The role of anti-citrullinated protein antibodies (ACPA) in the pathogenesis of rheumatoid arthritis

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and extra-articular manifestations. Many questions in the pathogenesis, clinical manifestation, and disease spectrum are answered after the discovery of the first autoantibody namely rheumatoid factor (RF). The finding of the second autoantibody named anti-citrullinated protein antibody (ACPA), which unearths the importance of protein citrullination process. It further provides the insight how immune cells and complement interact to perpetuate the inflammatory response. These two autoantibodies pave the way for our better understanding of RA. This review article focuses on the history, pathophysiology, and clinical association of these two autoantibodies in RA.

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The Role of Citrullinated Protein Antibodies in Predicting Erosive Disease in Rheumatoid Arthritis: A Systematic Literature Review and Meta-Analysis

International Journal of Rheumatology ◽

10.1155/2015/728610 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 46

Author(s):

A. A. Jilani ◽

C. G. Mackworth-Young

Keyword(s):

Rheumatoid Arthritis ◽

Meta Analysis ◽

Cost Effective ◽

Erosive Disease ◽

Peptide Antigens ◽

Cost Effective Treatment ◽

Joint Erosions ◽

Citrullinated Protein ◽

Citrullinated Peptide

Background. Autoantibodies to citrullinated peptides have been shown to be valuable in the diagnosis of rheumatoid arthritis (RA). The expanding repertoire of antibodies to citrullinated peptide antigens (ACPA) has been a topic of great interest in recent reviews and research studies, as has the ability of these autoantibodies to predict disease outcome.Objectives. The aim of this review was to provide an update on the relevance of ACPA as prognostic markers in RA. The ability to identify patients predisposed to an aggressive outcome at the time of initial diagnosis greatly facilitates the selection of appropriate and cost-effective treatment.Methods. A systematic review of the literature was carried out. Studies from 1967 up to June 2014 with data on prognostic value of ACPA were included. Quality assessment was done by using the modified Hayden list for prognostic studies. Meta-analysis was performed using BioStat software.Results. The results of 25 studies were selected for the final review. A total of 6421 patients with RA were included, mainly in inception cohorts, with follow-up duration ranging from one year to ten years. All studies carried prognostic data on all available isotypes of anticyclic citrullinated protein (CCP), while four had data on antimutated citrullinated vimentin (MCV). There was a single relevant study each on anticitrullinated enolase peptide 1 (CEP1) and antichimaeric fibrin/filaggrin citrullinated peptide 1 (CFFCP1). All studies showed ACPA to be strong predictors of joint erosions in RA. Other factors, particularly baseline erosions, showed an additive effect. Anti-MCV appeared to be a marker of a more aggressive form of disease. Ten studies had data on which a meta-analysis could be performed. This gave an overall odds ratio of 4.85 for ACPA (anti-CCP/MCV) positivity being predictive for the development of joint erosions. Two studies with data on anti-CEP1 and anti-CFFCP1 also showed this positive predictive role of ACPA for joint erosions.Conclusions. ACPA are strong predictors of severity in RA. Their use should be part of routine rheumatology practice.

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Familial Risks and Heritability of Rheumatoid Arthritis: Role of Rheumatoid Factor/Anti-Citrullinated Protein Antibody Status, Number and Type of Affected Relatives, Sex, and Age

Arthritis & Rheumatism ◽

10.1002/art.38097 ◽

2013 ◽

Vol 65 (11) ◽

pp. 2773-2782 ◽

Cited By ~ 81

Author(s):

Thomas Frisell ◽

Marie Holmqvist ◽

Henrik Källberg ◽

Lars Klareskog ◽

Lars Alfredsson ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Rheumatoid Factor ◽

Status Number ◽

Citrullinated Protein

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Role of Anti-Carbamylated Protein Antibodies Compared to Anti-Citrullinated Protein Antibodies in Indigenous North Americans With Rheumatoid Arthritis, Their First-Degree Relatives, and Healthy Controls

Arthritis & Rheumatology ◽

10.1002/art.39664 ◽

2016 ◽

Vol 68 (9) ◽

pp. 2090-2098 ◽

Cited By ~ 25

Author(s):

H. Koppejan ◽

L. A. Trouw ◽

J. Sokolove ◽

L. J. Lahey ◽

T. J. W. Huizinga ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Healthy Controls ◽

North Americans ◽

First Degree Relatives ◽

Citrullinated Protein

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Fluctuation in anti-cyclic citrullinated protein antibody level predicts relapse from remission in rheumatoid arthritis: KURAMA cohort

Arthritis Research & Therapy ◽

10.1186/s13075-020-02366-x ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Koichi Murata ◽

Hiromu Ito ◽

Motomu Hashimoto ◽

Kosaku Murakami ◽

Ryu Watanabe ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Prognostic Marker ◽

Antibody Level ◽

Clinical Variable ◽

Weak Correlation ◽

Citrullinated Protein ◽

Peptide Antibodies

Abstract Background The positivity of anti-citrullinated protein/peptide antibodies (ACPAs) is a clinically useful diagnostic and prognostic marker in rheumatoid arthritis (RA). However, the significance of ACPA titer and its fluctuation remain unclear. This study aimed to assess the role of ACPA titer and its fluctuation on disease activity and the prognosis of RA. Methods Data obtained from the Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort was analyzed. Patients whose ACPA was measured at least twice between 2011 and 2019 and whose ACPA was positive at least once were included in this study. The association between the clinical variable and ACPA titer or its change was investigated. Results ACPA titer was measured in a total of 3286 patients, 1806 of whom were ACPA-positive at least once. Among them, the ACPA titer level was measured more than once in 1355 patients. Very weak correlation was observed between the ACPA titer level and disease activity. Additionally, there was no trend in the fluctuation of ACPA titer level in each patient; ACPA titer level fluctuated in some patients, but not in others. Patients with high variable levels of ACPA titer were more likely to relapse from remission. In the analysis of two consecutive ACPA measurements, the titer changes predicted the relapse from remission within a year of the second measurement. Conclusions The ACPA titer level fluctuated in some patients. Very weak correlation was observed between the ACPA titer level and disease activity. Fluctuation in ACPA titer level predicted relapse from remission in patients with RA.

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Role of anti-citrullinated protein antibodies in diagnosis and prognosis of rheumatoid arthritis

Archives of Medical Science ◽

10.5114/aoms.2011.22067 ◽

2011 ◽

Vol 2 ◽

pp. 189-194 ◽

Cited By ~ 24

Author(s):

Mariusz Puszczewicz ◽

Cezary Iwaszkiewicz

Keyword(s):

Rheumatoid Arthritis ◽

Diagnosis And Prognosis ◽

Citrullinated Protein

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IgA anti-citrullinated protein antibodies (IgA ACPA) are associated with flares during DMARD tapering in rheumatoid arthritis

Rheumatology ◽

10.1093/rheumatology/keab585 ◽

2021 ◽

Author(s):

Maria V Sokolova ◽

Melanie Hagen ◽

Holger Bang ◽

Georg Schett ◽

Juergen Rech ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Factor ◽

Prognostic Markers ◽

Serum Levels ◽

Randomized Controlled ◽

Study Recruitment ◽

Disease Modifying ◽

Definition Of ◽

Citrullinated Protein

Abstract Objectives A substantial proportion of rheumatoid arthritis (RA) patients flare upon withdrawal of disease modifying anti-rheumatic drugs (DMARDs), thus the definition of prognostic markers is crucial. Anti-citrullinated protein antibody (ACPA)-positivity has been identified as a risk factor for flare. However, only the role of IgG is established in this context, while the role of IgA ACPA is poorly defined. We thus aimed to investigate the role of IgA ACPA in flare of RA. Methods Serum levels of IgA1 and IgA2 ACPA at baseline and after 12 months were measured in 108 patients from the randomized controlled RETRO study. RA patients in stable remission for at least 6 months at study recruitment were assigned to either one of the DMARD tapering arms or to continuation of DMARDs. Results In patients remaining in remission but not in the ones who flared, IgA2 ACPA levels and proportion of IgA2 in ACPA (IgA2%ACPA) significantly declined (median of 17.5%; p< 0.0001). This seemed to be independent of the treatment choice, as there was no difference in IgA2 ACPA dynamics between the study arms. IgA2% ACPA was associated with disease activity (DAS28) at flare (r = 0.36; p= 0.046). IgA and IgG ACPA showed a tendency towards independent contribution to the risk of flare with the highest risk if a patient had both antibody classes. Conclusion In this study, IgA ACPA was identified as a risk factor for flare in combination with IgG ACPA. IgA2 ACPA levels were associated with flare severity and declined in patients in stable remission.

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