(XLS) Click here for additional data file.(81K, xls) Acknowledgments The authors are indebted to the patients that generously have contributed the samples and time to this work. observed in the reference population. We used for analysis of all-cause mortality the Cox proportional hazard regression model with adjustment for age, sex and smoking. It showed a pattern for association with increased mortality of each of the three RA autoantibodies in antibody-specific analysis (hazards ratio (HR) from 1.37 to 1 1.79), but only the HR of the anti-CarP antibodies was significant (HR = 1.79, 95% CI 1.23 to 2.61, p = 0.002). In addition, the multivariate analysis that included all autoantibodies showed GW 501516 a marked decrease in the HR of RF and of anti-CCP antibodies, whereas the HR of anti-CarP remained significant. This increase was specific of respiratory system causes of death (HR = 3.19, 95% CI 1.52 to 6.69, p = 0.002). Therefore, our results suggest a specific relation of anti-CarP antibodies with the increased mortality in RA, and drive attention to their possible connection with respiratory diseases. Introduction Rheumatoid arthritis (RA) is an autoimmune systemic disease that affects primarily diarthrosis (joints with a wide range of movement and covered with synovial tissue) with inflammation, pain, disability and deformity [1,2]. It can also include extra-articular manifestations involving the lungs, the blood vessels or the skin. Other characteristics of the disease are systemic inflammation and alterations of the immune system, including the production of specific autoantibodies. RA is also associated with a notable increase in the death rate that has been quantified at about double the standard mortality rate of the population [3C6]. This increase has dire consequences as it shortens the life expectancy of patients with RA Rabbit polyclonal to IL18 by about 10 years. The excess mortality is due to multiple comorbidities, which include cardiovascular and cerebrovascular diseases, infections, lymphoma, and gastrointestinal diseases, as well as, a group of less common causes of death [3,4,6,7]. GW 501516 The mechanisms leading to increased mortality are not completely understood, although inflammation is associated with cardiovascular disease, and the cumulative burden of disability, decrepitude, pain and treatment side effects is suspected to cooperate with other comorbidities [3,4,7,8]. Accordingly, mortality is associated with RA disease activity and severity. These associations could, in turn, account for the increased mortality observed in patients with RA-specific autoantibodies [3,4,6,7,9C13], because they show a more severe disease [14C17]. However, a more direct effect of the anti-CCP antibodies could be also involved . The first identified RA-specific autoantibody is GW 501516 rheumatoid factor (RF) [1,2]. It consists of IgM antibodies directed against the Fc portion of IgG. It is present in about 70% of the RA patients, but also in a small fraction of patients with other inflammatory diseases or healthy subjects. More recently, several antibodies directed against post-translational modifications of proteins have been identified as RA-specific. The first antibodies of this type that were characterized recognize citrullinated proteins. They are analyzed as anti-cyclic citrullinated peptide antibodies (anti-CCP). These antibodies are very specific of RA, participate in its pathogenesis and are useful diagnostic, prognostic and treatment biomarkers [1,2]. Subsequently, the anti-carbamylated protein antibodies (anti-CarP) were discovered [19C23]. They are rarely assessed because we do not have yet a standardized assay for these antibodies. However, there is already evidence of their involvement in RA pathogenesis and of their possible utility as biomarkers. As mentioned, the presence of RA autoantibodies has been associated with mortality in multiple studies [3,4,6,7,9C13]. However, most studies have included only one antibody or have not compared their relative roles. In the minority of reports comparing antibodies, the results are often discordant [9C13]. This heterogeneity of results is evident.