TY - JOUR
T1 - IgG Anti–Citrullinated Protein Antibody Variable Domain Glycosylation Increases Before the Onset of Rheumatoid Arthritis and Stabilizes Thereafter
T2 - A Cross-Sectional Study Encompassing ~1,500 Samples
AU - Kissel, Theresa
AU - Hafkenscheid, Lise
AU - Wesemael, Tineke J.
AU - Tamai, Mami
AU - Kawashiri, Shin-ya
AU - Kawakami, Atsushi
AU - el-Gabalawy, Hani S.
AU - van Schaardenburg, Dirkjan
AU - Rantapää-Dahlqvist, Solbritt
AU - Wuhrer, Manfred
AU - van der Helm-van Mil, Annette H. M.
AU - Allaart, Cornelia F.
AU - van der Woude, Diane
AU - Scherer, Hans U.
AU - Toes, Rene E. M.
AU - Huizinga, Tom W. J.
N1 - Funding Information: The authors would like to thank personnel of the Department of Biobank Research (Umeå University), the Västerbotten Intervention Programme (Västerbotten, Sweden), the Northern Sweden MONICA study, and the County Council of Västerbotten for providing data and samples. We are grateful to Dr. Jan Wouter Drijfhout (Leiden University Medical Center) for providing the CCP-2 peptide, Carolien Koeleman (Leiden University Medical Center) for expert assistance with liquid chromatography, and Ellis Niemantsverdriet and Marloes Verstappen (Leiden University Medical Center) for assistance with sample and data collection. Funding Information: Supported by ReumaNederland (grants 17‐1‐402 and 08‐1‐34), the IMI funded project RTCure (777357), ZonMw TOP (grant 91214031), Target to B! (LSHM18055‐5GF), the Swedish Research Council (VR 2017‐00650), King Gustaf V's 80‐Year Fund, King Gustaf V's and Queen Victoria's Fund, the Swedish Rheumatism Association, and the Canadian Institutes of Health Research MOP grant (77700). Dr. Scherer is recipient of an NWO‐ZonMW clinical fellowship (90714509), an NWO‐ZonMW VENI grant (91617107), an NWO‐ZonMW VIDI grant (09150172010067), and a ZonMW Enabling Technology Hotels grant (435002030) and has received support from the Dutch Arthritis Foundation (15‐2‐402 and 18‐1‐205). Dr. Toes is recipient of a European Research Council (ERC) advanced grant (AdG2019‐884796). Publisher Copyright: © 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
PY - 2022/7
Y1 - 2022/7
N2 - Objective: The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of N-linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages. Methods: Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new-onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long-term drug-free remission (DFR) during up to 16 years follow-up. Results: IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset. Conclusion: The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre-disease phase and contributes to disease development.
AB - Objective: The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of N-linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages. Methods: Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new-onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long-term drug-free remission (DFR) during up to 16 years follow-up. Results: IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset. Conclusion: The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre-disease phase and contributes to disease development.
UR - http://www.scopus.com/inward/record.url?scp=85131010752&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/art.42098
DO - https://doi.org/10.1002/art.42098
M3 - Article
C2 - 35188715
SN - 2326-5191
VL - 74
SP - 1147
EP - 1158
JO - Arthritis & rheumatology (Hoboken, N.J.)
JF - Arthritis & rheumatology (Hoboken, N.J.)
IS - 7
ER -