This study shows that the phenotype of RA patients with or without anti-CCP antibodies does not differ at clinical presentation. In a large, prospective, early arthritis cohort we observed neither a significant difference in the reported first symptoms nor in the signs found in the physical examination at initial presentation between anti-CCP-positive patients and anti-CCP-negative patients. During follow-up, however, anti-CCP-positive RA patients have more swollen joints and show more radiological destruction than anti-CCP-negative RA patients. It is remarkable that at follow-up, in spite of the difference in magnitude of the disease characteristics, the distribution of swollen joints and the distribution of radiological joint space narrowing and bone erosions remains similar for RA patients with and without anti-CCP antibodies. This implies that although different associations with known risk factors are reported for anti-CCP-positive and anti-CCP-negative RA patients, the presence or absence of anti-CCP antibodies is not associated with a distinguishable clinical phenotype at presentation of disease.
Pathophysiologically, this may have implications. It was recently observed that the prominent genetic risk factor HLA class II alleles only associate with susceptibility to RA in the presence of anti-CCP antibodies but not with RA in the absence of these antibodies (unpublished data, [5
]). It has been shown in mice that citrullination of arginine in a peptide can lead to a higher binding affinity of that peptide for HLA-DRB*0401, an important shared epitope allele [12
], allowing peptide-specific T-cell induction. It can be speculated that also in humans citrullination may improve antigen presentation to CD4-positive T cells and that the genetic background (presence of shared epitope alleles) provides the basis for a citrulline-specific immune reaction.
It has been demonstrated that anti-CCP antibodies occur years before disease onset [3
]. This latter observation suggests that the induction of disease in anti-CCP-positive RA patients occurs years before presentation. The current study, however, shows that the age of onset of clinical disease is similar in RA patients with and without anti-CCP antibodies.
The risk factors such as HLA alleles differ between anti-CCP-negative RA and anti-CCP-positive RA [5
]. Although differences in risk factors presume different pathophysiological pathways for anti-CCP-positive RA and anti-CCP-negative RA, the initial phenotypical presentation of both patient groups is similar and is characterized by a symmetric polyarthritis of the same small joints. At follow-up the clinical phenotype remains comparable with regard to joint distribution, but the anti-CCP-positive patients have more inflamed joints and once there is inflammation also have more rapid joint destruction. This leads to a pathophysiological model in which one or more triggers lead to arthritis in similar joints in anti-CCP-positive patients and anti-CCP-negative patients. Antigens are subsequently citrullinated during inflammation; in the presence of anti-CCP antibodies the inflammation is aggravated, resulting in more severe radiological destruction. Further studies are needed to add insight into the pathogenic role of circulating anti-CCP antibodies in anti-CCP-positive RA and to unravel the risk factors associated with anti-CCP-negative RA.
In a study by Kastbom and colleagues [13
] several baseline disease characteristics of anti-CCP-positive RA patients and anti-CCP-negative RA patients were compared. This study observed no significant differences in baseline total swollen joint count, in C-reactive protein levels or in the Disease Activity Score (DAS)28 score between RA patients with and without anti-CCP antibodies, but showed a positive correlation between the number of fulfilled American College of Rheumatology criteria and the frequency of anti-CCP positivity [13
]. Furthermore, in that study anti-CCP-positive individuals were more often treated with disease-modifying antirheumatic drugs than were anti-CCP-negative patients [13
Although in the present study secular trends in the initial treatment strategies with disease-modifying antirheumatic drugs were present, these trends yielded the same effect for the anti-CCP-positive and anti-CCP-negative RA patients. Furthermore, the rheumatologists that treated the patients were not aware of the anti-CCP status of their patients. The more severe disease course in patients with anti-CCP antibodies is therefore probably not due either to a more delayed treatment of these patients or to confounding by treatment adapted to the anti-CCP status. We cannot exclude the fact that during follow-up the anti-CCP-positive patients that had more inflamed joints received more aggressive treatment. In the case of a more aggressive treatment during follow-up in anti-CCP-positive patients, however, this did not prevent the development of more severe radiological destruction in the RA patients with anti-CCP antibodies. The finding that the swollen joint count decreased during follow-up is probably due to the fact that patients were not treated with disease-modifying antirheumatic drugs at inclusion.
The sensitivity of anti-CCP2 antibodies for RA is reported to vary between 39% and 80% [14
]. The present study measured anti-CCP2 levels at inclusion (a very early stage of the disease) and reports a relatively low percentage (50%) of RA patients with anti-CCP antibodies. As cyclic-citrullinated peptide measurements were not repeated during follow-up, we cannot exclude that some RA patients that were anti-CCP-negative at inclusion have become anti-CCP-positive at a later stage in the disease. A relatively low prevalence of anti-CCP antibodies in early arthritis patients has been described previously [14
The present study shows that the second and third MCP joints have the highest erosion scores as well as the highest joint space narrowing scores and are, of all the MCP joints, the most frequently swollen. Although the present study was not designed to study the correlation between inflammation and destruction, the observed similarity in joints that are affected by swelling, erosions and joint space narrowing supports the concept that, in general, the mechanisms leading to clinical inflammation and radiological destruction are related.
The present study includes a detailed description on the distribution of affected joints in RA and shows that the MCP joints of the second and the third digits are most frequently inflamed and destroyed. Although to our experience rheumatologists generally feel that the joints of the second and third digits are more frequently inflamed than other joints of the hands, to our knowledge this phenotypic characterization has not been frequently described.