Polyarteritis Nodosa

Definition and EtiologyTop

Polyarteritis nodosa (PAN) is a necrotizing antineutrophil cytoplasmic antibody (ANCA)-negative vasculitis involving medium and small arteries. It can be distinguished from other vasculitides (mainly from microscopic polyangiitis) by the absence of pulmonary involvement, features of glomerulonephritis, or involvement of arterioles, capillaries, or venules. PAN is strongly associated with hepatitis B virus (HBV) infection (10%-80% of patients, according to various sources). A cutaneous form of PAN may also be associated with hepatitis C virus (HCV) infection. PAN usually affects patients aged 40 to 60 years and is more frequent in men than in women.

Clinical Features and Natural HistoryTop

The onset of PAN is usually associated with general symptoms (fatigue, weight loss, fever), which may persist for several months. Other signs and symptoms include:

1) Cutaneous manifestations: Palpable purpura (most frequent), livedo reticularis, ulcerations (on fingers, ankles, the anterior aspect of lower legs), subcutaneous nodules <2 cm in diameter (usually on the anterior aspect of lower extremities and dorsal aspect of feet).

2) Nervous system manifestations: Most frequently mononeuritis multiplex (usually fibular nerve palsy [foot drop]), less often symmetric peripheral neuropathy.

3) Renal manifestations: Hypertension related to extraglomerular vessel inflammation, features of renal failure. Rarely, it can lead to renal infarction (acute severe lumbar pain). PAN does not manifest as glomerulonephritis.

4) Gastrointestinal manifestations: Abdominal pain, most frequently due to intestinal ischemia from visceral vessel involvement (intestinal necrosis and perforation is rare).

5) Musculoskeletal manifestations: Arthralgias, myalgias, and arthritis.

Untreated disease has a fatal course and leads to death within 1 to 2 years. The cutaneous form (without internal organ involvement) has a mild course and may resolve spontaneously but frequently recurs.

DiagnosisTop

Diagnosis is based on clinical manifestations and histologic findings from biopsies of the involved organs.

Diagnostic Tests

Laboratory test results often reveal elevations in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels as well as anemia (usually normocytic). In patients with renal involvement there can be elevated serum creatinine levels and rarely moderate proteinuria and microscopic hematuria. Angiography of the visceral arteries reveals dilations (microaneurysms) of medium arteries, for instance, kidney, liver, or intestinal arteries.

Differential Diagnosis

Other vasculitides, in particular granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). ANCA testing is useful to help in the differentiation, as ANCA is negative in PAN. In young patients consider deficiency of adenosine deaminase 2 (DADA2), a systemic inflammatory vasculopathy caused by mutations in the CERC1 gene that frequently, although not always, resembles PAN clinically.

TreatmentTop

In mild cases glucocorticoids alone may be tried for remission induction (1 mg/kg of prednisone per day, up to 80 mg, for several weeks) and maintenance, with dose tapering over 6 to 8 months. In other cases treatment with immunosuppressive therapy in addition to glucocorticoids is recommended.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to lack of randomized trials in patients with PAN, limited to retrospective data, but increased due to effect size. Leib ES, Restivo C, Paulus HE. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med. 1979 Dec;67(6):941-7. doi: 10.1016/0002-9343(79)90634-x. PMID: 42314. Remission induction is recommended with a combination of cyclophosphamide (intravenous or oral) and glucocorticoids.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Guillevin L, Jarrousse B, Lok C, et al. Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa. J Rheumatol. 1991 Apr;18(4):567-74. PubMed PMID: 1676753. Guillevin L, Lhote F, Cohen P, et al. Corticosteroids plus pulse cyclophosphamide and plasma exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome patients with factors predicting poor prognosis. A prospective, randomized trial in sixty-two patients. Arthritis Rheum. 1995 Nov;38(11):1638-45. PubMed PMID: 7488285. Dosing is the same as in granulomatosis with polyangiitis (see Granulomatosis With Polyangiitis).

Treatment with a nonglucocorticoid immunosuppressive agent is recommended for up to 18 months of total immunosuppressive therapy. Azathioprine or methotrexate is typically used, but mycophenolate can also be considered.

In PAN associated with HBV infection, initial high-dose glucocorticoids (without cyclophosphamide) may be effective with dose tapering over 2 weeks. At the same time, use of plasmapheresis followed by antiviral treatment may be of benefit.Evidence 3 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the presence of small observational studies with no patient-important outcomes, imprecision, indirectness, and risk of bias. Guillevin L, Mahr A, Callard P, et al; French Vasculitis Study Group. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005 Sep;84(5):313-22. PubMed PMID: 16148731. In the cutaneous form of PAN oral glucocorticoids alone may be helpful. Hypertension requires aggressive antihypertensive treatment. As patients may have impaired renal arterial perfusion, angiotensin-converting enzyme inhibitors should be used with caution.

PrognosisTop

In treated patients 5-year survival rates are ≤80%. In the cutaneous form of PAN the prognosis is good, with only rare progression to systemic disease.