Triple Positivity for Anti–Citrullinated Protein Autoantibodies, Rheumatoid Factor, and Anti–Carbamylated Protein Antibodies Conferring High Specificity for Rheumatoid Arthritis

Verheul, Marije K.; Böhringer, Stefan; Delft, Myrthe A. M. van; Jones, Jonathan D. G.; Rigby, William F.C.; Gan, Ryan W.; Holers, V. Michael; Edison, Jess D.; Deane, Kevin D.; Janssen, Koen M. J.; Westra, Johanna; Brink, Mikael; Rantapää‐Dahlqvist, Solbritt; Huizinga, Tom W J; Mil, Annette H M van der Helm-van; Woude, Diane van der; Toes, René E. M.; Trouw, Leendert A.

doi:10.1002/art.40562

Cited by 95 publications

(69 citation statements)

References 51 publications

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“…We do not know the mechanism behind the predominant association of smoking with the concurrent presence of RA autoantibodies. However, it is well-known that the status of the RA autoantibodies is much more concordant than at random 25,28,40 . This circumstance reveals the existence of pathogenic mechanisms that are shared by the various antibodies.…”

Section: Discussionmentioning

confidence: 99%

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Regueiro

Rodríguez‐Rodríguez

López‐Mejías

et al. 2020

Sci Rep

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the major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anticitrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10-8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10-16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (Rf + 1+2 vs. Rf − 0+1+2 : oR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or AcarpA was found. therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms. Rheumatoid arthritis (RA) is a systemic autoimmune disease that can be divided in two pathogenic subgroups 1,2. The largest subgroup comprises the patients presenting RA specific autoantibodies. These antibodies include the rheumatoid factor (RF), which is directed against the Fc of the IgG, and antibodies against some post-translational protein modifications. The best characterized are anti-citrullinated protein antibodies (ACPA), which in the clinic are assayed as anti-cyclic citrullinated peptides or anti-CCP, and the anti-carbamylated protein antibodies (ACarPA), which are not yet analyzed beyond research studies. The antibody positive patients are known as seropositive and they represent more than two thirds of the total, while the remaining are the seronegative patients.

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Section: Discussionmentioning

confidence: 99%

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Regueiro

Rodríguez‐Rodríguez

López‐Mejías

et al. 2020

Sci Rep

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“…These patients had significantly more US-verified arthritis and tenosynovitis as compared to those who were not. However, with only three triple-positive patients, it is not possible to draw any conclusions, although it is in line with a recent study by Verheul et al demonstrating a high specificity for RA in triple seropositivity in RA [95] US is a valuable tool for the detection of arthritis, tenosynovitis and erosions in patients with SLE [96,97]. It can be assumed, that ACPA-positivity in SLE indicates a phenotype characterized by arthritis.…”

Section: Arthritis Confirmed By Ultrasound More Common In Acpa Positimentioning

confidence: 59%

Diagnostic and prognostic potential of joint imaging in patients with anti-citrullinated protein antibodies

Ziegelasch

2019

Linköping University Medical Dissertations

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The introduction of novel therapeutic strategies set new goals for the patients' outcome, which aims to achieve remission. This goal requires early diagnosis of RA and prompt efficient pharmacotherapy. The introduction of anti-citrullinated protein antibodies (ACPA) two decades ago allowed an earlier RA diagnosis. However, there are indications that ACPA positivity is still associated with higher rates of radiographic damage. As the small joints in hands and feet commonly are the first involved sites of inflammation, the role of different imaging modalities were studied regarding their diagnostic and prognostic impact for assessment of arthritis in RA. Further, ultrasound (US) and radiography were used to study the association between RA-specific antibodies and the occurrence of arthritis and joint damage in systemic lupus erythematosus (SLE).

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“…83 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. 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: 87%

“…In at‐risk individuals without arthralgia, triple positivity for autoantibodies (RF, ACPA, and anti‐CarP) has a higher association with disease development . 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 .…”

Section: Clinical Relevance Of Autoantibodies In Ramentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

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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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Triple Positivity for Anti–Citrullinated Protein Autoantibodies, Rheumatoid Factor, and Anti–Carbamylated Protein Antibodies Conferring High Specificity for Rheumatoid Arthritis

Cited by 95 publications

References 51 publications

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Diagnostic and prognostic potential of joint imaging in patients with anti-citrullinated protein antibodies

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

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