POS1008 CHARACTERIZATION OF ALPHA-1 ANTITRYPSIN FUNCTION IN ANCA-ASSOCIATED VASCULITIS

Background: Two separate genome-wide association studies demonstrated that polymorphisms in SERPINA1, encoding serine protease inhibitor alpha-1 antitrypsin (A1AT), are associated with increased risk of developing antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [1, 2]. It has been proposed that the functionality of A1AT is decreased in inflammatory conditions [3]. Objectives: This study aimed to gain insight into function of A1AT in AAV, including the relationships of A1AT genotype, and functional activity of A1AT, with targeted biomarkers and disease activity in AAV. Methods: Clinical data and peripheral blood samples were examined from 250 participants with AAV in a longitudinal cohort, and 80 healthy control individuals. Among those with AAV, 170 with wild-type (WT) A1AT genotype (MM) and 80 with mutant (mut) A1AT genotype (MS, MZ, SS, SZ, or ZZ) with available samples during active disease and remission were selected. Comprehensive analyses were performed, including A1AT total and functional levels, markers of neutrophil activation, and cyto/chemokines. Results: Participants with mut A1AT genotype were younger at diagnosis of AAV than those with WT A1AT genotype (Table 1). Among participants with AAV and WT A1AT genotype, 66.5% were PR3-ANCA positive and 26.5% were MPO-ANCA positive during their disease course, as compared to 73.8% and 17.5%, respectively, among those with mut A1AT genotype. Birmingham Vasculitis Activity Score/WG during active visits, and Disease Extent Index are presented in Table 1. Functional A1AT [4] was higher with WT A1AT genotype than with mut genotype during both active disease (p < 0.01) and remission (p < 0.01), and higher among participants with AAV and WT A1AT genotype than among healthy subjects (p < 0.01). Total and functional A1AT aligned with genotype (Table 1) and were consistently lower among those with Z alleles (data not shown). During active AAV, levels of proinflammatory cytokines IL-8 and IL-6 were similar across the A1AT genotype subgroups. The decline of these cytokines during remission of AAV was more distinct among those with WT A1AT genotype than those with mut genotype. In contrast, levels of IL-1α and IL-13 were more affected among those with mut genotype than those with WT A1AT genotype, resulting in significant increased levels during active disease (p=0.05 and p < 0.01, respectively). Levels of IL-8 and IL-6 among healthy control subjects were lower than those with WT A1AT genotype during remission (p < 0.01 and p < 0.01, respectively), but IL-1α and IL-13 were similar. During active AAV and remission, levels of the anti-inflammatory cytokine IL-10 were slightly higher among those with WT A1AT genotype than those with mut genotype (p=0.07 and p=0.20, respectively). By comparison, mean IL-10 among healthy subjects was lower than among those with WT A1AT genotype in remission (p < 0.01). Conclusion: A1AT genotype among people with AAV is associated with differences in age at diagnosis, inflammatory markers, and several cytokines. Further analyses will explore the relationships among A1AT functional levels and disease characteristics and activity of AAV. REFERENCES: [1] Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214-23. doi: 10.1056/NEJMoa1108735. PubMed PMID: 22808956. [2] Merkel PA, Xie G, Monach PA, Ji X, Ciavatta DJ, Byun J, et al. Identification of Functional and Expression Polymorphisms Associated With Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. Arthritis Rheumatol. 2017;69(5):1054-66. Epub 20170406. doi: 10.1002/art.40034. PubMed PMID: 28029757. [3] Mota A, et al. Alpha 1-antitrypsin activity is markedly decreased in Wegener's granulomatosis. Rheumatol Int. 2014 Apr;34(4):553-8. doi: 10.1007/s00296-013-2745-9. [4] Engelmaier A, Weber A. Sensitive and specific measurement of alpha1-antitrypsin activity with an elastase complex formation immunosorbent assay (ECFISA). J Pharm Biomed Anal. 2022;209:114476. Epub 2021 Nov 23. doi: 10.1016/j.jpba.2021.114476. PubMed PMID: 34838346. Acknowledgements: NIL. Disclosure of Interests: Lynn Fussner Amgen, Ivan Bilic Ivan Bilic is a full-time employee of Takeda Pharmaceutical Company, Carol McAlear: None declared, David Cuthbertson: None declared, Jie Cheng Jie Cheng is a full-time employee of Takeda Pharmaceutical Company, Elise Chen Elise Chen is a full-time employee of Takeda Pharmaceutical Company, Markus Weiller Markus Weiller is a full-time employee of Takeda Pharmaceutical Company, Ulrich Specks Consultant: Amgen, Argenix, AstraZeneca, Boehringer Ingelheim, CSL Vifor, Grant/research support: Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, GSK, Northstar Medical Radioisotopes, Takeda., Peter A Merkel Stock options: Kyverna, Q32, Sparrow, Consultant: AbbVie, Amgen, ArGenx, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Cabaletta, CSL Behring, Dynacure, GlaxoSmithKline, HiBio, InflaRx, Janssen, Kyverna, Novartis, NS Pharma, Q32, Regeneron, Sparrow, Takeda. Vistera., Grant/research support: AbbVie, Amgen, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Eicos, Electra, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Neutrolis, Takeda.