Pediatric Polyarteritis Nodosa 

Polyarteritis nodosa (PAN), the prototype of systemic vasculitis, was originally used as a catch-all for all forms of necrotizing vasculitis. Over decades, other forms (eg, Henoch-Schönlein purpura, Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and Kawasaki syndrome^[1] ) have been clearly distinguished from PAN. However, patients may develop an undifferentiated vasculitis or a vasculitis overlap syndrome; children with severe or catastrophic Kawasaki syndrome may not be indistinguishable from patients with PAN.

PAN is a chronic, systemic, nongranulomatous necrotizing inflammation of primarily medium-sized or small arteries that results in tissue ischemia and infarction. Presentations vary and may mimic other diseases because of the wide range of organ involvement, severity, and prognosis. Consequently, diagnosis and treatment may be challenging and difficult. A new classification divides PAN into 2 subtypes: systemic PAN and cutaneous polyarteritis.

Commonly, PAN is diagnosed when 3 of the 10 criteria developed by the American College of Rheumatology (ACR) are present. Steroids and immunosuppressive medications form the backbone of therapy. Treatment duration with corticosteroids and cyclophosphamide usually does not exceed 1 year. Surgery is necessary during diagnostic evaluation to perform biopsies. Surgery is required therapeutically in patients with peripheral gangrene and acute abdomen.

PAN causes transmural necrotizing inflammation of small or medium-sized muscular arteries. The kidneys, heart, liver, gastrointestinal (GI) tract, pancreas, testes, musculoskeletal system, central nervous system (CNS), and skin are involved.

The lesions are segmental and may involve only a part of the circumference only. The associated inflammation may cause weakening of the arterial wall, aneurysmal dilatation, and localized rupture. This development is perceived clinically as a nodule, which is also demonstrated by radiology. The area supplied by the involved vessels may slow impaired perfusion, leading to ulceration, infarct, or ischemic atrophy. Occasionally, the lesion may be excessively microscopic and produce no gross changes.

Immunopathogenetic mechanisms leading to vascular injury are incompletely understood and are probably heterogeneous. The following are some of the possible mechanisms.

Immune complexes

The origin of the immune complex is unknown. Various infections and superantigens have been implicated as causes of persistent antigenemia that subsequently leads to immune complex formation. The resultant immune complex activates the complement cascade, which activates and attracts neutrophils.

Antineutrophil cytoplasmic antibodies

Antineutrophil cytoplasmic antibodies (ANCAs) appear to play a significant role in causing endothelial damage. However, ANCAs are not present in all patients with PAN. In vitro, ANCAs can activate neutrophils to adhere more to endothelial cells and can stimulate neutrophils that have been primed with tumor necrosis factor alpha (TNF-α) to lyse cultured endothelial cells.

Two types of ANCA are recognized. Perinuclear ANCA (P-ANCA; antimyeloperoxidase) is often found in patients with microscopic polyangiitis (MPA). Cytoplasmic ANCA (C-ANCA; antiproteinase 3) has also been described in patients with PAN.

Adhesion molecules

Cytokine-induced expression of adhesion molecules (leukocyte function-associated antigen-1 [LFA-1], intercellular adhesion molecule-1 [ICAM-1], and endothelial-leukocyte adhesion molecule-1 [ELAM-1]) allows close contact between polymorphonuclear (PMN) and endothelial cells. The coexistence of cytokine-primed neutrophils, endothelium, and circulating ANCAs permit ANCAs to initiate a cascade of events leading to vasculitis.

Antiendothelial cell antibodies

Antiendothelial cell antibodies (AECAs) are directed against surface endothelial antigens and have been proposed as a pathogenic factor in vasculitis. AECAs are not disease-specific; they are found both in autoimmune vasculitis and systemic vasculitis. AECAs can cooperate in the endothelial injury by increasing endothelial adherence of granulocytes or monocytes through binding mediated by the Fc-gamma receptor.

Cytokines

Cytokines are potentially involved in the pathogenesis of vasculitis. A marked increase in interferon alfa (IFN-α) and interleukin (IL)–2 and a moderate increase in TNF-α and IL-1β have been reported in persons with PAN. IL-1 and TNF-α enhance endothelial damage by activating endothelial and PMN cells. Serum basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are angiogenic cytokines known to be elevated in patients with PAN.

In most cases, the cause of PAN is unknown. Possible causes include the following:

• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• HIV
• Cytomegalovirus (CMV)
• Parvovirus B19
• Human T-lymphotropic virus (HTLV)
• Streptococcal infection

PAN is a rare condition, both in the United States and worldwide. The incidence in the general US population is 0.7 cases per 100,000 people, and the prevalence is 6.3 cases per 100,000 people. In the United Kingdom, the annual incidence of MPA is 3.6 per million people, and the incidence of PAN is 2.4 per million people. In Kuwait, the combined annual incidence of the 2 conditions is 45 per million people.

PAN has been described in all age groups but predominantly affects individuals aged 40-60 years. It is rarely found in children; when it is, the mean age of onset is 9.05 ± 3.57 years. No racial predilection is observed.

The prognosis for individuals with PAN varies, and mortality can be as high as 20-30% despite aggressive therapy. The most frequent causes of death in PAN patients are GI hemorrhage and perforation, congestive heart failure (CHF), and infection. Even with histologic evidence of effective control of inflammation, occlusion can result from fibrosis.

The 1-year survival rate for individuals with PAN who tested positive for hepatitis B surface antigen (HBsAg) was 70%; the rate for individuals with PAN without infection was 85.