Granulomatosis with polyangiitis (ORPHA:900)
A rare anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis characterized by necrotizing inflammation of small and medium vessels (capillaries, venules and arterioles), resulting in tissue ischemia.
Epidemiology
The prevalence is estimated between 1/6,400 - 42,000 worldwide with annual incidence between 1/84,000-475,000. There is geographic and/or ethnic variation, with a higher incidence in colder regions and among Caucasians. Childhood-onset disease is characterized by female predominance, and adult-onset by a slight male predominance.
Clinical description
The average age of onset is 45 years but the disease may manifest at any age including childhood. The disease may present with various organ manifestations. Ear, nose and throat symptoms are present in 50-95% (persistent nasal obstruction, destructive sinusitis, crusting and/or hemorrhagic rhinitis, nasal septum deformity, saddle nose deformity, and otitis media), bronchopulmonary symptoms in 60-80% (nodules, alveolar hemorrage, bronchial and/or subglottic stenosis), and renal disease (typically extra-capillary necrotizing glomerulonephritis) in 60-80% of affected individuals. General signs (fever, arthralgia, myalgia, weight loss) are common. Skin lesions (purpura and cutaneous nodules) are observed in 10-50%, peripheral neuropathy (multineuritis) in 25%, central nervous system manifestations (headaches, sensorimotor deficit, hemiplegia and epilepsy) in 10%, and ocular anomalies (scleritis and orbital tumors) in 7-8% of patients.
Etiology
The pathogenesis of GPA is still under study. Genetic susceptibility factors, environmental agents, infectious episodes and anomalies in innate and adaptive immunity seem to play a role in the development of all ANCA-associated vasculitides. Genetic variants appear to correlate with antineutrophil cytoplasmic antibody (ANCA) antigen specificity rather than with clinical phenotype. Thus, cytoplasmic-ANCAs directed to proteinase 3 (PR3-ANCA), found in 60-80% of GPA cases, are associated with genetic variants in HLA-DP1A and HLA-DP1B (6p21.32) which encode a class II major histocompatibility complex, SERPINA1 (14q32.13) encoding alpha-1 antitrypsin, and PRTN3 (19p13.3) encoding the autoantigen proteinase 3.
Diagnostic methods
Diagnosis relies on clinical findings, imaging studies and biochemical testing, and detection of ANCAs in the serum, principally PR3-ANCAs. Histological analysis of biopsy specimens from affected organs confirms the diagnosis, showing necrotizing vasculitis and granulomatous inflammation.
Differential diagnosis
Differential diagnoses include other ANCA-associated vasculitides such as microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.
Management and treatment
Induction therapy comprises steroid pulses combined with either intravenous Rituximab or Cyclophosphamide. Disease remission is achieved in more than 80% of patients with these protocols. In cases of lacking or insufficient response, plasma exchange can be considered. Azathioprine and Methotrexate are efficacious agents for maintenance immunosuppression whereas Mycophenolate-Mofetil is less effective. Leflunomide is an alternative option for individuals intolerant to Azathioprine or Methotrexate. Anti-TNF antibodies (e.g. Infliximab and Adalimumab) have shown promising results in clinical trials as steroid-sparing agents.
Prognosis
While remission is achieved with treatment in 70-100% of cases, the disease relapses in more than 80% of patients within 10 years. Significant morbidity may emerge both from the disease and its treatment. Ten-year patient survival is around 75%.

                            Last update: 
                            January 2019


                            - Expert reviewer(s): 
                            Dr Laura CESCA  - Pr Franz SCHAEFER | ERKNet*


                                * European Reference Network