Research Category: Clinical
Name: Makoto Soejima Title: Postdoctoral Fellow Degree(s): MD, PhD
Campus Address: BSTS730, 200 Lothrop Street, Pittsburgh PA, 15261
Campus Phone: 412-383-7079 Division: Rheumatology Email Address: mas359@pitt.edu
Title: Effect of Disease Modifying Anti-Rheumatic Drugs (DMARDs) on anti-CCP2 and Anti-Citrullinated Protein Antibody (ACPA) Levels During Longitudinal Assessments in Rheumatoid Arthritis Patients
Authors: M. Soejima, A.M. Patel, D. Goudeau, D.M. Jones, C.L. Amity, L.M. Frydrych, D. Sippel, D.M. Jones, H.F. Eng, D. Kyle, M. Saul, S.R. Wisniewski, L.W. Moreland, M.C. Levesque and the RACER physicians group
Background: Anti-citrullinated protein antibodies (ACPA) are specific markers for rheumatoid arthritis (RA) and may have a pathogenic role in the development of rheumatoid synovitis, as evidenced by data from mouse models. ACPA are comprised of antibodies that bind several different citrullinated proteins. Individual ACPA appear to be a subset of antibodies that bind CCP2, which is a cyclic citrullinated peptide(s) that is widely used to detect ACPA and forms the basis for an important diagnostic test of RA. Unfortunately, the peptide sequence of CCP2 is proprietary and has not been published. Several studies have addressed whether anti-CCP2 levels decrease during treatment with anti-rheumatic disease modifying drugs (DMARDs), but the results vary between studies and most studies have concluded that there is no effect of therapy on anti-CCP2 levels. No studies have examined the effect of DMARDs on levels of individual ACPA. The importance of understanding therapy related changes of individual ACPA is two-fold: 1.) individual ACPA may serve as biomarkers of treatment related effects and 2.) individual ACPA may have a pathogenic role in RA as evidenced by family studies in which RA patients have antibodies that bind both individual ACPA and CCP2 but unaffected family members only have antibodies that bind CCP2.
Purpose: To determine the effect of anti-rheumatic therapies on levels of individual ACPA and anti-CCP2.
Methods: The UPMC Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry was established in 2010 as a prospective, longitudinal, registry of RA patients treated with various therapies. The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study was a randomized, controlled, trial of early RA patients that compared therapy with oral DMARDs only to an oral DMARD (methotrexate) plus an anti-tumor necrosis factor (TNF) therapy (etanercept). For analysis, RACER RA subjects were divided into treatment groups similar to TEAR subjects. One hundred fifteen RA patients with 3 longitudinal samples in the RACER registry and 108 RA patients with 4 longitudinal samples in the TEAR study (baseline, 6, 12 and 24 months after therapy initiation) were clinically assessed at each visit using a disease activity score. Serum levels of anti-CCP2 and individual ACPA were measured using ELISA. The effect of treatment on anti-CCP2 and ACPA levels was analyzed using a mixed effects regression model.
Results: Age, sex, race and disease duration were similar among the different treatment groups within each cohort. However, disease duration was longer in RACER subjects (14.5 ± 11.5 years) versus TEAR subjects (0.3 ± 0.5 years). There were no consistent reductions of anti-CCP2 levels following therapy in RACER or TEAR subjects (RACER: p = 0.1935; TEAR: p = 0.8518). In contrast, among RACER subjects, there were reductions of ACPA levels during treatment with oral DMARDs and with DMARDs plus biologics (p = 0.0748 for anti-citrullinated fibrinogen peptide (P6c) and p = 0.0752 for anti-citrullinated fillagrin peptide (P20c)) but not during therapy with Biologics only. In the TEAR cohort, there were similar reductions in levels of anti-P6c and anti-P20c levels during treatment with oral DMARDs but not during therapy with oral DMARDs plus anti-TNF therapies (P6c: p = 0.0028 and P20c: p = 0.0602).
Conclusions: This is the first study to demonstrate that reductions in ACPA levels are associated with anti-rheumatic treatment in patients with RA. In contrast, and consistent with prior published reports, we found that there were no similar reductions in anti-CCP2 levels during treatment with anti-rheumatic therapies. Importantly, we observed similar results in two separate cohorts. Recent studies suggest that most anti-CCP2 antibodies are low affinity and as evidenced by the family studies may not be pathogenic, while some ACPA, such as those that bind P6c and P20c, are associated with disease pathogenesis in mouse models and are associated with RA development in family studies. Taken together, these results suggest ACPA are differentially regulated compared to other low affinity anti-CCP2 antibodies. Our future studies will focus on cloning individual ACPA and low affinity non-ACPA anti-CCP2 antibodies and will focus on measuring the binding affinities of these monoclonal antibodies. These ACPA and anti-CCP2 monoclonal antibodies will be tested in mouse models of arthritis to assess their pathogenicity.
https://racer.pitt.edu/wp-content/uploads/formidable/ACPA-levels-in-RA-Poster-2011-ACR.ppt