Leiden University Scholarly Publications

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Wesemael, T.J. van (2026)

Exploring the landscape of rheumatoid arthritis: piecing together risk factors and autoantibodies

Doctoral Thesis
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and progressive tissue damage. Autoantibodies are a hallmark of RA. However, little is known about the risk factors and clinical outcomes associated with different isotypes of anti-modified protein antibodies (AMPAs), such as ACPA-IgG, AMPA-IgA, and AMPA-IgM. AMPAs found in RA include anti-citrullinated protein antibodies (ACPA), anti-acetylated protein antibodies (AAPA), and anti-carbamylated protein antibodies (anti-CarP). This thesis focuses on clarifying these aspects.
The main findings of this research reveal that ACPA-IgG is specifically associated with genetic risk factors, particularly the HLA-DRB1 shared epitope. This genetic predisposition is linked to the glycosylation of the variable domain of ACPA, which plays a significant role in disease development. In contrast, smoking is associated with the production of AMPA-IgA, supporting the mucosal origin hypothesis of RA.
Show moreRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and progressive tissue damage. Autoantibodies are a hallmark of RA. However, little is known about the risk factors and clinical outcomes associated with different isotypes of anti-modified protein antibodies (AMPAs), such as ACPA-IgG, AMPA-IgA, and AMPA-IgM. AMPAs found in RA include anti-citrullinated protein antibodies (ACPA), anti-acetylated protein antibodies (AAPA), and anti-carbamylated protein antibodies (anti-CarP). This thesis focuses on clarifying these aspects.
The main findings of this research reveal that ACPA-IgG is specifically associated with genetic risk factors, particularly the HLA-DRB1 shared epitope. This genetic predisposition is linked to the glycosylation of the variable domain of ACPA, which plays a significant role in disease development. In contrast, smoking is associated with the production of AMPA-IgA, supporting the mucosal origin hypothesis of RA.
Clinically, ACPA was found to be a key biomarker for both radiological progression and the likelihood of achieving sustained drug-free remission. Anti-CarP, on the other hand, was associated with radiological progression in ACPA-negative patients, while AAPA showed no additional value in predicting clinical outcomes such as radiological progression or remission. These findings underscore the clinical relevance of autoantibodies in disease prognosis and treatment strategies for RA.
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Rheumatoid arthritis
Autoantibodies
Risk factors
Smoking
Genetics
Anti-citrullinated protein antibodies (ACPA)
Anti-acetylated protein antibodies (AAPA)
Anti-carbamylated protein antibodies (anti-CarP)
All authors
Wesemael, T.J. van
Supervisor
Woude, D. van der; Toes, R.E.M.
Committee
Trouw, L.A.; Brouwer, E.; Oei, E.H.G.; Steenbergen, H.W. van
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2026-01-14
ISBN (print)
9789083548944