The role of anti-citrullinated protein antibody reactivities in an inception cohort of patients with rheumatoid arthritis receiving treat-to-target therapy

Maria Karolina Jonsson, Aase Haj Hensvold, Monika Hansson, Anna-Birgitte Aga, Joseph Sexton, Linda Mathsson-Alm, Martin Cornillet, Guy Serre, Siri Lillegraven, Bjørg-Tilde Svanes Fevang, Anca Irinel Catrina, Espen Andre Haavardsholm, Maria Karolina Jonsson, Aase Haj Hensvold, Monika Hansson, Anna-Birgitte Aga, Joseph Sexton, Linda Mathsson-Alm, Martin Cornillet, Guy Serre, Siri Lillegraven, Bjørg-Tilde Svanes Fevang, Anca Irinel Catrina, Espen Andre Haavardsholm

Abstract

Background: Anti-citrullinated protein antibody (ACPA) reactivities precede clinical onset of rheumatoid arthritis (RA), and it has been suggested that ACPA reactivities towards distinct target proteins may be associated with differences in RA phenotypes. We aimed to assess the prevalence of baseline ACPA reactivities in an inception cohort of patients with early RA, and to investigate their associations with disease activity, treatment response, ultrasound findings and radiographic damage.

Methods: Disease-modifying antirheumatic drug (DMARD)-naïve patients with early RA, classified according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria, were included in the ARCTIC trial and assessed in the present analysis. During follow up, patients were monitored frequently and treatment was adjusted according to a predetermined protocol, starting with methotrexate monotherapy with prednisolone bridging. Analysis of 16 different ACPA reactivities targeting citrullinated peptides from fibrinogen, alpha-1 enolase, vimentin, filaggrin and histone was performed using a multiplex chip-based assay. Samples from 0, 3, 12 and 24 months were analysed. Controls were blood donors with similar characteristics to the patients (age, gender, smoking status).

Results: A total of 217 patients and 94 controls were included. Median [25, 75 percentile] number of ACPA reactivities in all patients was 9 [4, 12], and were most prevalent in anti-cyclic citrullinated peptide /rheumatoid factor-positive patients 10 [7, 12]. Disease activity measures and ultrasound scores at baseline were lower in ACPA reactivity-positive compared to ACPA reactivity-negative patients. ACPA reactivity levels decreased after 3 months of DMARD treatment, most pronounced for fibrinogenβ 60-74 to 62% of baseline antibody level, with least change in filaggrin 307-324 to 81% of baseline antibody level, both p < 0.001. However, outcomes in disease activity measures, ultrasound and radiographic scores after 12 and 24 months were not associated with baseline levels or changes in ACPA reactivity levels and/or seroreversion after 3 months.

Conclusions: The clinical relevance of analysing ACPA reactivities in intensively treated and closely monitored early RA was limited, with no apparent associations with disease activity, prediction of treatment response or radiographic progression. Further studies in larger patient materials are needed to understand the role of ACPA reactivities in patients with RA classified according to the 2010 ACR/EULAR criteria and treated according to modern treatment strategies.

Trial registration: www.ClinicalTrials.gov, NCT01205854 . Registered on 21 September 2010.

Keywords: Biomarkers; Imaging; Inflammation; Outcomes; Rheumatoid arthritis.

Conflict of interest statement

Ethics approval and consent to participate

The protocol for the ARCTIC trial was approved by the local ethics committee of the South-Eastern Norway Regional Health Authority (2010/744) and the study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All patients provided written informed consent.

Competing interests

MKJ reports grants from Norwegian Extra Foundation for Health and Rehabilitation and the Western Norway Regional Health Authority. AHH: none. MH: none. ABA: none. JS: none. LMA is an employee of Thermo Fisher Scientific. MC: none. GS is co-inventor of several international patents for ACPA antigens held by BioMérieux Cy and licensed to Eurodiagnostica Cy and Axis-Shield Cy for commercialization of the CCP2 assays; according to French law he receives a part of the royalties paid to the Toulouse III University and the University Hospital of Toulouse. SL: none. BTSF: none. AIC: none. EAH has received investigator-initiated grants from AbbVie, Pfizer, MSD, UCB Pharma and Roche.

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Figures

Fig. 1
Fig. 1
Number of anti-citrullinated protein antibody (ACPA) reactivities according to autoantibody status. a All patients with rheumatoid arthritis (RA). b Controls. c Patients with anti-cyclic citrullinated peptide (anti-CCP)+ RA. d Patients with anti-CCP- RA. e Patients with rheumatoid factor (RF)+ RA. f Patients with RF- RA. g Patients with anti-CCP+/RF+ RA. h Patients with anti-CCP-/RF- RA
Fig. 2
Fig. 2
Relative change in levels of various anti-citrullinated protein antibody (ACPA) reactivities in patients with early rheumatoid arthritis (RA) (only baseline seropositive patients included) a Relative change between baseline and 3, 12 and 24 months, b Relative change after 3 months, comparing patients on methotrexate monotherapy at 24 months (n = 113) to patients on triple and/or biological disease-modifying antirheumatic drugs (bDMARDs) at 24 months (n = 82). Fib, fibrinogen; Vim, vimentin; H, histone; CEP-1, citrullinated enolase peptide-1; Fil, Filaggrin, numbers referring to amino acid sequence
Fig. 3
Fig. 3
Proportion of patients with radiographic progression by number of baseline ACPA reactivities after 12 months (n = 199) and 24 months (n = 195)

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