Pediatric Polyarteritis Nodosa 

  • Author: Akaluck Thatayatikom, MD; Chief Editor: Lawrence K Jung, MD   more...
 
Updated: Nov 16, 2011
 

Background

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.

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Pathophysiology

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.

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Etiology

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
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Epidemiology

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.

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Prognosis

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.

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Contributor Information and Disclosures
Author

Akaluck Thatayatikom, MD  Associate Professor and Chief, Department of Pediatrics, Division of Pediatric Allergy, Immunology, and Rheumatology, University of Kentucky College of Medicine

Akaluck Thatayatikom, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Rheumatology, Childhood Arthritis and Rheumatology Research Alliance, and Clinical Immunology Society

Disclosure: Nothing to disclose.

Chief Editor

Lawrence K Jung, MD  Chief, Division of Pediatric Rheumatology, Children's National Medical Center

Lawrence K Jung, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, Clinical Immunology Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Christine B Bernal, MD Clinical Faculty, Faculty of Medicine and Surgery, University of Santo Tomas, Philippines; Head, Section of Pediatric Rheumatology, University of Santo Tomas Hospital, Philippines

Christine B Bernal, MD is a member of the following medical societies: Philippine Medical Assocation

Disclosure: Nothing to disclose.

James M Oleske, MD, MPH François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Donald A Person, MD Expert Consultant in Pediatrics, Pediatric Rheumatology, and Telemedicine, Tripler Army Medical Center; Emeritus Professor of Pediatrics, F Edward Herbert School of Medicine, Uniformed Services University of the Health Sciences; Retired Clinical Professor of Pediatrics and Public Health, University of Hawaii, John A Burns School of Medicine

Donald A Person, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Rheumatology, American Medical Association, American Pediatric Society, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Association of Military Surgeons of the US, Clinical Immunology Society, Federation of American Societies for Experimental Biology, Pediatric Infectious Diseases Society, Society for Experimental Biology and Medicine, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Muthukumar Vellaichamy, MD, FAAP Clinical Assistant Professor, Department of Pediatrics, University of Kansas School of Medicine-Wichita, Wesley Medical Center

Muthukumar Vellaichamy, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. [Guideline] Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. Oct 26 2004;110(17):2747-71. [Medline].

  2. Meeuwissen J, Maertens J, Verbeken E, Blockmans D. Case reports: testicular pain as a manifestation of polyarteritis nodosa. Clin Rheumatol. Nov 2008;27(11):1463-6. [Medline].

  3. Richard T, Delree P, Fumiere E, Vanhaeverbeek M. [Polyarteritis nodosa limited to the right leg]. Rev Med Brux. May-Jun 2008;29(3):206-7. [Medline].

  4. Nakamura T, Kanazawa N, Ikeda T, et al. Cutaneous polyarteritis nodosa: revisiting its definition and diagnostic criteria. Arch Dermatol Res. Jan 2009;301(1):117-21. [Medline].

  5. Huang MN, Wu CH. Polyarteritis nodosa and antiphospholipid syndrome causing bilateral renal infarction. J Rheumatol. Jan 2009;36(1):197. [Medline].

  6. Bagci P, Erdamar S, Erzin Y, Karatas A, Tuncer M. A case of polyarteritis nodosa diagnosed after recurrent, multiple intestinal perforations. Turk J Gastroenterol. Mar 2009;20(1):71-2. [Medline].

  7. Ventura F, Antunes H, Brito C, Pardal F, Pereira T, Vieira AP. Cutaneous polyarteritis nodosa in a child following hepatitis B vaccination. Eur J Dermatol. May 25 2009;[Medline].

  8. Ebert EC, Hagspiel KD, Nagar M, Schlesinger N. Gastrointestinal involvement in polyarteritis nodosa. Clin Gastroenterol Hepatol. Sep 2008;6(9):960-6. [Medline].

  9. Chan M, Luqmani R. Pharmacotherapy of vasculitis. Expert Opin Pharmacother. Jun 2009;10(8):1273-89. [Medline].

  10. Koc O, Ozbek O, Gumus S, Demir A. Endovascular management of massive gastrointestinal bleeding associated with polyarteritis nodosa. J Vasc Interv Radiol. Feb 2009;20(2):277-9. [Medline].

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Differential diagnosis of polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA).
Histopathology of kidney of individual with polyarteritis nodosa demonstrates transmural inflammation of arterial wall with heavy infiltrate of polymorphonuclear cells, eosinophils, and mononuclear cells, along with fibrinoid necrosis of inner half of vessel wall.
Histopathology of lung of individual with polyarteritis nodosa demonstrates arterial wall with heavy infiltrate of polymorphonuclear cells, eosinophils, and mononuclear cells and fibrinoid necrosis of vessel wall.
Histopathology of kidney of individual with polyarteritis nodosa demonstrates transmural inflammation of arterial wall with heavy infiltrate of polymorphonuclear cells, eosinophils, and mononuclear cells; fibrinoid necrosis of inner half of vessel wall; and thrombus.
 
 
 
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