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Abstract Number: 0033

Refined Autoantibody Profiles in RA Reveal That Primarily ACPAs Binding Non-glycine Citrulline Motifs Are Associated with Shared Epitope Alleles

Linda Mathsson-Alm1, Helga Westerlind2, Isabel Gehring3, Monika Hansson2, Nasim Ghasemzadeh1, Jessica Rojas-Restrepo3, Saedis Saevarsdottir4, Joseph Sexton5, Siri Lillegraven6, Espen Haavardsholm6, Merete Hetland7, Hilde Hammer8, Tore K. Kvien9, Bente Glintborg10, Leonid Padyukov2, Johan Askling2 and Caroline Grönwall2, and the Danish Rheumatologic Biobank Study Group (the Biomarker Protocol), Swedish Rheumatology Quality Register Biobank Study Group (SRQb), 1Thermo Fisher Scientific, Uppsala, Sweden, 2Karolinska Institutet, Stockholm, Sweden, 3Thermo Fisher Scientific, Freiburg, Germany, 4University of Iceland, Reykjavik, Iceland, 5Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway, Oslo, Norway, 6Diakonhjemmet Hospital, Oslo, Norway, 7Rigshospitalet Glostrup and University of Copenhagen, Glostrup, Denmark, 8Diakonhjemmet Hospital, Oslo, Oslo, Norway, 9Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway and University of Oslo (UiO), Institute of Clinical Medicine, Oslo, Norway, Oslo, Norway, 10DANBIO, Rigshospitalet Glostrup and University of Copenhagen, Virum, Denmark

Meeting: ACR Convergence 2024

Keywords: Anti-CCP, Autoantibody(ies), autoantigens, rheumatoid arthritis, risk factors

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Session Information

Date: Saturday, November 16, 2024

Title: RA – Etiology & Pathogenesis Poster

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: Carriage of HLA-DRB1 shared epitope (SE) alleles and a history of smoking, have been identified as the most prominent risk factors for development of autoantibody positive rheumatoid arthritis (RA). The hallmark autoantibodies, anti-citrullinated protein antibodies (ACPA) can target various antigens, resulting in heterogeneous ACPA profiles among patients. Their exact nature and etiological significance remain unknown. ACPA are multi-reactive and bind citrulline-amino acid motifs where “cit-gly” is a common target. We investigated the co-occurrence of RA-specific autoantibodies, and ACPA-patterns by recognized citrulline (cit)-motifs in relation to HLA-DRB1 and smoking.

Methods: We measured rheumatoid factor (RF) IgM IgG and IgA, anti-cyclic citrullinated peptide (CCP2) IgG and IgA, and IgG to 15 anti-cit- peptides elected to cover different cit-motifs and 4 Carb/Acet-peptides, in 6,907 patients from five Scandinavian RA cohorts [1]. Analyses were performed centrally using fluoroenzyme immunoassay and custom-made multiplex solid-phase microarray. Cutoffs was set based on 400 healthy controls and high signals were 3x cutoff. HLA-DRB1 SE alleles were imputed from SNP genotyping data.

Results: Compared to using only CCP2-IgG and/or RF-IgM, seropositivity increased from 76% to 84% when all autoantibody tests were included. Single-cit peptides derived from four multi-cit peptides (Cit Fiba36-50, Cit Fibb60-74, Cit TNC5, Cit Vim60-75) showed differential binding patterns, supporting recognition of cit-motifs rather than long peptides. Four cit-peptides (Cit Fibb36-52, Cit Fibb60-74-Cit3, Cit Fil307-324, Cit Vim60-75-Cit1) (table 1) captured 97% of IgG anti-CCP2+ patients. Different ACPA overlapped, but when dichotomizing patients based on high reactivity ( >3x cutoff) to peptide cit-motifs, non-glycine but not glycine-motif ACPA associated with HLA-SE alleles (figure 1). In IgG anti-CCP2+ patients, 90% of those with only high non-glycine ACPA were HLA-SE allele carriers, compared to 67% in the group with glycine-motif only ACPA, yielding an odds ratio (OR) of 4.5 (95% CI: 1.9-11, Fisher’s exact test). Smoking status did not correlate with fine-specificity subsets or IgG anti-Carb/Acet but independently associated with IgA/IgM RF and IgA/IgG anti-CCP2 double positivity.

Conclusion: While glycine-motifs are commonly citrullinated and prevalent ACPA-targets, our data in this large cohort of routine care treated patients with RA reveals that HLA-SE alleles are primarily associated with ACPA to non-glycine cit-motif, providing new insight in ACPA epitope spreading. The association between IgA and smoking supports a chronic mucosal response. Our results advance our understanding of citrulline responses in relation to key environmental and genetic RA risk factors.

Reference:

1. Westerlind et al RMD Open 2023 Sep;9(3):e003027

Supporting image 1

Table 1. ACPA fine-specificities by multiplex array in 6900 RA patients

Supporting image 2

Figure 1. ACPA fine-specificities to citrulline peptides with glycine-motifs compared to non-glycine motifs. A. Overlap between high reactivity to glycine (gly) and non-glycine peptides in the patients. B. Frequency of HLA-DRB1 SE alleles in IgG CCP2+ patients with different ACPA reactivity patterns.


Disclosures: L. Mathsson-Alm: Thermo Fisher Scientific, 3; H. Westerlind: None; I. Gehring: Thermo Fisher Scientific, 3; M. Hansson: None; N. Ghasemzadeh: Thermo Fisher Scientific, 3; J. Rojas-Restrepo: Thermo Fisher Scientific, 3; S. Saevarsdottir: deCODE genetics/Amgen, 2; J. Sexton: None; S. Lillegraven: None; E. Haavardsholm: None; M. Hetland: AbbVie/Abbott, 5, 12, Paid to my institution, no personal fee, Bristol-Myers Squibb(BMS), 5, 12, Paid to my institution, no personal fee, Eli Lilly, 5, 12, Paid to my institution, no personal fee, Medac, 6, 12, Paid to my institution, no personal fee, Merck/MSD, 5, 12, Paid to my institution, no personal fee, Novartis, 5, 6, Pfizer, 5, 6, 12, Paid to my institution, no personal fee, Sandoz, 5, 6, 12, Paid to my institution, no personal fee, UCB, 6, 12, Paid to my institution, no personal fee; H. Hammer: AbbVie/Abbott, 1, 6, Eli Lilly, 6, Novartis, 1, 6, UCB, 6; T. Kvien: AbbVie/Abbott, 1, 2, 5, Bristol-Myers Squibb(BMS), 5, Galapagos, 5, Gilead, 2, Grünenthal, 6, Janssen, 2, 6, Novartis, 2, 5, Pfizer, 2, 5, Sandoz, 2, 6, UCB, 2, 5; B. Glintborg: AbbVie/Abbott, 5, Bristol-Myers Squibb(BMS), 5, Pfizer, 5, Sandoz, 5; L. Padyukov: None; J. Askling: None; C. Grönwall: None.

To cite this abstract in AMA style:

Mathsson-Alm L, Westerlind H, Gehring I, Hansson M, Ghasemzadeh N, Rojas-Restrepo J, Saevarsdottir S, Sexton J, Lillegraven S, Haavardsholm E, Hetland M, Hammer H, Kvien T, Glintborg B, Padyukov L, Askling J, Grönwall C. Refined Autoantibody Profiles in RA Reveal That Primarily ACPAs Binding Non-glycine Citrulline Motifs Are Associated with Shared Epitope Alleles [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/refined-autoantibody-profiles-in-ra-reveal-that-primarily-acpas-binding-non-glycine-citrulline-motifs-are-associated-with-shared-epitope-alleles/. Accessed .
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