Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study

Elizabeth V Arkema,Elizabeth W Karlson,Jeremy Sokolove,Susan Malspeis,Karen H Costenbader,Catriona A Wagner,Barbara L Goldstein,Bernard Rosner,Francine Grodstein,William Robinson

doi:10.1186/ar4342

Abstract

IntroductionThe aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles.MethodsWe identified 192 women in the Nurses’ Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use. Reactivities to 18 ACPAs were measured using a custom BioPlex platform. We used conditional logistic regression to calculate the relative risk (RR) of RA for any ACPA-positive and peptide-specific ACPA-positive and examined RRs by time between blood draw and RA onset. Measures of multiplicative and additive interaction between any ACPA-positive and HLA-SE were calculated.ResultsAll ACPAs by peptide groups were significantly associated with RA risk, RRs ranged from 4.7 to 11.7. The association between ACPA and RA varied over time with the strongest association in those with blood draw less than 5 years before onset (RR 17.0 [95% CI 5.8 to 53.7]) and no association 10 or more years prior to onset (RR 1.4 [95% CI 0.5 to 4.3]). Individuals with both HLA-SE and any ACPA-positive had the highest risk of RA. HLA-SE-positive RA cases showed reactivity to more ACPA types than HLA-SE negative (χ2 test for trend, P = 0.01).ConclusionsThere is increasing ACPA reactivity up to 10 years before RA onset with the strongest association within 5 years of RA onset. The magnitude of the response to ACPAs, in combination with the presence of HLA-SE, is most important for identifying those individuals with the highest risk of RA.

Highlights

The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles
In this large, prospective cohort study of women followed for many years, we have demonstrated that the majority of a panel of 18 different ACPAs targeted to epitopes in the rheumatoid synovium are strongly associated with risk of future RA
We found that has focusedHuman leukocyte antigen (HLA)-SE-positive RA cases showed reactivity to more ACPA subtypes than HLA-SE-negative cases and that antibodies to citrullinated clusterin and vimentin were most strongly associated with HLA-SE-positive RA

Summary

Introduction

The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles. Past case–control studies have found that having both HLA-SE and anti-CCP antibodies confers a greater risk of developing RA than either one alone [14,15,16]. Most studies of individual ACPAs and RA risk have included patients with early or well-established RA, and those that have included pre-RA patients have not examined the combined effect of ACPA and HLA-SE. Our objective in the present study was to characterize reactivity to ACPAs targeted to epitopes found in the rheumatoid synovium in the preclinical period before RA onset using a nested case–control design within the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) cohorts. We aimed to understand the interaction between ACPA and HLA-SE in determining RA risk within this preclinical window

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