INTRODUCTION	Section 2 of 11
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Background: Classic polyarteritis nodosa (PAN or c-PAN) is a systemic vasculitis characterized by necrotizing inflammatory lesions affecting predominately medium and small muscular arteries, preferentially at vessel bifurcations, resulting in microaneurysm formation, thrombosis, aneurysmal rupture with hemorrhage, and organ infarction. Kussmaul and Maier first described the disease in 1866 after observing areas of focal inflammatory exudations that gave rise to palpable nodules along the course of the arteries in a patient with advanced disease. PAN, like other vasculitides, is generally multisystem and has protean manifestations but most commonly affects skin, joints, peripheral nerves, the gut, and the kidney vasculature.

Pathophysiology: For many years, PAN was used as a generic term to describe any type of systemic vasculitis. In 1948, Davson et al described a microscopic PAN characterized by a diffuse necrotizing glomerulonephritis. Microscopic polyarteritis, or microscopic polyangiitis (MPA), is recognized today as a systemic vasculitis with similar clinical features to classic PAN, with the additional manifestations of small vessel involvement resulting in rapidly progressive glomerulonephritis (RPGN) and pulmonary capillaritis.

The distinction between PAN and MPA was better defined by histologic criteria in the Chapel Hill Consensus Conference (CHCC) in 1994. According to the CHCC, the presence of vasculitis in arterioles, venules, and capillaries is necessary for the diagnosis of MPA, although small- and medium-sized arteries also may be involved in this disease. In contrast, c-PAN has no involvement of microscopic vessels and no glomerulonephritis. Therefore, PAN and MPA are differentiated by the absence or presence of microscopic vessel involvement, respectively, rather than by the involvement of medium-sized arteries.

Unlike MPA, c-PAN is sometimes associated with viral infections, especially hepatis B virus (HBV). c-PAN is thus further subclassified as either HBV- or non–HBV-related PAN, which is a clinically important distinction that affects treatment.

The pathogenesis of c-PAN is unknown. Evidence for immune complex–induced disease is confined to HBV-related PAN. c-PAN is not associated with antineutrophil cytoplasmic antibodies (ANCA).

Frequency:

• In the US: PAN is a rare disease, with an estimated annual incidence ranging from 4.6 cases per 1,000,000 population in England to 77 cases per 1,000,000 population in a population of Alaskan Eskimos hyperendemic for hepatitis B.

Mortality/Morbidity: Untreated, the prognosis for c-PAN is very poor, with a 5-year survival rate of 13% or less. Studies performed during the 1950s, 1960s, and 1970s showed that the addition of high-dose glucocorticoids (GCs) dramatically improved the 5-year survival rate to about 55%. A regimen of GCs and the cytotoxic agent cyclophosphamide (CY) achieved a 5-year survival rate of 82% in retrospective studies, but this added benefit of CY has not been demonstrated in prospective studies.

A recent 1992 study showed an overall 7-year survival rate of 81% in a prospective study of 78 patients with PAN treated with GCs; however, GCs alone failed to control the disease, and deterioration or relapse occurred in 33% of patients.

In 1991, a prospective study of a large population of patients with PAN showed that the addition of CY to the GC regimen improved the control of PAN by decreasing the incidence of relapses but did not improve the survival rate. However, the combination of GCs and CY does improve the survival rate in the subset of patients with PAN and more severe organ involvement.

Race: PAN has been diagnosed in people of all racial groups.

Sex: PAN affects men and women equally.

Age: PAN has been diagnosed in patients of every age; however, it is predominantly observed in patients aged 40-60 years.

	CLINICAL	Section 3 of 11
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History: PAN is generally an acute multisystem disease with a relatively short prodrome (ie, weeks to months) and with flares usually occurring within a short period after the initial clinical manifestations. Relapses are rare, occurring in less than 10% of patients.

The vasculitis of PAN has a predilection for medium-sized arteries of the extremities, the GI tract and liver, the kidneys, and the vasa nervorum. The lungs and the renal glomeruli tend to be spared. The consequences of this arteritis include painful skin ulceration and extremity gangrene, bowel infarction, hepatic infarction or intrahepatic bleed, renovascular hypertension and renal infarction, and mononeuritis multiplex.

Constitutional features including fever, anorexia and weight loss, arthralgia, and arthritis are common. Clinical features include the following:

• At presentation, most patients with PAN appear acutely ill with constitutional symptoms such as malaise, fever, and weight loss.

• Often, associated pain from peripheral neuropathy or musculoskeletal, GI, or cutaneous involvement is present.

• Peripheral neuropathy of the mononeuritis type is often the most frequent and earliest symptom of PAN, with a 50-70% incidence.

• Musculoskeletal manifestations are common, including myalgias (30-73%), arthralgias (50%), and asymmetric polyarthritis (20%).

• Cutaneous involvement is observed in 25-60% of cases. The spectrum of lesions includes palpable purpura, infarctions, ulcerations, livedo reticularis, and ischemic changes of the distal digits. Subcutaneous nodules are infrequent. Limited cutaneous forms of PAN, sometimes associated with myalgias, arthralgias, and peripheral neuropathy, may occur.

• One study by Soufir et al (1999) of a small number of patients showed a high frequency of hepatitis C virus (HCV) in patients with limited cutaneous PAN.

• GI tract involvement is one of the most severe manifestations of PAN, and patients most commonly present with abdominal pain (34% of patients).

• The spectrum of disease ranges from single organ involvement to fulminant polyvisceral failure.

Physical: Suspect PAN in patients with constitutional symptoms, musculoskeletal symptoms, and multisystem involvement. The emergence of multiple mononeuropathies 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.

• Neurologic manifestations

• Mononeuritis multiplex (multiple mononeuropathies)

• Both sensory and motor neuropathies may occur and are usually asymmetric.

• The sciatic nerve is commonly affected.

• The onset of sensory neuropathy may be sudden, with pain and paresthesias radiating in the distribution of a peripheral nerve, followed within hours to days by motor deficit of the same peripheral nerve.

• CNS involvement is rare (10% of cases or less), but motor deficiencies, strokes, and, sometimes, brain hemorrhages can occur.

• A report by Guillevin (1997) found psychiatric disturbances, mainly severe depression, in 8% of patients.

• Musculoskeletal manifestations

• Despite often intense myalgias, creatine kinase levels are usually within the reference range.

• A nondeforming asymmetric arthritis, usually involving the larger joints of the lower extremities, is common early in the disease.

• Findings from synovial fluid from affected joints are nondiagnostic, revealing only mild inflammation.

• Cutaneous manifestations: Painful skin ulceration, livedo reticularis, and ischemia and/or gangrene are the most common skin manifestations of PAN.

• Gastrointestinal manifestations

• GI involvement may manifest as mesenteric thrombosis and ischemia, with consequent intractable abdominal pain and weight loss, infarction, bowel perforation, hemorrhage, pancreatitis, appendicitis, and cholecystitis.

• Examine patients with severe abdominal pain for peritoneal signs. Marked right upper quadrant (RUQ) or left upper quadrant (LUQ) tenderness may be present in patients with hepatic or splenic infarction respectively.

• Renal manifestations

• Renal involvement is estimated to occur in 30-60% of patients with PAN.

• PAN causes vascular nephropathy, in contrast to MPA, which causes glomerulonephritis. This can lead to profound hypertension and oliguric renal failure.

• The acute necrotizing renal arteritis in PAN can lead to thrombosis and renal infarction with severe costophrenic pain and tenderness.

• Erosion into perivascular tissues causes aneurysm formation.

• Renal vessels may develop multiple microaneurysms and stenoses. Rupture of aneurysms may cause massive retroperitoneal or intraperitoneal hemorrhage.

• Chronic renal failure may occur several months or years after recovery from PAN, secondary to renal scars. In some of these cases, kidney transplant has been shown to be successful in recovery of renal function.

• Cardiac manifestations

• Clinical cardiac involvement (10-30%) causes coronary arteritis, the signs and symptoms of which may include hypertension (most common), tachycardia out of proportion to fever, congestive heart failure, cardiomegaly, pericardial friction rubs, and arrhythmias. However, angina and myocardial infarction are rare, and coronary angiography findings are usually normal.

• Of interest, a recent case report documented an unusual case of acute myocardial infarction secondary to spontaneous coronary artery dissection in a patient who was subsequently found to have PAN.

• Ophthalmologic manifestations

• Ocular manifestations of PAN include retinal vasculitis, retinal detachment, and cotton-wool spots.

• All patients with systemic PAN should have a screening ophthalmologic examination.

Causes:

• c-PAN is a primary systemic necrotizing vasculitis. However, a secondary PAN-like syndrome may be associated with systemic autoimmune diseases such as rheumatoid arthritis (RA) or Sjögren syndrome. Also, certain viral infections are associated with c-PAN. Most importantly, HBV infection, characterized by hepatitis B surface antigen positivity (HBsAg⁺), can cause a vasculitis that almost always takes the form of c-PAN. Polyarteritis may occur at any time in patients who are HBsAg⁺. Also, the activity of the arteritis does not parallel the activity of the hepatitis.

• According to studies from the early 1990s, the incidence of HBV-related PAN is estimated at 7% of the total population with PAN, a significant decrease from earlier reports of up to one third of patients with systemic PAN. This decrease may be related to the current widespread use of vaccines against viral hepatitis.

• Only 1% or less of the total population of patients who are HBV positive develop PAN. Clinical symptoms of non–HBV-related and HBV-related PAN are the same except for orchitis, which appears to be more frequent in groups with HBsAg⁺.

• Other viral infections may also be associated with arteritis, occasionally PAN, including HIV, cytomegalovirus (CMV), parvovirus B-19, human T-cell lymphotrophic virus type 1 (HTLV-1), and HCV. However, unlike HBV, these viruses are associated with a varying spectrum of vasculitides. PAN has also been described with hairy cell leukemia, but most of those patients were also HBV-positive.