Granulomatosis With Polyangiitis

Question 1

Granulomatosis with polyangiitis

Answer 1

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).

Question 2

ANCA associated vasculitis

AAV is an umbrella term for three conditions:

Answer 2

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.

Question 3

Inciting events - AAV

Answer 3

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

Question 4

The presence of ANCA is the hallmark of AAV.

Answer 4

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.

Question 5

ANCA antigen targets

The two ANCA antigen targets associated with AAV are:

Answer 5

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

Question 6

GPA is characterised by a necrotising vasculitis with …

Answer 6

GPA is characterised by a necrotising vasculitis with granulomas.

Question 7

GPA is a multi-system disorder that presents with a wide range of clinical features.
Constitutional symptoms

Answer 7

Fever
Lethargy
Weight loss
Anorexia

Question 8

Ear, nose and throat

ENT involvement is extremely common in GPA, seen in around 90%

Answer 8

Nasal crusting
Rhinosinusitis
Earache and otitis media
Nasal discharge (may be bloody)
Polychondritis (inflammation of cartilage)
Sensorineural hearing loss

Question 9

GPA - Pulmonary features

Answer 9

Hoarseness
Cough
Dyspnea (pulmonary consolidation or effusions may be seen)
Stridor (may be suggestive of tracheal or subglottic stenosis)
Wheezing
Haemoptysis
Pleuritic pain

Question 10

Renal features - GPA

Answer 10

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)

Question 11

GPA - Approximately 50% develop a vasculitic rash, which is characterised by palpable …, particularly on the lower limbs.

Answer 11

Approximately 50% develop a vasculitic rash, which is characterised by palpable purpura, particularly on the lower limbs.

Question 12

Ophthalmic GPA

Answer 12

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

Question 13

Neurological

Neurological involvement is less common in GPA, seen in only 15% of patients compared to 70% in MPA.

Answer 13

Mononeuritis multiplex
Sensory neuropathy
Cranial nerve abnormalities

Question 14

The key investigations to confirm the diagnosis of suspected AAV are biopsy and ANCA serology

Answer 14

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

Question 15

Bedside

GPA tests

Answer 15

Urinalysis: assessment of blood and protein

Red cell casts: seen under microscopy. Suggestive of glomerulonephritis

Question 16

Vasculitis screen

Answer 16

ANCA
ANA
Complement
Anti-GBM
Hepatitis serology (B, C)
HIV
\+/- Cryoglobulins

Question 17

The treatment of GPA involves immunosuppression to achieve long-term disease remission.

Answer 17

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

Question 18

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:

Answer 18

Active glomerulonephritis
Pulmonary haemorrhage
Cerebral vasculitis
Progressive peripheral or cranial neuropathy
Orbital pseudotumor
Gastrointestinal bleeding due to vasculitis
Pericarditis / myocarditis

Question 19

Induce remission

GPA

Answer 19

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.

Question 20

Maintain remission in GPA

Answer 20

Multiple agents may be used for maintenance therapy including rituximab, azathioprine, methotrexate or mycophenolate. These are typically used as monotherapy.

Question 21

GPA is a multi-systemic disease that can be life-threatening and lead to organ failure.

Complications?

Answer 21

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)

Question 22

Over …% of patients with GPA should recover renal function and be dialysis independent.

Answer 22

Over 50% of patients with GPA should recover renal function and be dialysis independent.

Question 23

GPA prognosis

Answer 23

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.