Third‐Generation Anti–Cyclic Citrullinated Peptide Antibodies Improve Prediction of Clinical Arthritis in Individuals at Risk of Rheumatoid Arthritis

Matteo, Andrea Di; Mankia, Kulveer; Duquenne, Laurence; Mähler, Michael; Corscadden, Diane; Mbara, Katie; Garcia-Montoya, Leticia; Nam, J.; Emery, Paul

doi:10.1002/art.41402

Cited by 33 publications

(28 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a UK cohort enrolling patients with anti-CCP2 and nonspecific musculoskeletal symptoms, 30% progressed to clinical arthritis within 3 years, which was predicted by the concurrent presence of RF or anti-CCP3, respectively (104,105). Further illustrating the prognostic importance of ACPA, inflammatory arthritis developed in only 1.3% within one year in a large anti-CCP2 negative control population with recent-onset musculoskeletal pain (106).…”

Section: Autoantibodies Before Ra Diagnosismentioning

confidence: 99%

“…It needs to be pointed out, however, that higher levels of autoantibodies often coincide with increased number of autoantibody classes present. The two cohorts studying anti-CCP2 positive patients with musculoskeletal pain found both RF and anti-CCP2 levels to be independently prognostic for arthritis development (105,107). However, in the study recruiting patients based on symptoms only, regardless of autoantibody status, neither anti-CCP2 nor RF levels turned out to be significant predictors of arthritis (99), although statistical power was limited.…”

Section: Do Antibody Levels Matter?mentioning

confidence: 99%

See 1 more Smart Citation

Autoantibodies in Rheumatoid Arthritis – Laboratory and Clinical Perspectives

2021

View full text Add to dashboard Cite

Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.

show abstract

Section: Autoantibodies Before Ra Diagnosismentioning

confidence: 99%

Section: Do Antibody Levels Matter?mentioning

confidence: 99%

Autoantibodies in Rheumatoid Arthritis – Laboratory and Clinical Perspectives

2021

View full text Add to dashboard Cite

show abstract

“…In addition, within cases, an increasing number of positive biomarkers (anti‐CCP3, RF‐IgM, and sCP) in a sample yielded an increasing PPV for a diagnosis of RA within 3 years. Furthermore, these findings add to the understanding that anti‐CCP3 can be present in pre‐RA ( 10 ).…”

Section: Discussionmentioning

confidence: 61%

Combinations of Anticyclic Citrullinated Protein Antibody, Rheumatoid Factor, and Serum Calprotectin Positivity Are Associated With the Diagnosis of Rheumatoid Arthritis Within 3 Years

Bettner¹,

Peterson

Bergstedt

et al. 2021

ACR Open Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective To evaluate the prevalence of elevations of anti‐cyclic citrullinated peptide‐3 (anti‐CCP3) antibody, rheumatoid factor IgM (RF‐IgM) and serum calprotectin (sCP) in pre–rheumatoid arthritis (RA) as well as the diagnostic accuracies of these biomarkers for the timing of diagnosis of future RA. Methods A total of 215 RA cases, each with approximately three pre‐RA diagnoses and one post–RA diagnosis serum sample, and controls were identified from the Department of Defense Serum Repository. All case samples and a single sample from each control subject were tested for anti‐CCP3 (IgG), RF‐IgM, and sCP. The diagnostic accuracies of biomarkers for future RA were evaluated. Results Anti‐CCP3, RF‐IgM, and sCP were elevated in pre‐RA, with anti‐CCP3 and sCP significantly elevated compared with RF‐IgM at the earliest time points. Within the cases, the combination of anti‐CCP3 and RF‐IgM positivity had a positive predictive value (PPV) of 35.6% for a diagnosis of RA in 3 years or less, which is significantly higher than the PPV of 18.7% for anti‐CCP3 positivity alone (P < 0.001). A combination of anti‐CCP3, RF‐IgM, and sCP had the highest PPV (53.0%) for a diagnosis of RA in 3 years or less; however, this was not significantly higher than the PPV for anti‐CCP3 and RF‐IgM positivity (P = 0.248). Conclusion Anti‐CCP3, RF‐IgM, and sCP are elevated in pre‐RA; furthermore, combinations of elevations of these biomarkers are more commonly seen in the period of less than or equal to 3 years to diagnosis. This may be considered in creating inclusion criteria in prevention trials in RA. In addition, the biologic relationships of these biomarkers in pre‐RA need exploration.

show abstract

“…Notably, the ACPA assay utilized herein was the anti-CCP3 assay and therefore it is not clear that findings herein are applicable to all ACPA assays which may have differing predictive values for future IA/RA (38,39) In addition, there are multiple other factors including other autoantibody systems [e.g. antibodies to carbamylated antigens and/or other modified proteins (40)], inflammatory markers [e.g.…”

Section: Discussionmentioning

confidence: 99%

Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis

et al. 2022

View full text Add to dashboard Cite

Background/PurposeIn rheumatoid arthritis (RA) autoantibodies including antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF) can be predictive of incident clinical RA. However, there is limited understanding of how antibody changes over time impact prediction of the likelihood and timing the likelihood and timing of future clinical RA.Materials and MethodsWe evaluated relationships between ACPA, the shared epitope (SE), RF isotypes and incident RA in a prospective cohort of 90 ACPA(+) individuals without baseline arthritis identified through health-fair testing (i.e. Healthfair). We also evaluated ACPA and RF isotypes and time-to-diagnosis of RA in a retrospective cohort of 215 individuals with RA from the Department of Defense Serum Repository (DoDSR).ResultsTwenty-six of 90 (29%) of ACPA(+) Healthfair participants developed incident RA. Baseline or incident dual RF-IgA and RF-IgM positivity was associated with increased risk for incident RA (HR 3.09; 95% CI 1.15 to 8.29) although RFs were negative in ~50% of individuals with incident RA. SE was associated with increased risk of RA (HR 2.87, 95% CI 1.22-6.76). In the DoDSR cohort, triple positivity for ACPA, RF-IgA and RF-IgM was present a median of 1-2 years prior to RA diagnosis, with some sex-specific differences.ConclusionThese findings can be used to counsel individuals at-risk for future RA and to design clinical trials for RA prevention. The findings also suggest that RF could be a surrogate outcome as a success of an immunologic intervention in RA prevention. Additional studies are needed to understand the biologic of different patterns of autoantibody elevations in RA evolution.

show abstract

Third‐Generation Anti–Cyclic Citrullinated Peptide Antibodies Improve Prediction of Clinical Arthritis in Individuals at Risk of Rheumatoid Arthritis

Cited by 33 publications

References 38 publications

Autoantibodies in Rheumatoid Arthritis – Laboratory and Clinical Perspectives

Autoantibodies in Rheumatoid Arthritis – Laboratory and Clinical Perspectives

Combinations of Anticyclic Citrullinated Protein Antibody, Rheumatoid Factor, and Serum Calprotectin Positivity Are Associated With the Diagnosis of Rheumatoid Arthritis Within 3 Years

Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis

Contact Info

Product

Resources

About