Polyarteritis nodosa (PAN) is a systemic necrotizing arteritis involving predominately medium-size vessels, although sometimes affecting smaller vessels. Vasculitic lesions characteristically occur at the bifurcations or branches of vessels and are often segmental. Almost any organ can be involved, but frequently the skin, peripheral nerves, kidneys, gastrointestinal (GI) tract, and joints are the principal organs affected [7].

Clinical manifestations vary from mild localized disease to multisystem organ failure. Patients generally complain of malaise, weight loss, fevers, abdominal or lower-extremity pain, myalgias, or arthralgias. Clinical parameters include hypertension and azotemia with proteinuria but rarely glomerulonephritis. Peripheral neuropathy occurs in up to 60% of cases, usually involving a mixed sensorimotor and mononeuritis multiplex [8]. Sudden-onset paresthesias associated with motor deficits are common manifestations. CNS involvement, including seizures, focal events, and altered mental status, are less common [9]. Musculoskeletal symptoms including arthralgias (50%), and less frequently, arthritis can occur [7]. Vasculitis of skeletal muscles may cause severe myalgias, and muscle biopsy can be useful diagnostically [10]. Abdominal pain may have a variety of causes, including intestinal angina, mesenteric thrombosis, and localized gallbladder or liver disease. Acute GI bleeding, perforation, and infarction are rare but are associated with a high mortality if the diagnosis is not established promptly [11]. Cardiac involvement, observed in nearly 60% of autopsy series, is often clinically silent and includes congestive heart failure, pericarditis, myocardial infarctions, and conduction abnormalities [12,13]. Cutaneous lesions include nonspecific palpable purpura, livedo reticularis, tender nodular lesions, digital infarcts, and ulcers [14]. Arteritis of the eye, testes, pancreas, ovaries, breasts, and involvement of the temporal arteries may develop rarely.

The pathogenesis of polyarteritis is unknown. Hepatitis B surface antigen has been found in a minority of patients with PAN. The presence of circulating immune complexes of hepatitis B surface antigen and deposition of surface antigen and immunoglobulin in vessel walls has suggested that immune mechanisms may play a role in some forms of polyarteritis [15,16]. Hepatitis C has rarely been associated with PAN [17]. Pathologically, fibrinoid necrosis and pleomorphic cellular infiltration, predominantly with lymphocytes, macrophages, and varying degrees of polymorphonuclear leukocytes involve the entire wall of small and medium muscular arteries. Thromboses and aneurysms can be found in lesions [18].

The diagnosis of PAN focuses on the most frequent areas of involvement, namely, nerve, skin, and GI systems. Laboratory parameters usually include elevated sedimentation rate, elevated C-reactive protein (CRP), and thrombocytosis. Antineutrophil cytoplasmic antibody (ANCA), antinuclear antibody (ANA), and rheumatoid factor are not typically present in PAN. Mesenteric angiography often shows evidence of aneurysms including the renal, hepatic, and mesenteric arteries, and areas of arterial stenosis alternating with normal or dilated vessels [18]. Sural nerve biopsies are easily accessible sources of nerve tissue when a mononeuritis is present, although the location of biopsy may be guided by electromyography.

Although there is no consensus for treatment of PAN, administration of corticosteroids at 1 mg per kg per day orally is indicated in nearly all cases. In fulminant disease, daily intravenous (IV) methylprednisolone, 1 g per day for 3 days, is reasonable followed by daily oral or intravenous corticosteroids. In the presence of GI involvement, intravenous dosing may need to be continued especially in life-threatening cases. The use of a second drug is guided by the severity of presentation and if there is failure to respond to steroids alone. A severity of illness scoring system (the Five Factor Score) has been developed based on five different parameters, namely, proteinuria more than 1 g per day, azotemia, GI involvement, cardiomyopathy, and CNS involvement. The presence of two or more of these factors portends a mortality of nearly 50% [7]. A review of long-term follow-up of these patients suggests that those with more severe illness as defined with one of the above factors have a higher survival rate when treated with cyclophosphamide [19]. Cyclophosphamide may be given orally, usually 2 mg per kg per day, though adjustment should be made for renal failure (Table 196.2). If the oral route is not feasible, then intravenous dosing of 500 to 1,000 mg per m² monthly is
appropriate (see Table 196.3). Plasmapheresis (PE) in combination with antiviral therapy is indicated in hepatitis B-associated PAN, though PE does not improve outcome in non–hepatitis B virus PAN [29,30].

A variety of drugs, viral infections, connective tissue diseases such as rheumatoid arthritis, and underlying malignancies may cause a necrotizing angiitis that may be indistinguishable from polyarteritis [31,32,33,34,35,36].

Microscopic polyangiitis is a necrotizing vasculitis that involves small vessels, including arterioles, capillaries, and venules. As noted previously, cases of microscopic polyangiitis previously classified as part of the PAN classification were distinguished mainly by the presence of segmental necrotizing glomerulonephritis. Clinical presentations may involve concomitant capillaritis with or without alveolar hemorrhage and rapidly progressive glomerulonephritis, the so-called pulmonary renal syndrome, although more indolent and slower presentations have been described. Glomerulonephritis occurs in nearly all cases, and pulmonary involvement ranging from cough and dyspnea to frank hemoptysis occurs in up to 30% of cases. Neuropathy and cutaneous vasculitis occur in up to 50% of cases [14,35,36].

Pathologically, renal lesions show segmental necrosis, minimal immune or pauci-immune deposition, and crescent formation. In the lung, there is edema of the alveolar wall, neutrophilic invasion, type II epithelial cell hyperplasia, and a paucity of immune deposits. These findings may not be histologically different from those found in patients with Wegener’s granulomatosis, and clinically the two entities may be difficult to distinguish. ANCA is found in about 75% of cases, mostly specific for myeloperoxidase (MPO), though occasionally ANCA proteinase 3 (PR3) has been described [36].

Diagnosis is typically made with a biopsy of lung, kidney, skin, or nerve in conjunction with a positive ANCA result. Treatment is similar as described for Wegener’s granulomatosis, with corticosteroids at 1 mg per kg per day oral or intravenous methylprednisolone, and cyclophosphamide orally or intravenously [36]. Recent studies comparing rituximab with cyclophosphamide therapy for initial remission induction suggest similar efficacy and toxicities, while rituximab maybe more effective for relapsing disease [27,28]. PE may have a role in the treatment of severe renal disease with evidence suggesting a lower reduced frequency of dialysis, but no mortality benefit [21]. There are no prospective data available regarding the efficacy of PE in diffuse alveolar hemorrhage (DAH), although retrospective data suggest a benefit [37]. In the face of DAH and severe respiratory failure in the setting of a systemic vasculitis, PE in addition to corticosteroids and cyclophosphamide is reasonable as long as every effort has been made to exclude infection. In relapsing disease, intravenous immunoglobulin may be of benefit [20].

Churg-Strauss syndrome (CSS) is characterized by the presence of eosinophilic infiltrates and granulomas in the respiratory tract and necrotizing vasculitis in the setting of asthma and peripheral eosinophilia. Typically, patients have a preceding history of asthma and allergic rhinitis and then develop constitutional symptoms of fatigue and weight loss followed by systemic symptoms such as mononeuritis, cardiomyopathy, pulmonary infiltrates, or abdominal pain [14]. Pulmonary disease includes fleeting or diffuse infiltrates and nodular lesions,

and peripheral infiltrates occur in up to 75% of patients [38]. The diagnosis of eosinophilic pneumonia may be suggested in the context of peripheral infiltrates and peripheral eosinophilia. Rarely alveolar hemorrhage may occur. Peripheral neuropathy occurs in up to 75% of patients with CSS, whereas renal involvement is much less common than in microscopic polyangiitis and Wegener’s granulomatosis. Other sources of morbidity and mortality include GI involvement with bleeding and bowel perforation, cardiac involvement causing arrhythmias, myocarditis, pericarditis, and congestive heart failure [38,39]. The etiology of CSS is unknown. ANCA is positive in approximately 38% to 60% of cases, mostly myeloperoxidase [40,41,42]. As mentioned earlier, the presence of more than one of the five prognostic factors (i.e., proteinuria ≥ 1 g, azotemia, GI involvement, cardiomyopathy, and CNS involvement) has been associated with a higher mortality and should guide the choice of treatment, suggesting corticosteroids as mentioned above for limited disease and addition of cyclophosphamide in the setting of severe disease [19].

Cryoglobulins are immunoglobulins that precipitate below 37°C. There are three types: Type I, seen in myeloproliferative disorders; type II, or mixed essential cryoglobulins; and type III, mixed polyclonal. Types II and III are most closely associated with hepatitis C infection. Typical involvement includes cutaneous vasculitis, arthritis, and peripheral neuropathy. Abnormal liver enzymes suggest hepatitis C infection; complement levels, especially C4, are decreased [43,44]. Infrequently, cryoglobulinemic vasculitis may be life threatening with severe renal, GI, and pulmonary involvement including alveolar hemorrhage [45,46]. Therapy in severe cases consists of corticosteroids and cyclophosphamide with careful attention to the potential risk of increased hepatitis C replication. In severe cases involving progressive glomerulonephritis, PE or cryofiltration may be of additional benefit [47,48,49]. The use of rituximab combined with pegylated interferon and ribavirin may be useful in refractory cases [50].