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).
AAV is an umbrella term for three conditions:
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.
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.
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.
The two ANCA antigen targets associated with AAV are:
These ANCA-antigen targets help to define the likely AAV:
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.
These may form prodromal symptoms over weeks to months before the development of specific organ involvement.
ENT involvement is extremely common in GPA, seen in around 90%
Wide range of symptoms may be present in both upper and lower airways
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.
Approximately 50% develop a vasculitic rash, which is characterised by palpable purpura, particularly on the lower limbs.
Neurological involvement is less common in GPA, seen in only 15% of patients compared to 70% in MPA.
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
Other investigations are aimed at determining organ involvement.
The treatment of GPA involves immunosuppression to achieve long-term disease remission.
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.
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:
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.
Multiple agents may be used for maintenance therapy including rituximab, azathioprine, methotrexate or mycophenolate. These are typically used as monotherapy.
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.
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.
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