eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Polyarteritis Nodosa

Author: Akaluck Thatayatikom, MD, Associate Professor and Chief, Department of Pediatrics, Division of Pediatric Allergy, Immunology, Rheumatology, University of Kentucky, Lexington
Contributor Information and Disclosures

Updated: Jun 17, 2009

Introduction

Background

In 1866, Kussmaul and Meier first described polyarteritis nodosa (PAN), a disease of small-sized and medium-sized arteries. Although any organ can be affected, polyarteritis nodosa most commonly involves the skin, joints, peripheral nerves, GI tract,¹ and kidney. Disease manifestations are diverse and complex, ranging from a benign cutaneous form to a severe disseminated form. Polyarteritis nodosa is also observed as a complication of hepatitis B (HB) and hepatitis C (HC) infection.²

In the literature, polyarteritis nodosa has often been described along with microscopic polyangiitis (MPA). The Chapel Hill consensus conference defines these 2 different disorders with differing prognoses. According to the new nomenclature, polyarteritis nodosa causes necrotizing inflammation of medium-sized or small-sized arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Conversely, MPA causes necrotizing vasculitis with few or no immune deposits affecting small vessels (capillaries, venules, arterioles). Necrotizing arteritis involving small-sized and medium-sized arteries may be present. Necrotizing glomerulonephritis and pulmonary capillaritis often occur in MPA (see Media file 1).

This article concentrates on these 2 entities that, although rare in children, present similarly as in adults. The topics of Infantile Polyarteritis Nodosa and Kawasaki Disease are covered in separate articles of this journal in addition to the overview article on Vasculitis and Thrombophlebitis.

Pathophysiology

Pathogenesis

Immunopathogenetic mechanisms leading to vascular injury are incompletely understood and are probably heterogeneous. Some of the possible mechanisms follow.

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 (ANCA) appear to play a significant role in causing endothelial damage. However, ANCA are not present in all patients with PAN. In vitro, ANCA can activate neutrophils to adhere more to endothelial cells and to stimulate neutrophils that have been primed with tumor necrosis factor (TNF-α) to lyse-cultured endothelial cells. Two types of ANCA are recognized. Perinuclear ANCA (P-ANCA; antimyeloperoxidase) are often found in patients with microscopic polyarteritis or MPA. Cytoplasmic ANCA (C-ANCA; antiproteinase 3) have also been described in patients with polyarteritis nodosa.

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 ANCA permit ANCA to initiate a cascade of events leading to vasculitis.

Antiendothelial cell antibodies

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

Cytokines

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

Pathology

Polyarteritis nodosa causes transmural necrotizing inflammation of small-sized or medium-sized muscular arteries. Kidneys, heart, liver, GI tract, pancreas, testes, skeletal muscular system, central nervous system (CNS), and skin are involved. The lesions are segmental and may involve partial circumference only. The associated inflammation process may cause weakening of the arterial wall, aneurysmal dilatation, and localized rupture. This 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.

Frequency

United States

Polyarteritis nodosa is a rare condition. The incidence in the general population is 0.7 cases per 100,000 people, and the prevalence is 6.3 cases per 100,000 people.

International

Polyarteritis nodosa is a rare condition worldwide. In the United Kingdom, annual incidence of MPA is 3.6 per million people; incidence of polyarteritis nodosa is 2.4 per million people. In Kuwait, combined annual incidence is 45 per million people.

Mortality/Morbidity

The mortality rate can be as high as 20-30%, despite aggressive therapy.

Race

No racial predilection is observed.

Sex

A slightly higher incidence is found in males. Male-to-female ratio is 1.6:1 to 2:1.

Age

Polyarteritis nodosa has been described in all age groups. Polyarteritis nodosa is rarely found in children. Mean age of 9.05 ± 3.57 years. Polyarteritis nodosa predominantly affects individuals aged 40-60 years.

Clinical

History

Nonspecific signs and symptoms are the hallmarks of polyarteritis nodosa (PAN). In 1990, the American College of Rheumatology (ACR) developed the criteria for the classification of polyarteritis nodosa. The primary purpose of these guidelines was to allow for a more homogeneous patient population in research studies and treatment protocols.

The 1990 ACR criteria for the classification of polyarteritis nodosa (traditional format) includes the following:

• Weight loss of greater than 4 kg since illness began, not due to dieting or other factors
• Livedo reticularis (ie, mottled reticular pattern) on the skin of portions of the extremities or torso
• Testicular pain or tenderness that is not due to infection, trauma, or other causes³
• Diffuse myalgias (excluding shoulder and hip girdle) or weakness of muscles or tenderness of leg muscles⁴
• Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy
• Development of hypertension (with diastolic blood pressure >90 mm Hg)
• Elevation of BUN (>40 mg/dL) or creatinine (>1.5 mg/dL) levels that is not due to dehydration or obstruction
• Presence of hepatitis B (HB) surface antigen or antibody in serum
• Arteriogram demonstrating aneurysms or occlusions of the visceral arteries that are not due to arteriosclerosis, fibromuscular dysplasia, or other noninflammatory causes
• Biopsy of small-sized or medium-sized artery containing polymorphonuclear (PMN) cells - Histologic changes demonstrating the presence of granulocytes or granulocytes and mononuclear leukocytes in the artery wall

Note: For classification purposes, Polyarteritis nodosa is diagnosed in a patient if at least 3 of these 10 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 82.2% and a specificity of 86.6%.

Consider polyarteritis nodosa whenever the following symptoms present independently or in combination:

• General
  • Fever
  • Malaise
  • Weight loss
  • Anorexia
• Organ specific
  • CNS: Peripheral (mononeuritis multiplex, cranial nerve palsy) and central (motor deficits, strokes, brain hemorrhages) symptoms are observed.
  • Skin: Vascular purpura, subcutaneous nodules, livedo reticularis, distal gangrene, and ischemic atrophy are symptoms of polyarteritis nodosa.⁵
  • Musculoskeletal: One half of patients with polyarteritis nodosa have myalgia. The arthritis is an asymmetric, episodic, nondeforming polyarthritis, which predominantly affects the larger joints, especially in the lower extremities, early in the course of disease in 20% of patients. Later in the course of illness, a larger percentage of patients have a more involved polyarticular distribution.
  • Renal: Rapid renal failure as a consequence of multiple infarcts,⁶ renin dependent hypertension, nephritic syndrome, nephrotic syndrome, rapidly progressive glomerulonephritis (RPGN), and ureteral stenosis is a symptom of PAN. PAN seldom leads to renal failure. RPGN is more characteristic of microscopic polyangiitis (MPA).
  • GI: GI symptoms of polyarteritis nodosa are abdominal pain,⁷ digestive tract bleeding, bowel perforation, and malabsorption.
  • Cardiac and pulmonary: Cardiomegaly, pericarditis, coronary artery involvement leading to ischemia and infarction, pneumonopathy and infiltrates, and pleural effusions (PEs) are symptoms of polyarteritis nodosa.
  • Reproductive: Orchitis is a symptom in males.
  • Ocular: Amblyopia and eye pain are symptoms of polyarteritis nodosa.

Physical

• General
  • Fever
  • Weight loss
• Organ specific
  • Nervous system (as many as 26% of individuals with polyarteritis nodosa, though this may represent referral patterns unique to the Hospital for Sick Children in the United Kingdom): Peripheral disease (mononeuritis multiplex, cranial nerve palsy, distal sensorimotor polyneuropathy) has been noted early in 50-70% of patients as a direct result of occlusion to the vasa vasorum. Central disease occurs late and includes motor deficits, strokes, brain hemorrhages, and diffuse encephalopathy.
  • Skin manifestations (occur in approximately 40% of individuals with polyarteritis nodosa): Vascular purpura is typically papulopetechial but sometimes may be bullous or vesicular. Infiltration (induration) is not common; however, if present, infiltration is the ideal site for biopsy. Present in 15% of patients with polyarteritis nodosa, subcutaneous nodules are transient and should undergo biopsy as soon as observed. Livedo reticularis is common. Distal gangrene may be observed as the consequence of ischemia.
  • Musculoskeletal: One half of patients complain of arthralgia or myalgia. In blind muscle biopsies, 30-50% reveal arteritis.
  • Renal (most frequently affected, 63% of individuals with polyarteritis nodosa and/or MPA): In persons with classic polyarteritis nodosa, vascular nephropathy is a common manifestation. Renal failure can occur because of multiple infarcts. RPGN is more characteristic of MPA. Hypertension develops from renal artery involvement. Ureteral involvement, which can be unilateral or bilateral, occurs because of periureteral vasculitis and secondary fibrosis. Intrarenal, perirenal, or retroperitoneal hemorrhage and/or hematoma result from the rupture of microaneurysms (less frequent in persons with MPA).
  • GI involvement (reported in 15% of individuals with polyarteritis nodosa; however, involvement at autopsy found in 50% of patients): Abdominal pain can be the first symptom of GI vasculitis. Ischemia most often is in the small intestine; rarely is ischemia found in the colon or stomach. Digestive tract bleeding and bowel perforation can occur. Polyarteritis nodosa may present as malabsorption, pancreatitis, or vasculitis of the appendix or gall bladder. Liver involvement, such as infarction and hematoma, can occur in the absence of HB virus (HBV) infection. Poor prognostic indicators include relapse after surgery or medical treatment, malabsorption, and pancreatitis.
  • Cardiac (26% of individuals with polyarteritis nodosa) and pulmonary (21% of individuals with polyarteritis nodosa) involvement: Cardiomegaly, systolic dysfunction, tricuspid and mitral valve regurgitation, pericarditis, coronary artery involvement leading to ischemia and infarction, pneumonopathy and infiltrates, and PEs are signs of polyarteritis nodosa. Congestive heart failure (CHF) may be present as an indication of coronary arteritis and hypertension. As many as 62% of individuals with polyarteritis nodosa have been reported to have coronary artery involvement leading to ischemia and infarction. Cardiac abnormalities are present in 90% of such persons at autopsy.
  • Ocular manifestations: Retinal vasculitis, retinal detachment, and cotton wool spots (cytoid bodies) are signs of polyarteritis nodosa.
  • Orchitis: Testicular biopsy reveals vasculitis in 25% of persons with polyarteritis nodosa.
  • Clinical characteristics of HBV-related polyarteritis nodosa: Malignant hypertension, renal infarction, and orchiepididymitis more often were associated with HBV infection.
• Limited forms of polyarteritis nodosa
  • Skin: Cutaneous polyarteritis nodosa manifestations are well known. Lower extremities are involved most frequently with palpable purpura, painful nodes surrounded by livedo reticularis, and necrotic lesions. Histologic lesions are identical to those observed in persons with systemic polyarteritis nodosa. The outcome is favorable, relapses are frequent, and systemic polyarteritis nodosa may develop.
  • Other organs: Organs such as appendix, gallbladder, uterus, testes, and peripheral nervous system can be involved without systemic involvement.

Causes

• Unknown in most cases
• HBV
• Hepatitis C (HC) virus
• HIV
• Cytomegalovirus
• Parvovirus B19
• Human T-lymphotrophic virus
• Streptococcus species infection

• Search for CME/CE on This Topic »

• Polyarteritis Nodosa (Neurology)
• Polyarteritis Nodosa (Rheumatology)
• Infantile Polyarteritis Nodosa (Pediatrics: General Medicine)
• Polyarteritis Nodosa (Radiology)

• Steroids Can Induce Remission of Polyarteritis Nodosa Without Poor-Prognosis Factors

• Kawasaki Disease After Vaccination: Reports to the Vaccine Adverse Event Reporting System 1990-2007
• Advances in Childhood Vasculitis
• European League Against Rheumatism/European Vasculitis Study Group Recommendations for the Management of Vasculitis