Anti-carbamylated protein antibodies precede disease onset in monkeys with collagen-induced arthritis

Marije K Verheul,Leendert A Trouw,Michel P M Vierboom,Rene E M Toes,Bert A ’T Hart

doi:10.1186/s13075-017-1455-1

Abstract

BackgroundRheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein (anti-CarP) antibodies are rheumatoid arthritis (RA)-associated autoantibodies. Besides their presence in human serum, anti-CarP antibodies have also been described in rodent models of arthritis, while ACPA are not consistently detectable. Data on these RA-associated autoantibodies in primates are not available. Therefore, we investigated the presence of RF, anti-CarP antibodies and ACPA in rhesus monkeys before and after collagen-induced arthritis immunizations.MethodsIn previous studies, arthritis was induced in groups of rhesus monkeys by immunisation with collagen following pre-treatment with placebo, abatacept or Roactemra. Previously collected serum was used to measure, autoantibodies by ELISA, detecting anti-CarP antibodies, RF-IgM and antibodies against CCP2, citrullinated myelin basic protein and citrullinated fibrinogen.ResultsOut of the three autoantibodies, only anti-CarP antibodies were detectable in resus monkeys with arthritis. RF-IgM and ACPA were undetectable and below the detection limit of the ELISA. The level of anti-CarP antibodies increases over time and, similar to in humans and mice, these autoantibodies were already detectable before clinical disease onset. Furthermore, preventive treatment with abatacept (CTLA4/IgG1-Fc fusion protein) inhibited the development of anti-CarP antibodies after immunization, while this was less evident for preventive Roactemra (anti-IL6-receptor) treatment. Moreover, disease progression was only reduced following abatacept treatment.ConclusionRhesus monkeys develop anti-CarP antibodies upon induction of collagen-induced arthritis, while we were unable to detect RF or ACPA. Also, the development of anti-CarP antibodies could be inhibited by preventive abatacept treatment.

Highlights

Rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein antibodies are rheumatoid arthritis (RA)-associated autoantibodies
The presence of RA-associated autoantibodies was measured in 10 rhesus monkeys at the last two available time points after collagen-induced arthritis (CIA) induction
Of the three investigated RA-associated autoantibodies, only anti-CarP antibodies but not ACPA or RF were detected in monkeys with CIA

Summary

Introduction

Rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and anti-carbamylated protein (anti-CarP) antibodies are rheumatoid arthritis (RA)-associated autoantibodies. Besides their presence in human serum, anti-CarP antibodies have been described in rodent models of arthritis, while ACPA are not consistently detectable. Data on these RA-associated autoantibodies in primates are not available. Anti-CarP antibodies have been detected in serum in up to 46% of patients with RA in several cohorts around the world and are shown to be associated with the development of joint damage [5,6,7,8,9,10]. Many clinical associations have been identified for all three of the autoantibodies discussed, their role in the pathogenesis of RA is still under debate

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