80. Clinical characteristics of patients with ANCA-associated vasculitis with and without alpha-1 antitrypsin deficiency alleles
Creators: name: Fussner1, Lynn
name: Cuthbertson2, David
name: Grayson3, Peter
name: Jayne4, David
name: McAlear5, Carol A.
name: Walsh6, Michael
name: Siminovitch7, Katherine
name: Specks8, Ulrich
name: Merkel5, Peter A.
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> There are multiple reasons to suspect that alpha-1 antitrypsin (A1AT) genotype impacts disease characteristics in ANCA-associated vasculitis (AAV). A1AT serves as the predominant endogenous inhibitor of proteinase 3 (PR3), a major target antigen of ANCA, and interferes with ANCA-induced activation of both monocytes and neutrophils. Additionally, two separate, large genome wide association studies found that mutations in SERPINA1, the gene encoding A1AT, are associated with increased risk of developing AAV. This report describes the clinical characteristics of a large cohort of patients with AAV with and without A1AT deficiency. <strong>Methods:</strong> DNA was obtained from patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and linked to clinical data utilizing standardized for Demographics and clinical characteristics are described and compared between patients with and without A1AT deficiency alleles. <strong>Results:</strong> Genotype data from a total of 2145 unique patients with GPA and MPA were identified and analyzed. While 1805 (84.2%) of these patients had normal A1AT genotype (MM), 340 patients (15.9%) had at least one A1AT deficiency allele (Z and/or S) – 203 (9.5%) with any S alleles, 142 (6.6%) with any Z alleles. Among these, was the most frequently identified abnormal genotype with 186 patients (8.7%), followed by MZ (127, 5.9%), SS (12, 0.6%), ZZ (10, 0.5%), and SZ (5, 0.2%). Clinical characteristics of patients with and without A1AT deficiency alleles are presented in Table 1. Mean age at AAV diagnosis was similar among patients with (48.3 ± 15.9 years) and without A1AT deficiency alleles (48.4 ± 17.8 years among those with MM, p=0.950), as was sex (51.0% female among those with deficiency alleles vs. 49.2% among MM, p=0.533). Hispanic, Latino, or Spanish origin was more common among patients with A1AT deficiency alleles (4.4% of patients with any deficiency alleles vs. 0.8% without, p=0.001). Patients with deficiency alleles were more frequently described as having a clinical phenotype of GPA (90.3% with deficiency alleles vs. 83.5% MM, p=0.003), and were more frequently PR3-ANCA positive (74.5% with deficiency alleles vs. 63.3% MM, p&lt;0.001). However, more patients with deficiency alleles were ANCA-negative as well (5.2% with deficiency alleles vs. 2.9% MM, p=0.029). <strong>Conclusions:</strong> In this large cohort of patients with AAV nearly 1/6 had one or more A1AT deficiency allele. MS, a genotype that is often not associated with clinically significant decrease in A1AT levels, was the most frequently identified abnormal genotype among these patients with AAV. While the sample size was small for homozygous and compound heterozygous deficiency genotypes, the presence of A1AT deficiency alleles was associated with ethnicity, clinical phenotype, and ANCA serotype. Further investigation is needed to evaluate relationships with specific disease manifestations, including organ involvement, relapsing course, and cumulative damage. <strong>Disclosures: </strong>Merkel: Consulting: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Sparrow, Takeda, Talaris. Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, enentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, Takeda. Royalties: UpToDate. Remaining authors: None <strong>Table 1</strong>. Clinical characteristics of patients with ANCA-associated vasculitis with and without alpha-1 antitrypsin deficiency alleles Characteristic Any Deficiency Allele MM<br> Genotype <em>P </em>value (Chi-square) Age at diagnosis, mean ± standard deviation N=899 (145, 754) 48.3 (15.9) 48.4 (17.8) 0.950 Female, n (% of genotype) N=2124 (335, 1789) 171 (51.0%) 880 (49.2%) 0.533 Ethnicity: Hispanic, Latino, or Spanish origin, n (% of genotype) N=851 (137, 714) 6 (4.4%) 6 (0.8%) 0.001 Clinical phenotype GPA, n (% of genotype) MPA, n (% of genotype) Indeterminate or unknown, n (% of genotype) N=1813 (289, 1524) 261 (90.3%) 11 (3.8%) 17 (5.8%) 1273 (83.5%) 140 (9.2%) 111 (7.3%) 0.003 0.002 0.393 ANCA Specificity PR3-ANCA only, n (% of genotype) MPO-ANCA only, n (% of genotype) PR3- &amp; MPO-ANCA, n (% of genotype) Atypical ANCA, n (% of genotype) ANCA-Negative, n (% of genotype) N=2077 (306, 1788) 228 (74.5%) 56 (18.3%) 6 (2.0%) 0 (0.0%) 16 (5.2%) 1131 (63.3%) 427 (23.9%) 28 (1.6%) 1 (0.1%) 51 (2.9%) &lt;0.001 0.032 0.614 0.029 Sample size (N) values represent the total number of patients with available data on specific characteristic (any deficiency allele, MM genotype).