Granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) is an antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis, typically affecting small and medium sized blood vessels.

The other two ANCA-associated systemic vasculitides are eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) and microscopic polyangiitis.

GPA is a rare condition, with an annual incidence rate of 2.1-14.4 per million in Europe. Is thought to have an autoimmune aetiology, and causes blood vessel inflammation and necrosis which can be organ- and life- threatening as a result of stenosis, occlusion or aneurysm formation.

GPA can affect any organ, but classically involves a triad of upper- and lower- respiratory tract symptoms and glomerulonephritis.

The aetiology of granulomatosis with polyangiitis (GPA) is not fully understood.

GPA is thought to have an autoimmune aetiology given its association with other autoimmune conditions and responsiveness to immunosuppressive therapy.

Environmental, drug-related, infectious and genetic risk factors have also been suggested:

• Environmental
  • Exposure to silica dust inhalation, mercury and lead may be potential adjuvant triggers.

• Drugs
  • Propylthiouracil, hydralazine, sulfasalazine, phenytoin and allopurinol are examples of drugs which have been reported to cause ANCA seroconversion and potentially may be implicated.

• Infection
  • No causative infectious agent as been identified, however the nasal carriage of Staphylococcus aureus may be a contributing factor for disease relapse in patients with GPA.

• Genetic
  • A genome-wide associated study (GWAS) in Europe demonstrated associations between patients with proteinase-3 (PR3) ANCA and alpha-1-antitrypsin, PR3, and HLA-DP.

Granulomatosis with polyangiitis (GPA) is an immune-mediated disease which involves a complex immune response to endothelial damage and inflammation.

• GPA is an anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, along with microscopic polyangiitis (MP) and eosinophilic granulomatosis with polyangiitis (EGPA).

• ANCA is produced by B-cell activation in response to a trigger (likely autoimmune but environmental, infectious, and genetic triggers have also been suggested).

• ANCA is divided into cytoplasmic ANCA (cANCA) and perinuclear ANCA (pANCA).
  • C-ANCA and pANCA target certain granule proteins inside neutrophils: myeloperoxidase (MPO) and proteinase 3 (PR3), respectively.

• In patients with GPA, 80-90% are positive for cANCA (autoantibodies against PR3) whilst a minority are positive for pANCA.

Endothelial damage and inflammation

• It is thought that vascular injury causes recruitment of inflammatory cells to the site, and priming of neutrophils by cytokines causing translocation of MPO and PR3 to the neutrophil membrane.
• These exposed antigens form a complex with ANCA, causing vascular endothelial attachment, degranulation of the neutrophils and further inflammation of the blood vessels due to release of more cytokines.

Immune-mediated granulomatosis

• ANCA-associated vasculitides also cause T-helper cell mediated granulomatosis.
• Cytokines such as IL-12 and interferon gamma can activate T-helper 1 cells, which promote the cell mediated response by activating monocytes and macrophages.
• These activated monocytes and macrophages are recruited to the area of inflammation in the vessel and form granulomas.

Granulomatosis with polyangiitis (GPA) can affect people of any age or ethnicity but typically presents in Caucasian, middle-aged adults.

Patients commonly experience a prodrome of non-specific systemic inflammatory symptoms such as fever, malaise, arthralgias and weight loss. This often precedes the development of more organ-specific symptoms such as rhinosinusitis, cough, dyspnoea, hearing loss, purpura, urinary sediment or neurological dysfunction.

The classic triad of organ involvement includes:

1) Upper respiratory tract (90%)

• Sinusitis
• Nasal crusting, nasal discharge, epistaxis, nasal septal perforation, saddle nose deformity
• Subglottic stenosis
  • May present as hoarseness or stridor.
• Otitis media, hearing loss, ear pain.

2) Lower respiratory tract (78%)

• Dyspnoea
• Cough
• Pleuritis
• Haemoptysis
• Pulmonary infiltrates or nodules may be seen on imaging

3) Glomerulonephritis (75%)

• Microscopic haematuria
• Urinary sediment
• Typically causes a pauci-immune rapidly progressive glomerulonephritis (RPGN) leading to chronic kidney disease

Other common organ manifestations:

1) Ocular (60%)

• Scleritis/episcleritis
  • May present as eye pain, redness and tearing.
• Orbital mass (often as an extension of sinus disease)
  • May present as proptosis, diplopia or visual loss.

2) Cutaneous (50%)

• Skin lesions including leukocytoclastic angiitis (lower extremity purpura and ulceration), petechiae, nodules and vesicles

3) Neurological (15%)

• Mononeuritis multiplex
• Peripheral sensorimotor polyneuropathy
• Cranial neuropathy

GPA less commonly involves organ systems such as the gastrointestinal, cardiac, lower genitourinary and endocrine systems.

Due to the varied manifestations of granulomatosis with polyangiitis (GPA), the diagnosis can be complex and requires differentiation from other vasculitides, systemic infections, connective tissue diseases, granulomatous disorders, malignancies, and cocaine abuse.

Some of the important differentials to consider include:

Vasculitides

• Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome)
  • Similarities: non-specific prodrome of fever, malaise, weight loss and arthralgia; upper and lower respiratory tract and renal manifestations; antineutrophil cytoplasmic antibody (ANCA) positive (however more likely to be associated with pANCA in EGPA than in GPA).
  • Differences: asthma (90%), cardiac and gastrointestinal manifestations common; peripheral or tissue eosinophilia.
• Microscopic polyangiitis (MPA)
  • Similarities: non-specific prodromal symptoms; glomerulonephritis common, causing haematuria and proteinuria; ANCA positive.
  • Differences: usually an absence of upper respiratory tract (URT) involvement.

Systemic infections

• E.g. Sepsis, infective endocarditis (IE)
  • Similarities: constitutional symptoms of fever, malaise, arthralgia; multi-organ involvement; potential renal, respiratory and cutaneous manifestations; raised biochemical inflammatory markers.
  • Differences: positive cultures on specimens e.g. blood; possible valvular vegetations on echocardiogram in IE; possible benefit of procalcitonin in differentiating infection from non-infective inflammatory state.

Malignancy

• Pulmonary malignancy (primary or secondary)
  • Similarities: non-specific constitutional symptoms; respiratory tract symptoms such as cough, dyspnoea, haemoptysis; chest x-ray appearances may show nodules, cavities, pleural effusions etc.
  • Differences: absence of extrapulmonary features of systemic vasculitides; lung tissue biopsy positive for malignancy.
• Lymphoma
  • Similarities: non-specific constitutional symptoms; may be associated with cutaneous manifestations of vasculitis.
  • Differences: presence of lymphadenopathy or hepatosplenomegaly; tissue biopsy positive for lymphoma.

Granulomatosis with polyangiitis (GPA) can be a life- or organ- threatening disease; untreated GPA has a median survival of 5 months. This highlights the importance of aggressive management and compliance with therapy.

The management of GPA can broadly be divided into two components: induction of remission, and maintenance of remission.

Induction of remission

• Initial immunosuppression with a corticosteroid and a second immunosuppressive agent.
• The choice of therapy is determined by the severity of the disease and the threat to organs and life.

For life/organ-threatening disease:

• First-line therapy:
  • Methylprednisolone IV for 3-5 days (followed by oral prednisolone) and cyclophosphamide.
  • This therapy is typically given for 3-6 months to induce remission.
  • Therapy adjunct: plasmapheresis (in selected patients with severe organ involvement and non-responsive to initial induction therapy).
• Second-line therapy:
  • Methylprednisolone IV for 3-5 days (followed by oral prednisolone) and rituximab IV.

For non-life/organ- threatening disease:

• First-line therapy:
  • Methylprednisolone IV for 3-5 days (followed by oral prednisolone) and methotrexate (with folic acid).
• Second-line therapy:
  • Oral prednisolone and cyclophosphamide.
  • Oral prednisolone and rituximab.

Maintenance of remission

• First-line therapy:
  • Prednisolone and methotrexate (with folic acid).
  • Prednisolone and azathioprine.
• Duration of maintenance therapy is usually 2 years following remission, but can vary.

All therapy options should be complemented with osteoporosis prophylaxis and pneumocystis jiroveci prophylaxis.

GPA is considered a chronic disease and is predominantly managed in the outpatient setting. Patients attend regular reviews by a range of specialists such as rheumatologists, respiratory specialists, otolaryngologists, nephrologists, and dermatologists, and maintain regular contact in primary care with their GP. Admission to hospital and/or intensive care is sometimes required as a result of complications of GPA or its treatment, for example in cases of severe infection, sepsis, respiratory failure and renal failure.

Common complications relating to granulomatosis with polyangiitis (GPA) can broadly be divided into two categories:

Complications as a result of active GPA

• Chronic kidney disease
  • Dialysis or renal transplant may be indicated.
  • Common cause of death in patients with GPA.
• Saddle nose deformity
• Conductive or sensorineural deafness
• Venous thromboembolism

Treatment-related complications

• Infection
  • Highest cause of mortality in patients with GPA.
• Osteoporosis
• Bone marrow toxicity
• Diabetes mellitus
• Malignancy
  • Cyclophosphamide increases the risk of bladder cancer, skin cancer, leukaemia and lymphoma.
• Gonadal failure
  • Related to cyclophosphamide use.
• Pulmonary fibrosis

The mortality rate of granulomatosis with polyangiitis (GPA) has improved considerably since the introduction of immunosuppressive therapies.

• Untreated, GPA has a median survival of 5 months, with a 90% mortality rate within 2 years.

• Since the introduction of effective immunosuppressive therapies, the mortality rate has improved; treatment studies have published variable mortality data, ranging from 5 to 44% mortality at 4 to 10 years.

• 75% of those on immunosuppressive therapies achieve remission, however up to half of these patients relapse.

• Considerable morbidity and mortality associated with GPA remains, broadly categorised into:
  • Irreversible organ damage relating to active vasculitis before treatment effect or during relapse. E.g. Renal failure, respiratory failure.
  • Complications relating to immunosuppressive therapy. E.g. Infection, malignancy.