The close association between different type II human leukocyte antigen (HLA) molecules and the risk of RA is well established. These major histocompatibility complex (MHC) class II molecules share the same amino acid sequence (QKRAA or QRRAA) in positions 69 to 74 of the β-chain, namely the 'shared epitope'. Recent works have demonstrated that this 'shared epitope' preferentially binds peptides containing the non-standard amino acid citrulline (deiminated arginine) [11
]. In addition, an abnormally increased function of the enzyme peptidylarginine deiminase 4 (PAD4; responsible for the deimination of arginine) and an elevated anti-CCP autoantibody production in patients with RA have been demonstrated [12
]. These facts have built the first bridge between cellular and humoral autoimmunity in a major rheumatic disease, supporting a pathogenetic role for an abnormal metabolism of citrulline in the development of RA [13
Patients with SLE are often part of the control group when determining the specificity of anti-CCP antibodies for RA [15
], although some studies have been performed specifically on patients with SLE. These studies contribute some clues to the role of anti-CCP antibodies in rhupus. Mediwake and colleagues [16
], in a study exploring the predictive value of anti-CCP antibodies to distinguish erosive arthritis in SLE, found ten patients (out of 231) with erosive arthritis, two of whom had anti-CCP antibodies. In concord with this, Hoffman and colleagues [15
] demonstrate that three patients with erosive arthritis, included in a cohort of 235 patients with SLE, were positive for anti-CCP antibodies. These authors suggest that the presence of anti-CCP antibodies can predispose for a chronic RA-like arthritis in patients with SLE. Additionally Weissman and colleagues [17
] demonstrated that patients with SLE can display radiographic abnormalities similar to those of RA, although the presence of marginal erosions is a rare finding.
In the present study we demonstrate that the patients with rhupus show a very similar arthritis pattern (including erosive disease) and similar autoantibody production (RF and anti-CCP antibodies) to those in patients with RA. In addition, patients with rhupus display a clinical and serological profile indistinguishable from patients with SLE. Moreover, the presence of other coexistent autoimmune diseases was similar in all groups of patients (two patients with rhupus, three patients with RA, and three patients with SLE also had SS).
We found high titers of anti-CCP antibodies in four of seven (57%) patients with rhupus, a frequency similar to that reported for RA [4
]. This finding, together with the clinical similarity, supports the contention that rhupus belongs to the RA spectrum. The high prevalence of anti-CCP antibodies in RA found in our study could be explained by a selection bias because only patients with RA with an aggressive disease (namely erosive arthritis and RF+
) were included. In contrast, the mean ACR criterion for SLE was similar between patients with rhupus and those with SLE, including the 'robust' features of SLE such as renal and neurological involvement, and anti-dsDNA and anti-Sm antibodies. These clinical and serological features shared between patients with rhupus and those with SLE also place rhupus in the SLE spectrum.
Titration of anti-CCP antibodies in the rhupus group clearly shows a bimodal distribution, suggesting the existence of two different subpopulations. Because of the small number of patients, we are unable to define the differential features underlying each subset. However, two of three patients negative for anti-CCP antibodies were also negative for both RF and anti-dsDNA antibodies.