Background Deficiency in α-1-antitrypsin (AAT), which is the main proteinase 3 (PR3) inhibitor, is now recognized as a pathogenic factor in some cases of anti-PR3 anti-neutrophil cytoplasmic antibodies (ANCA) related granulomatosis with polyangiitis (GPA). However, the clinical impact of AAT deficiency remains poorly established in this setting.
Objectives The purpose of our study was to describe the clinical phenotypes and outcomes of anti-PR3 GPA patients according to their AAT status.
Methods A retrospective monocentric study carried out in Caen University Hospital led to identify anti-PR3 GPA patients, from 09/21/2011 to 06/10/2016. AAT dosage and phenotype (isoelectric focusing in agarose gel) were performed for all patients. Categorical variables were reported as percentages and compared using Chi2 or Fisher's tests according to expected frequencies. Continuous variables were expressed as means and analysed using Student's t-test. Associations between survival, renal survival or relapse-free survival, and AAT phenotype were evaluated by the log-rank test. A p-value <0.05 was considered to be statistically significant.
Results Among the 72 identified anti-PR3 GPA patients, 40 (56%) were male. Median age at diagnosis was 60.5 years old. Patients mainly had constitutional symptoms (51, 71%), pulmonary (52, 72%), ear, nose or throat (ENT) (49, 68%), rheumatologic (45, 63%), and renal (44, 61%) involvements. Median initial BVAS score was 38 (maximum score: 63). Twelve (17%) deaths and 33 (46%) relapsing patients were noted (median follow-up: 55 months). Forty-eight (67%) patients had MM phenotype, 10 (14%) MZ phenotype, 8 (11%) MS phenotype, 3 (4%) M-variant phenotype, 2 (3%) ZZ phenotype and 1 (1%) ZS phenotype. Allele frequencies of M, Z and S allele were 81, 10 and 6%, respectively. The whole patient cohort had the same immunosuppressant drug regimen.
Only intra-alveolar hemorrhage (IAH), that was more frequent in Z or S deficient allele patients, and ENT involvement, that was more frequent in those with Z allele, were significantly associated with AAT deficiency. Among the 13 patients carrying Z allele, 9 had normal AAT level, including 6 without any biologic inflammatory parameter at the time of AAT dosage. Global survival, renal survival or relapse-free survival were identical between Z carriers compared to non-Z carriers (respectively 0.77, 0.75 and 1), and between Z or S carriers compared to those without (respectively 0.91, 0.44 and 0.32).
Conclusions This study confirms the epidemiological association of anti-PR3 GPA with AAT deficiency, and find an interesting higher risk of IAH in this setting. The identical prognosis of both subgroups should be related to other therapeutic added in IAH, including plasma exchanges. Prospective studies are required to specify these data and to assess the need for replacement therapy in AAT deficient patients.
Disclosure of Interest None declared