ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATOGENESIS
Granulomatosis with polyangiitis (GPA)
formerly called Wegener´s granulomatosis
David Goldemund M.D.
Updated on 30/01/2024, published on 18/06/2023
- granulomatosis with polyangiitis (GPA) (formerly known as Wegener´s granulomatosis) is a necrotizing, granulomatous vasculitis primarily affecting small vessels in the upper respiratory tract, lungs, and kidneys; neurologic symptoms, including stroke, are relatively rare (< 7%)
- GPA belongs to a spectrum of disorders known as ANCA-associated vasculitides (AAV), which includes other conditions like microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA)
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 participated in experiments on concentration camp inmates. After this discovery, the current name, “granulomatosis with polyangiitis” was introduced
ANCAs (antineutrophil cytoplasmic antibodies)
ANCAs are autoantibodies directed against specific components of neutrophils. ANCAs are associated with several autoimmune diseases – ANCA-Associated Vasculitides (AAV)
- granulomatosis with polyangiitis (GPA) – proteinase 3 (PR3) ANCAs (C-ANCA); GPA is the most common (estimated incidence of 10-20 cases per million; peak incidence at 64-75 years of age)
- microscopic polyangiitis (MPA) – particularly myeloperoxidase (MPO) ANCAs (p-ANCA or MPO-ANCA); this condition predominantly affects small blood vessels
- eosinophilic granulomatosis with polyangiitis (EGPA) (AKA Churg-Strauss syndrome) – MPO ANCAs; a rare disease involving vasculitis with eosinophil infiltration
Etiopathogenesis
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 documented
- cytoplasmic ANCA (c-ANCA) reacts with the serine proteinase 3 and causes endothelial injury hrough the activation of neutrophils
- perinuclear-ANCA (p-ANCA or MPO-ANCA) is directed against myeloperoxidase; p-ANCA is typical for MPA
- ANCA antibodies are present in most patients with GPA (80-90% in active multisystemic disease); however, ANCA-negative cases have been documented
- other contributing factors include:
- 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 those seen 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 (pulmonary nodules, alveolar hemorrhage)
- kidneys (glomerulonephritis)
Early stage
- upper respiratory tract (90%)
- chronic rhinitis, sinusitis, mediootitis, mastoiditis
- epistaxis
- conductive hearing disorders
- possible 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 (~ 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 failure
- 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
- PNS (28%)
- 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, CICs (circulating immune complexes) + complement abnormalities
- CBC
- anemia (most commonly normocytic, normochromic; sometimes sideropenic due to recurrent 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
- 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
- small vessel disease (not specific for GPA)
- 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)
- cartilage involvement (+2)
- c-ANCA positivity (+5)
- pulmonary nodules, masses, 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 multidisciplinary team, including rheumatologists and nephrologists
- individualized treatment plan and regular follow-up for each patient are required
- treatment involves the use of immunosuppressive agents in different combinations
- cyclophosphamide (CYC), glucocorticoids (GC), rituximab (RTX), azathioprine (AZA), methotrexate (MTX), and plasma exchange (PE)
- other therapies: mycophenolate mofetil, cyclosporine, and intravenous immunoglobulin (IVIG)
- treatment decisions are based on the classification of patients according to the severity of their disease
- severe disease (a life-threatening disease or organ-threatening disease) warrants the use of cyclophosphamide
- severe disease (a life-threatening disease or organ-threatening disease) warrants the use of cyclophosphamide
- treatment is divided into 2 phases
- induction phase (aims to control active disease and reduce inflammation)
- 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
- cyclophosphamide (CYC) + glucocorticoids (GC)
- non-severe disease
- methotrexate + oral 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 prevent relapses
- the duration of maintenance therapy is usually 12-24 (36) months
- in patients at high risk of relapse, maintenance therapy may need to be continued indefinitely
- in patients at high risk of relapse, maintenance therapy may need to be continued indefinitely
- oral corticosteroids + methotrexate, azathioprine, or rituximab are used
- the choice of maintenance therapy is determined based on the patient’s individual response to treatment and their specific risk factors and comorbidities
| PREDNISONE start 1mg/kg/day, then taper |
| + |
| METHOTREXATE (MTX) 7.5-20 mg weekly PO, tapered over 12-18 months contraindicated in patients with ClCr < 50 mL/min |
AZATHIOPRINE (AZA) 2 mg/kg/day |
Prognosis
- morbidity and mortality may be caused by irreversible organ dysfunction or as 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 is associated with a worse prognosis and a higher mortality rate
- early initiation of therapy can significantly improve the prognosis; 80-90% of patients survive 5 years and are able to lead a relatively normal life
- untreated disease has a poor prognosis; up to 70% of patients die within 1 year
- severe renal involvement is associated with a worse prognosis and a higher mortality rate
- granulomatosis is prone to relapses; whoch can occur in up to 50% of patients, sometime several years after the initial diagnosis; relapses may be triggered by infections or reductions in corticosteroid doses
- major relapse: repeat pulse methylprednisone and cyclophosphamide
- minor relapse: increase maintenance dose
