Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
The majority of patients with established Rheumatoid arthritis (RA) have autoantibodies against the Fc of IgG (Rheumatoid factors-RhF) and to citrullinated protein antigens (ACPAs). As ACPAs recognize epitopes on many different proteins, the full complement of reactivity is unknown so they are usually detected using cyclic citrullinated peptides (CCP). Seropositivity for RhF and/or ACPA is a strong predictor of a positive clinical response to rituximab (RTX) therapy. Although playing an important pro-inflammatory role in RA, ACPA, measured using CCP as substrate, are less dynamic than RhF in relation to RTX treatment. Using an antigen array comprising citrullinated antigens identified as present in RA synovia we have explored changes in fine specificity and levels of IgG- and IgA-ACPAs following RTX.
17 patients with active RA (DAS28 ≥ 5.1) fulfilling ACR criteria were included. All had undergone one cycle of RTX (2 weekly infusions of 1g), showed adequate depletion in the peripheral blood (<5 CD19+ cells/μl) at 1-3 months, and had clinically responded (ΔDAS28≥1.2) at 3 months. Follow-up was from 4-13 months up to re-treatment or relapse. A custom, bead-based, antigen array comprising 30 putative RA-associated citrullinated, and 20 corresponding native antigens was used for measurement of ACPA (assessed using mean fluorescence intensity-MFI). To compensate for number of binding sites per antigen, MFI were Z-normalised. Positive results were regarded as those with SD>1 above population mean.
Before RTX, IgG- and IgA-ACPA often shared specificities to a variable number of citrullinated and native antigens. Post-RTX, the overall median % decrease in MFI for ACPA from baseline to when B-cells were depleted, was modest for IgG-CCP (7.3%) and more pronounced for IgA-CCP (20.0%). At relapse, median % decrease in MFI for IgG-CCP was 3.3% but IgA-CCP remained high at 20.5%. The patterns of antibody binding to individual peptide or protein epitopes were considerably more dynamic than those to CCP. In general, the same citrullinated epitopes were recognized by both IgA- and IgG-ACPA in each sample but additional specificities could be present in either autoantibody class. IgG- and IgA-ACPA also tended to respond in parallel to RTX treatment. Prior to relapse, steep rises in IgG- or IgA-ACPA recognizing individual, or several, epitope specificities were observed, particularly when relapse occurred several months after B cell return (9/17 patients). Rises usually occurred in ACPA specificities present before RTX but new epitope specificities could emerge.
The use of multiplex antigen arrays for analysis of the ACPA response in RA patients after RTX has revealed that populations of ACPA-producing cells behave differently in response to B cell depletion therapy. Recognition of particular epitopes was highly variable and dynamic, suggesting some derivation from short-lived parent plasmablasts, which were not reflected in the relatively static, ‘global’ IgG-CCP measurements. IgA-ACPA responses to RTX therapy were also varied and did not necessarily recognize the same epitopes although patterns of response were similar to those of IgG-ACPA.
L. J. Lahey,
M. J. Leandro,
W. H. Robinson,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-use-of-multiplex-bead-array-to-follow-the-effect-of-rituximab-on-igg-and-iga-serum-autoantibody-responses-to-citrullinated-epitopes-in-patients-with-rheumatoid-arthritis/