Matsui and colleagues [23] reported similar correlations in a group of RA patients. non-RA patients (n = 2,245), the corresponding values were 2% and 4%, respectively. In patients with at least two samples (n = 3,769), ACPA status was more stable CR2 than IgM-RF status in RA patients. ACPA- or IgM-RF-negative non-RA patients seldom became positive. ACPA positivity was unrelated to age in both RA and non-RA patients. IgM-RF positivity was unrelated to age in RA patients; however, it increased with age in non-RA patients. The correlation between autoantibody levels and inflammatory markers was low in general and was somewhat higher for IgM-RF than for ACPA. Conclusions ACPA status is more stable in time and with increasing age than IgM-RF status, further establishing its role as a disease-specific marker. ACPA and IgM-RF levels are only moderately correlated with markers of inflammation. Introduction One of the frequent characteristics of rheumatoid arthritis (RA) is the presence of antibodies to citrullinated proteins/peptides (ACPAs) and/or IgM rheumatoid factor (IgM-RF) [1]. IgM-RF targets the Fc fragment of IgG and is observed in about 60% to 65% of RA patients, but it is also frequently observed in other inflammatory diseases [2,3]. ACPAs comprise a group of antibodies that are highly specific for RA: among those are antibodies against cyclic citrullinated peptide (CCP) [4]. ACPAs target citrullinated proteins and are observed in around 70% of RA patients. In contrast to IgM-RF, ACPA is highly specific for RA (specificity 80% versus 96%, respectively) [3]. Besides their well-established superior specificity for RA, several other properties of ACPA are distinct from IgM-RF. About 50% to 70% of early-RA patients are ACPA-positive, and this phenotype remains fairly stable thereafter [2,5,6], Valrubicin even during treatment with tumour necrosis factor (TNF)-blocking agents [7]. On the other hand, IgM-RF levels decrease during antirheumatic treatment [8] and 17% of IgM-RF-positive RA patients turned negative after 6 months of anti-TNF treatment [9]. Furthermore, IgM-RF [10], but not ACPA [11], is sometimes present in healthy older persons, suggesting that RF can be a consequence of nonspecific immune activation. Moreover, it has been suggested that IgM-RF production also is a consequence of the rheumatoid inflammation whereas ACPA may have pathophysiological properties. Evidence supporting this concept is emerging [12]. For instance, ACPA precedes IgM-RF in the preclinical phase [13] and the change in IgM-RF levels during anti-TNF treatment is associated with the change in acute-phase response; this is not observed for ACPA [9]. These data suggest that ACPA and IgM-RF represent two different autoantibody systems. ACPAs are disease-specific, their presence is fairly stable in time and does not increase with age, and ACPA levels are not correlated with the acute-phase response. On the other hand, IgM-RF is less disease-specific, its presence increases with age in healthy/non-RA individuals, and its levels are correlated with the acute-phase response. Most of these data have emerged from studies of selected populations with small sample sizes. In the present study, we sought to confirm the stability of ACPA in time, the increased IgM-RF frequency with age, and the correlation of IgM-RF with the acute-phase response using a repository of over 22,000 serum samples collected from over 18,000 patients attending a rheumatology clinic network in The Netherlands. Materials and methods ACPA and IgM-RF levels were determined in 22,427 samples, which were collected from 18,658 patients between August 2003 and August 2007. These patients attended one of the outpatient rheumatology clinics of the Jan van Breemen Institute in the Amsterdam region of The Netherlands. Each patient’s final diagnosis was obtained from the International Classification of Diseases version 10 diagnosis registration system, which reflects the opinion of the treating rheumatologist. The diagnosis was categorized into five groups according to the following codes: RA, polyarthritis or oligoarthritis, spondylarthropathy (including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy), osteoarthritis, and other (including arthralgia, fibromyalgia, and no final diagnosis). The latter four groups were also Valrubicin combined and classified as ‘non-RA’. The disease duration at the Valrubicin time of autoantibody testing was variable and unknown. For the association between age and autoantibody positivity, patients were grouped according to their age at the first available sample: younger than 30, 30 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, and 80 years old or older. The local ethics committee approved the study protocol and waived the need for informed patient consent. Laboratory investigations All measurements were routinely performed at the certified clinical laboratory of the Jan van Breemen Institute. After the first sample, sequential samples were obtained as a part of routine or protocollar care. In the case of routine care, samples were obtained at the request of the rheumatologist at a nonspecific.