What are the treatment approaches for different types of vasculitis (inflammation of blood vessels) in children?

Vasculitis in Children: Comprehensive Overview and Treatment Approaches

Classification by Vessel Size and Disease Frequency

The most common vasculitides in children are IgA-associated vasculitis (Henoch-Schönlein purpura) and Kawasaki disease, which are generally self-limiting, while ANCA-associated vasculitides, polyarteritis nodosa, and Takayasu arteritis are rare but require aggressive immunosuppression. 1, 2

Common Self-Limiting Vasculitides

Henoch-Schönlein Purpura (IgA-Associated Vasculitis):

• Diagnosed based on typical clinical findings: palpable purpura on lower extremities and buttocks, arthritis/arthralgia, abdominal pain, and renal involvement 1, 3
• Direct immunofluorescence shows IgA deposition, distinguishing it from IgG/IgM-associated vasculitis with prognostic significance 4
• Most cases are self-limiting and respond to leg elevation, avoidance of prolonged standing, and NSAIDs 4
• For mild recurrent or persistent disease, colchicine and dapsone are first-choice agents 4
• Severe cutaneous or systemic disease requires systemic corticosteroids 4

Kawasaki Disease:

• Most common vasculitis in infants, with coronary artery aneurysms as the major complication 1, 3
• Early treatment with intravenous immunoglobulin and aspirin is required within the first 10 days to minimize risk of coronary complications 1
• Treatment should not be delayed while awaiting complete diagnostic criteria if clinical suspicion is high 1

Rare Severe Vasculitides Requiring Aggressive Treatment

ANCA-Associated Vasculitis (AAV) in Children

Disease Categorization for Treatment Decisions:

Patients must be categorized by severity 5, 6:

• Localized: Upper/lower respiratory tract disease without systemic involvement
• Early systemic: Any involvement without organ-threatening disease
• Generalized: Renal or organ-threatening disease, creatinine <500 μmol/L (5.6 mg/dL)
• Severe: Renal or vital organ failure, creatinine >500 μmol/L (5.6 mg/dL)
• Refractory: Progressive disease unresponsive to glucocorticoids and cyclophosphamide

Induction Treatment for AAV

For Generalized and Severe Disease:

Combination therapy with cyclophosphamide and glucocorticoids is the standard induction regimen 5, 6:

• Cyclophosphamide: 2 mg/kg/day orally (maximum 200 mg/day) OR intravenous pulse therapy 5
• Glucocorticoids: 1 mg/kg/day (maximum 60 mg/day) 5, 6
• Pulse intravenous methylprednisolone 1,000 mg daily for 1-3 days prior to initial treatment in severe cases 7

Rituximab as Alternative First-Line Agent:

• In pediatric patients (ages 6-17), rituximab 375 mg/m² BSA once weekly for 4 weeks has demonstrated 56% remission at 6 months, 92% at 12 months, and 100% at 18 months 7
• Factors favoring rituximab: younger patients concerned about fertility, relapsing disease 6
• Factors favoring cyclophosphamide: severe renal disease 6
• For markedly reduced or rapidly declining renal function, combination of rituximab and cyclophosphamide should be considered 6

Critical Treatment Principles:

• Treatment should not be delayed while waiting for biopsy results in rapidly deteriorating patients 6
• Patients should receive minimum 3 doses of intravenous methylprednisolone (30 mg/kg/day, not exceeding 1g/day) prior to first rituximab infusion 7
• Pre-medication with antihistamine and acetaminophen prior to rituximab infusion 7

Supportive Measures During Induction

Mandatory prophylaxis 5:

• Pneumocystis jiroveci prophylaxis: trimethoprim/sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily 5
• Mesna (2-mercaptoethanesulfonate sodium) with cyclophosphamide to prevent hemorrhagic cystitis by binding toxic acrolein metabolites 5

For Early Systemic (Non-Organ Threatening) Disease:

Methotrexate plus glucocorticoids is a less toxic alternative 5:

• Methotrexate: oral or parenteral administration 5
• Glucocorticoids: 1 mg/kg/day (maximum 60 mg/day) 5
• This approach avoids cyclophosphamide-related toxicity including bladder cancer risk and fertility issues 5

Plasma Exchange for Severe Renal Disease

Plasma exchange is recommended for selected patients with rapidly progressive severe renal disease to improve renal survival 5:

• Indicated when creatinine >500 μmol/L (5.6 mg/dL) 5
• Used in conjunction with cyclophosphamide and glucocorticoids 5

Maintenance Therapy After Remission

Once remission is achieved (BVAS = 0), maintenance therapy prevents relapse 5, 7:

• Azathioprine is first-line maintenance agent 5, 7
• Leflunomide as alternative 5
• Methotrexate as alternative 5
• Low-dose glucocorticoids (approximately 5 mg/day prednisone) continued for at least 18 months 7

Rituximab for Maintenance:

• In adults, rituximab 500 mg every 6 months for 18 months showed superior efficacy: major relapse occurred in 5% versus 29% with azathioprine 7
• In pediatric patients, 14 of 25 (56%) received additional rituximab at or after month 6 for maintenance 7

Monitoring During Treatment

Essential monitoring parameters 5:

• Complete blood count: watch for acute leukopenia or progressive decline requiring dose adjustment 5
• Renal function: declining function may necessitate dose adjustment or drug change 5
• Blood glucose while on glucocorticoid therapy 5
• Urinalysis with microscopic examination at each visit 6
• ANCA levels: persistence, increase, or change from negative to positive may predict relapse 6
• Disease activity using Birmingham Vasculitis Activity Score (BVAS) 6

Refractory Disease

For progressive disease despite optimal therapy 5:

• Mycophenolate mofetil 5
• 15-deoxyspergualin 5
• Rituximab: achieved remission in 42/46 (91%) patients with refractory or relapsing AAV in open-label trials 5
• Infliximab 5
• Anti-thymocyte globulin 5

Primary CNS Vasculitis in Children

Childhood primary angiitis of the CNS is subcategorized into large-to-medium vessel (angiography-positive) or small vessel disease 5:

Diagnostic Approach

Clinical presentation includes 5:

• Headaches and altered consciousness 5
• Recurrent stroke 5
• Ischemic or hemorrhagic stroke with encephalopathic changes 5
• Stroke with fever, multifocal neurological events, unexplained skin lesions, glomerulopathy, or elevated ESR 5

Laboratory findings 5:

• ESR usually normal or minimally elevated 5
• Other acute-phase reactants characteristically normal 5
• CSF: increased opening pressure, elevated protein, lymphocytic pleocytosis (rarely >250 cells/mm³) 5

Imaging 5:

• MRI abnormal in >90% of cases: progressive multifocal parenchymal lesions on T2-weighted imaging 5
• MRA/CTA typically negative in small-vessel vasculitis 5
• Catheter angiography most sensitive for large-vessel disease: shows segmental narrowing, occlusions, peripheral aneurysms, or may be unremarkable 5
• Cortical-leptomeningeal biopsy is most specific diagnostic test, but negative result does not exclude diagnosis due to focal nature 5

Treatment Approach

Some children with arteritis stabilize or improve without specific treatment in the context of self-limiting or treated infection (e.g., post-varicella angiopathy, transient cerebral arteriopathy) 5

For progressive primary CNS vasculitis and systemic vasculitides 5:

• Corticosteroids and cytotoxic agents are required 5
• Pulse cyclophosphamide has been used successfully in children with isolated CNS angiitis 5
• Distinguishing transient/nonprogressive from progressive arteriopathies at presentation is challenging and requires close monitoring 5

Polyarteritis Nodosa (PAN) in Children

PAN is a rare medium-vessel vasculitis requiring aggressive treatment 1, 3:

Treatment Regimen

Cyclophosphamide plus glucocorticoids for remission induction 5:

• Same dosing as ANCA-associated vasculitis 5
• Level of evidence 1B, grade of recommendation A 5

For Hepatitis B-Associated PAN:

• Combination of antiviral therapy, plasma exchange, and glucocorticoids is recommended 5
• This addresses both the viral trigger and the inflammatory vasculitis 5

Takayasu Arteritis in Children

Takayasu arteritis is a large-vessel vasculitis affecting the aorta and its major branches 5, 3:

Clinical Features

Presentation includes 5:

• Diminished or absent carotid or radial pulses 5
• Cervical bruits 5
• Asymmetrical blood pressure measurements 5
• Fever and elevated ESR 5

Diagnostic Imaging

• MRA can support diagnosis 5
• Aortography provides most accurate assessment 5

Treatment Approach

All patients should receive non-biological glucocorticoid-sparing agents in combination with glucocorticoids 6:

• Initial glucocorticoid dose: 1 mg/kg/day (maximum 60 mg/day) 6
• Maintain high-dose glucocorticoids for one month before gradual tapering 6
• Adjunctive immunosuppressive therapy such as methotrexate or tocilizumab as steroid-sparing agents 6

Surgery may be required 5:

• Used to relieve chronic vascular insufficiency 5
• Reserved for cases with significant stenosis or occlusion 5

Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis)

Treated similarly to other ANCA-associated vasculitides 5:

• Cyclophosphamide plus glucocorticoids for generalized disease 5
• Five Factor Score predictive of mortality: score of 0 versus >2 had 5-year survival of 88.9% versus 55% 5

Mixed Essential Cryoglobulinemic Vasculitis

For non-viral (hepatitis C negative) cryoglobulinemic vasculitis 5:

• Immunosuppressive therapy recommended 5
• Should be managed in conjunction with hepatologist 5

For Hepatitis C-Associated Cryoglobulinemic Vasculitis:

• Antiviral therapy is recommended as primary treatment 5
• Level of evidence 1B, grade of recommendation B 5

Critical Monitoring for Long-Term Complications

Cyclophosphamide-related bladder cancer risk 5:

• Investigation of persistent unexplained hematuria mandatory in patients with prior cyclophosphamide exposure 5
• Mesna reduces but does not eliminate bladder toxicity risk 5

Other long-term complications requiring surveillance 5:

• Cardiovascular disease 5
• Neoplasia 5
• Cerebrovascular events 5
• Renal dysfunction 5
• Metabolic abnormalities 5

Management Setting

Patients with primary small and medium vessel vasculitis should be managed in collaboration with, or at centers of expertise 5:

• Particularly important for rare vasculitides requiring complex immunosuppression 5
• Patients with AAV should be treated at centers with experience in AAV management 6

Common Pitfalls to Avoid

Critical errors that worsen outcomes 5, 6:

• Delaying treatment while waiting for biopsy results in rapidly deteriorating patients 6
• Using alternate-day glucocorticoid therapy, which increases relapse risk 6
• Inadequate initial immunosuppression in severe disease 6
• Failing to provide Pneumocystis prophylaxis with cyclophosphamide 5
• Not using Mesna with cyclophosphamide to prevent hemorrhagic cystitis 5
• Discontinuing maintenance therapy too early, leading to relapse 5