• Polyarteritis nodosa (PAN) is a systemic panmural necrotizing vasculitis affecting medium-sized and small arteries
    • large arteries, capillaries, and venules are not affected  [Stone, 2002]
  • middle-aged and older men are most commonly affected  (prevalence ∼ 30 per 1 million)
  • PAN most commonly affects the skin and joints, kidneys (70-80%), CNS (2-10%), and PNS and GIT; the respiratory system usually remains unaffected
    • a limited form of the disease is called cutaneous polyarteritis nodosa (CPAN)  (Subbanna, 2014)
  • PAN is usually not associated with anti-neutrophil cytoplasmic antibodies (ANCA)

Pathophysiology, etiology

  • primary PAN is idiopathic
    • PAN may be associated with recessive loss-of-function mutations of the gene encoding adenosine deaminase 2; the condition is also called DADA2 (Deficiency of Adenosine DeAminase 2) (Elkan, 2014)
  • secondary PAN is less frequent and is associated with hepatitis B and C, malignancies (hairy cell leukemia), or other rheumatologic diseases (Sjögren´s syndrome, rheumatoid arthritis)
    • PAN cases have decreased with the use of the hepatitis B vaccine
  • medium and small arteries are affected
    • the process starts in the intima
    • necrotizing inflammation leads to the formation of stenoses (due to intimal proliferation) and microaneurysms (rosette appearance)
  • stenosis with reduced blood flow may lead to thrombosis
  • PAN affects multiple systems, with the kidney being the most commonly affected organ
  • based on histology, 3 stages are distinguished
    • acute (polymorphonuclear leukocytes)
    • subacute (mononuclear leukocytes)
    • chronic (fibrinoid necrosis, aneurysm formation, thrombosis)

Clinical presentation

Systemic symptoms (developing over weeks to months)

  • fever, night sweats
  • inappetence, weight loss
  • fatigue
  • muscle and joint pain

Neurologic symptoms

  • peripheral neuropathy (50-70%; frequent and early symptom)
    • mononeuritis multiplex and distal polyneuropathy
    • radial, ulnar, and peroneal nerves are the most commonly involved nerves
  • CNS involvement (2-10%; usually late in the course of the disease)
    • stroke/TIA, ICH or SAH
      • due to direct involvement of medium and small arteries or due to cardioembolism
    • headache, epileptic seizures
    • neuropsychiatric symptoms (encephalopathy, psychosis, depression)
    • myelopathy (mostly due to a hematoma from an aneurysm rupture)

Skin manifestations (40%)

  • erythematous nodules and petechiae
  • painful subcutaneous nodules
  • livedo reticularis  Livedo reticularis
  • skin necrosis Skin necroses in polyarteritis nodosa (PAN)
  • cutaneous manifestations may be limited, often visible on the lower extremities

GI involvement (50-70%)

  • abdominal pain
    • continuous or intermittent; often occurs after meals (intestinal angina due to mesenteric arteritis)
  • nausea, vomiting
  • intestinal infarction and perforation
  • GI bleeding (from ulcers)
    • perform a stool occult blood test despite a negative history of GI bleeding
  • pancreatitis, cholecystopathy, etc.

Renal involvement (80-90%)

  • proteinuria, erythrocyturia
  • renal failure
  • renal hypertension

Cardiovascular symptoms (70%)

  • chest pain, palpitations
  • myocarditis
  • MI
  • heart failure with dyspnea

PAN-associated strokes (PANAS)

  • strokes usually occur at a later stage of the disease (after 2-3 years); however, early lacunar syndromes have also been reported  [Reichart, 2000]
  • clinically, lacunar infarcts are predominant   [Reichart, 2000]
  • the etiology is complex
    • vasculitis affecting small and medium-sized arteries (aneurysms, stenoses, thrombi)
    • microangiopathy (with contribution of hypertension and corticotherapy)
    • cardioembolic strokes

Diagnostic evaluation

Blood tests

  • ↑ESR, ↑CRP
  • normochromic anemia, eosinophilia, thrombocytosis
  • autoantibodies
    • c-ANCA+ (30%)
    • antinuclear antibodies
    • complement levels (C3 and C4)
    • cryoglobulins
    • serum and urine immunofixation electrophoresis (SPEP and UPEP)
    • rheumatoid factor
    • immunodeficiency virus serology
  • hepatitis B and hepatitis C serologies
  • assessment of organ involvement
    • urea/creatinine
    • liver enzymes
    • creatinine kinase
  • CSF – normal or polynuclear pleocytosis

Vascular imaging

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Brain and spine MRI

  • MRI findings are not pathognomonic for PANAS; small ischemias predominate (although there may be territorial strokes of cardioembolic origin) [Provenzale, 1996]
  • leptomeningeal enhancement may be seen [Razek, 2014]


  • a biopsy of an affected organ should be performed to confirm the diagnosis (usually liver, kidney, or skin biopsy)
  • biopsy typically reveals necrotizing arteritis with a mixed inflammatory infiltrate

Differential diagnosis

  • DDx of PAN is broad and includes infectious processes and other vasculitides
  • infectious mimics (endocarditis, mycotic aneurysm with emboli, and HIV)
  • other vasculitides
    • granulomatosis with polyangiitis (GPA)
    • microscopic polyangiitis
    • eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
    • immunoglobulin A vasculitis (Henoch-Schönlein purpura)
    • cryoglobulinemic vasculitis
    • drug-induced vasculitis


Prompt treatment with corticosteroids and/or cyclophosphamide may result in remission


  • start with CORTICOSTEROIDS
    • remission is achieved in up to 50% of cases
    • use standard initial and maintenance doses
    • use corticosteroids alone in patients with mild symptoms (incl. cutaneous PAN), normal renal function, and no significant end-organ damage or ischemia
  • corticosteroids should be combined with other immunosuppressive agents (cyclophosphamide) for moderate to severe disease or in patients with resistance or intolerance to glucocorticoids

Immunosupressive drugs

  • immunosuppressive drugs are used in moderate to severe cases or in cases that do not respond to corticosteroids
  • imunsupressive drugs provide steroid-sparing effect
  • for long-term treatment, combine steroids with, e.g., AZATHIOPRINE
  • in moderate-sever PAN and in patients whose symptoms progress despite treatment, add CYCLOPHOSPHAMIDE
nonsevere PAN severe PAN
oral glucocorticoids (1mg/kg)
azathiprine / methotrexate
glucocorticoids IV bolus
(7 to 15 mg/kg to a maximum of 500-1000 mg administered intravenously once daily for three days)
oral cyclophosphamide
(2 mg/kg daily for 3-4 months until remission)
IV cyclophosphamide
( 15 mg/kg administered at weeks 0,2 and 4, and then every three weeks)
  after the course of cyclophosphamide switch to azathioprine / methotrexate for up to 18 months

Antivirals in hepatitis B or C

  • start antivirals for hepatitis-associated PAN
  • in severe hepatitis B-associated PAN, short-term treatment with glucocorticoids and plasma exchange may be used in addition to antiviral therapy
    • PE should be reserved for  severe and progressive disease for whom use of immunosuppressive therapy is contraindicated or ineffective

Symptomatic therapy

  • hypertension management
    • angiotensin-converting enzyme (ACE) inhibitors are preferred
    • alternative agent (calcium channel blocker) should be used if the glomerular filtration rate declines by more than 30% after initiation of therapy
  • surgery (bowel perforation, cholecystitis, aneurysms, etc.)
  • standard acute stroke treatment (incl. recanalization) and stroke prevention (antiplatelets, risk factors compensation, etc.)


  • untreated PAN has a poor prognosis
    • 10-20% of patients die within 5 years (of which 50% die within the first 3 months)
    • most common causes of death are renal failure and mesenteric, cardiac, or stroke)
  • immunosuppressive therapy leads to remission in ~ 90% of patients
  • after remission, the risk of relapse is ~ 60%/ 5 years
    • relapse rates are lower than for ANCA-associated vasculitides
    • patients with hepatitis B have a low risk of relapse and usually recover if seroconversion occurs (HBsAg is negative or undetectable)
  • the prognosis is best for patients with skin involvement; negative prognostic features are:
    • renal insufficiency
    • cardiomyopathy
    • GI involvement
    • CNS involvement

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Polyarteritis nodosa (PAN)
link: https://www.stroke-manual.com/polyarteritis-nodosa-pan/