eMedicine Specialties > Rheumatology > Vasculitis

Polyarteritis Nodosa

Author: Dana Jacobs-Kosmin, MD, Attending Physician, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center; Clinical Assistant Professor of Medicine, Jefferson Medical College
Coauthor(s): Mahendra Agraharkar, MD, MBBS, FACP, President, Space City Associates of Nephrology; Medical Director, Chronic Home Dialysis Unit, DaVita Reliant Dialysis Center and DaVita South Shore Dialysis Center; Kanwarpreet Baweja, MD, Fellow in Nephrology, Division of Renal Diseases and Hypertension, University of Texas Health Science Center; Vasanta P Weiss, MD, Consulting Staff, Department of Nephrology, University of Virginia Medical Center; Bruce A Baethge, MD, Faculty, Texas A&M Medical School; J Mark Jackson, MD, Associate Clinical Professor, Department of Internal Medicine, Division of Dermatology, University of Louisville
Contributor Information and Disclosures

Updated: Feb 12, 2009

Introduction

Background

Classic polyarteritis nodosa (PAN or c-PAN) is a systemic vasculitis characterized by necrotizing inflammatory lesions that affect medium and small muscular arteries, preferentially at vessel bifurcations, resulting in microaneurysm formation, aneurysmal rupture with hemorrhage, thrombosis, and, consequently, organ ischemia or infarction. Kussmaul and Maier first described PAN in 1866. The autopsy of a patient with fever, weight loss, abdominal pain, and polyneuropathy revealed areas of focal inflammatory exudations that gave rise to palpable nodules along the course of medium-sized arteries.¹ PAN, like other vasculitides, generally affects multiple systems and has protean manifestations, but most commonly affects skin, joints, peripheral nerves, the gut, and the kidney.

Pathophysiology

Vascular lesions in medium-sized muscular arteries occur mainly at bifurcations and branch points. Inflammation may start in the vessel intima and progress to include the entire arterial wall, destroying both the internal and external elastic lamina, resulting in fibrinoid necrosis.² Aneurysms develop in the weakened vessel, carrying a subsequent risk for rupture and hemorrhage. Thrombi may develop at the site of the lesions. As lesions progress, proliferation of the intima or media may result in obstruction and subsequent tissue ischemia or infarction.³ PAN spares large vessels (the aorta and its major branches), the smallest vessels (capillaries and small arterioles), and the venous system.²

Insight into PAN requires some understanding of how this rare disease has been defined. Periarteritis nodosa was a term used from the mid 1800s to the 1900s to describe a spectrum of systemic vasculitic disorders including, for example, diseases that manifested as arterial aneurysms, as well as those that caused diffuse necrotizing glomerulonephritis.^4,5 The term periarteritis nodosa was changed to polyarteritis nodosa in the mid 1900s to reflect the transmural inflammation of arteries caused by this disorder.²

The understanding of vasculitides continued to increase by the 1980s with the discovery of antineutrophil cytoplasmic antibodies (ANCAs). Microscopic polyangiitis (MPA; formerly called microscopic polyarteritis) is an ANCA-associated systemic vasculitis that has some features similar to those of classic PAN, with the additional involvement of renal glomeruli and pulmonary capillaries.

In 1990, the American College of Rheumatology developed classification criteria for vasculitides, including PAN; these criteria made no distinction between PAN and MPA. Three of the following 10 criteria must be present to classify a vasculitis as PAN:⁶

• Weight loss of 4 kg or more
• Livedo reticularis
• Testicular pain/tenderness
• Myalgia or leg weakness/tenderness
• Mononeuropathy or polyneuropathy
• Diastolic blood pressure greater than 90 mm/Hg
• Elevated BUN and creatinine levels
• Infection with hepatitis B virus (HBV)
• Abnormality on arteriography
• Biopsy of small- or medium-sized artery containing polymorphonuclear neutrophils

The strong association of MPA with ANCA, as well as the pathologic and clinical differences between MPA and PAN, demonstrate that PAN and MPA are likely separate disorders. It was not until 1994 that histologic criteria to distinguish PAN from MPA were defined at the international Chapel Hill Consensus Conference (CHCC).⁷ According to the CHCC criteria, the presence of vasculitis in arterioles, venules, and capillaries defines the diagnosis of MPA (although small- and medium-sized arteries may also be involved in MPA) and excludes the diagnosis of PAN.

The pathogenesis of PAN is unknown, and no animal model is available for study. In some cases, PAN is associated with viral infections, especially HBV. Evidence for immune complex–induced disease is confined to HBV-related PAN; the role of immune complexes in non–HBV-related PAN remains unclear.² Impaired function of endothelial cells may be part of idiopathic PAN or a consequence of it; in HBV-PAN, virus replication may directly injure the vessel wall.⁸ Endothelial dysfunction can perpetuate the inflammation through cytokine and adhesion molecule production.³

Frequency

United States

PAN is a rare disease. Older estimates placed the prevalence as high as 77 cases per 1,000,000 population, for example, in a population of Alaskan Eskimos hyperendemic for HBV infection.⁹

International

Depending on the definitions used, the annual estimated incidence ranges from 1.6 cases per million in south Sweden to 4.6 cases per million in England to 30.7 per million adults in Paris, France.^10,11

Mortality/Morbidity

Permanent morbidity due to PAN is relatively rare, although patients may develop peripheral neuropathy, renal insufficiency or renal failure, and/or hypertension.

Untreated PAN carries a very poor prognosis.

• In an early series of patients with PAN (which likely also included patients with MPA), the survival rate at 5 years was less than 15%.¹²
• Death associated with PAN occurs as a result of uncontrolled vasculitis, infectious complications related to treatment-induced immunosuppression, and vascular complications of the disease, such as myocardial infarction or stroke.
• The mortality rate is higher in patients with acute abdominal syndromes.¹³

Race

PAN has been diagnosed in people of every race and ethnicity.³

Sex

PAN may be more common in men than in women.³

Age

PAN has been diagnosed in persons of every age; however, it is predominantly observed in individuals aged approximately 45-65 years.³

Clinical

History

Polyarteritis nodosa (PAN) is an acute multisystem disease with a relatively short prodrome (ie, weeks to months).² Delays in diagnosis are not uncommon. The spectrum of disease ranges from single-organ involvement to fulminant polyvisceral failure. Pertinent and common historical features of PAN include the following:

• Constitutional
  • Fever
  • Malaise
  • Fatigue
  • Anorexia and weight loss
• Musculoskeletal
  • Myalgia
  • Arthralgia in large joints or, less commonly, arthritis
• Neurologic - Numbness, burning, pain, or weakness involving distal nerves and beginning asymmetrically
• Cutaneous
  • Itching, burning, painful, or asymptomatic lesions
  • Lacy discoloration of the skin
• Gastrointestinal
  • Abdominal pain that may be postprandial
  • Nausea/vomiting
  • Melena
  • Hematochezia
  • Diarrhea
  • Constipation
• Renal - Flank pain

Less common symptoms reported in PAN include the following:

• Genitourinary - Testicular pain, usually unilateral
• Cardiac
  • Chest pain
  • Dyspnea
  • Palpitations
• Ophthalmologic - Blurred vision
• Neuropsychiatric
  • Headache
  • Psychosis¹⁴
  • Depression

Physical

The emergence of multiple mononeuropathies in persons with PAN is an important clue to an underlying arteritis. Evidence of organ or extremity ischemia, including hypertension and renal insufficiency (renovascular disease), are further clues to the diagnosis. Lung involvement is rare.

• Constitutional: Fever may be observed.
• Musculoskeletal: A nondeforming asymmetric arthritis, usually involving the larger joints of the lower extremities, has been reported in PAN.
• Neurologic
  • Both sensory and motor neuropathies may occur and are usually asymmetric.
  • Mononeuritis multiplex (multiple mononeuropathy) is the successive ischemia or infarction of "named nerves" (eg, ulnar, radial, peroneal, sural). Nerve involvement is initially asymmetric; however, upon additional nerve lesions, the clinical picture may resemble symmetric polyneuropathy. (History of asymmetry at onset and by electrodiagnostic studies can be helpful in this case).¹⁵
  • CNS involvement is rare (≤10% of cases), but motor deficiencies, strokes, and, sometimes, brain hemorrhages can occur.
• Cutaneous²
  • Livedo reticularis that does not blanch with active pressure
  • Ulcerations, especially on the lower extremities near the malleoli and on the calf
  • Digital ischemia that may be accompanied by splinter hemorrhages and, sometimes, gangrene
  • Nodules, usually on the lower extremities (like ulcers) (Nodules are the least common skin manifestation of PAN.)
• Gastrointestinal¹³
  • Tender abdomen with or without rigidity, guarding, diminished bowel sounds
  • GI bleeding
• Renal
  • Hypertension
  • Costophrenic tenderness
  • Retroperitoneal or intraperitoneal hemorrhage
• Cardiac
  • Hypertension
  • Tachycardia out of proportion to fever
  • Pericardial friction rub
  • Arrhythmias
• Ophthalmologic
  • Retinal vasculitis
  • Retinal detachment
  • Cotton-wool spots
• Genitourinary - Testicular tenderness
• Psychiatric
  • Psychosis
  • Depression

Causes

The cause of primary idiopathic PAN is unknown.

Some syndromes, including rheumatic diseases, malignancies, and infections have been associated with clinical syndromes indistinguishable from idiopathic PAN.

• Rheumatoid arthritis (RA) and Sjögren syndrome have been associated with PAN. Notably, the incidence of RA-associated vasculitis has decreased greatly since the 1980s, possibly attributable to improvements in the management of RA.¹⁶
• Hematologic malignancies, such as hairy cell leukemia, have been associated with PAN–like vasculitides.¹⁷
• Viral infections, including HIV infection, hepatitis C infection and, most strongly, HBV infection have been associated with PAN.
• Other infectious organisms have been reported in association with PAN or PAN–like diseases, but causal evidence is inconsistent. These organisms include varicella-zoster virus, parvovirus B-19, cytomegalovirus, human T-cell leukemia virus, streptococcal species, Klebsiella species, Pseudomonas species, Yersinia species, Toxoplasma gondii, Rickettsiae, trichinosis, and sarcosporidiosis.^18,19
• Hepatitis C may be linked to cutaneous PAN, a benign limited form of PAN. In one study of 16 patients with cutaneous PAN, 5 tested positive for hepatitis C.²⁰

HBV was once the cause of up to 30% of PAN cases.¹⁰ Widespread use of the hepatitis B vaccines has significantly decreased the incidence of HBV-PAN, which is now estimated to account for less than 8% of all PAN cases.²¹

• HBV-associated vasculitis almost always takes the form of PAN.
• HBV-PAN may occur at any time during the course of acute or chronic hepatitis B infection but typically occurs within 6 months of infection.⁸
• The activity of the arteritis does not parallel that of the hepatitis, and symptoms are the same as those of idiopathic PAN. Small studies have found that GI manifestations, malignant hypertension, renal infarction, and orchiepididymitis were more common in HBV-PAN.⁸

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