ISCHEMIC STROKE / ETIOPATOGENESIS / VASCULITIDES

Polyarteritis nodosa (PAN)

David Goldemund M.D.
Updated on 05/02/2024, published on 24/05/2023

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
skin necrosis
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]

Biopsy

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

Management

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

Corticosteroids

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) or 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.)

Prognosis

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