Radiographic damage in patients with RA is one of the most important outcome measures in clinical trials and observational studies as well as in daily practice [5, 7, 8, 10, 18, 48]. It is regarded as resulting from previous inflammation of the joints and is correlated with functional disability at increasing levels over time [33, 34]. Other predictors include, baseline radiographic scores, the presence of IgM-RF and/or anti-CCP antibodies, specific HLADRB1 genotypes and high disease activity, disability scores and levels of acute-phase reactants [19–36, 54, 55]. Machold et al,  demonstrated that, despite early treatment, substantial damage occurred in some patients with a very early arthritis was associated with presence of strong 'constitutive' predictors such as anti-CCP antibodies and RF as well as the presence of high long-term clinical disease activity as indicated by the level of CRP, swollen joint counts and the absence of a good clinical response (assessed by the failure to achieve lasting low disease activity).
Several authors reported that baseline radiographic damage scores predict subsequent radiographic progression [56–59]. In the present study, as well as reported in literature the joint damage at baseline was a significant predictor of progression. Our prospective analysis has confirmed that the predictive accuracy of subsequent radiographic progression is greatly improved by taking into consideration the total inflammatory burden, estimated as the AUC for continuous measures of the DAS28-CRP. The AUC analysis captures two dimensions of the disease activity (magnitude and duration) in a single continuous measure [44, 60]. Analysis of AUC is commonplace in other areas of medicine, for example pharmacology, quality of life research in an obvious extension. Thus, AUC of the DAS28-CRP is a very robust measure, responsive to the disease characteristics. Disease outcome is thought to be the result of the exposure to disease activity over time, rather than the result of initial disease activity [33, 34].
In a cohort of active early RA patients, Knijff-Dutmer and Cohen et al  found a linear relationship between time integrated disease activity parameters and progression of radiographic damage was also seen. Similar results were reported by Molenaar et al  and Welsing et al . They showed the correlation between the disease activity and the radiographic bone damage evaluated by Sharp/van der Heijde method in patients with RA follow-up for 2 years and 9 years, respectively. The hypothesis that chronic inflammation and joint destruction are closely linked is further supported by recent data from imaging studies [36, 61, 62] that demonstrated that in early RA bone damage occurs proportionately to the level of synovitis, but not in its absence. Using CRP for calculation of the DAS28 is an attractive alternative to ESR for a number of reasons. CRP level correlates more closely than ESR with subjective (morning stiffness, pain and fatigue after walking) and semi-objective (grip strength, articular index) and clinical parameters of RA disease activity [28, 32], whereas ESR can be influenced by a number of unrelated factors, such as age, gender or plasma proteins. Laboratory tests used to calculate CRP are faster than those used to measure ESR, and measurements can be standardized in a central laboratory for multicenter clinical trials. Further, serum CRP level also has prognostic value in terms of progressive joint damage and functional status and outcome [28–30, 32]. In a 3-year follow-up, van Leeuwen et al.  demonstrated a highly significant correlation between time integrated CRP values and radiographic progression of disease in patients with newly diagnosed RA. Plant et al.  prospectively examined the relationship between time-integrated CRP levels and radiographic progression in previously normal joints and already damaged joints in patients with active RA treated with DMARDs; after a 5-year follow-up period, the mean Larsen score increased from 15.9 to 36.2. Time-averaged CRP levels correlated significantly with the mean change in Larsen score over the 5-year period and a stronger correlation was seen in patients with disease duration 2 years at study entry.
Moreover, our study showed that both the presence of anti-CCP antibodies and IgM-RF correlates to the radiographic bone damage. The search for new predictive and prognostic biomarkers in patients with RA are of clinical importance [28, 30, 58, 59] Various studies have attempered to identify prognostic factors of radiographic progression in patients with early RA. RF is one of the most powerful predictors of joint damage in early RA populations in most studies [19, 26, 29, 32, 33, 65, 66]. With this regard, Knijff-Dutmer et al  showed a correlation between a persistent disease activity evaluated by the calculation of the AUC and radiographic bone damage progression. A weak correlation between the radiographic damage progression and the presence of IgM-RF was found was also confirmed by Drossaers-Bakker et al  and by Lindqvist et al . Among several autoantibodies described in recent years in patients with RA [20, 23, 25, 28], synthetic cyclic peptides containing citrulline CCP antibodies has been proposed as a new biomarker of disease severity, since it has been found to be more sensitive than the IgM-RF by all who have published studies on this area. Positivity of anti-CCP has been found in our and in several studies, to have prognostic properties in early (and very early) arthritis, although anti-CCP antibodies may not be present at disease manifestation but may develop later in a percentage of RA patients [21–24, 27]. Recent reports confirm the prognostic significance of these antibodies in early RA to be even greater than IgM-RF [69–71]. Berglin et al. reported that anti-CCP antibodies detected in preclinical phases of RA predict a poor radiographic outcome in early RA after 2 years of follow-up, whereas IgM-RF does not. Kroot et al,  in a study of patients with early RA found that anti-CCP positive patients at follow up had developed significantly more radiographic damage than patients without this antibody. However, in a multiple regression analysis the presence of IgM-RF was a better predictor of radiographic change (modified Sharp score) after three years than the presence of anti-CCP. Similar to our results, Bukhari et al  found that the presence of anti-CCP antibodies at baseline was strongly associated with both prevalent erosions (odds ratio [OR] 2.53]) and developing erosions at 5 years (OR 10.2). These ORs were higher than those for IgM-RF (OR 1.63 and 3.4, respectively).
The present study has several limitations. First, this study encompassed a relatively short period of observation, and the changes in radiographic progression seen over 3 years may not necessarily extrapolate to longer observation periods. Secondly, only a small percentage of patients received TNF-blocking agents in combination with MTX, during the follow up. Agents that block TNF, have been shown to significantly reduce joint inflammation, slow radiographic progression of joint damage, and improve physical function in clinical studies of both advanced and early RA [13, 18, 72, 73] and this may have had some influence on the rate of the radiographic progression in this study. Further, blood tests were performed at several independent laboratories and the magnitude of intra and inter-laboratory error of ESR, CRP, anti-CCP antibodies and IgM-RF positivity has not been established and may well be significant.