Polyarteritis Nodosa (PAN)

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

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

A monogenic form of PAN that is linked to mutations in the adenosine deaminase 2 (ADA2) gene has been identified (1). It is inherited in an autosomal recessive manner and presents with a vasculopathy similar to PAN. In addition, patients with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, which is an autoinflammatory condition characterized by somatic mutations in the ubiquitin-like modifier-activating enzyme 1 (UBA1) gene, may present with PAN (2).

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 polymorphonuclear leukocytes 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.

Most commonly affected are the kidneys, skin, peripheral nerves, joints, muscles, and gastrointestinal tract. Less often affected are the liver and heart. Renal ischemia and infarction occur, but glomerulonephritis is not a feature of PAN. Purpura (usually resulting from small-vessel inflammation) and lung parenchymal inflammation are not characteristic of PAN.

PAN mimics many disorders. The course may be acute and prolonged, subacute and fatal after several months, or insidious, chronic, and debilitating. Symptoms of PAN 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 the organ or organ system predominantly affected:

• Peripheral nervous system: Patients usually present with asymmetric peripheral neuropathy, such as multiple mononeuropathy (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.

• Central nervous system: 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.

• Gastrointestinal: 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, 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.

• 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 of PAN 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. Unlike in granulomatosis with polyangiitis (GPA), biopsy is unlikely to show marked parenchymal inflammation.

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.

Laboratory tests are nonspecific. Leukocytosis up to 20,000 to 40,000/microL (20 to 40 × 10⁹/L), proteinuria, and microscopic hematuria are the most common abnormalities. Patients may have thrombocytosis, markedly elevated erythrocyte sedimentation rate and/or C-reactive protein, anemia caused by blood loss or renal failure, hypoalbuminemia, and elevated serum immunoglobulins. Aspartate aminotransferase and alanine aminotransferase are often mildly elevated. Testing for hepatitis B and C should be done. Because glomerulonephritis is not a feature of PAN, red blood cell casts are not evident on urinalysis.

Other testing (eg, antineutrophil cytoplasmic antibodies [ANCA], rheumatoid factor, anticyclic citrullinated peptide [anti-CCP] antibody, 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 rheumatoid arthritis, systemic lupus erythematosus, or Sjögren syndrome.

• Treatment of hepatitis B when indicated

Treatment of polyarteritis nodosa depends on the severity of the disease (1

With treatment, 5-year survival is approximately 80% but may be lower for patients with hepatitis B (1). Prognosis is better if disease remission is achieved within 18 months after diagnosis. Relapses are less common than in other vasculitic disorders.

The following findings are associated with a poor prognosis:

• Renal insufficiency

• Gastrointestinal involvement

• Neurologic involvement