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Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis

Lönnblom, Erik ; Leu Agelii, Monica ; Sareila, Outi ; Cheng, Lei ; Xu, Bingze ; Viljanen, Johan ; Hafström, Ingiäld ; Andersson, Maria L.E. LU orcid ; Bergström, Göran and Hultgård Ekwall, Anna Karin , et al. (2023) In Arthritis and Rheumatology 75(7). p.1110-1119
Abstract

Objective: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints. Methods: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts... (More)

Objective: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints. Methods: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE). Results: Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98–100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19–26%) of early RA patients seronegative for anti–cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE. Conclusion: A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA. (Figure presented.).

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis and Rheumatology
volume
75
issue
7
pages
10 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:36718635
  • scopus:85151780585
ISSN
2326-5191
DOI
10.1002/art.42463
language
English
LU publication?
yes
additional info
Funding Information: Supported by The Swedish Foundation for Strategic Research, Vinnova, Sweden's innovation agency, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Rheumatism Association, the Foundation for Assistance to Disabled People in Skane, ALF VästraGötaland Region, Sweden, and the Swedish Heart Lung Foundation. Funding Information: We thank the patients who participated in the study. We acknowledge Burcu Ayoglu and Peter Nilsson (Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH-Royal Institute of Technology, Stockholm, Sweden) for providing the platform for sample analysis and help with establishing our own platform and Peter M. Nilsson (Faculty of Medicine, Lund University, Lund, Sweden) for providing human samples MFM ÅUS (Malmö Förebyggande Medicin; Återundersökning). Publisher Copyright: © 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
id
8a4963be-5f29-465e-b3ea-d790607dc7ea
date added to LUP
2024-01-12 14:56:31
date last changed
2024-04-13 09:07:01
@article{8a4963be-5f29-465e-b3ea-d790607dc7ea,
  abstract     = {{<p>Objective: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints. Methods: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE). Results: Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98–100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19–26%) of early RA patients seronegative for anti–cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE. Conclusion: A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA. (Figure presented.).</p>}},
  author       = {{Lönnblom, Erik and Leu Agelii, Monica and Sareila, Outi and Cheng, Lei and Xu, Bingze and Viljanen, Johan and Hafström, Ingiäld and Andersson, Maria L.E. and Bergström, Göran and Hultgård Ekwall, Anna Karin and Rudin, Anna and Kastbom, Alf and Sjöwall, Christopher and Jacobsson, Lennart T.H. and Kihlberg, Jan and Gjertsson, Inger and Holmdahl, Rikard}},
  issn         = {{2326-5191}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1110--1119}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis and Rheumatology}},
  title        = {{Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis}},
  url          = {{http://dx.doi.org/10.1002/art.42463}},
  doi          = {{10.1002/art.42463}},
  volume       = {{75}},
  year         = {{2023}},
}