Granulomatosis with polyangiitis
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.
- Incidence: 1.00 cases per 100,000 person-years
- Peak incidence: 60-70 years
- Sex ratio: more common in males 1.5:1
|Granulomatosis with polyangiitis||1|
|Eosinophilic granulomatosis with polyangiitis||0.20|
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:
- Exposure to silica dust inhalation, mercury and lead may be potential adjuvant triggers.
- Propylthiouracil, hydralazine, sulfasalazine, phenytoin and allopurinol are examples of drugs which have been reported to cause ANCA seroconversion and potentially may be implicated.
- 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.
- 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.
- 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.
- 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.
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%)
- 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.
- Pulmonary infiltrates or nodules may be seen on imaging
- 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%)
- 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.
- Skin lesions including leukocytoclastic angiitis (lower extremity purpura and ulceration), petechiae, nodules and vesicles
- Mononeuritis multiplex
- Peripheral sensorimotor polyneuropathy
- Cranial neuropathy
GPA less commonly involves organ systems such as the gastrointestinal, cardiac, lower genitourinary and endocrine systems.
Some of the important differentials to consider include:
- 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.
- 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.
- 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.
- Similarities: non-specific constitutional symptoms; may be associated with cutaneous manifestations of vasculitis.
- Differences: presence of lymphadenopathy or hepatosplenomegaly; tissue biopsy positive for lymphoma.
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.
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
- Highest cause of mortality in patients with GPA.
- Bone marrow toxicity
- Diabetes mellitus
- Cyclophosphamide increases the risk of bladder cancer, skin cancer, leukaemia and lymphoma.
- Gonadal failure
- Related to cyclophosphamide use.
- Pulmonary fibrosis
- 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.