ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATOGENESIS

Granulomatosis with polyangiitis (GPA)

formerly called Wegener´s granulomatosis

Created 18/06/2023, last revision 29/06/2023

granulomatosis with polyangiitis (GPA) (formerly Wegener´s granulomatosis) is a necrotizing, granulomatous vasculitis affecting most commonly small vessels in the upper respiratory tract, lungs, and kidneys; neurologic symptoms, incl. stroke, are rare (< 7%)
GPA belongs to a spectrum of disorders called ANCA-associated vasculitides (AAV)

Why Granulomatosis with polyangiitis (GPA) replaced the former name Wegener´s granulomatosis

The former name “Wegener´s granulomatosis” comes from the German pathologist Friedrich Wegener (1907-1990). Wegener was a member of the Nazi Party and it is believed that he took part in experiments on concentration camp inmates. After this discovery, the current name “granulomatosis with polyangiitis” was introduced.

ANCAs (antineutrophil cytoplasmic antibodies)

ANCAs are autoantibodies that target certain components of neutrophils. ANCAs are associated with several autoimmune diseases – ANCA Associated Vasculitides (AAV)

granulomatosis with polyangiitis (GPA) – proteinase 3 (PR3) ANCAs (C-ANCA); of the three AAVs, GPA is the most common (estimated incidence of 10-20 cases per one million; peak incidence at 64-75 years of age)
microscopic polyangiitis (MPA) – particularly myeloperoxidase (MPO) ANCAs (p-ANCA or MPO-ANCA); condition that affects small blood vessels
eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome) – MPO ANCAs; a rare disease involving blood vessel inflammation with eosinophil infiltration

Etiopathogenesis

the exact cause of GPA is unknown
a cellular component and a role of autoantibodies are presumed
- ANCA antibodies are present in most patients with GPA (80-90% in active multisystemic disease); however, ANCA-negative cases have been described
- cytoplasmic ANCA (c-ANCA) react with the serine proteinase 3 and cause endothelial injury by activating neutrophils,
- perinuclear-ANCA (p-ANCA or MPO-ANCA) are directed against myeloperoxidase; p-ANCA are typical for MPA
other contributing factors are:
- genetic factors
- infection (as an initiating factor for inflammation)
  - Staphylococcus aureus colonization
  - association with various viruses, including hepatitis C virus (HCV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and parvovirus
- some medications (phenytoin, antithyroid drugs, allopurinol)
the granulomas are not well-formed (unlike in sarcoidosis) and consist of giant cells surrounded by plasma cells, lymphocytes, and dendritic cells
- these cells can damage the submucosa and penetrate the surrounding tissue, cartilage, or bone, causing necrosis and permanent deformities
- granulomas may ultimately result in stenosis or arterial occlusion

Clinical presentation

PGA most commonly involves

upper respiratory tract (sinusitis, rhinitis, saddle nose deformity, otitis media, mastoiditis, hearing loss) + lower respiratory tract (lung nodules, alveolar hemorrhage)
kidneys (glomerulonephritis)

Early stage

upper respiratory tract (90%)
- chronic rhinitis, sinusitis, mediootitis, mastoiditis
- epistaxis
- conductive hearing disorders
- the potential destruction of nasal cartilage with septal perforation or development of the saddle nose
lower respiratory tract disorders:
- cough, chest pain, dyspnea, stridor, hemoptysis from necrotizing granulomas in the bronchi
- bilateral or unilateral pulmonary infiltrates and/or nodules
- subglottic, tracheal, or bronchial stenosis

Late stage

nonspecific symptoms of generalized systemic disease
- weight loss
- intermittent fever
- fatigue
- polyarthralgia/myalgia (approx. 70%)
skin involvement
- palpable purpura (commonly involving the lower extremities)
- skin ulceration, subcutaneous nodules (granulomas)
renal involvement ( in 80-90% of patients within 2 years of disease onset)
- rapidly progressive ANCA-positive glomerulonephritis leading to renal insufficiency
nervous system involvement
- PNS (28%)
  - mononeuritis multiplex
  - polyneuritis
  - cranial neuropathy
- CNS (2-9%)
  - small vessel vasculitis
  - encephalopathy with seizures
  - destruction of neurohypophysis (diabetes insipidus)
  - meningeal infiltration (hypertrophic pachymeningitis)
  - intracranial hemorrhage
involvement of other organs
- scleritis and conjunctivitis (necrotizing anterior scleritis may cause blindness!), ulcerative keratitis, uveitis
- orbital mass (pseudotumor) with diplopia, proptosis
- pleuritis
- pericarditis, valvular lesions, and coronary arteritis
- diarrhea, enterorrhagia, abdominal pain
- conductive and sensorineural hearing loss

Diagnostic evaluation

Laboratory tests

↑CRP, ESR, CIK + complement abnormalities
CBC
- anemia (most commonly normocytic, normochromic; sometimes sideropenic due to repeated GIT or alveolar hemorrhage)
- sometimes leukocytosis, thrombocythemia
rheumatoid factor (RF) positivity in some patients
renal function panel, electrolytes, urinalysis with detection of proteinuria (> 0,3 g/24h) and erythrocyturia
detection of c-ANCA and p-ANCA (MPO-ANCA)
- blood test (ELISA or immunofluorescence test)
- highly sensitive (50-60% positive in the early phase and up to 95% in the generalized phase)
- an important marker for diagnosing and monitoring autoimmune conditions, although their presence alone does not confirm the presence of disease ( ⇒ may be positive in polyarteritis nodosa, allergic granulomatosis and RA)
- levels correlate with disease activity – may help to assess response to therapy; titers decrease with successful treatment
- p-ANCA positive in < 10% of GPA cases
histology
- biopsy of the nasal mucosa (granulomas, necrosis) or in the upper respiratory tract
- renal biopsy
  - focal segmental necrotizing glomerulonephritis
  - granulomatous inflammation within the wall of an artery or in the perivascular space
- sural nerve biopsy
- skin biopsy

Neuroimaging

X-ray of the paranasal sinuses
X-ray or HRCT of the lungs
- butterfly or nodular opacities resolving after successful therapy
CT, MRI (no pathognomonic radiographic features )
- small vessel disease (not specific for GPA)
- inflammatory thickening of the dura mater
- granulomatous changes in the orbit and paranasal sinuses
angiography
ultrasound
endoscopy (incl. biopsy)

Diagnostic criteria

The ELK criteria (Ears, nose, throat or upper respiratory tract, Lung, and Kidney)

any typical manifestation involving the ELK + positive c-ANCA or typical histopathologic finding

The ACR 2022 criteria (GPA ≥5 points (Robson, 2022)

bloody nasal discharge, nasal crusting, or sino-nasal congestion (+3)
cartilaginous involvement (+2)
c-ANCA positivity (+5)
pulmonary nodules, mass, or cavitation on chest imaging (+2)
granuloma or giant cells on biopsy (+2)
conductive or sensorineural hearing loss (+1)
inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1)
pauci-immune glomerulonephritis (+1)
p-ANCA (antimyeloperoxidase ANCA) positivity (−1)
eosinophil count ≥1×10⁹ /L (−4)

Differential diagnosis

Other forms of ANCA-Associated Vasculitides (AAV)

microscopic polyangiitis (MPA)
Churg- Strauss syndrome
drug-induced ANCA-associated vasculitis

Other autoimmune disorders

systemic lupus erythematosus (SLE)
sarcoidosis
rheumatoid arthritis (RA)
amyloidosis

Infections

infective endocarditis
mycobacterial infections
disseminated fungal infections
disseminated gonococcal infection
streptococcal pneumonia with glomerulonephritis

Malignancies

lymphomatoid granulomatosis
lymphomas
carcinomatosis

Drug toxicity

intranasal cocaine
amphetamines
levamisole

Management

guided by a rheumatologist and nephrologist
treatment involves the use of immunosuppressive agents in a variety of combinations
- cyclophosphamide (CYC), glucocorticoids (GC), rituximab (RTX), azathioprine (AZA), methotrexate (MTX), and plasmapheresis (PE)
- other therapies: mycophenolate mofetil, cyclosporine, and intravenous immunoglobulin (IVIG)
treatment decisions are based on classifying patients according to the extent of their disease
- severe disease (a life-threatening disease or organ-threatening disease) warrants the use of cyclophosphamide
treatment is divided into 2 phases
- induction
- maintenance (to prevent relapse)

Induction of remission

severe disease
- cyclophosphamide (CYC) + glucocorticoids (GC)
  - start GC with IV pulse for 1-3 days before starting oral GC
non-severe disease
- methotrexate + glucocorticoids
- rituximab was not inferior to daily cyclophosphamide for induction of remission and may be superior in relapsing disease
duration: 3-6 months

Maintaining of remission

initiated after induction of remission is achieved (usually after 3-6 months) to avoid relapses
duration of maintenance therapy is usually 12-24 (36) months
- in patients at high risk of relapse, maintenance therapy is continued indefinitely
oral corticosteroids + methotrexate, azathioprine, or rituximab are used

Prognosis

morbidity and mortality may be caused by irreversible organ dysfunction or due to the consequences of intensive/prolonged use of glucocorticoids or immunosuppressive agents
prognosis depends on the degree of renal impairment and whether therapy is initiated early
- severe renal involvement has a worse prognosis and a higher rate of mortality
- with early therapy, the disease has a good prognosis; 80-90% of patients survive 5 years and can lead a relatively normal life
- untreated disease has a poor prognosis, and up to 70% of patients die within 1 year
granulomatosis is prone to relapses; they are frequent, occurring in up to 50% of patients, even several years after diagnosis, often in association with infection or reduced doses of corticosteroids
- major relapses: pulse methylprednisone and cyclophosphamide
- minor relapses: increased dose of maintenance therapy