EXTENDED REPORT Presence of anticitrullinated protein antibodies in a large population-based cohort from the Netherlands

Objectives To determine the prevalence of anticitrullinated protein antibodies (ACPAs) and their association with known rheumatoid arthritis (RA) risk factors in the general population. Methods Lifelines is a multidisciplinary prospective population-based cohort study in the Netherlands. Crosssectional data from 40 136 participants were used. The detection of ACPA was performed by measuring antiCCP2 on the Phadia-250 analyser with levels ≥6.2 U/mL considered positive. An extensive questionnaire was taken on demographic and clinical information, including smoking, periodontal health and early symptoms of musculoskeletal disorders. RA was defined by a combination of self-reported RA, medication use for the indication of rheumatism and visiting a medical specialist within the last year. Results Of the total 40 136 unselected individuals, 401 (1.0%) had ACPA level ≥6.2 U/mL. ACPA positivity was significantly associated with older age, female gender, smoking, joint complaints, RA and first degree relatives with rheumatism. Of the ACPA-positive participants, 22.4% had RA (15.2% had defined RA according to our criteria and 7.2% self-reported RA only). In participants without RA, 311 (0.8%) were ACPA-positive. In the non-RA group, older age, smoking and joint complaints remained significantly more frequently present in ACPA-positive compared with ACPA-negative participants. Conclusions In this large population-based study, the prevalence of ACPA levels ≥6.2 U/mL was 1.0% for the total group and 0.8% when excluding patients with RA. Older age, smoking and joint complaints were more frequently present in ACPA-positive Lifelines participants. To our knowledge, this study is the largest study to date on ACPA positivity in the general, mostly Caucasian population. INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune disease primarily targeting the joints. It is thought that early treatment with disease-modifying antirheumatic drugs (DMARDs) and possibly steroids can prevent progression of the disease and may even change or prevent the development of erosive disease. A systemic review in early RA demonstrated that longer symptom duration is associated with more radiographic progression and lower chance of DMARD-free sustained remission, supporting the idea of a therapeutic ‘window of opportunity’. Early detection of RA is therefore crucial. Previous studies have shown that persons with arthralgia are at risk for developing RA. This risk is even higher when the arthralgia is combined with anticitrullinated protein antibody (ACPA) positivity. Patients with clinically suspected arthralgia who show subclinical inflammation on MRI were more often ACPA-positive than those without inflammation on MRI, and were at high risk of developing arthritis. Individuals with new nonspecific musculoskeletal symptoms but without clinical synovitis were at high risk of rapidly progressing to RA when they tested ACPA-positive. Therefore, ACPA status can provide important information on both diagnosis and prognosis. 8–10 Depending on the method of ACPA detection and the cut-off value used, 55–91% of patients with RA are considered ACPA-positive compared with 0–9% of healthy control subjects. It has been shown that the switch to ACPA positivity can occur up to 10 years before a patient develops arthritis. Early serum samples from patients with classified RA that were blood bank donors were ACPA-positive in 31–41% of cases. 15 16 Similarly, first-degree relatives (FDRs) are more likely ACPA-positive than regular controls. 17 In a prospective study of 374 individuals who reported arthralgia and had a positive ACPA and/or IgM-rheumatoid factor (RF) status, 35% developed arthritis after a median follow-up of 12 months. Patients who developed arthritis were more often ACPA-positive. However, the presence of antibodies alone had insufficient predictive power and needed to be combined with other clinical parameters. The European League Against Rheumatism Standing Committee on Investigative Rheumatology has pointed out that better insights in early symptoms, ACPA testing and risk factors from patient history are necessary for the development of a predictive model for RA in the years to come. 19 To date, little is known about the presence of ACPA in the general population. One recent population-based study in Japan (n=9575) showed an ACPA positivity prevalence of 1.7% and a Turkish study (n=941) showed a prevalence of 1.0%. So far, only one other population-wide study has been published on the prevalence of ACPA positivity in Europe. In this Swedish twin study (n=12 590) 2.8% were ACPA-positive, including patients with RA. The exact relationship between known RA risk factors, such as age, gender, tobacco, joint complaints and having FDR with RA 23 24 and the development of ACPA positivity needs to be further investigated. 1184 van Zanten A, et al. Ann Rheum Dis 2017;76:1184–1190. doi:10.1136/annrheumdis-2016-209991 Clinical and epidemiological research To cite: van Zanten A, Arends S, Roozendaal C, et al. Ann Rheum Dis 2017;76:1184–1190. Handling editor Tore K Kvien ► Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ annrheumdis-2016-209991). Department of Rheumatology and Clinical Immunology, Groningen, The Netherlands Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Department of Rheumatology, LUMC, Leiden, The Netherlands Correspondence to Dr E Brouwer, University Medical Center Groningen, Rheumatology and Clinical Immunology, P.O. Box 30001, Groningen 9700 RB, The Netherlands; [email protected] Received 31 May 2016 Revised 18 November 2016 Accepted 20 November 2016 Published Online First 2 January 2017 group.bmj.com on July 13, 2017 Published by http://ard.bmj.com/ Downloaded from