articleLevels of anti-citrullinated protein antibodies and IgM rheumatoid factor are not associated with outcome in early arthritis patients : a cohort study

Introduction: To investigate whether baseline levels of anti-citrullinated protein antibody (ACPA) or IgM rheumatoid factor (IgM-RF) and changes in the year thereafter are associated with disease activity, functional and radiographic outcome in early arthritis patients, and provide additional information over baseline autoantibody status. Methods: In 545 early arthritis patients ACPA and IgM-RF levels, disease activity (DAS28), the Health Assessment Questionnaire (HAQ) and Sharp/Van der Heijde Score (SHS) were assessed annually. Baseline status, levels and first-year changes of the autoantibodies were associated with these measures at the two-year follow-up and sub-analysed according to autoantibody status. Results: The mean age was 52.7 years, 69% was female, at baseline 56% was ACPA positive, 47% IgM-RF positive. At the two-year follow-up the mean DAS28 was 2.88, and the median HAQ and SHS were 0.38 and 1, respectively. At one year, ACPA and IgM-RF levels had decreased by 31% and 56%, respectively. A switch from negative to positive occurred in 2% for ACPA and 3% for IgM-RF. Positive ACPA and RF status were both associated with SHS at two years (P < 0.001), but baseline levels only showed a minor correlation of ACPA with DAS28 and HAQ at two years. Level changes were not associated with the outcome parameters. Conclusions: Baseline levels and first-year changes of ACPA and IgM-RF are hardly associated with outcome after two years. Seroconversion seldom occurs. Therefore, it does not appear useful to repeat ACPA or IgM-RF measurements. Introduction Rheumatoid arthritis (RA) is often accompanied by autoimmune phenomena, notably anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Although ACPA-positive RA cannot be distinguished from ACPAnegative RA at first presentation [1,2], several studies have demonstrated that the presence of ACPA is prognostic for disease severity, radiographic erosions, as well as the development of RA in synovitis of recent onset [1,3-8]. Recently, higher ACPA levels have been found in patients who developed RA compared with those who did not develop RA [9]. Most studies assessed the predictive value of the presence of ACPA [3,8,10-15]. However, it is as yet unclear whether high levels of ACPA predict poorer outcome [16-20]. In a prospective study of 104 early RA patients, higher baseline ACPA levels were associated with erosive disease after two years [20]. Another study of 99 early RA patients reported a small, almost significant correlation between baseline serum ACPA levels and radiographic progression after five years [18]. A third study of 238 early RA patients found a higher radiographic progression rate after 10 years of high-positive ACPA versus low-positive ACPA patient groups [19]. Two studies assessed levels of ACPA in patients with longstanding RA. One of these reported a weak association (in 180 patients) between ACPA levels and radiographic progression rate [16]. The other was a crosssectional study of 241 RA patients with a mean disease duration of 8.6 years, in which mean ACPA levels were similar in patients with or without erosions [17]. RF, mostly measured as immunoglobulin (Ig)M-RF, is still widely used as a serological marker for the diagnosis of RA, although it is also frequently observed in other * Correspondence: d.v. schaardenburg@janvanbreemen.nl 1 Jan van Breemen Institute, department of rheumatology, Dr. Jan van Breemenstraat 2, 1056 AB Amsterdam, The Netherlands © 2010 Ursum et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ursum et al. Arthritis Research & Therapy 2010, 12:R8 http://arthritis-research.com/content/12/1/R8 Page 2 of 7 inflammatory diseases [21] and in healthy elderly persons [22] suggesting that RF can be a consequence of nonspecific immune activation. Its presence is a prognostic marker of disease activity and erosive disease [10,20]. Higher IgM-RF levels have been associated with a higher risk for the development of RA[23]. IgM-RF levels also seem to be associated with future radiographic damage: in three studies, in which 78 to 149 early RA patients participated, a correlation was found between baseline IgMRF levels and radiographic damage after two to three years [20,24,25]. Reports of ACPA or IgM-RF levels and outcome in early arthritis are therefore still few and to our knowledge no data are available on changes in levels of ACPA or IgM-RF as a predictor of disease outcome. Changes in autoantibody levels could possibly serve as markers of response to therapy and thus be related to outcome. Therefore, we investigated whether baseline status or levels of ACPA or IgM-RF and their changes in the year thereafter are associated with disease activity, functional and radiographic outcome in a large group of early arthritis patients, and whether analysis of levels provides additional information over baseline antibody status. Materials and methods The early arthritis cohort at the Jan van Breemen Institute, a large rheumatology clinic in Amsterdam, has been described previously [26]. The cohort consists of patients aged older than 18 years with peripheral arthritis of two or more joints and a symptom duration of less than three years, who were referred from 1995 onwards. Patients who were previously treated with a disease modifying anti-rheumatic drug (DMARD) and those with spondylarthropathy, reactive arthritis, crystal-induced arthropathy, systemic lupus erythematosus, Sjögren's syndrome, or osteoarthritis were excluded. The study was approved by the local medical ethics committee and all patients gave written informed consent to be included in the study. For the present analysis, all patients with available ACPA and IgM-RF data at baseline and after one year, and available outcome measures at two-years follow up were included. Antibody measurements ACPA levels were measured as anti-cyclic citrullinated peptide antibodies (second generation anti-CCP ELISA, Axis Shield, Dundee, UK). The anti-CCP test was performed according to the instructions of the manufacturer with a cut-off level for positivity set at 5 Arbitrary Units (AU)/ml. The day to day variation (CV) was 7.4% (n = 98). Anti-CCP levels in sera reaching 1000 AU were not further diluted. IgM-RF was measured by in-house ELISA as described previously [27]. The cut-off level for IgM-RF antibody positivity is set at 30 IU determined on the basis of receiver operator characteristics (ROC) curves described previously [27]. Outcome measures Disease activity was assessed with the Disease Activity Score in 28 joints (DAS28) [28]. Functional status was measured by the validated Dutch version of the Health Assessment Questionnaire (HAQ) [29]. Radiographic damage was assessed with the Sharp/Van der Heijde Score (SHS) by one experienced rheumatologist, who was blinded to the other variables. Two rheumatologists, with an intraclass correlation coefficient of 0.95, each performed part of the scoring. Analysis The baseline characteristics were age, sex, symptom duration, percentage of patients who fulfilled the American College of Rheumatology (ACR) criteria for RA and the percentage IgM-RF and ACPA positivity were compared between those patients included in the study (n = 545) and those excluded (n = 1309). The change in ACPA level was calculated as an absolute change and as a relative change compared with baseline. Outcome measures at the two-year follow up were DAS28, HAQ and SHS, all used as continuous variables. Differences between groups with positive or negative autoantibody status were tested using Mann-Whitney U test or the chi-squared test. Correlations were determined by Pearson rho or Spearman rho as appropriate. Partial correlations were used to correct for baseline values. For an association between change in ACPA level and dichotomous variables, logistic regression analysis was used. Subanalyses were performed for positive and negative autoantibody status at baseline. All analyses were performed using SPSS version 16.0 (SPSS Institute Inc., Cary, NC, USA).