Studies on the role of anti-citrullinated protein antibodies in rheumatoid arthritis

Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA) and present in about two thirds of all patients at diagnosis. They can be detected already before disease onset and have direct pathogenic effect mediated partly through the Fc (fragment crystalizable) portion with attached Fc-glycan structure. On these grounds we aimed to further characterize ACPA’s role in the pathogenesis of RA both as a risk factor and a disease biomarker. To this end we investigated ACPA occurrence in a population-derived twin cohort and ACPA in a cohort of early-untreated RA patients in relation to disease outcomes. First we screened a large population-derived twin cohort (N= 12,590; median age 64, range 48-93 years) for occurrence of ACPA using an ACPA test used in clinical routine: the Anti-CCP2 (IgG) test. Through linking the twin cohort with the Swedish National Patient Register we identified ACPA-positive individuals without RA (N=226) and ACPA-positive patients with RA (N=124). ACPA-positive individuals without RA had lower ACPA concentration and fewer different ACPA reactivities as compared to patients with ACPA-positive RA. Heritability estimates for having ACPA with or without RA were generally lower than expected (10% (95% CI: 0-43) for ACPA without RA; 23% (95% CI: 0-45) for ACPA; and 41% (95% CI: 0-74) for ACPA-positive RA). Heavy smoking and HLA-SE associated with ACPA occurrence with and without RA. Environmental factors (including smoking) appeared to be more important than genetic in determining which individuals develop ACPA, while genetic factors (and in particular HLA-SE) had a relatively larger impact in determining which ACPA-positive individuals that will ultimately develop arthritis. We also confirmed that presence of ACPA and especially high titers of ACPA have a high diagnostic accuracy for RA in a population based setting. Following this, we then screened a cohort of early-untreated RA patients (N=183) for occurrence of ACPA using either the Anti-CCP2 test or ELISA for detection of reactivities against specific citrullinated peptides. We demonstrated that ACPA (and especially anti-citrullinated-vimentin antibodies) associated with markers of bone loss (as measured by ELISA detection of serum RANKL and/or presence of bone erosions on radiographs of hands and feet). Treatment with methotrexate (MTX) significantly lowered both ACPA and RANKL serum levels. In a subgroup of these patients (N=59) we investigated the Fc-glycosylation patterns of serum IgG in relation to disease outcome further. A general low abundance of galactosylated glycans, partially restored by MTX treatment, was observed in the serum of early-untreated RA samples. This was more evident among future non-responders as compared to responders to MTX treatment. The galactosylation status of the IgG-Fc had good predictive value for MTX response. In conclusion we showed that environmental as well as genetic factors are important for ACPA occurrence, which in turn has a high diagnostic accuracy for RA. In early-untreated RA, ACPA associate with bone loss and is modulated by methotrexate treatment. Further, Fc-glycosylation patterns of antibodies are generally altered in early-untreated RA and might serve as a predictive factor for therapeutic response

Derecho de Sucesiones

La muerte de una persona es uno de los hechos jurídicos que mayor trascendencia acarre dentro del ordenamiento jurídico, no solo por implica el fin de la existencia de la persona, sino por todas aquellas consecuencia de índole patrimonial que ocasiona; por esta razón, su inclusión se convierte en un imperativo categórico para la buena formación del estudiantado. La prolongación de la personalidad jurídica del difunto en sus herederos es una de la ficciones legales de mayor importancia, de forma que constituye el mecanismo por medio del cual la ciencia jurídica ha configurado la transmisión de tanto de los derechos como de las obligaciones del de cuius, así se proporciona una efectiva seguridad jurídica concretada en el hecho de que, salvo en el caso de los derechos y obligaciones personalísimos, todas, las relaciones patrimoniales de la persona no extinguen por el hecho de su fallecimiento. Para comprender la trascendencia y significancia del Derecho sucesorio y de sus instituciones es insoslayable estudiar sus orígenes en Derecho romano, así como su evolución histórica; de esta manera, el estudiantado tendrá una visión integral de la materia objeto de nuestro estudio

Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL

Objectives Our knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods 15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment.Results Disease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders.Conclusions TCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders

Distinct Fluorescence Optical Imaging Patient Clusters Emerge for Seropositive and Seronegative Rheumatoid Arthritis

Objective To investigate whether digital activity fluorescence optical imaging (FOI) patterns of inflammation can identify distinct rheumatoid arthritis (RA) phenotypes. Methods The hands of newly diagnosed patients with RA were evaluated by clinical examination, musculoskeletal ultrasound, and FOI. Inflammation on FOI was defined when capillary leakage and/or fluorophore perfusion was present. The FOI composite image was quantified into a digital disease activity (DACT) score, using novel computerized algorithms. Unsupervised clustering on FOI inflammatory patterns was used to identify subgroups of patients relative to anticyclic citrullinated peptides (ACPA) and/or rheumatoid factor (RF). Results Of 1326 examined hand joints in 39 patients with RA (72% female; 56% ever‐smokers; 54% RF positive and 69% ACPA positive), 400 (30%) showed inflammation by FOI, and 95% (37 of 39) of patients had DACT‐FOI scores greater than 1. Unsupervised analysis on FOI patterns revealed two patient clusters, cluster 1 (n = 29) and cluster 2 (n = 10). The proportion of seropositive patients was significantly higher in cluster 1 versus cluster 2 (90%, 26 of 29 vs. 30%, 3 of 10; P < 0.01), whereas C‐reactive‐protein levels (minimum‐maximum) were significantly higher in cluster 2 (20 mg/l [1‐102]) versus cluster 1 (2 mg/l [0‐119]; P = 0.01). A wider variety and proportion of inflamed joints emerged for patients with RA in cluster 2 versus cluster 1, in which inflammation was more concentrated around the wrists and the right metacarpophalangeal 2 (MCP2), bilateral MCP3, and, to a lesser degree, left MCP2 and proximal interphalangeal joint and tendon regions. Cluster 1 displayed lower mean (±SD) DACT scores compared with cluster 2 (3.6 ± 2.1 vs. 5.4 ± 2.1; P = 0.03). Conclusion FOI‐based digital quantification of hand joint inflammation revealed two distinct RA subpopulations with and without ACPA and RF related autoantibodies

Additional file 1: Table S1. of IgG Fc galactosylation predicts response to methotrexate in early rheumatoid arthritis

Demographic characteristics of the nationwide EIRA cohort. Table S2. Characterized complement pathway proteins and IgG-isotype proteins. Table S3. Individual IgG-Fc glycan distribution values in IgG1 and in IgG2 in control subjects, as well as in patients with RA prior to and following MTX treatment. Table S4. Significant differences for the 19 characterized glycan species when comparing healthy versus all, good, moderate, and nonresponding patients prior to and following MTX treatment. Table S5. IgG1 and IgG2 Fc glycan distributions grouped according to structural features, comparing healthy control subjects and patients with RA prior to and following MTX treatment. Table S6. Intra- and interindividual differences in the patients with RA, comparing individual glycan species prior to and following MTX treatment. Table S7. Complete list, ranking, and correlation (with response versus no response to MTX) of the features used in the OPLS-DA model shown in Fig. 3b. Figure S1. Extracted ion chromatograms of IgG1 and IgG2 Fc glycans quantified in a control subject and a patient with RA. Figure S2. Intraindividual changes in galactosylation status on IgG1 and on IgG2 for good and moderate responders and for nonresponders. Figure S3. Intraindividual correlation between the aGal/Gal status of glycans with different types of structural features and of IgG1 and IgG2 substituted glycans. Figure S4. Significant differences between control subjects and patients with early RA at baseline in the classical pathway initiating complements C1 and C9. Figure S5. Intraindividual correlation between the classical and lectin pathway inhibitor C4bBPα versus FA2/(FA2G1 + FA2G2). (DOCX 1180 kb

Three-dimensional spatial transcriptomics uncovers cell type dynamics in the rheumatoid arthritis synovium

The inflamed rheumatic joint is a highly heterogeneous and complex tissue with dynamic recruitment and expansion of multiple cell types that interact in multifaceted ways within a localized area. Rheumatoid arthritis synovium has primarily been studied either by immunostaining or by molecular profiling after tissue homogenization. Here, we use Spatial Transcriptomics to study local cellular interactions at the site of chronic synovial inflammation. We report comprehensive spatial RNA-seq data coupled to quantitative and cell type-specific chemokine-driven dynamics at and around organized structures of infiltrating leukocyte cells in the synovium.QC 20210322</p

Three-dimensional spatial transcriptomics uncovers cell type dynamics in the rheumatoid arthritis synovium

The inflamed rheumatic joint is a highly heterogeneous and complex tissue with dynamic recruitment and expansion of multiple cell types that interact in multifaceted ways within a localized area. Rheumatoid arthritis synovium has primarily been studied either by immunostaining or by molecular profiling after tissue homogenization. Here, we use Spatial Transcriptomics to study local cellular interactions at the site of chronic synovial inflammation. We report comprehensive spatial RNA-seq data coupled to quantitative and cell type-specific chemokine-driven dynamics at and around organized structures of infiltrating leukocyte cells in the synovium.QC 20210322</p