Anti-CCP antibodies as a marker of rhupus

Sir, We have read with interest the works on rhupus, a clinical condition characterized by the coexistence of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), recently published in Lupus. These publications prompted us to investigate the prevalence and characteristics of rhupus in our cohort of patients with SLE, fulfilling international classification criteria. This was a cross-sectional analytical study conducted in 377 Colombian patients with SLE and undertaken between February 1996 and June 2013. The patients’ sociodemographic and cumulative clinical and laboratory data were obtained by interview, standardized report form, physical examination and chart review. The variables were registered at any time during the course of the disease as described elsewhere. Likewise, the relevant laboratory variables associated with SLE were recorded. All of the patients underwent antibodies determination, including IgM rheumatoid factor (RF) and IgG anti-cyclic citrullinated peptide (anti-CCP3), as described elsewhere. Factors associated with rhupus were assessed by bivariate analysis and classification and regression trees (CART) analysis, with complex interactions not captured by logistic regression. The variables included in the statistical model were polyautoimmunity and multiple autoimmune syndrome, familial autoimmunity, gender, age at onset, smoking and coffee consumption, toxic exposure, comorbidities, cardiovascular disease, history of infections, malar rash, discoid rash, photosensitivity, oral ulcers, positive antinuclear antibody, arthritis, serositis, renal, neurologic, hematologic and immunologic disorder. Likewise, positivity for antibodies, lupus anticoagulant and complement status were variables also included. The statistical analyses were performed in R 3.0. 2. and Salford Predictive Modeler v.7. Briefly, CART is a non-parametric approach in which a series of recursive subdivisions separate out the data by dichotomization. The aim is to identify, at each partition step, the best predictive variable and its best corresponding splitting value, while optimizing a statistical criterion. A battery of different statistical criteria (e.g. Gini index, entropy, class probability and Twoing) are used to determine the splitting rule decreasing the most the relative cost of the tree. The best split at each dichotomy node is chosen by either a measure of between-node dissimilarity or iterative hypothesis testing of all possible splits to find the most homogeneous one (less impurity). Although RF and anti-CCP3 were observed in 42.1% and 5.6%, respectively, only 24 patients had rhupus (6.4%). In these patients the frequencies of RF and anti-CCP3 were 72.22% and 55.5%, respectively. The erosive disease presented in 13 out of 24 patients (54.2%). Patients with rhupus were significantly older (46.42 13.47 vs. 36.37 13.47 years, P< 0.001) and had a later age at onset of the disease (35.90 15.25 vs. 28.84 12.58 years, P1⁄4 0.017). However, the duration of the disease was similar in rhupus and in SLE patients (9 7.5 vs. 7.5 7.3 years, P1⁄4 0.324). The mean age at onset of RA was 30 11.63 years. RA preceded SLE in 15 patients (62.5%). The positive and negative predictive values of anti-CCP3 for rhupus were 0.62 and 0.91, respectively. The CART model displayed a high proportion of patients with SLE and anti-CCP3 who develop RA (node 4, Figure 1). This model had an area under the curve of 0.74, which represents an adequate predictive performance. In conclusion, we confirm the association of anti-CCP antibodies with rhupus. As a corollary, the presence of such autoantibodies in patients with SLE should alert clinicians to the coexistence of RA.