Chapter 35. Polyarteritis Nodosa

• Subacute onset of constitutional complaints (eg, fever, weight loss, malaise, arthralgias), lower extremity nodules and ulcerations, mononeuritis multiplex, and intestinal angina (postprandial pain caused by the involvement of mesenteric vessels).
• Cutaneous polyarteritis nodosa (PAN) is a variant of the systemic disease in which vasculitis is limited to the skin, usually presenting as nodules that break down into ulcers.
• Angiogram or biopsy of an involved organ required for diagnosis.
• Angiography may reveal microaneurysms in the kidneys or gastrointestinal tract.
• Biopsies of the skin and peripheral nerves (with sampling of the adjacent muscle) are the least invasive ways of confirming the diagnosis histopathologically.

Classic PAN is characterized by necrotizing inflammation of muscular arterioles and medium-sized arteries that spares the smallest blood vessels (eg, capillaries). PAN is not associated with glomerulonephritis, although it can cause renovascular hypertension and renal infarctions through its involvement of the medium-sized intrarenal vasculature. Features that distinguish PAN from other forms of systemic vasculitis are confinement of the disease to the arterial as opposed to the venous circulation, the sparing of the lung, and the absence of granulomatous inflammation.

Reported annual incidence rates of PAN range from 2 to 9 cases per million people per year. A higher incidence (77 cases/million) was reported in an Alaskan area hyperendemic for hepatitis B virus (HBV). With the availability of the HBV vaccine, however, the percentage of cases associated with HBV has declined substantially (now <10% of all cases in the developed world). PAN appears to affect men and women with approximately equal frequencies and to occur in all ethnic groups.

Symptoms and Signs

PAN can involve virtually any organ system with the exception of the lungs. The disease demonstrates a predilection for certain organs, particularly the skin, peripheral nerves, gastrointestinal tract, and kidneys. A nearly universal complaint among patients is some type of pain, caused by myalgias, arthritis, peripheral nerve infarction, testicular ischemia, or mesenteric vasculitis.

Constitutional Symptoms

Fevers are a common feature of PAN. The characteristics of the fever vary substantially among patients, ranging from periods of low-grade temperature elevation to spiking febrile episodes accompanied by chills (patterns of low-grade fever are more common than are hectic fevers). Tachycardia with or without fever may be another feature of PAN. Malaise, weight loss, and myalgias are also common.

Skin and Joints

Vasculitis of medium-size arteries may produce several types of skin lesions. These cutaneous findings include livedo racemosa (Plate 48), nodules, papules, ulcerations, and digital ischemia leading to gangrene. All of these findings or combinations of them may occur in the same patient. The livedo racemosa (often termed “livedo reticularis”), which may have a diffuse distribution over the extremities and buttocks, does not blanch with the application of pressure to the skin. Nodules, papules, and ulcers tend to occur on the lower extremities, particularly near the malleoli, in the fleshy parts of the calf, and over the dorsal surfaces of the feet. Nodules frequently evolve into ulcerations that have scalloped borders (Figure 35–1) and heal with scarring.

Although the principal skin manifestations relate to disease caused by arteritis in medium-sized muscular arteries and arterioles, crops of purpura (caused by the involvement of smaller blood vessels) occur in a minority of patients. Digital ischemia, often accompanied by splinter hemorrhages, sometimes leads to tissue loss.

Arthralgias of large joints (knees, ankles, elbows, wrists) occur in up to 50% of patients; however, true synovitis is seen in substantially fewer patients.

Peripheral Nerves

Mononeuritis multiplex, the infarction of named nerves by inflammation in the vasa nervorum, occurs in approximately 60% of patients with PAN. The most commonly involved nerves are the sural, peroneal, radial, and ulnar. Vasculitic neuropathy tends to involve the longest (ie, distal) nerves first and usually begins asymmetrically. Thus, the first motor symptoms of vasculitic neuropathy may be a foot or wrist drop (resulting from infarctions of the peroneal and radial nerves, respectively). In advanced stages, the neuropathy may mimic a confluent, symmetric polyneuropathy. Careful history taking, however, may unmask its initial asymmetry. Both sensory and motor findings are characteristic of vasculitic neuropathy because with the exception of the sural nerve (a pure sensory nerve), peripheral nerves typically have mixed sensory and motor fibers bundled within the same nerve.

Gastrointestinal Tract

The gastrointestinal manifestations of PAN occur in approximately half of all patients and are among the most challenging symptoms to diagnose correctly because of their nonspecific nature. Postprandial abdominal pain (“intestinal angina”) is common. Involvement of the mesenteric arteries in PAN may lead to the disastrous complications of mesenteric infarction or aneurysmal rupture, each of which is associated with a high mortality rate. Angiography of the mesenteric vessels reveals multiple microaneurysms (Figure 35–2A). These range in size from lesions that are barely visible to the naked eye to several centimeters in diameter. Sometimes PAN is detected at cholecystectomy or appendectomy in the absence of other disease manifestations. In such cases, surgical removal of the involved organ may be curative.

Intraparenchymal Renal Inflammation

This major feature of PAN is found in 40% of patients. The inflammatory process targets the renal and interlobar arteries (the medium-sized, muscular arteries within the kidney) and occasionally also involves the smaller arcuate and interlobular arteries. Angiography may reveal microaneurysms within the kidney or large, wedge-shaped renal infarctions (Figure 35–2B). Renal artery involvement or involvement of intra-renal arterioles in PAN may lead to renin-mediated hypertension. Red blood cell casts on urinalysis imply glomerulonephritis and thus usually implicate another disease (eg, microscopic polyangiitis). However, both proteinuria and hematuria may be observed in PAN.

Cardiac Symptoms

Tachycardia may reflect either direct cardiac involvement or a general inflammatory state. Congestive heart failure and myocardial infarction sometimes occur. Specific heart lesions are rarely diagnosed while the patient is alive; however, autopsy series indicate that cardiac involvement is present in a majority of patients with PAN. Patchy necrosis of the myocardium caused by subclinical arteriolar involvement is a common finding at autopsy.

Miscellaneous

Central nervous system involvement occurs in a small percentage of patients with PAN. The usual presentations are encephalopathy and strokes. Renin-mediated hypertension may contribute to both of these neurologic complications. Other unusual presentations of PAN include involvement of the eyes (scleritis), pancreas, testicles, ureters, breasts, and ovaries.

Laboratory Findings

Although the laboratory features of PAN are often strikingly abnormal and help characterize the disease process as inflammatory, they do not distinguish PAN from a host of other inflammatory diseases. Anemia, thrombocytosis, and elevation of acute phase reactants are typical (Table 35–1). The erythrocyte sedimentation rate and C-reactive protein are often useful in longitudinal evaluations of disease activity but are imperfect for this purpose.

One of the diagnostic challenges in PAN is the fact that the disorder is not associated with any of the autoantibodies found in other immune-mediated conditions. Assays for antinuclear antibodies and rheumatoid factor are generally negative in patients with PAN, albeit low titers of these antibodies are detected in a minority of patients. Patients with HBV-associated PAN are generally hypocomplementemic, regardless of whether they have demonstrable cryoglobulins. When associated with HBV, PAN usually develops within weeks to months of the acute viral infection.

When tested by immunofluorescence, the sera of some patients with PAN are positive for antineutrophil cytoplasmic antibodies (ANCAs). However, specific enzyme immunoassays for antibodies to proteinase-3 or myeloperoxidase (the two antigens known to be associated with systemic vasculitis) are negative. Thus, PAN is not considered to be a form of ANCA-associated vasculitis.

Special Tests

The diagnosis of PAN requires either a tissue biopsy or an angiogram that demonstrates microaneurysms.

Biopsy

In the skin, medium-sized arteries lie within the deep dermis and in the subdermal adipose tissue. Thus, the diagnosis of PAN can be made by obtaining biopsy specimens of the skin that capture lobules of subcutaneous fat. Biopsies of nodules, papules, and the edges of ulcers have higher yields than biopsies of livedo racemosa.

PAN is a panarteritis characterized by transmural necrosis and a homogeneous, eosinophilic appearance of the blood vessel wall (fibrinoid necrosis). The cellular infiltrate is pleomorphic, with both polymorphonuclear cells and lymphocytes present in varying degrees at different stages. Degranulation of neutrophils within and around the arterial wall leads to leukocytoclasis. During later stages, complete occlusion may occur secondary to endothelial proliferation and thrombosis. Throughout involved tissues, the coexistence of acute and healed lesions is typical.

Nerve Conduction Studies

Nerve conduction studies are useful in detecting the typical axonal pattern of nerve injury and identifying involved nerves for biopsy. Because muscle tissue is highly vascular and may harbor involved vessels even in the absence of symptoms or signs of muscle involvement, biopsies of adjacent muscle should be performed simultaneously (eg, the gastrocnemius, if the sural nerve is biopsied). Blind biopsies of asymptomatic organs such as the testicle, however, are rarely diagnostic.

Angiography

The vascular wall inflammation in PAN may be strikingly segmental, affecting only part of the circumference of a given artery. Segmental necrosis, in turn, leads to aneurysm formation. Lesions known as microaneurysms can occur throughout the mesenteric and renal vasculature. Even in patients without gastrointestinal symptoms, mesenteric angiography may demonstrate telltale microaneurysms.

Conventional, catheter-based angiography generally has a higher resolution than computed tomography or magnetic resonance angiograms and remains the gold-standard approach to the detection of microaneurysms. The interpretation of angiograms requires experience. Alternating areas of vascular narrowing and dilatation can be caused by a variety of non-vasculitic processes, including (most commonly) vasospasm. The finding of true microaneurysms, however, is diagnostic of PAN in the proper setting.

Even when flagrant inflammation is present, PAN may elude diagnosis for weeks or months. Except for evidence obtained from angiography or biopsy, the disease has no individual features that are pathognomonic. Many connective tissue diseases must be considered in the differential diagnosis of PAN (Table 35–2). However, systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disorders usually can be distinguished from PAN by the presence of specific autoantibodies (eg, anti-Ro/SS-A, anti-La/SS-B, anti-Sm, anti-RNP). These are absent in PAN. Less specific autoantibodies such as antinuclear antibodies and rheumatoid factor are often present in PAN but are nondiagnostic because of their poor specificities.

In its early phases, rheumatoid arthritis may mimic PAN, but the arthritis of PAN is usually migratory and always nondestructive. Rheumatoid vasculitis, which has features very similar to PAN, almost always occurs in patients with severe, long-standing, destructive joint disease, not simultaneously with or before the arthritis. Similarly, although the fever pattern of PAN recalls that of Still disease in a minority of patients, the evanescent, salmon-colored rash of Still disease does not occur in PAN. Moreover, diffuse polyarthritis develops in 95% of patients with Still disease within 1 year (or earlier) of disease onset. The catastrophic antiphospholipid syndrome, which causes digital ischemia, strokes, and other arterial thrombotic events, may be confused with PAN. However, venous events, which are even more common than arterial events in most patients with the antiphospholipid syndrome, are not characteristic of PAN.

The lack of pulmonary involvement in PAN helps distinguish it from most cases of ANCA-associated vasculitis. The occurrence of pulmonary lesions (pulmonary nodules, cavities, infiltrates, or alveolar hemorrhage) in combination with systemic vasculitis shifts the differential diagnosis in favor of other vasculitides, such as granulomatosis with polyangiitis (formerly Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). In addition, features of small-vessel disease (eg, purpura) are generally absent in PAN. Isolated peripheral nervous system vasculitis, a form of vasculitis that involves the peripheral nervous system alone, may mimic PAN and require similar therapy. In addition, in a subset of cases, the predominant features of PAN imitate the presentation of giant cell arteritis (eg, headache, jaw claudication, fever, and polymyalgias). Findings of histopathologic features of PAN on temporal artery biopsy specimens have been reported.

The multiorgan system inflammatory nature of PAN may be mimicked by numerous bacterial, mycobacterial, or fungal infections. These must be excluded with great caution before beginning a treatment course for vasculitis. Finally, a host of other systemic or single-organ diseases may mimic PAN in their individual organ features. These include inflammatory bowel disease, sarcoidosis, erythema nodosum, cholesterol emboli, fibromuscular dysplasia, and malignancies (particularly lymphoma). PAN may occur as a complication of hairy cell leukemia.

Livedoid vasculopathy is a thrombotic process that involves small blood vessels in the skin. It may cause skin lesions that are very difficult to distinguish from those of PAN on the basis of clinical findings alone. Nodules and particularly ulcers involving the lower extremities are typical of livedoid vasculopathy. Skin biopsy is required to distinguish PAN from livedoid vasculopathy. The distinction is critical because treatment approaches to these two disorders are divergent: immunosuppression or antiviral therapies in PAN, as opposed to anticoagulation in livedoid vasculopathy.

In patients with idiopathic PAN, glucocorticoids and cytotoxic agents remain the cornerstones of treatment. Approximately half of patients with PAN achieve remissions or cures with high doses of glucocorticoids alone. Cyclophosphamide (eg, 2 mg/kg/d orally or 0.6 g/m2/mo intravenously, decreased in the setting of renal dysfunction) is indicated for patients whose disease is refractory to glucocorticoids or who have serious involvement of major organs. Prophylaxis against Pneumocystis jiroveci pneumonia is an important consideration in patients treated with these medications.

Treatment of HBV-associated PAN with immunosuppressive agents has deleterious long-term effects on the liver. Fortunately, the availability of effective antiviral agents has revolutionized the treatment of HBV-associated cases in recent years. One effective strategy involves the initial use of prednisone (1 mg/kg/d) to suppress the inflammation. Patients begin 6-week courses of plasma exchange (approximately three exchanges per week) simultaneously with the start of prednisone. The doses of glucocorticoids are tapered rapidly (over approximately 2 weeks), followed by the initiation of antiviral therapy (eg, lamivudine 100 mg/d or entecavir 0.5–1.0 mg/d).

Advanced mononeuritis multiplex can be a severely disabling problem from which recuperation is measured in months or years, if at all. Residual nerve dysfunction in the form of muscle weakness or painful neuropathy is common. The patient's ultimate degree of recovery is difficult to predict. The occurrence of bowel perforation and rupture of a mesenteric microaneurysm are potentially catastrophic events in PAN, requiring emergency surgical intervention and associated with high mortality rates. Patients treated with levels of immunosuppression required for PAN are at substantial risk for opportunistic infection and other complications of treatment.

Appearance of symptoms suggesting mononeuritis multiplex may signal the need for cyclophosphamide and thereby trigger a prompt consultation with the neurologist (electrophysiologist) for diagnostic confirmation and with the rheumatologist for treatment.

Postprandial abdominal pain may be a symptom of intestinal angina. A period of bowel rest, hospitalization for the exclusion of other causes, surgical consultation, and consideration of intensified immunosuppression may be necessary.

Fever in a patient receiving or recently treated with high doses of glucocorticoids or cyclophosphamide or both is considered to be an infection until proven otherwise.

In contrast to the ANCA-associated vasculitides, which are more prone to recurrences, PAN is generally considered to be a “one-shot” disease. For patients with HBV-associated PAN, seroconversion to anti-HBe antigen antibody usually signals the end of the active phase of vasculitis. Among those with idiopathic PAN, disease recurrences are observed in perhaps 10% of cases.