Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

T1D was associated with poorer sleep and high prevalence of OSA. Poor sleep quality, shorter sleep duration, and OSA were associated with suboptimal glycemic control in T1D patients.

Aims: Rheumatoid arthritis is a chronic inflammatory condition that affects approximately 1% of the world's population. There are a wide number of guidelines and recommendations available to support the treatment of rheumatoid arthritis; however, the evidence used for these guidelines is predominantly based on studies in Caucasian subjects and may not be relevant for rheumatoid arthritis patients in the Asia-Pacific region. Therefore, the Asia Pacific League of Associations for Rheumatology established a Steering Committee in 2013 to address this issue. Materials and methods:The AGREE II instrument and the ADAPTE Collaboration framework were applied to systematically identify, appraise, synthesize, and adapt international rheumatoid arthritis guidelines for use in the Asia-Pacific region.Results: Forty rheumatoid arthritis treatment recommendations, based on evidence and expert opinion, were drafted and are presented in this report. Conclusion: The Asia Pacific of Associations for Rheumatology rheumatoid arthritis treatment recommendations are intended to serve as a reference for best practice management of rheumatoid arthritis in Asia-Pacific, focusing on local issues to ensure the delivery of basic care for these patients, and to improve their outcomes. In addition, the document will serve as a reference for national rheumatology associations in Asia-Pacific for developing guidelines in their respective countries.

Objective. Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and are present years before the onset of symptoms. The avidity of autoantibodies can have a strong impact on their effector potency. This study was undertaken to analyze the avidity of ACPAs in serum samples obtained from ACPA-positive healthy individuals (predisease), patients with early disease, and patients with established RA as well as the avidity maturation over time in samples from healthy subjects who later developed RA.Methods. We measured ACPA avidity in serum samples from ACPA-positive healthy individuals, symptomatic individuals, and patients with established RA in 5 collections from The Netherlands, Canada, and Austria. We determined the dynamics of avidity maturation of ACPAs from the predisease stage to established disease in 1 case from the native North American population and in 10 cases from a Dutch blood donor cohort.Results. The overall ACPA response was characterized by low-avidity antibodies. Higher-avidity ACPAs were observed in symptomatic patients only, while lowavidity ACPAs were observed in both healthy subjects and patients. In longitudinal samples obtained from subjects prior to disease onset, ACPA avidity increased over time until disease onset. No further avidity maturation was observed after disease onset.Conclusion. Our findings indicate that avidity maturation of the ACPA response takes place prior to disease onset.

These observations indicate that the natural evolution of ACPA differs from the development of antibodies against recall antigens. These data also indicate that ACPA avidity maturation and isotype switching are disconnected, whereby extensive isotype switching occurs in the setting of restricted avidity maturation. Intrinsic differences between the RA-specific autoantibody system and protective antibody responses against pathogens could be of relevance for designing novel B cell-targeted therapies for RA.

AimTo assess the potential risk of tuberculosis (TB) in patients treated with anti-tumor necrosis factor-alpha (TNF-α) agents in Asia.MethodsAbsolute risk increase (ARI) of TB was estimated for three widely used anti-TNF-α therapies using published standardized incidence ratios (SIR) from the French Research Axed on Tolerance of bIOtherapies registry and incidence (absolute risk [AR]) of TB in Asia. Assuming an association of increased TB risk with anti-TNF-α therapy and country TB AR (incidence), the ARI of TB by country was calculated by multiplying the SIR of the anti-TNF-α therapy by the country's TB AR. The numbers needed to harm (NNH) for each anti-TNF-α agent and numbers needed to treat (NNT) to reduce one TB event using etanercept therapy instead of adalimumab or infliximab were also calculated for each country.ResultsThe ARI of TB with anti-TNF-α therapies in Asian countries is substantially higher than Western Europe and North America and the difference between etanercept versus the monoclonal antibodies becomes more evident. The NNH for Asian countries ranged from 8 to 163 for adalimumab, 126 to 2646 for etanercept and 12 to 256 for infliximab. The NNT to reduce one TB event using etanercept instead of adalimumab therapy ranged from 8 to 173, and using etanercept instead of infliximab therapy the NNT ranged from 13 to 283.ConclusionHigher numbers of patients are at risk of developing TB with anti-TNF-α therapy in Asia compared with Western Europe and North America. The relative lower risk of TB with etanercept may be particularly relevant for Asia, an endemic area for TB.

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Anti-citrullinated protein antibodies (ACPA) are specifi c for rheumatoid arthritis (RA), their presence is predictive for development to RA and have been implicated in diseasepathogenesis in animal studies. Despite the important implications for diagnoses and etiology, the natural development and biology of the ACPA response is poorly studied. Here the authors determined the avidity and avidity maturation of the ACPA response and compared this to the avidity of antibodies against recall-antigens.Our data show that the avidity of ACPA against several citrullinated antigens is considerably lower as compared to the avidity of antibodies against recall antigens such as tetanus toxoid or diphtheria toxoid. Intriguingly, despite high titers and extensive isotype switching, no avidity maturation in the ACPA response was observed during longitudinal follow-up.Our data indicate that the natural evolution of ACPA differs from the development of antibodies against prototype T cell dependent recall antigens. Moreover, these data point to an independency of avidity maturation and isotype-switching where full-isotype switching is taking place in the face of restricted and/or hampered avidity maturation.As avidity maturation of ACPA differs from avidity maturation of antibodies to recall antigens, our data are of relevance to the design of anti-B cell therapeutics.