Granulomatosis With Polyangiitis Flashcards
Granulomatosis with polyangiitis
Granulomatosis with polyangiitis (GPA) is one of the anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) that can present with rapidly progressive renal impairment and other systemic manifestations.
In the UK, the incidence is estimated at 10.2 cases per 1,000,000 people. It is slightly more common in men (1.5:1 male to female ratio) and typically presents in middle-age (35-55 years old).
ANCA associated vasculitis
AAV is an umbrella term for three conditions:
Microscopic polyangiitis (MPA)
Granulomatosis with polyangiitis (GPA): previously known as Wegener’s granulomatosis
Eosinophilic granulomatosis with polyangiitis (EGPA): previously known as Churg-Strauss syndrome
These conditions are all small vessel vasculitides that can affect arterioles, capillaries and venules. They are characterised by a positive ANCAs, which are involved in the pathogenesis of these conditions.
Inciting events - AAV
Infections (e.g. staphylococcal infection)
Medications (e.g. use of hydralazine, minocycline, propylthiouracil or allopurinol among others): these have been shown to cause ANCA seroconversion. In other words, development of ANCA autoantibodies.
Alpha-1-antitrypsin (AAT): theoretical link with GPA because AAT is the natural inhibitor of PR3.
Environmental exposures: possible link with cigarette smoke and silica dust
The presence of ANCA is the hallmark of AAV.
ANCA antibodies may be seen in a variety of immune-mediated conditions.
In AAV, they have characteristic staining patterns and associate with antigen targets myeloperoxidase and proteinase 3. In other immune-mediated disorders, the staining pattern is variable and the target antigen may be different including lactoferrin or elastase, among others.
ANCA antigen targets
The two ANCA antigen targets associated with AAV are:
Myeloperoxidase (MPO): typically associated with p-ANCA due to the perinuclear staining pattern on immunofluorescence Proteinase 3 (PR3): typically associated with c-ANCA due to the cytoplasmic staining pattern on immunofluorescence
GPA is characterised by a necrotising vasculitis with …
GPA is characterised by a necrotising vasculitis with granulomas.
GPA is a multi-system disorder that presents with a wide range of clinical features.
Constitutional symptoms
Fever
Lethargy
Weight loss
Anorexia
Ear, nose and throat
ENT involvement is extremely common in GPA, seen in around 90%
Nasal crusting Rhinosinusitis Earache and otitis media Nasal discharge (may be bloody) Polychondritis (inflammation of cartilage) Sensorineural hearing loss
GPA - Pulmonary features
Hoarseness
Cough
Dyspnea (pulmonary consolidation or effusions may be seen)
Stridor (may be suggestive of tracheal or subglottic stenosis)
Wheezing
Haemoptysis
Pleuritic pain
Renal features - GPA
Glomerulonephritis may develop in up to 85% within two years of presentations. Can cause a rapid deterioration in renal function leading to end-stage renal disease unless aggressive treatment with immunosuppression.
Asymptomatic haematuria Proteinuria (usually sub-nephrotic range) Nephritic syndrome (haematuria, proteinuria, acute kidney injury with oligo-/anuria and hypertension)
GPA - Approximately 50% develop a vasculitic rash, which is characterised by palpable …, particularly on the lower limbs.
Approximately 50% develop a vasculitic rash, which is characterised by palpable purpura, particularly on the lower limbs.
Ophthalmic GPA
Conjunctivitis: red, inflamed eye
Corneal ulceration: painful eye with visual disturbance
Episcleritis/scleritis: painful, irritated sclera
Optic neuropathy: visual impairment
Uveitis: features depend on anterior (painful, red eye), or posterior (floaters, visual changes) involvement
Neurological
Neurological involvement is less common in GPA, seen in only 15% of patients compared to 70% in MPA.
Mononeuritis multiplex
Sensory neuropathy
Cranial nerve abnormalities
The key investigations to confirm the diagnosis of suspected AAV are biopsy and ANCA serology
Biopsy: should be targeted to affected organ (e.g. nose, kidneys). Presence or absence of granulomatous inflammation helps differentiate MPA from GPA.
ANCA: urgent serology should be taken to see whether specificity towards PR3 or MPO is present
Bedside
GPA tests
Urinalysis: assessment of blood and protein
Red cell casts: seen under microscopy. Suggestive of glomerulonephritis
Vasculitis screen
ANCA ANA Complement Anti-GBM Hepatitis serology (B, C) HIV \+/- Cryoglobulins
The treatment of GPA involves immunosuppression to achieve long-term disease remission.
Induce remission: high-dose immunosuppression, often used in combination to control inflammation
Maintain remission: long-term use of oral immunosuppression to keep disease from relapsing
Deciding on therapy to induce and then maintain remission depends on whether there is life- or organ-threatening involvement. Life- or organ-threatening involvement is defined as:
Active glomerulonephritis
Pulmonary haemorrhage
Cerebral vasculitis
Progressive peripheral or cranial neuropathy
Orbital pseudotumor
Gastrointestinal bleeding due to vasculitis
Pericarditis / myocarditis
Induce remission
GPA
If there is life- or organ-threatening involvement, corticosteroids are used in combination with rituximab (monoclonal antibody against CD-20 found on B lymphocytes) or cyclophosphamide (alkylating chemotherapeutic agent used in systemic inflammatory conditions). A set protocol is used to determine dosing and frequency of administration.
Maintain remission in GPA
Multiple agents may be used for maintenance therapy including rituximab, azathioprine, methotrexate or mycophenolate. These are typically used as monotherapy.
GPA is a multi-systemic disease that can be life-threatening and lead to organ failure.
Complications?
End-stage renal disease Myocarditis and dangerous arrhythmias Pulmonary haemorrhage and chronic pulmonary disease Life-threatening GI bleeding Destructive sinuses and saddle nose deformities Deafness and blindness Permanent neurological injury Death (high mortality untreated)
Over …% of patients with GPA should recover renal function and be dialysis independent.
Over 50% of patients with GPA should recover renal function and be dialysis independent.
GPA prognosis
The rate of remission is highly variable in GPA and unfortunately the relapse rate is much higher compared to MPA. Approximately, 50% of patients have disease relapse with 5 years of diagnosis. Renal involvement is associated with a poorer prognosis.
