Polyarteritis Nodosa

Synonyms:

Periarteritis nodosa, macroscopic polyarteritis nodosa,

polyarteritis

Etiology:

Unknown

Associations:

Hepatitis B and C infection; rarely HIV, hairy cell leukemia

Histology:

Medium-sized vessel arteritis, lesser involvement of smaller

vessels

Evaluation:

Serologic assessment for hepatitis B, C virus, creatinine,

erythrocyte sedimentation rate or C-reactive protein,

urinalysis; may include muscle, nerve biopsy, visceral

arteriography

Treatment:

Systemic steroids, plasma exchange, antiviral therapy in HBV

and HCV-associated cases, pulse cyclophosphamide

Prognosis:

Poor without treatment, 75% survival with

immunosuppressive treatment

Polyarteritis nodosa is a systemic vasculitis that involves predominantly medium-sized vessels. In 1852, Rokitansky described a man who presented with fever, abdominal pain, and bloody diarrhea, and shortly thereafter expired. Autopsy findings included small aneurysms of the arterial system, sparing the arteries of the brain and the large arteries. The aneurysms were identified as inflammatory and the disease was named periarteritis nodosa by Kussmaul and Maier in 1866. The term polyarteritis nodosa was introduced by Ferrari in 1903 to emphasize the transmural inflammation that characterizes this vasculitis (1). Because polyarteritis nodosa has overlapping features with other forms of systemic vasculitis, the nosology has been confusing. Interpretation of data from case series in the literature is difficult because many series are comprised of patients now regarded as having had different diseases. This summary of polyarteritis nodosa will describe the disease in its classic form and briefly discuss the other entities that may have a similar pattern of vasculitis.

The etiology of polyarteritis nodosa is unknown, but many cases occur in individuals infected with hepatitis B virus (HBV), and, occasionally, hepatitis C virus (2). Cases associated with hepatitis B are immune complex-mediated. HBV surface antigen may be found in active lesions, implicating a role in pathogenesis. HBV-associated cases usually manifest in the first six months of infection and may be the presenting sign of the infection (3). Benign cutaneous PAN is a subset of the disease in which disease appears to remain limited to the skin. This variant has been described in a small series of patients with hepatitis C infection. None of the patients were infected with HBV (4). In another larger series of 79, no patients had evidence of hepatitis B infection, and one patient had hepatitis C infection (5). PAN unassociated with viral hepatitis is probably not immune complex-mediated (3). Other viruses reported to be associated with polyarteritis nodosa include HIV (6) and herpes zoster (7). PAN has also been reported to be associated with hairy cell leukemia (8).

Polyarteritis nodosa may present without specific features early in its evolution. Typically, symptoms slowly arise over a period of months—fever, weight loss, malaise, arthralgias without arthritis, and myalgias. Cutaneous findings generally do not occur at the outset, but eventually develop in many patients with PAN. Cutaneous manifestations include livedo reticularis, which is reticulated violaceous erythema usually occurring on the lower extremities, due to cutaneous arterial insufficiency. This finding may be accompanied by stellate necrosis, nodules, ulcers, and acral ischemia, which may include necrosis (Figure 37.1). These changes are most frequently present on the lower extremities. Mononeuritis multiplex, caused by neural infarcts, occurs in the majority of patients with PAN and is directly caused by vasculitis. The long peripheral nerves are involved most prominently, especially the sural and superficial peroneal nerves. The neuritis usually

Figure 37.1. Multiple bilateral pretibial erythematous and slightly violaceous nodules.

starts asymmetrically, but as the vasculitis progresses, it may become more symmetric and mimic other peripheral neuropathies. Gastrointestinal manifestations due to arterial insufficiency include abdominal pain and bloody diarrhea. These symptoms indicate the presence of mesenteric arteritis and are associated with high mortality. Renal vasculitis is common in PAN, and results in wedge-shaped infarcts. Cardiac involvement occurs in the majority of cases, but frequently cannot be diagnosed clinically. Tachycardia occurs in a considerable number of patients. Coronary thrombosis is one of the more important complications of PAN. It may occur without any antecedent symptoms. Other organ systems that may be involved are the pancreas, brain, testes, ovaries, breast, and eyes. Lungs are typically spared.

Localized variants of polyarteritis are also known, including the cutaneous variant, benign cutaneous PAN. This localized form is frequently limited to a region or even a single extremity. These patients tend to present with painful nodules on the lower extremities, associated with edema and, occasionally, neuropathy. Ulceration occurs in approximately 50%, and may be associated with a more prolonged course (5). Other organ systems may have localized PAN, examples of which include appendix, bowel, breast, testis, gallbladder, and uterus (9). Clinical follow-up is warranted in cases that appear to be localized because some will eventually develop systemic disease.

The pathologic changes in polyarteritis nodosa involve medium-sized and small arteries, sometimes arterioles (Figure 37.2A and 37.2B). Aortic and other large vessel

Inflamed Septum
Figure 37.2. (A) Inflamed artery deep within subcutaneous interlobular septum. (B) Subcutaneous artery infiltrated by lymphocytes and neutrophils.

involvement is rare. Biopsy specimens of skin are frequently not specific, and thus biopsy specimens taken from sural nerve, kidney, testis, liver, skeletal muscle, or rectum are preferable. The arteritis of PAN is typically segmental. In acute lesions, there is a necrotizing vasculitis with fibrinoid necrosis. Transmural lymphocytes, neutrophils, eosinophils, and rarely granulomas are seen. Microaneurysms with nodule formation are typical, giving the disease its name. Acute lesions frequently coexist with proliferative fibrotic healing lesions (10).

The diagnosis of polyarteritis nodosa is frequently delayed because initial manifestations of the disease are generally nonspecific and may not display clinical findings that point to a vasculitis. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa include the following features:

1. Weight loss greater than or equal to 4 kg

2. Livedo reticularis

3. Testicular pain or tenderness

4. Mononeuropathy or polyneuropathy

5. Diastolic blood pressure >90 mm Hg

6. Elevated blood urea nitrogen or serum creatinine levels

7. Presence of hepatitis B reactants in the serum

8. Arteriographic abnormality

9. Presence of granulocyte or mixed leukocyte infiltrate in an arterial wall on biopsy

10. Myalgias

The presence of three or more yields a diagnostic sensitivity of 82% and a specificity of 87% (11). The Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis restricts the classification of polyarteritis nodosa to those cases with vasculitis limited to medium-sized and small arteries without involvement of smaller vessels, after exclusion of cryoglobulinemic vasculitis, Henoch-Schonlein purpura, and other forms of immune complex vasculitis (12). Depending on the classification scheme used, patients may be labeled as having microscopic poly-angiitis or polyarteritis nodosa.

The clinical presentation of systemic vasculitis is frequently nonspecific. Accurate classification requires a working knowledge of different forms of vasculitis, including clinical, laboratory, and pathological features. Polyarteritis nodosa frequently presents in the skin as a medium-vessel arteritis. The differential diagnosis includes other vasculitides that typically involve smaller vessels, but occasionally present in a manner virtually indistinguishable from polyarteritis nodosa. These entities include microscopic polyangiitis, Churg Strauss syndrome, Wegener's granulomatosis, rheumatoid vasculitis, systemic lupus erythematosus vasculitis, and mixed cryo-globulinemia. Of these, microscopic polyangiitis (MPA) and PAN have been grouped together most closely in the literature. Distinguishing clinical features of MPA not generally seen in PAN include palpable purpura, pulmonary involvement, and lack of gastrointestinal tract and neuropathy early in the disease (13). Evidence further supporting a distinction between these two entities is the presence of circulating IgG and IgM antibodies to endo-thelial cell antigens, which cannot be detected in PAN or other forms of small- and medium-sized vessel systemic vasculitis (14), and the presence of circulating anti-neutrophil cytoplasmic antibodies (ANCA) in MPA, but rarely in PAN (15). Differences between PAN and MPA are highlighted in Table 37.1.

Laboratory evaluation is a useful tool in narrowing the differential diagnosis in the vasculitides. Circulating anti-neutrophil cytoplasmic antibodies (ANCA) are an important part of the evaluation. These may occur in cytoplasmic, perinuclear, or atypical patterns. A screening ANCA is performed by indirect immunofluorescence, and if positive, confirmed with enzyme immunoassays for anti-proteinase 3 (PR3, cytoplasmic-ANCA) and anti-myeloperoxidase (MPO, perinuclear-ANCA). Negative studies for ANCA do not completely exclude any form of systemic vasculitis, but typical ANCA profiles can be helpful in the classification of vasculitis. These patterns are included in Table 37.1.

A histologically distinctive feature of several forms of systemic vasculitis is the so-called "Churg Strauss granuloma," also referred to as Winkelmann's granuloma, cutaneous necrotizing extravascular granuloma, or palisaded neutrophilic and granulomatous dermatitis. This lesion most commonly presents as persistent papules or plaques on extremities, sometimes ulcerating. Microscopically, a diffuse dermal infiltrate of some combination of neutro-phils, eosinophils, and granulomas is found, sometimes palisaded, and most commonly without frank vasculitis. The Churg Strauss granuloma may occur in many disorders, including Churg Strauss syndrome, Wegener's granulomatosis, systemic lupus erythematosus, and rheumatoid arthritis. It is not, however, a feature of PAN, MPA, or cryoglobulinemia. Table 37.1 summarizes some of the important clinical, laboratory, and pathological features of forms of vasculitis that may present in a manner similar to that of PAN.

In addition to systemic vasculitis, the clinical differential diagnosis for polyarteritis nodosa includes other arterial occlusive diseases such as cholesterol emboli, lupus anticoagulant, monoclonal cryoglobulinemia, septic emboli, coumadin necrosis, and calciphylaxis. These can sometimes be distinguished based on clinical setting, but histopathologic evaluation in each will provide ready distinction from PAN.

Laboratory findings in polyarteritis nodosa may include serologic evidence of hepatitis B or hepatitis C infection, elevated blood urea nitrogen and creatinine, increased erythrocyte sedimentation rate and C-reactive protein, leukocytosis, proteinuria, pyuria, and hematuria. Anti-

Table 37.1. Differential Diagnosis of Polyarteritis Nodosa and Vasculitides Affecting Medium-sized Arteries (2,3,16-18)

Clinical

Laboratory

Pathology

Polyarteritis nodosa

Microscopic polyangiitis

Churg-Strauss syndrome

Wegener's granulomatosis

Rheumatoid arthritis

Systemic lupus erythematosus

Mixed cryoglobulinemia

Neuropathy 60%, Renal 25%-50%, Skin 30%-40%, Pulmonary rare

Renal 90%, Skin 40%, Pulmonary 50%, Neurologic 30%, ENT 35% History of atopy, asthma; drug or allergy shot trigger; Skin 60%—nodules, PAN-like lesions, necrotizing vasculitis, Churg-Strauss granuloma; Pulmonary 70% , Neurologic 70%, ENT 50% Skin 40%, Renal 80%, Pulmonary 90%, ENT 90%

Deforming erosive arthritis

Arthritis, nephritis, malar erythema

Skin 90%, Renal 55%, Musculoskeletal 70%; may have connective tissue disease, malignancy, infection including HBV, HCV

Serologic evidence of HBV or HCV; p-ANCA rare; Decreased complement levels in hepatitis-associated cases; Aneurysms by arteriography MPO p-ANCA 60%, PR3 c-ANCA 30%, Normal complement

Peripheral eosinophilia

occasional p-ANCA, Normal complement; CXR—nodules, cavities, fixed infiltrates

ANCA negative RF+, decreased complement

ANCA negative ANA+, decreased complement

ANCA negative circulating cryoglobulins, polyclonal

Skin—medium-vessel involvement predominates, particularly in benign cutaneous form

Skin—panvasculitis most common

Skin—vasculitis of different-sized vessels, tissue-eosinophils, Churg-Strauss granuloma

Renal—arteritis with glomerular sparing

Renal—necrotizing glomerular lesions, crescents

Renal—segmental necrotizing glomerulonephritis

Skin—pandermal vasculitis, nonspecific chronic and granulomatous inflammation with diffuse pattern, Churg-Strauss granuloma Skin—pandermal vasculitis, Churg-Strauss granuloma Skin—may have pandermal vasculitis, Churg-Strauss granuloma

Skin—pandermal vasculitis

Renal—segmental necrotizing glomerulonephritis

Renal—spared

Renal—mesangial, diffuse or focal proliferative, or membranous glomerulonephritis Renal—

membranoproliferative glomerulonephritis

MPO = myeloperoxidase PR3 = proteinase 3

c-ANCA = cytoplasmic antineutrophil cytoplasmic antibody p-ANCA = perinuclear antineutrophil cytoplasmic antibody CXR = chest X-ray HBV = hepatitis B virus HCV = hepatitis C virus neutrophil cytoplasmic antibodies are found only rarely in PAN, but can be used to help differentiate PAN from other forms of systemic vasculitis.

Tissue evaluation to identify vasculitis is important in establishing a diagnosis of PAN. Site selection for biopsy should be based upon clinical evidence of involvement of that site, possibly including data from visceral arteriogra-phy and nerve conduction studies. Multiple biopsy speci mens from different sites in addition to angiography are more likely to detect evidence of PAN, but are associated with considerable morbidity. Using a decision analysis model, a more conservative approach of biopsy has been advocated. Electromyography and nerve conduction studies should be used to localize potential areas of muscle or nerve involvement. If no abnormal areas are identified or if biopsy specimens are not diagnostic, then visceral angiography should be performed. If arteriography is normal, then blind muscle biopsy is recommended (19, 20).

Treatment of polyarteritis nodosa includes systemic corticosteroids and immunosuppressives. A remission rate of approximately 50% is established with the use of prednisone, but significant liver dysfunction may be a consequence of treatment in patients with coexistent viral hepatitis (21). In HBV-associated cases, one treatment regimen includes a combination of prednisone and plasma exchange, with rapid tapering of prednisone to minimize liver damage, followed by initiation of antiviral therapy (22). Monthly pulse cyclophosphamide is useful in patients refractory to systemic steroids or those with severe systemic disease. A clinical trial of 6 versus 12 pulses of cyclophosphamide in a group of patients with poor prognostic factors with PAN and MPA found the group with 12 pulses to have similar survival to the group with 6, but with lower relapse rates (23).

With the exception of benign cutaneous polyarteritis nodosa, prognosis in polyarteritis nodosa is poor without treatment. However, survival may be 75%-80% with immunosuppressive therapy (2). Poor prognostic indicators are presence of nephropathy, age greater than 50 years, gastrointestinal tract involvement, cardiomyopathy, and central nervous system involvement (22).

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