Association of severe rheumatoid arthritis with heterozygosity for α‐antitrypsin deficiency

Abstract

Genetic types of α1‐antitrypsin (protease inhibitor types, or Pi types) were determined in 108 patients with rheumatoid arthritis. These patients were selected for severely destructive disease and had classical rheumatoid arthritis according to ARA criteria, were seropositive, and had joint erosions shown by X‐ray. Heterozygotes for the deficiency Z allele (Pi types MZ, SZ, etc.) were found among 9.2 % of patients and 3.5 % of a control adult population. The increased frequency in patients was statistically significant. Heterozygotes were most frequent among female patients with an early onset of disease. Heterozygosity for α1‐antitrypsin deficiency may be a factor in familial recurrence of rheumatoid arthritis. Among 98 patients with juvenile rheumatoid arthritis not selected for severity, 4.1 % were Z heterozygotes compared with 1.3 % of control children, not a statistically significant difference. Reduced concentrations of α1‐antitrypsin in Z heterozygotes may be inadequate to inhibit the proteolytic enzymes released into the joints of adults with rheumatoid arthritis during phagocytosis of immune complexes. This may be a factor promoting severe joint destruction.

Point Mutation of a Non-Elastase-Binding Site in Human α1-Antitrypsin Alters Its Anti-Inflammatory Properties

“…Recent years have witnessed an expansion of potential clinical applications for hAAT treatment beyond that of straightforward augmentation therapy for genetic hAAT deficiency; these include type 1 diabetes ( 37 , 50 – 52 ), allogeneic and xenogeneic transplants ( 44 – 46 , 53 , 54 ), graft-versus-host disease ( 53 , 55 , 56 ), acute myocardial infarction ( 57 – 59 ), inflammatory bowel disease ( 52 , 60 ), rheumatoid arthritis ( 61 – 63 ), multiple sclerosis ( 41 ), and osteoporosis ( 64 , 65 ). Collectively, these represent an extension of earlier preclinical studies that portray hAAT as possessing anti-inflammatory and immunoregulatory properties ( 3 , 4 , 26 , 35 ).…”

Alpha-1 Antitrypsin: A Potent Anti-Inflammatory and Potential Novel Therapeutic Agent

“…The combination therapy also inhibited IL-6 expression from LPS-stimulated mouse fibroblasts which may indicate a mechanism of arthritis inhibition (Grimstein et al 2010a). Of major importance reduced levels of AAT, as associated with heterozygotes for the Z allele, was suggested to play a contributory role to the development of RA (Cox and Huber 1976) and may be a factor promoting severe joint destruction (Cox and Huber 1980).…”

AB0114 Prevalence of Antibodies Against Carbamylated Proteins in a Cohort of Italian Rheumatoid Arthritis Patients

“…2 Previous studies of the prevalence of allelles associated with deficient states of A1AT in RA have given conflicting results. 3,4 Objectives: We set out to examine the A1AT phenotype of an RA cohort, and to determine if heterozygosity is associated with higher levels of auto-antibodies for ANA, RF and anti-CCP. Methods: Qualitative detection and characterisation of A1AT phenotypes in 135 RA patients was performed using the Hydrasys electrophoresis platform (Sebia) and the Hydragel 18 A1AT Isofocusing kit (Sebia).…”

“…Methods: Wistar rats (3-6 per group) were immunized twice with methylated bovine serum albumin (mBSA) in complete Freund's adjuvant and Bordetella pertussis antigen followed by local arthritis induction (intra-articular mBSA injection with 3 repeated injections in the right knee (RA) with the contralateral left knee serving as internal control [3]. Therapeutic interventions were performed with MTX (1mg/kg; 1/week x4, i.p.).…”