The risk of individual autoantibodies, autoantibody combinations and levels for arthritis development in clinically suspect arthralgia

Brinck, Robin M. ten; Steenbergen, H.W. van; Delft, Myrthe A. M. van; Verheul, Marije K.; Toes, René E. M.; Trouw, Leendert A.; Mil, Annette H. M. van der Helm – van

doi:10.1093/rheumatology/kex340

Cited by 62 publications

(52 citation statements)

References 21 publications

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“…Taken together, these data suggest that the dramatic interaction between the HLA-DRB1 SE and smoking in conferring a risk of RF-positive RA (8) and ACPA-positive RA (6,23) requires the simultaneous presence of both of these antibodies. Interestingly, the presence of both RF and ACPAs also appears to provide the highest risk for subsequent development of RA in antibody-positive, but still nonarthritic, individuals (24,25). The synergizing effects between ACPAs, RF, and immune complexes have also been described in models of effector phases of joint inflammation in RA (26)(27)(28).…”

Section: Discussionmentioning

confidence: 96%

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Complex Relationships of Smoking, HLA–DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population‐Based Case–Control Study

Hedström

Rönnelid

Klareskog

et al. 2019

Arthritis & Rheumatology

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Objective Smoking is associated with an increased risk of rheumatoid arthritis (RA) in subsets of patients defined according to the presence or absence of anti–citrullinated protein antibodies (ACPAs) and rheumatoid factors (RFs). Moreover, an interaction between smoking and the HLA–DRB1 shared epitope (SE) has been demonstrated to be a risk factor for seropositive RA. The aim of this study was to investigate the interplay between smoking and the HLA–DRB1 SE with regard to risk of RA in different patient subsets based on ACPA and RF status. Methods Incident cases of RA (3,645 cases, 5,883 matched controls) were divided into 4 subgroups based on the presence or absence of RF and anti–cyclic citrullinated peptide 2 (anti‐CCP2) antibodies. The influence of smoking on the risk of disease was determined in each RA subgroup, using logistic regression models with calculation of odds ratios and 95% confidence intervals (95% CIs). The potential interaction between smoking and HLA–DRB1 SE genes was evaluated by calculating the attributable proportion due to interaction (AP). Results In the RF+/anti‐CCP2+ subset of RA patients, both smoking and the presence of the HLA–DRB1 SE conferred independent disease risks, and there was a strong interaction between the 2 risk factors (AP 0.4, 95% CI 0.3, 0.5). In the RF−/anti‐CCP2+ patient subset, the HLA–DRB1 SE conferred an increased risk of RA, whereas the independent influence of smoking was limited. However, there was a significant interaction between the HLA–DRB1 SE and smoking (AP 0.2, 95% CI 0.02, 0.5). In the RF+/anti‐CCP2− patient subset, there was an increased risk of disease among smokers, which was only marginally affected by the presence of the HLA–DRB1 SE, and no interaction between the 2 factors was observed (AP 0.002, 95% CI −0.3, 0.3). In the RF−/anti‐CCP2− patient subset, neither smoking nor the presence of the HLA–DRB1 SE conferred an increased risk of RA. Conclusion These findings demonstrate different effects of smoking and HLA–DRB1 in the 4 serologically defined RA subsets.

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Section: Discussionmentioning

confidence: 96%

“…Interestingly, the presence of both RF and ACPAs also appears to provide the highest risk for subsequent development of RA in antibody‐positive, but still nonarthritic, individuals . The synergizing effects between ACPAs, RF, and immune complexes have also been described in models of effector phases of joint inflammation in RA .…”

Section: Discussionmentioning

confidence: 99%

Complex Relationships of Smoking, HLA–DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population‐Based Case–Control Study

Hedström

Rönnelid

Klareskog

et al. 2019

Arthritis & Rheumatology

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“…Imaging studies indicate that this clinical phenotype may also feature subclinical synovitis . Although arthralgia in conjunction with a broad autoantibody response is a strong predictor of imminent RA onset, a linear progression toward these features has been difficult to demonstrate . In particular, the existing longitudinal data suggest that a considerable proportion of individuals with ACPA do not develop RA.…”

Section: Discussionmentioning

confidence: 99%

N‐Linked Glycans in the Variable Domain of IgG Anti–Citrullinated Protein Antibodies Predict the Development of Rheumatoid Arthritis

Hafkenscheid

Moel

Smolik

et al. 2019

Arthritis & Rheumatology

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Objective Anti–citrullinated protein antibodies (ACPAs) are disease‐specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor N‐linked glycans in the antibody variable (V) domain. The corresponding N‐glycosylation sites in ACPA V‐region sequences result from somatic hypermutation, a T cell–dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA. Methods We analyzed 2 independent sets of serum samples obtained from 126 ACPA‐positive first‐degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross‐sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity‐purified and subjected to ultra high‐performance liquid chromatography–based glycan analysis. Results In both data sets, FDR‐derived IgG ACPA displayed markedly lower levels of V domain glycans (<50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V‐domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V‐domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 [95% confidence interval 1.46–25.2]; P = 0.013). Conclusion Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA‐positive individuals and may serve to better target prevention measures.

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“…Moreover, in a meta‐analysis investigating various cohorts of presymptomatic individuals, triple positivity resulted in high specificity (98%‐100%), but low sensitivity (11%‐39%) for prediction of RA development . However, in individuals who have already progressed to the stage of arthralgia, anti‐CarP did not have an additive value to ACPA and RF in predicting arthritis onset . Once disease has developed, the value of anti‐CarP regains its importance: The presence of anti‐CarP has been independently associated with higher disease activity at baseline and over time, as well as with radiographic damage .…”

Section: Clinical Relevance Of Autoantibodies In Ramentioning

confidence: 97%

“…84 However, in individuals who have already progressed to the stage of arthralgia, anti-CarP did not have an additive value to ACPA and RF in predicting arthritis onset. 85 Once disease has developed, the value of anti-CarP regains its importance:…”

Section: Clini C Al Rele Van Ce Of Autoantibod Ie S In R Amentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

117

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. In the last few decades, new insights into RA‐specific autoantibodies and B cells have greatly expanded our understanding of the disease. The best‐known autoantibodies in RA—rheumatoid factor (RF) and anti‐citrullinated protein antibodies (ACPA)—are present long before disease onset, and both responses show signs of maturation around the time of the first manifestation of arthritis. A very intriguing characteristic of ACPA is their remarkably high abundance of variable domain glycans. Since these glycans may convey an important selection advantage of citrulline‐reactive B cells, they may be the key to understanding the evolution of the autoimmune response. Recently discovered autoantibodies targeting other posttranslational modifications, such as anti‐carbamylated and anti‐acetylated protein antibodies, appear to be closely related to ACPA, which makes it possible to unite them under the term of anti‐modified protein antibodies (AMPA). Despite the many insights gained about these autoantibodies, it is unclear whether they are pathogenic or play a causal role in disease development. Autoreactive B cells from which the autoantibodies originate have also received attention as perhaps more likely disease culprits. The development of autoreactive B cells in RA largely depends on the interaction with T cells in which HLA “shared epitope” and HLA DERAA may play an important role. Recent technological advances made it possible to identify and characterize citrulline‐reactive B cells and acquire ACPA monoclonal antibodies, which are providing valuable insights and help to understand the nature of the autoimmune response underlying RA. In this review, we summarize what is currently known about the role of autoantibodies and autoreactive B cells in RA and we discuss the most prominent hypotheses aiming to explain the origins and the evolution of autoimmunity in RA.

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The risk of individual autoantibodies, autoantibody combinations and levels for arthritis development in clinically suspect arthralgia

Cited by 62 publications

References 21 publications

Complex Relationships of Smoking, HLA–DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population‐Based Case–Control Study

Complex Relationships of Smoking, HLA–DRB1 Genes, and Serologic Profiles in Patients With Early Rheumatoid Arthritis: Update From a Swedish Population‐Based Case–Control Study

N‐Linked Glycans in the Variable Domain of IgG Anti–Citrullinated Protein Antibodies Predict the Development of Rheumatoid Arthritis

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

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