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Polyarteritis Nodosa (PAN)

(Polyarteritis; Periarteritis Nodosa)

by Carmen E. Gota, MD

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries and occasionally affects small muscular arteries, resulting in secondary tissue ischemia. The kidneys, skin, joints, muscles, peripheral nerves, and GI tract are most commonly affected, but any organ can be. However, the lungs are usually spared. Patients typically present with systemic symptoms (eg, fever, fatigue). Diagnosis requires a biopsy or arteriography. Treatment with corticosteroids and immunosuppressants is often effective.

PAN is rare (about 2 to 33 cases/million). It affects mainly middle-aged adults, and incidence increases with age, peaking in people in their 50s.

Etiology

Most cases are idiopathic. About 20% of patients have hepatitis B or C.

The cause is unknown, but immune mechanisms appear to be involved. The variety of clinical and pathologic features suggests multiple pathogenic mechanisms. Drugs may be a cause. Usually, no predisposing antigen is identified. Patients with certain lymphomas and leukemias, RA, or Sjögren syndrome may develop a systemic vasculitis similar to PAN (sometimes called secondary PAN).

Pathophysiology

PAN is characterized by segmental, transmural necrotizing inflammation of muscular arteries, most commonly at points of bifurcation. Unlike other vasculitic disorders, PAN does not involve postcapillary venules or veins. Lesions in all stages of development and healing are usually present. Early lesions contain PMNs and occasionally eosinophils; later lesions contain lymphocytes and plasma cells. Granulomatous inflammation does not occur. Intimal proliferation with secondary thrombosis and occlusion leads to organ and tissue infarction. Weakening of the muscular arterial wall may cause small aneurysms and arterial dissection. Healing can result in nodular fibrosis of the adventitia.

Mostly commonly affected are the kidneys, skin, peripheral nerves, joints, muscles, and GI tract. Often affected are the liver and heart. Renal ischemia and infarction occur, but glomerulonephritis is not a feature of PAN. Purpura is not a characteristic of PAN.

Symptoms and Signs

PAN mimics many disorders. The course may be acute and prolonged, subacute and fatal after several months, or insidious, chronic, and debilitating. Symptoms depend mainly on location and severity of the arteritis and extent of secondary ischemia. Only one organ or organ system may be affected.

Patients typically present with fever, fatigue, night sweats, loss of appetite, weight loss, and generalized weakness. Myalgias with areas of focal ischemic myositis and arthralgias are common. Affected muscles are tender and may be weak. Arthritis may occur.

Symptoms and signs vary, depending on organ or organ system predominantly affected:

  • Peripheral nervous system: Patients usually present with asymmetric peripheral neuropathy, such as mononeuritis multiplex with signs of motor and sensory involvement of the peroneal, median, or ulnar nerves. As additional nerve branches are affected, patients may appear to have a distal symmetric polyneuropathy.

  • CNS: Headache and seizures can result. In a few patients, ischemic stroke and cerebral hemorrhage occur, sometimes resulting from hypertension.

  • Renal: If small- and medium-sized arteries in the kidneys are affected, patients may have hypertension, oliguria, uremia, and a nonspecific urinary sediment with hematuria, proteinuria, and no cellular casts. Hypertension may worsen rapidly. Rupture of renal arterial aneurysms can cause perirenal hematomas. In severe cases, multiple renal infarcts with lumbar pain and gross hematuria may occur. Renal ischemia and infarction can lead to renal failure.

  • GI: Vasculitis of the liver or gallbladder causes right upper quadrant pain. Perforation of the gallbladder with acute abdomen may occur. Vasculitis of medium-sized mesenteric arteries causes abdominal pain, nausea, vomiting (with or without bloody diarrhea), malabsorption, intestinal perforation, and acute abdomen. Aneurysms may develop in hepatic or celiac arteries.

  • Cardiac: Some patients have coronary artery disease, which is usually asymptomatic, but may cause angina. Heart failure may result from ischemic or hypertensive cardiomyopathy.

  • Cutaneous: Livedo reticularis, skin ulcers, tender erythematous nodules, bullous or vesicular eruptions, infarction and gangrene of fingers or toes, or a combination may occur. The nodules in PAN resemble erythema nodosum (inflammation of subcutaneous fat) but, unlike nodules in erythema nodosum, the nodules in PAN can ulcerate, and have necrotizing vasculitis that is visible on biopsy within the walls of medium-sized arteries, usually located in the deep dermis and subcutaneous fat.

  • Genital: Orchitis with testicular pain and tenderness can occur.

Diagnosis

  • Clinical findings

  • Biopsy

  • Arteriography if no clinically involved tissue is available for biopsy

PAN can be difficult to diagnose because findings can be nonspecific. The diagnosis should be considered in patients with various combinations of symptoms, such as unexplained fever, arthralgia, subcutaneous nodules, skin ulcers, pain in the abdomen or extremities, new footdrop or wristdrop, or rapidly developing hypertension. The diagnosis is further clarified when clinical findings are combined with certain laboratory results and other causes are excluded.

Diagnosis is confirmed by biopsy showing necrotizing arteritis or by arteriography showing the typical aneurysms in medium-sized arteries. Magnetic resonance angiography may show microaneurysms, but some abnormalities may be too small for it to detect. Thus, magnetic resonance angiography is not the test used primarily for diagnosis. Biopsy of clinically uninvolved tissue is often useless because the disease is focal; biopsy should target sites suggested by clinical evaluation. Samples of subcutaneous tissue, sural nerve, and muscle, if thought to be involved, are preferred to samples from the kidneys or liver; kidney and liver biopsies may be falsely negative because of sampling error and may cause bleeding from unsuspected microaneurysms. If clinical findings are absent or minimal, electromyography and nerve conduction studies may help select the site of muscle or nerve biopsy. If skin lesions are present, surgical skin biopsies that include deeper dermis and subcutaneous fat should be done. (Punch biopsies of the skin that sample the epidermis and superficial dermis miss the lesions of PAN.) Even though microscopic lesions in the testes are common, testicular biopsy should not be done if testicular symptoms are absent and if other possible sites are accessible because the yield is low. Also, men may be reluctant to have testicular biopsy.

Laboratory tests are nonspecific. Leukocytosis up to 20,000 to 40,000/μL, proteinuria, and microscopic hematuria are the most common abnormalities. Patients may have thrombocytosis, markedly elevated ESR, anemia caused by blood loss or renal failure, hypoalbuminemia, and elevated serum immunoglobulins. AST and ALT are often mildly elevated. Testing for hepatitis B and C should be done. Other testing (eg, antineutrophil cytoplasmic antibodies [ANCA], rheumatoid factor, anticyclic citrullinated peptides [CCP], antinuclear antibodies [ANA], C3 and C4 complement levels, cryoglobulin levels, nuclear antigens and antibodies to extractable nuclear antigens such as anti-Smith, anti-Ro/SSA, anti-La/SSB, and anti-RNP) may suggest other diagnoses, such as RA, SLE, or Sjögren syndrome.

Prognosis

Without treatment, 5-yr survival is < 15%. With treatment, 5-yr survival is > 80% but may be lower for patients with hepatitis B. Prognosis is better if disease remission is achieved within 18 mo after diagnosis.

The following findings are associated with a poor prognosis:

  • Renal insufficiency

  • GI involvement

  • Neurologic involvement

Treatment

  • Corticosteroids alone or with cyclophosphamide, methotrexate, or azathioprine, depending on disease severity

  • Addition of lamivudine and plasma exchange for patients with hepatitis B

Treatment depends on the severity of the disease. For systemic symptoms but no serious neurologic, renal, GI, or cardiac manifestations, corticosteroids may be sufficient, at least initially. For severe disease with neurologic, renal, GI, or cardiac manifestations, cyclophosphamide plus corticosteroids may improve outcome. For moderate disease, corticosteroids plus methotrexate or azathioprine can be used. Hypertension should be treated aggressively.

Hepatitis B–related PAN

Treatment aims at rapidly suppressing inflammation, then eliminating the virus and inducing seroconversion via plasma exchange. A short course of corticosteroids is used for a few weeks. Lamivudine 100 mg po once/day is given for a maximum of 6 mo. A lower dose is used in patients with renal insufficiency. Plasma exchanges are scheduled as follows: 3 times/wk for 3 wk, 2 times/wk for 2 wk and once/wk until hepatitis B e antigen (HBeAg) converts to hepatitis B e antibody (anti-HBe) or until clinical recovery is sustained for 2 to 3 mo. Although this approach has not been proved to improve survival when compared with immunosuppressive therapy only, it may reduce the risk of long-term complications of hepatitis B and suppress the side effects of long-term treatment with corticosteroids and immunosuppressants.

Traditional treatment with corticosteroids, sometimes with cytotoxic immunosuppressants (mainly cyclophosphamide), was often effective in the short term but did not prevent relapses and complications (eg, chronic hepatitis, cirrhosis) due to persistence of the hepatitis B virus; immunosuppressive therapy in patients with hepatitis B facilitates viral replication, which can lead to active viral hepatitis and liver failure.

Patients with hepatitis C who develop PAN are treated for hepatitis C.


Key Points

  • PAN is a rare systemic vasculitis affecting medium-sized arteries.

  • The kidneys, skin, joints, muscles, peripheral nerves, and GI tract are most often affected.

  • Suspect PAN if patients have combinations of unexplained fever, arthralgia, subcutaneous nodules, skin ulcers, pain in the abdomen or extremities, new footdrop or wristdrop, or rapidly developing hypertension.

  • Confirm the diagnosis by biopsy or arteriography.

  • Renal insufficiency, GI involvement, or neurologic involvement portends a less favorable prognosis.

  • Treat with corticosteroids alone or with cyclophosphamide, methotrexate, or azathioprine, depending on disease severity.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CYTOXAN (LYOPHILIZED)
  • EPIVIR
  • IMURAN
  • OTREXUP

* This is a professional Version *