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

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 ACPA-negative 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 cross-sectional 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 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 IgM-RF 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.

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.

The well-known association between ACPA or RF status and radiographic outcome was confirmed in the present study. Therefore, we focussed on ACPA and IgM-RF levels at baseline and changes in the year thereafter in relation to outcome at two years, to investigate whether this would provide additional prognostic information in early arthritis patients.

The results were that baseline levels were only marginally associated with later radiographic damage. The first-year change in IgM-RF levels was modestly associated with SHS at the two-year follow up; however, this association was lost in the subgroup of patients with a positive baseline status.

It was also noted that ACPA and RF rarely switched from negative to positive after one year: in 2 and 3%, respectively. On the other hand, decreases in levels over the first year occurred in the majority of patients, with a median decrease in level of 22% for ACPA and 28% for RF. Recently, another study in very early RA patients reported an increase of ACPA levels of 10% and a decrease of IgM-RF levels of 14% [30]. The marked decrease found in the present study is probably due to treatment, because it is similar to what has been found in reaction to TNF-blocking therapy in established RA [31]. The differential decrease supports the notion that RF is more a disease activity marker and ACPA more a disease-specific marker [31, 32].

At baseline, ACPA levels and status were associated only with SHS at baseline, while IgM-RF levels and status were associated with DAS28 and SHS at baseline, as was also reported previously [20, 30]. For the two-year outcome, there was only a correlation between baseline autoantibody levels and SHS, as had been found before [18, 20, 24, 30], although most studies [3, 8, 10‐15] only addressed autoantibody status. High autoantibody levels at baseline seem to be modestly associated with future radiographic damage. However, in the present study these associations were lost when stratifying for autoantibody status. Previous studies did not analyse separately according to autoantibody status. Therefore, their results could be a reflection of autoantibody status.

The present results show that changes in ACPA level during the first year of follow up are not correlated to the outcome at two years, while there was a weak but negative correlation in the first-year change in IgM-RF levels and SHS at two years. One earlier study reported the absence of a relation between changes in antibody levels and changes in disease activity in the same time period [2]. We are not aware of any study reporting changes in levels as a predictor for outcome later in the disease course.

In conclusion, measurement of ACPA or RF levels in the first year in early arthritis patients does not provide additional information over autoantibody status at baseline in the prediction of the outcome after two years. As seroconversion of autoantibody status after one year is rare, except for downward seroconversion of IgM-RF, it does not seem useful in general to repeat these tests. It is more the presence than the levels of the autoantibodies that counts.