POLYARTERITIS NODOSA

February 22, 2005

Megan Frost MSIII & Glen E. Hastings MD
Definition1: Polyarteritis nodosa (PAN) is an inflammatory necrotizing vasculitis that tends to
occur at bifurcations & branchings of small and medium sized muscular arteries but not venules.
Fibrinoid necrosis of the vascular wall results in occlusion & infarction, aneurismal dilatation or
fracture & hemorrhage. Involvement of the renal and visceral arteries is characteristic but
involvement of the arterioles of the renal glomeruli or the pulmonary arteries does not occur1.
PAN can affect almost any organ system in the body, but is classically seen in the skin, kidneys,
gastrointestinal tract, peripheral nerves, and joints. Glomerulonephritis and pulmonary capillaritis
are not associated with PAN, although hematurea resulting from renal infarction is common.
Differential Diagnosis1,2: Pan must be differentiated from 3 similar inflammatory vasculitities &
from Systemic Lupus Erythematosus (SLE), a systemic disease with similar protein clinical
manifestations which is also mediated by tissue binding antibodies & immune complex deposition
that differs from PAN, MPA, Wegeners granulomatosis & Churg-Straus Syndrome in that the
organ damage in SLE is not limited to the vasculature but also involves the dermal-epidermal
junction of the skin as well as solid organs.
Systemic Lupus Erythematosus (SLE)2 results from a generalized hyperactive T-cell &
B-lymphocyte response that results in sustained over production of pathogenic antibodies
& the subsequent deposition of immune complexes in various target organs, which elicits
an immune response much like that described below for the vasculidities. SLE is most
frequently seen in women because estrogens bind T & B lymphocytes & prolong the
immune response; of African or South-East-Asian ethnic origin because of increased
affinity of the FC receptor on Ig immunoglobulins for aberrant immune complexes.
Antinuclear antibody (ANA) positive in SLE. Anti-Smith antibody is specific for SLE but
present in only 25%. High titers of anti-dsDNA are specific to SLE & correlate with
disease activity. The presence of 4 of the findings in Table 1 identifies SLE 95% of the
time with a sensitivity of 75%:
Table 1: Diagnostic Criteria for SLE
Malar rash

Discoid rash

Microscopic Polyangiitis
Photosensitivity
Oral Ulcers
Arthritis
Sinusitis
(MPA) 1 is often confused with
Renal Disorder
Neurological Disorder
PAN. MPA is an inflammatory
Hematological Disorder
Immunological Disorder
necrotizing vasculitis that
Elevated ANA Titer
affects capillaries, arterioles &
venules but in contrast to PAN, its lesions exhibit few or no immune complexes & the
vasculitis of MPA does involve the glomeruli & the pulmonary capillaries thereby causing
glomerulonephritis & pulmonary infiltrates. MPA may also affect medium sized arteries.
pANCA is usually present.
Wegeners Granulomatosis1 is granulomatous vasculitis that involves small arteries &
veins of the upper & lower respiratory tract in 90-95% of cases & the glomeruli in 77%,
producing both intravascular & extravascular granulomata which present as pulmonary
infiltrates that sometimes cavitate & hemorrhage. Renal damage shows as progressive
crescentic glomerulonephritis. Necrotizing granulomatous lesions of the upper airways,
sinuses & nasopharynx occur. 90% of patients with Wegeners are cANCA positive.
Churg-Straus Syndrome1 is a necrotizing vasculitis of small & medium sized muscular
arteries that presents as asthma with frequent exacerbations, pulmonary infiltrates &
marked eosinophilia in 80% of cases. Mononeuritis multiplex occurs in 72%, allergic
rhinitis & sinusitis in 62%, skin lesions in 51% & heart disease in 14%.
All of the conditions described above are considered immune-complex diseases in which some
type of disordered immune response results in the deposition of immune complexes in the
vascular wall under conditions of antigen excess. Once deposited the immune complexes
activate compliment C5a attracting neutrophils that infiltrate the vessel wall or membrane
releasing metaloproteinases that damage the tissue. The site of predominant deposition of these

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complexes determines the clinical picture that is seen. If the patient presents skin rash suspect
SLE, with hypertension, neurological, GI & ischemic symptoms or signs, suspect PAN. If
glomerulonephritis or respiratory vasculitis are present suspect SLE or MPA. If pulmonary
cavitary lesions or nasopharyngeal lesions occur, suspect Wegeners. If asthma & eosinophilia
predominate think of Churg-Straus Syndrome.
Epidemiology3:
PAN is a rare condition in the US. Its incidence in the general population is 0.7 per 100,000 & the
prevalence is 6.3 per 100,000.3 PAN predominantly affects persons aged 40-60 with no racial or
ethnic predilection. The mean age of onset is 481. It is rare in children. A slightly higher
incidence is found in males. Male-to-female ratio is 1.6:11. The mortality rate can be as high as
20-30%, despite aggressive therapy.3
Pathophysiology1: PAN causes a segmental vasculitis and tends to involve the bifurcations of
small & medium sized arteries. The involvement of veins, venules, arterioles, and capillaries is
not usually seen in PAN, but is found in MPA . Acutely, polymorphonuclear leukocytes infiltrate
the layers of the vessel wall and the perivascular areas. This causes intimal proliferation which
then leads to degeneration of the vessel wall. Later mononuclear cells infiltrate the vessel and
then fibrinoid necrosis begins which causes occlusion of the vessel lumen, thrombosis, and
ischemia of the tissue supplied by the vessel. The lesions then heal with collagen deposition
which further exacerbates the occlusion. The lesions can produce an aneurysmal dilatation of the
artery or a hard nodule.
Immune Pathology: Studies in animal models dating back to the 1930s implicated the arterial
deposition of circulating immune complexes in the pathogenesis of PAN and other systemic
necrotizing vasculitides.4 Before widespread vaccination for hepatitis B, up to one third of all
cases of PAN were caused by HBV in about 10% of cases this is true today. In such cases viral
antigenantibody complexes are readily demonstrated in blood vessel walls in conjunction with
reductions in serum complement2,4. Such immune complexes activate compliment C5a which
attracts neutrophils into the vessel wall.
The immune complexes also elicit a marked increase in interferon- and interleukin (IL)-2 and a
moderate increase in TNF & IL-1b. IL-1 & TNF activate endothelial cells & neutrophils.
In vitro, ANCA (anti-cytoplasmic neutrophil antibodies) can activate neutrophils to adhere more to
endothelial cells and to stimulate neutrophils that have been primed with tumor necrosis factor
(TNF) to lyse cultured endothelial cells1. It is uncertain if this has any pathogenetic significance.
Nonetheless cANCA & pANCA are useful as diagnostic tests for cANCA is present in 90% of
Wegeners patients but rare in PAN or Churg-Straus Syndrome & unusual in MPA. pANCA
(Perinuclear ANCA; antimyeloperoxidase) is present in 75% of patients with MPA & 48% with
Churg-Straus Syndrome.
This presence of ANCAs in MPA, Churg-Straus & Wegeners suggests stronger relationship
between MPA Churg-Straus & Wegeners than with PAN & may also in some manner be related
to the propensity for glomerulonephritis and pulmonary capillaritis not shared by PAN.
Clinical Manifestations: PAN usually present with hypertension and symptoms or sign
suggesting ischemia but may also present with nonspecific complaints involving almost any
system of the body. Fever, weight loss and malaise are present in over one half of cases.1 Often
patients present with vague symptoms like those listed previously and headache, abdominal pain,
and myalgias. Any organ system, usually except the lungs (lungs are involved in MPA) and the
follicular arteries of the spleen, may be involved in PAN1:
Nervous system: Peripheral disease has been noted early in 50-70% of patients as a
direct result of occlusion to the vasa vasorum.5 The most common manifestation is
mononeuritis multiplex, usually manifested by rapid development of focal neuritic pain
and associated sensorimotor deficits.6 Cranial neuropathies (most often CN III and VIII)
may also be observed. It is typically an early manifestation of the disease and represents
a major clue to the diagnosis. Central disease occurs 2-3 years after onset of PAN and
usually manifests as diffuse encephalopathy6 and can includes motor deficits, strokes,

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brain hemorrhages, seizures and diffuse encephalopathy. In the brain, the most
consistent changes are found in the small meningeal arteries with less consistent
involvement of parenchymal vessels.5 Cerebral angiography most frequently shows
alternating segments of narrowing and widening of small- and medium-sized arteries or
occlusion of small arteries6.
Skin: Skin manifestations occur in approximately 40% of individuals with PAN1,3.
Vascular purpura typically is papulopetechial but sometimes may be bullous or vesicular.
Any infiltration of subcutaneous nodules should be biopsied immediately. Livedo
reticularis, mottled reticular pattern over the skin or portions of the extremities or torso is
common. Distal gangrene may be observed as the consequence of ischemia. Skin
involvement is usually in the legs and is very painful.
Musculoskeletal: One half of patients complain of arthralgia or myalgia3
Renal: The kidney is the most frequently affected site occurring in 63% of individuals with
PAN and/or MPA.3 In persons with classic PAN, vascular nephropathy is a common
manifestation. Renal failure can occur because of multiple infarcts. Rapidly progessing
glomerulonephritis is more characteristic of MPA. Ureteral involvement, which can be
unilateral or bilateral, occurs because of periureteral vasculitis and secondary fibrosis.
GI: GI involvement can be found in up to 50% of patients on autopsy3. Abdominal pain
can be the first symptom of GI vasculitis. Abdominal pain syndromes are the most
common, followed by nausea or vomiting, melena, hematochezia, non-bloody diarrhea,
constipation, and overt gastrointestinal bleeding that requires transfusions.7 Acute
cholecystitis, gallbladder infarction, perforation of the bowel and infarction of the bowel
also occur7. This can often be mistaken for inflammatory bowel disease.
Cardiac: There are usually no clinical symptoms from damage to the heart, but 26% of
individuals with PAN do have cardiac manifestations3. Cardiomegaly, systolic
dysfunction, tricuspid and mitral valve regurgitation, pericarditis, and coronary artery
involvement leading to ischemia and infarction can all be found in PAN3.
Ocular manifestations: Retinal vasculitis, retinal detachment, and cotton wool spots
(cytoid bodies) are signs of PAN.
Orchitis: Testicular biopsy reveals vasculitis in 25% of persons with PAN2.
Diagnosis: 1990 Criteria For the Classification of Polyarteritis Nodosa8
The presence of any 3 criteria in Table 2 yields a sensitivity of 82% and a specificicy of 87%.4:for
PAN: Table 2: Diagnostic Criteria for Polyarteritis Nodosa8
Weight loss 4 kg not due to dieting or other factors
Livedo reticularis (A mottled reticular pattern over the skin of the extremities or torso.)
Testicular pain or tenderness, not due to infection, trauma, or other obvious cause.
Myalgia, weakness or tenderness of leg muscles (excluding shoulder and hip girdle).
Mononeuropathy or polyneuropathies.
Diastolic BP >90 mm Hg.
BUN >40 mg/dl or creatinine >1.5 mg/dl, not due to dehydration or obstruction.
Hepatitis B virus antigen or antibody in the serum.
Arteriographic abnormalities showing aneurysms or occlusions of the visceral arteries, not due to
arteriosclerosis, fibromuscular dysplasia, or other non-inflammatory cause.
Biopsy of small or medium-sized artery showing granulocytes &/or mononuclear leukocytes infiltrating the
artery wall.

Laboratory1,2,3:

The anemia of chronic disease may be found in PAN.

WBCs are elevated with predominance of polys in 75% of PAN patients1.

Elevated ESR & Hypergammaglobulinemia but not increased ANA titer occurs in PAN.

30% of PAN patients have a positive test of Hep B surface antigen1.

p-ANCAs are usually found in MPA & Churg-Straus Syndrome & cANCA in Wegeners.
Neither are common in patients with PAN.

Polyarteritis Nodosa: Page 4 of 4.

Treatment: PAN related to hepatitis B infection is treated with a 2-week course of prednisone, 1
mg/kg/day, followed by antiviral therapy (interferon gamma-2b) plus ribavirin (Rebetron) for 1
year or until seroconversion, whichever occurs first. Plasma exchange, 60 mL/kg/session, 34
sessions/week for a total of 30 sessions is recommended after the steroid therapy6.
The principal treatment of idiopathic PAN is cyclophosphamide (Cytoxan). In most cases, monthly
intravenous pulses continued for 1 year (0.6 gm/m2, adjusted to achieve leukopenia but maintain
neutrophil counts above 1500/mm3) will suffice, and this mode of administration is associated with
significantly less infectious morbidity than daily oral cyclophosphamide, which should be reserved
for patients with refractory disease1,6 . A combination of oral prednisone, 1mg/kg/day and
cyclophosphamide, 2 mg/kg/day is a classic treatment used for PAN. This treatment regimen has
been reported to result in up to a 90% remission rate even following discontinuation of therapy.1
Prognosis: In untreated patients, the 5-year survival rate is 13%, with 40% to 50% of deaths
occurring in the first 3 months1,6. Death usually results from renal failure, GI complications, bowel
infarcts or perforations, or cardiovascular causes1. In treated patients, 5-year survival rate is
increased to over 40%1.
Bibliography:
1. Sneller MC, Langford CA, Fauci AS. The Vascular Syndromes, Chapter 306 pp 2002-14
in Harrisons Principles of Internal Medicine, 14th ed. Editors: Kasper, Braunwald, Fauci,
Hauser, Longo & Jameson. McGraw Hill: 2005.
2. Hahn BH. Systemic Lupus Erythematosus, Chapter 300 pp 1960-7 in Harrisons
Principles of Internal Medicine, 14th ed. Editors: Kasper, Braunwald, Fauci, Hauser,
Longo & Jameson. McGraw Hill: 2005.
3. Vellaichamy, M. Polyarteritis Nodosa. http://www.emedicine.com/ped/topic1844.htm.
January 8, 2004.
4. Johns Hopkins Vasculitis Center. Types of Vasculitis: Polyarteritis Nodosa.
http://vasculitis.med.jhu.edu/typesof/polyarteritis.html.
5. Paula De Carvalho Panzeri Carlotti A. Polyarteritis nodosa with central nervous system
involvement mimicking meningoencephalitis. Pediatr Crit Care Med 2004;5(3):286-8.
6. Nadeau SE. Neurologic manifestations of systemic vasculitis. Neurol Clin
2002;20(1):123-50.
7. Levine SM. Gastrointestinal involvement in polyarteritis nodosa (1986-2000):
presentation and outcomes in 24 patients. Am J Med 2002;112(5):386-91.
8. American College of Rheumatology. 1990 Criteria for Classification of Polyarteritis
Nodosa. http://www.rheumatology.org/publications/classifications/polyart.asp. 1990.