did not respond. Withdrawal of the TNF inhibitor was briskly followed by relapse, suggesting that control of active disease is possible, but treatment is needed to maintain control.

The presence of antiendothelial antibodies and plasmablast expansion in patients with active Takayasu arteritis suggest a role for B-cell–based therapies. Reports using rituximab, monoclonal anti-CD20 antibody for disease control and steroid sparing in patients with Takayasu arteritis show promise.[8] Treatment regimens have been the 4-week lymphoma protocol (375 mg/m2 weekly for 4 wk) or the 2-week fixed-dose rheumatoid arthritis protocol (1000 mg repeated once 14 d later). Patients were able to taper prednisone and had no new disease manifestations. Peripheral plasmablasts decreased in number, rising again with signs of relapse.

Similarly, case reports of tocilizumab (monoclonal anti–IL-6 receptor antibody) have described remission induction in Takayasu arteritis resistant to other treatments.[9, 10] IL-6 levels are elevated in Takayasu patients and correspond with disease activity, making this an attractive target for therapy.[34]

IL-6 blockade reduces production of Th17 cells, indirectly reducing levels of TNF-aα and IL-6. Treated patients showed lower C-reactive protein levels and reversal of some ischemic changes (pulses improved). FDG-PET scans showed decreased FDG uptake in the great vessels. After 6 monthly infusions, patients were transitioned to weekly methotrexate as maintenance.[9]

A 3-year-old girl was treated with tocilizumab[35] and stenosis of the brachiocephalic artery demonstrated increased flow along with normal inflammatory markers. This child continued for over 2 years on tocilizumab and mycophenolate mofetil.

Anecdotal reports of matrix metalloproteinase inhibition using minocycline suggest that this may be a useful adjunctive therapy, which may also allow lower doses of corticosteroids and, thus, reduced toxicity. This does not replace immunosuppressive therapy with steroids and other treatments.

 

Medication

Medication Summary

Daily high-dose corticosteroid administration is the mainstay of initial therapy. The authors have used prednisone at 1-2 mg/kg/day for 4-6 weeks. Maintain high-dose treatment until all evidence of active disease has resolved. Then, taper the prednisone dosage over a month to decrease morbidity from corticosteroid treatment. However, although 60% of patients respond to this treatment, 40% relapse on steroid taper.

Patients not responding to corticosteroids or who relapse during corticosteroid taper require an additional agent. Steroid toxicity should be minimized.

Regimens including weekly methotrexate or daily or monthly intravenous (IV) cyclophosphamide have been used in individuals with glucocorticoid-resistant Takayasu arteritis. Ozen et al used daily oral cyclophosphamide, which was well tolerated in a small series of children.[24] The toxicity of cyclophosphamide limits its use to a limited number of severely ill children.

The TNF inhibitors etanercept and infliximab can be used in patients on steroid tapering. Infliximab may have an advantage in that the dose can be escalated if needed. Mycophenolate mofetil may be helpful in steroid-resistant patients; reports date back to 1999. Most of these patients were not able to entirely discontinue steroids.

Immunosuppressive agents

Class Summary

These agents are used to suppress inflammation, thus delaying progression of thrombosis, stenosis, and aneurysm.

Prednisone

Prednisone is an immunosuppressant for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear cell activity. Prednisone stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Methotrexate (Rheumatrex, Trexall)

Methotrexate inhibits tetrahydrofolate reductase and has potent anti-inflammatory effects, which are possibly mediated through adenosine receptors. It has an unknown mechanism of action in the treatment of inflammatory reactions, but it may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that is believed to act cytotoxically on dividing cells by cross-linking cellular deoxyribonucleic acid (DNA). It is processed in the liver to active metabolites; byproducts (eg, acrolein) accumulate in the bladder and cause cystitis.

Cyclosporine (Sandimmune, Neoral, Gengraf)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease for a variety of organs. The doses used in autoimmune diseases are generally lower than those used in transplant patients. Initiate administration at the lowest dose possible, then taper to the lowest effective dose as soon as possible. Attempt to discontinue cyclosporine to determine if therapy can stop.