Research Article: Anti-carbamylated protein autoantibodies associated with mortality in Spanish rheumatoid arthritis patients

Date Published: July 3, 2017

Publisher: Public Library of Science

Author(s): Laura Vidal-Bralo, Eva Perez-Pampin, Cristina Regueiro, Ariana Montes, Rosana Varela, Maria Dolores Boveda, Juan J. Gomez-Reino, Antonio Gonzalez, Masataka Kuwana.


Patients with rheumatoid arthritis (RA) have an increased mortality rate that is associated with the presence of RA-specific autoantibodies in many studies. However, the relative role of rheumatoid factor (RF), anti-CCP antibodies and the most recently established RA-autoantibodies, directed against carbamylated proteins (anti-CarP antibodies), is unclear. Here, we have assessed the role of these three antibodies in 331 patients with established RA recruited from 2001 to 2009 and followed until November 2015. During this time, 124 patients died (37.5%). This death rate corresponds to a mortality rate 1.53 (95% CI 1.26 to 1.80) folds the 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 trend for association with increased mortality of each of the three RA autoantibodies in antibody-specific analysis (hazards ratio (HR) from 1.37 to 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 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.

Partial Text

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 [3–6]. This increase has dire consequences as it shortens the life expectancy of patients with RA 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]. 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 [3,4,6,7,9–13], because they show a more severe disease [14–17]. However, a more direct effect of the anti-CCP antibodies could be also involved [18].

We have included patients with established RA meeting the 1987 American College of Rheumatology classification criteria in this study [24]. Their recruitment took place from 2001 to 2009 at the Rheumatology Unit in our Hospital. We also obtained samples, demographic data and smoking information, together with the written informed consent. The Ethics Committee for Clinical Research of Galicia approved the study. All patients were Spanish Caucasians. Information on survival since recruitment until November 2015 was collected from the electronic medical records of the patients, which are kept across all levels, from primary care to tertiary level hospitals, of the public and private health centers of Galicia in the IANUS system [25]. The last entry for each patient was the date of death or of the last follow-up visit. Causes of death were obtained from the same IANUS system in 68 patients and from the Galician Death Registry in the remaining 56 patients according with the International Classification of Diseases (ICD) 9 and 10 revisions. They were grouped in four categories: circulatory system, respiratory system, neoplasms and other, which included the remaining causes of death of less frequency.

The 331 patients included in this study were recruited from the outpatient Rheumatology clinic without any selection except fulfilling the ACR classification criteria. They showed characteristics of established RA as shown in Table 1, with an excess of women, advanced age and long time since the start of the first disease symptoms (Data in S1 Table). They were also typical in the fraction showing RA-specific autoantibodies: RF = 60.1%, anti-CCP = 64.7% and anti-CarP = 32.9%, and in the overlap between them (Fig 1), corresponding with concordances of γ = 0.82 between anti-CCP and RF, 0.66 between anti-CCP and anti-CarP, and 0.64 between RF and anti-CarP (p for all of them < 2.0 x 10−16). The frequency of ever smokers was low (Table 1), but characteristic of the smoking habit in the area covered by our hospital. Smoking showed a notable difference between women and men (5.3% of the women, 95% CI 3.1 to 8.9%, vs. 52.3% of the men, 95% CI 41.9 to 62.6%). Here, we have found that the increased mortality of patients with RA was associated with the presence of anti-CarP antibodies. This association was the only significant among the autoantibodies and clearly dominant over the trends observed with RF and anti-CCP antibodies. In addition, the anti-CarP antibodies were specifically associated with deaths attributed to respiratory diseases. The anti-CarP antibodies, which are a new type of RA autoantibodies, were associated with increased mortality in Spanish patients with RA, and this association was dominant over the other RA-specific autoantibodies. In addition, it showed specificity for deaths due to respiratory diseases. However, these results require further validation because the relative roles of the different RA autoantibodies are difficult to disentangle due to their high concordance in patients.   Source:


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