Granulomatosis with Polyangiitis

An antineutrophil cytoplasmic antibody associated small to medium vessel vasculitis characterised by necrotising granulomatous inflammation predominantly affecting the upper and lower respiratory tract and the kidneys, historically termed Wegener granulomatosis, with a course ranging from limited disease confined to the airways to fulminant multisystem disease with rapidly progressive glomerulonephritis and life threatening pulmonary haemorrhage.

Pathophysiology

Antineutrophil cytoplasmic antibodies, predominantly directed against proteinase 3, activate primed neutrophils, causing degranulation and endothelial injury with formation of necrotising granulomatous lesions and pauci immune (minimal immune complex deposition) vasculitis affecting small and medium vessels. The granulomatous component is a distinguishing pathological feature from the other antineutrophil cytoplasmic antibody associated vasculitides.

Upper airway involvement is frequently the earliest and most characteristic manifestation, including persistent rhinorrhoea, sinusitis, nasal crusting and epistaxis, with progression in some patients to nasal septal perforation and the characteristic saddle nose deformity from cartilage destruction. Otitis media, subglottic stenosis causing stridor and hoarseness, and oral ulceration also occur.

Pulmonary involvement includes cough, haemoptysis, pleuritic chest pain and, on imaging, nodules that may cavitate, infiltrates or, in severe disease, diffuse alveolar haemorrhage presenting with acute breathlessness, falling haemoglobin and haemoptysis, a life threatening emergency.

Renal involvement with rapidly progressive glomerulonephritis is a major cause of morbidity and mortality if untreated, often clinically silent in early stages, underscoring the importance of active screening with urinalysis and renal function testing in every patient.

Cutaneous manifestations include palpable purpura, nodules and ulceration, and ocular involvement ranges from conjunctivitis and episcleritis to orbital pseudotumour with proptosis.

Peripheral neuropathy, particularly mononeuritis multiplex, constitutional symptoms and, less commonly, cardiac involvement complete the multisystem picture.

Antineutrophil cytoplasmic antibody testing is positive in the great majority, with a cytoplasmic staining pattern and proteinase 3 specificity typical, though a proportion of limited disease, particularly confined to the upper airway, may be antineutrophil cytoplasmic antibody negative.

Tissue biopsy (nasal mucosa, lung or kidney depending on the accessible site of active disease) showing necrotising granulomatous inflammation and pauci immune vasculitis provides definitive confirmation and is particularly valuable where serology is negative or the clinical picture is atypical.

Urinalysis with microscopy for red cell casts and dysmorphic red cells, and renal function testing, are essential in every patient given the frequently silent onset of glomerulonephritis.

Chest imaging (radiograph and, where indicated, computed tomography) assesses for nodules, cavitation, infiltrates and alveolar haemorrhage, and sinus imaging characterises upper airway involvement.

Full blood count, inflammatory markers and assessment of overall organ involvement complete the diagnostic workup, with disease extent and severity guiding treatment intensity.

Induction of remission for severe, organ or life threatening disease uses high dose corticosteroids combined with either rituximab or cyclophosphamide, with rituximab increasingly preferred given comparable efficacy and a more favourable long term toxicity profile, particularly regarding fertility and malignancy risk.

Plasma exchange is reserved for the most severe presentations, particularly diffuse alveolar haemorrhage or rapidly progressive glomerulonephritis with severe renal impairment.

Limited disease without organ threatening features may be managed with methotrexate and corticosteroids rather than cyclophosphamide or rituximab.

Maintenance therapy following successful induction uses rituximab, azathioprine or methotrexate, continued for at least eighteen to twenty four months given the substantial relapse risk characteristic of this condition.

Long term monitoring for relapse using clinical assessment, inflammatory markers, antineutrophil cytoplasmic antibody titre and urinalysis, alongside surveillance for treatment related complications including infection, infertility and malignancy, underpins ongoing management of this chronic relapsing disease.

Subglottic stenosis, where present, may require dilation or local corticosteroid injection independent of systemic immunosuppressive intensity, given its tendency to persist as a fibrotic complication even with disease remission elsewhere.