Pediatric Takayasu Arteritis Treatment & Management

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

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. ^[24]

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.

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.

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. ^[25]

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. ^{[26, 27]} Case reports suggest disease control and steroid sparing. In a series of 21 patients, ^[28] 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. ^[29] 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. ^{[30, 31, 32]} 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. ^[33]  

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. ^[34] In a series of 15 patients, ^[30] 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. ^[35]

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 ^[36] 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.