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Anti-citrullinated peptide/protein antibodies (ACPAs) are the most specific serological biomarkers for rheumatoid arthritis (RA). They have both diagnostic and prognostic value, and are related to more aggressive joint disease in RA. However, a single biomarker cannot differentiate RA subtypes. So, simultaneous analysis of target citrullinated peptides, using a multiplex array based on chimeric peptides composed of several domains of human proteins, could be useful. In this work, eight chimeric peptides and the corresponding native arginine-containing control peptides were obtained by solid-phase peptide synthesis. The study included RA and psoriatic arthritis (PsA) patients attending the Rheumatology Unit of the Hospital Clinic in Barcelona, as well as healthy blood donors (BD) at the same hospital. Our main aim was to explore the diagnostic value of the novel multiplex array compared to a commercial ELISA-based ACPA assay in a serum-saving way. Using the combination of the eight chimeric peptide antigens in the multiplex array, 61.4% of the RA cohort were positive for 3 or more peptides; while, the healthy BD and PsA cohorts did not show any reactivity with the tested peptides. These results indicate that we have developed a highly specific multiplex assay based of chimeric citrullinated peptides derived from filaggrin, fibrin, vimentin and human enolase proteins for the detection of ACPAs in a serum-saving way.

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.

In agreement with EULAR recommendations, a DMARD in combination with a biotherapy is the reference treatment because of the superior long-term clinical and radiographic outcomes. Methotrexate (MTX) is the cornerstone of combination therapy but is in some cases contra-indicated or poorly tolerated. This observational study aimed to compare the effectiveness and safety of TCZ in combination with either MTX or leflunomide (LEF) in the treatment of patients with active rheumatoid arthritis (RA) and an inadequate response to one or more DMARDs and/or biological agents in a real-world setting.We performed an ambispective review of 91 patients with active RA who were routinely treated with TCZ plus MTX or LEF. A comparative study between the two combinations of treatment was performed at 6 months of follow-up considering 3 outcomes: improvement of RA disease activity, evolution of functional disability, and tolerability and side effect profile.Of the 91 patients, 62 received TCZ with MTX and 29 received TCZ with LEF. Eighty-one patients were followed for 6 months, and the remaining 10 patients discontinued treatment due to serious adverse events. At baseline, there were no significant differences between the groups in terms of the main clinical and laboratory data or in the number of previous DMARDs and biological agents used. At 6 months, there were no significant differences between the combinations in terms of disease activity and functional disability. Serious adverse events occurred in 11% and 10% of the patients treated in combination with MTX and LEF, respectively.Our preliminary data support the argument that LEF is an effective and safe (equivalent) alternative to MTX for combination treatment with TCZ.

BACKGROUND:Angiogenesis is considered an important factor in the pathogenesis of Rheumatoid Arthritis (RA) where it has been proposed as a therapeutic target. In other settings, active angiogenesis is characterized by pathologic, immature vessels that lack periendothelial cells. We searched for the presence of immature vessels in RA synovium and analyzed the dynamics of synovial vasculature along the course of the disease, particularly after therapeutic response to TNF antagonists. METHODOLOGY/PRINCIPAL FINDINGS:Synovial arthroscopic biopsies from RA, osteoarthritis (OA) and normal controls were analyzed by double labeling of endothelium and pericytes/smooth muscle mural cells to identify and quantify mature/immature blood vessels. To analyze clinicopathological correlations, a cross-sectional study on 82 synovial biopsies from RA patients with variable disease duration and severity was performed. A longitudinal analysis was performed in 25 patients with active disease rebiopsied after anti-TNF-alpha therapy. We found that most RA synovial tissues contained a significant fraction of immature blood vessels lacking periendothelial coverage, whereas they were rare in OA, and inexistent in normal synovial tissues. Immature vessels were observed from the earliest phases of the disease but their presence or density was significantly increased in patients with longer disease duration, higher activity and severity, and stronger inflammatory cell infiltration. In patients that responded to anti-TNF-alpha therapy, immature vessels were selectively depleted. The mature vasculature was similarly expanded in early or late disease and unchanged by therapy. CONCLUSION/SIGNIFICANCE:RA synovium contains a significant fraction of neoangiogenic, immature blood vessels. Progression of the disease increases the presence and density of immature but not mature vessels and only immature vessels are depleted in response to anti-TNFalpha therapy. The different dynamics of the mature and immature vascular fractions has important implications for the development of anti-angiogenic interventions in RA.