1. DEFINITION
A primary systemic necrotizing vasculitis predominantly affecting medium-sized and small muscular arteries. It leads to microaneurysm formation, thrombosis, and infarction of involved organs. By definition, it spares capillaries, venules, and arterioles, and is not associated with glomerulonephritis.
2. ETIOLOGY AND PATHOPHYSIOLOGY
- Idiopathic: Most common form in children.
- Genetic/Monogenic: Deficiency of Adenosine Deaminase 2 (DADA2). Autosomal recessive mutation in the ADA2 (CECR1) gene; increasingly recognized as a major cause of familial or early-onset cPAN.
- Infection-triggered: Notably associated with recent Streptococcal infections. Unlike adult PAN, Hepatitis B and C associations are extremely rare in children.
- Pathology: Fibrinoid necrosis of the vessel wall with inflammatory cell infiltration (predominantly neutrophils and mononuclear cells), destruction of the internal elastic lamina leading to aneurysms, intimal proliferation, and eventual vessel occlusion.
3. CLINICAL FEATURES
Highly variable, multisystem involvement.
- Constitutional: Prolonged unexplained fever, severe fatigue, weight loss.
- Cutaneous (Most frequent in children): Livedo reticularis, painful subcutaneous nodules, palpable purpura, ischemic digital ulceration/gangrene.
- Musculoskeletal: Severe myalgia (especially calf muscles), arthralgia, arthritis out of proportion to joint swelling.
- Renal: Renovascular hypertension (due to renal artery stenosis/microaneurysms), microscopic hematuria, mild proteinuria. (Note: True glomerulonephritis is absent).
- Gastrointestinal: Severe colicky abdominal pain (bowel angina), gastrointestinal bleeding, bowel perforation, ischemic strictures.
- Neurological: Mononeuritis multiplex, peripheral neuropathy, early-onset ischemic strokes (highly characteristic of DADA2).
- Cardiac: Coronary artery aneurysms, heart failure (less common but fatal).
4. INVESTIGATIONS
- Laboratory: Strikingly elevated ESR and CRP. Leukocytosis, thrombocytosis, anemia of chronic disease.
- Immunology: ANCA is characteristically NEGATIVE.
- Infectious workup: ASOT / Anti-DNase B (to rule out streptococcal association), HBV, HCV.
- Genetics: Targeted sequencing or whole exome sequencing for ADA2 gene mutations.
- Imaging (Vascular): CT/MR Angiography or conventional catheter angiography of renal, mesenteric, and celiac arteries.
- Hallmark finding: “Beads on a string” appearance (alternating microaneurysms and focal stenoses).
- Histopathology (Definitive): Deep skin biopsy (including subcutaneous fat), muscle, or sural nerve biopsy showing necrotizing arteritis of medium/small arteries without granulomas.
5. CLASSIFICATION CRITERIA (EULAR/PRINTO/PRES 2008)
Requires systemic illness with evidence of necrotizing vasculitis OR angiographic abnormalities (aneurysm/stenosis) PLUS at least 1 of the following 5 criteria:
- Skin involvement (livedo reticularis, subcutaneous nodules, infarcts).
- Myalgia or muscle tenderness.
- Systemic hypertension.
- Peripheral neuropathy (sensory or motor).
- Renal involvement (proteinuria, hematuria, or impaired function).
6. MANAGEMENT
A. Induction Therapy (To achieve remission)
- Mild/Moderate Disease: High-dose systemic Corticosteroids (Oral Prednisolone 1-2 mg/kg/day).
- Severe/Organ-threatening Disease: Intravenous Methylprednisolone pulses followed by oral steroids PLUS IV Cyclophosphamide (typically 6 monthly pulses).
B. Maintenance Therapy
- Tapering oral steroids.
- Steroid-sparing agents: Azathioprine, Methotrexate, or Mycophenolate Mofetil (MMF).
C. Genotype-Specific Therapy (DADA2)
- TNF-alpha Inhibitors: Etanercept, Infliximab, or Adalimumab are the absolute drugs of choice for DADA2-associated PAN, dramatically preventing strokes and inducing remission.
- Hematopoietic Stem Cell Transplant (HSCT) for refractory cases of DADA2.
D. Adjunctive Therapy
- Strict blood pressure control (often requiring multiple antihypertensives).
- Antiplatelet agents (low-dose aspirin) if thrombotic risk or severe stenosis is present.
- Antibiotics (Penicillin prophylaxis) if there is a documented streptococcal trigger.
7. PROGNOSIS
- Untreated cPAN is highly fatal (GI perforation, strokes, cardiac involvement).
- With appropriate immunosuppression, survival exceeds 90%, but relapses are common.
- Long-term morbidities include residual hypertension, neuropathic pain, and medication toxicities.