Medical Care
The management of children with Kawasaki disease involves hospital admission and treatment with intravenous immunoglobulin (IVIG) and high-dose aspirin in the acute phase of the illness. [36] Subsequently, daily low-dose aspirin is given for 6-8 weeks until follow-up echocardiography. IVIG-resistant disease may be treated with methylprednisolone and/or other immunosuppressive therapies (see Kawasaki Disease “Treatment of IVIG-Resistant Disease”). Guidelines from the American College of Rheumatology and the Vasculitis Foundation conditionally recommend the use of adjunctive glucocorticoids with IVIG as initial therapy for patients with acute Kawasaki disease who are at high risk for IVIG resistance or the development of coronary artery aneurysms. [37]
The management of children with Henoch-Schönlein purpura is primarily symptomatic, and most patients do not require hospital admission. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be given for joint pain or swelling. Corticosteroids may be considered in selected patients (ie, those with severe GI symptoms), [38] but is an area of controversy in the literature. [39] Clinically significant nephritis is typically treated with steroids and other immunosuppressive therapies.
Patients with chronic vasculitides should be managed by a multidisciplinary group of specialists (eg, rheumatologists, cardiologists, nephrologists) and require long-term follow-up for monitoring of relapses, disease activity, end-organ damage and morbidity associated with therapy.
Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet's disease. [40]
No therapeutic trials have looked at management of vasculitis in the pediatric population, and practice has been based on adult guidelines, which have been summarized. [41, 42, 43] These recommendations provide general guidance that should be modified based on the features of each individual’s illness.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis
In general, adult patients with ANCA vasculitis are categorized according to different levels of severity to assist treatment decisions, as proposed by the European Vasculitis Study (EUVAS) group. [41]
Table 1. EUVAS disease categorization of ANCA-associated vasculitis (Open Table in a new window)
Category |
Definition |
Localized |
Upper and/or lower respiratory tract disease without any other systemic involvement or constitutional symptoms |
Early systemic |
Any, without organ-threatening or life-threatening disease |
Generalized |
Renal or other organ-threatening disease, serum creatinine >500 μmol/L (5.6 mg/dL) |
Severe |
Renal or other vital organ failure, serum creatinine >500 μmol/L (5.6 mg/dL) |
Refractory |
Progressive disease unresponsive to glucocorticoids and cyclophosphamide |
Induction therapy
Optimal induction therapy for patients with generalized disease (renal or other major organ involvement) is a subject of intensive study. Initial guidelines suggested a combination of cyclophosphamide and high-dose glucocorticoids. However, there have been 3 randomized controlled trials investigating the use of rituximab as an induction agent in adults with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). [44, 45, 46] These studies have shown that rituximab is likely as effective as cyclophosphamide in inducing remission.
The most recent treatment recommendations [43] suggest that either regimen be considered and that rituximab may be preferred when cyclophosphamide avoidance is desired (eg, due to toxicity). Some evidence suggests that granulomatous manifestations (eg, orbital granulomas) may not respond to rituximab as well as vasculitic manifestations. [47] With either regimen, high-dose prednisone (1 mg/kg) should be maintained for 1 month. When rapid effect is needed, intravenous (IV) pulsed methylprednisolone may be used in addition to the oral prednisone.
A study by van Daalen et al reported that rituximab treatment for ANCA-associated vasculitis had lower malignancy risk than in cyclophosphamide treatment and that rituximab was not associated with an increased malignancy risk compared with the general population. [48]
Local guidelines for the prevention of glucocorticoid-induced osteoporosis should be followed in all patients. Cyclophosphamide use should be limited to 3-6 months because of potential for long-term toxicity. However, no consensus about whether pulse IV cyclophosphamide is superior to daily oral therapy. All patients who receive cyclophosphamide should also receive prophylaxis against Pneumocystis jiroveci (trimethoprim-sulfamethoxazole or pentamidine), especially those with GPA.
For patients with mild-to-moderate or limited disease, methotrexate can be used as a less toxic alternative for induction. However, there is some evidence that induction with methotrexate may be associated with a higher risk of relapse. [49]
Plasma exchange is recommended as adjunctive therapy for patients with rapidly progressive severe renal disease.
Maintenance therapy
Evidence suggests that once remission is achieved with either a cyclophosphamide- or rituximab-based regimen, maintenance therapy is required to prevent relapse. One alternative is to use either methotrexate or azathioprine. A recent study has also suggested the use of biannual rituximab as maintenance therapy. [50] The use of low-dose glucocorticoids (10 mg/d of prednisone) is also recommended. Maintenance therapy should be continued for at least 18-24 months, and early cessation is associated with an increased risk of relapse.
Refractory or relapsing disease
The RAVE trial, [44] a randomized, controlled, double-blinded study of cyclophosphamide versus rituximab in ANCA vasculitis, included a planned subgroup analysis of patients with refractory or relapsing disease. The findings demonstrated that rituximab was particularly effective in this population. Several other small series also report the effectiveness of rituximab in patients with refractory or relapsing disease. Other options for refractory or relapsing disease include IVIG, mycophenolate mofetil, infliximab, 15-deoxyspergualin, and antithymocyte globulin. [41]
Systemic polyarteritis nodosa
Patients with severe disease should receive a combination of cyclophosphamide and glucocorticoids. However, a selected group of patients with mild polyarteritis nodosa may be successfully treated with glucocorticoids alone.
Cutaneous polyarteritis nodosa
Some patients respond to NSAIDs alone; however, most require treatment with prednisone. Steroid-sparing agents may be needed (eg, methotrexate, mycophenolate mofetil, colchicine, IVIG). Penicillin prophylaxis may prevent disease exacerbations in patients with evidence of triggering streptococcal infections. [5]
Large vessel vasculitis
A paucity of large controlled trials in the management of large-vessel vasculitis is noted, even in adult patients. Treatment recommendations are based on the EUVAS guidelines. [42]
Induction therapy usually involves high-dose glucocorticoid (prednisone, 1 mg/kg/d). The initial high dose should be maintained for a month and then gradually tapered. Azathioprine or methotrexate have been used as adjuncts to steroid therapy in patients with Takayasu arteritis to improve disease control and to facilitate reduction of the steroid dose. Cyclophosphamide has been used in adults with Takayasu arteritis resistant to glucocorticoids. In addition, tumor necrosis factor (TNF)-α inhibitors (eg, infliximab, etanercept) have been tried with encouraging results, including in a small study of 4 children. [51]
Primary CNS vasculitis
Initiate treatment with high-dose steroids and monthly IV cyclophosphamide for 6 months, followed by maintenance with mycophenolate mofetil or azathioprine for 18 months. Anti-thrombotic therapy (heparin followed by antiplatelet) may be added for large-vessel disease. [27] See Behcet Syndrome and Anti-GBM Antibody Disease for specific treatment of these conditions.
Thrombophlebitis/hypercoagulable state
Anticoagulation is indicated for any patient with a thrombotic episode and an underlying hypercoagulable state. This usually involves initial treatment with heparin with subsequent transition to warfarin.
Refer to Antiphospholipid Antibody Syndrome for details on treatment. Generally, anticoagulant prophylaxis is not indicated in the absence of a thrombotic event. No studies in the optimal management of pediatric patients with antiphospholipid antibody syndrome have been done. The adult literature suggests that patients with documented venous or arterial thrombotic events should be managed with warfarin. [52]
Surgical Care
With involvement of the aorta and renal arteries, angioplasty and stenting of stenotic vessels has been used to improve flow (eg, in Takayasu arteritis). A significant proportion of vessels may develop restenosis, but good response to repeat procedure is noted. [53] In addition, reconstructive surgery with graft implantation may be required. Note that vascular procedures must be done during periods of inactive disease.
Patients with granulomatosis with polyangiitis (formerly Wegener granulomatosis) may develop subglottic stenosis; these lesions can be amenable to endoscopic management with local corticosteroid injection and/or mitomycin-C application. [54] Note that in granulomatosis with polyangiitis, repeated procedures are often necessary, and some patients may require tracheostomy insertion.
Consultations
Consultations may include the folllowing:
-
Pediatric rheumatologist
-
Pediatric nephrologist (if renal involvement)
-
Pediatric cardiologist (if large vessel involvement)
-
Pediatric otolaryngologist (for upper respiratory tract involvement)
-
Pediatric hematologist (for thrombophilic disorders)
-
Pediatric neurologist (for CNS involvement)
-
Vascular surgeon or interventional radiologist, as indicated
Diet and Activity
Diet
Therapy with prednisone requires adherence to low-salt and low-fat diet with extra calcium and vitamin D.
A low-salt diet is indicated if the patient is hypertensive.
Activity
No limitations are indicated unless anticoagulants are used (then avoid contact sports).
-
Preferred sites of vascular involvement by selected vasculitides.
-
Patient with Wegener granulomatosis and saddle-nose deformity.
-
Tender erythematous nodules in cutaneous polyarteritis nodosa (PAN).
-
Nodules on sole of foot in cutaneous polyarteritis nodosa (PAN).
-
Necrotic lesions of polyarteritis nodosa (PAN).
-
Chest radiography in Churg-Strauss syndrome (CSS) with pulmonary infiltrates.
-
CT of sinuses in a patient with Wegener granulomatosis (WG) showing erosion and loss of sinus walls.
-
CT chest in a patient with Churg-Strauss syndrome (CSS) showing multiple nodules.
Tables
Category |
Definition |
Localized |
Upper and/or lower respiratory tract disease without any other systemic involvement or constitutional symptoms |
Early systemic |
Any, without organ-threatening or life-threatening disease |
Generalized |
Renal or other organ-threatening disease, serum creatinine >500 μmol/L (5.6 mg/dL) |
Severe |
Renal or other vital organ failure, serum creatinine >500 μmol/L (5.6 mg/dL) |
Refractory |
Progressive disease unresponsive to glucocorticoids and cyclophosphamide |
