Background Deficiency of alpha-1 protease inhibitor, or alpha-1-antitrypsin (A1AT) is a frequent genetic disorder, which is characterized by low serum level of A1AT and usually manifests as pulmonary emphysema and liver disease. Also the deficiency of A1AT is known to be associated with granulomatosis with polyangiitis (GPA). The influence of A1AT deficiency on GPA clinical course is not clarified.
Objectives The aim of this study was to estimate the prevalence of pathological A1AT phenotypes in GPA and other systemic vasculitis and to define the influence of A1AT phenotype on clinical course of GPA.
Methods We enrolled 86 patients with systemic vasculitis, including GPA (N=47), microscopic polyangiitis (MPA, N=16), eosinophilic granulomatosis with polyangiitis (EGPA, N=12), polyarteriitisnodosa (PN, N=11). 46 healthy donors were included in the control group. All blood samples underwent A1AT phenotyping by isoelectrofocusing (IEF) and turbidimetric A1AT measurement. The results of phenotyping were compared to clinical data, such as BVAS activity rate (Birmingham Vasculitis Activity Score), VDI index (vasculitis damage index), organs involvement, inflammatory markers, including antineutrophil cytoplasmic antibodies (ANCA), total IgG concentration and serum levels of C3, C4 complement factors.
Results Pathological A1AT phenotypes were found in 17% (8/47) of GPA patients, 6,25% (1/16) of MPA patients, 2% (1/46) of healthy donors and were never found in EGPA, PN. The abnormal phenotypes in GPA were 1PiZZ, 4PiMZ, 2PiMF, 1PiMS, and 1PiMS phenotype was identified in MPA patient. Lesion of lung and upper respiratory tract was observed in all patients with pathological phenotypes A1AT (N=8), while in normal phenotype A1AT it was present in 72% and 82% respectively. The mean concentration of A1AT was significantly lower in GPA patients with abnormal A1AT phenotypes, than in patients with normal phenotype A1AT (respectively 1003±148.8 and 1964±127.9 mg/L, p<0,01). The average activity by BVAS index in GPA was significantly higher in patients with pathological phenotype A1AT than in patients with normal phenotype A1AT (24,63±2,897 and 18,05±1,444 points, p<0,05). Also we revealed excess levels of VDI in cohort of patients with abnormal phenotype A1AT rather, than in cohort of patients with normal phenotype A1AT (6,3±3,1 versus 5,4±2,6, p<0,05). The average values concentration of antibodies to proteinase-3 in GPA patients with abnormal phenotype A1AT were significantly higher compared to GPA patients with normal phenotype A1AT (respectively 142,4±25,24 and 86,784±14,98 RU/ml, p<0,05). In GPA patients with mutated A1AT phenotypes levels of serum creatinine concentrations (p<0,01), levels of total IgG concentration and serum levels of C3 and C4 complement factors (p<0.05) also were significantly higher than in group of GPA patients with normal A1AT phenotype.
Conclusions Pathological A1AT phenotypes are more often observed in GPA patients who have more severe GPA clinical course and higher immunological disease activity.
Disclosure of Interest None declared