Granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis.

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. The change in terminology of the conditions reflects the movement away from honorific eponyms linked to Nazi Germany.

AAV usually develops from an initiating event.

AAV is thought to develop due to an ‘initiating’ or ‘inciting’ event in a genetically predisposed individual. 

Genetic risk

Several genetic elements have been identified as possible risk factors for development of AAV. These include variants in Proteinase 3 (PR3), SERPINA1 gene (affected in alpha-1-antitrypsin deficiency), and certain human leucocyte antigens (e.g. HLA-DP, HLA-DRB1-15) that are needed for antigen processing.

Inciting events

• 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

These ANCA-antigen targets help to define the likely AAV:

• MPA: almost 90% of patients are ANCA positive with the vast majority MPO-ANCA (p-ANCA)
• GPA: approximately 90% ANCA positive. Of these, 80-90% have PR3-ANCA (c-ANCA). A small majority have MPO-ANCA (p-ANCA).
• EGPA: approximately 50% are ANCA positive. MPO-ANCA (p-ANCA) is more common, but PR3-ANCA (c-ANCA) can also be seen. The frequencies vary depending on study.

Of note, the ANCA-antigen complex present (i.e. MPO-ANCA or PR3-ANCA) may be more clinically relevant in determining the clinical phenotype (signs and symptoms) than a formal distinction between AAV subtypes.

GPA is characterised by a necrotising vasculitis with granulomas.

GPA is characterise by the presence of inflammation in small vessels with pauci-immune (minimal evidence of hypersensitivity under the microscope), necrotising vasculitis with evidence of granulomas. The absence of granulomas would be supportive of MPA.

This vasculitis may affect multiple organ systems including ears, nose and throat, lungs, kidneys, skin, eyes and nervous system. Both MPA and GPA are closely related conditions based on clinical presentations and organs involved. 

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

Constitutional symptoms

These may form prodromal symptoms over weeks to months before the development of specific organ involvement. 

• 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

Pulmonary

Wide range of symptoms may be present in both upper and lower airways

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

Renal

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)

Skin

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

Ophthalmic

• 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

Other

• Gastrointestinal tract: bleeding
• Cardiovascular system: pericarditis or myocarditis
• Bones and joints: arthralgia

The optimum way of classifying small vessel vasculitides is still to be established.

Over the years, there have been many attempts to define and classify AAV and to differentiate between MPA, GPA and EGPA.

The original American College of Rheumatology (ACR) criteria was used to define GPA in 1990. The Chapel Hill Consensus Conference criteria (CHCC) was subsequently used to define each condition. Based on CHCC, GPA is defined as:

“Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (eg, capillaries, venules, arterioles, arteries and veins). Necrotizing glomerulonephritis is common.”

Therefore, the key differentiation between GPA and MPA is the presence of granulomatous inflammation on biopsy.

The European Medicines Agency algorithm also came up with a series of steps to enable diagnosis of EGPA or GPA, of which MPA was a diagnosis of exclusion. There is now suggestion that these small vessel vasculitides should be defined based on ANCA serology (e.g. MPO-ANCA vasculitis and PR3-ANCA vasculitis).

Diagnosis if based on presence of typical clinical features, ANCA positivity and characteristic biopsy findings.

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

Other investigations are aimed at determining organ involvement.

Bedside

• Urinalysis: assessment of blood and protein
• Red cell casts: seen under microscopy. Suggestive of glomerulonephritis

Routine bloods

• FBC
• ESR/CRP
• U&E
• LFT
• Bone profile
• Coagulation

Vasculitis screen

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

Imaging

• Chest x-ray: look for infiltrates, consolidation, effusions
• CT chest: better at assessing degree of pulmonary involvement compared to chest x-ray
• CT sinuses: may be used to look for sinus involvement

Special

• Biopsy of affected tissue (usually nose, skin or kidneys)
• Nasoendoscopy
• Bronchoscopy +/- bronchoalveolar lavage

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

General principles

As with many immune-mediated disorders, the aim of treatment is to induce and then maintain remission. This is achieved with the use of immunosuppressive agents.

• 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

Choice of therapy

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

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

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

Response to treatment

Patients need to be monitored to ensure they have achieved remission and to monitor for signs of relapse. Furthermore, immunosuppressive agents will require monitoring according to local protocols.

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

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

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.