High levels of memory B cells are associated with response to a first tumor necrosis factor inhibitor in patients with rheumatoid arthritis in a longitudinal prospective study

Tumor necrosis factor inhibitor (TNFi) therapy is effective for rheumatoid arthritis (RA). Some reports suggested that the therapy affects B-cell homeostasis. We studied the effect of TNFi therapy on the distribution of peripheral B-cell subsets and elucidated B-cell-related biomarkers to predict the TNFi response. Peripheral B cells were analyzed for expression of CD19, CD27, CD38, and IgD in 31 healthy donors and 96 RA patients, including 21 who were followed 3 months after TNFi introduction. Treatment with steroids significantly altered the distribution of B-cell subsets. After adjustment for age, gender and steroid dose, patients with RA had similar B-cell subset proportions as controls. B-cell subset distribution did not differ by use of TNFi at baseline or before and after TNFi introduction. TNFi responders (according to European League Against Rheumatism criteria) at 3 months had significantly higher proportion of CD27+ memory B cells at baseline, and >= 26% CD27+ cells at inclusion was associated with a relative risk of 4.9 (1.3 to 18.6) of responding to TNFi treatment. CD27+ cells produced 3 times more TNFalpha than did naive B cells, and were correlated with interferon-gamma produced from CD4+ cells in patients without TNFi treatment. In patients with RA, high levels of baseline memory B cells were associated with response to TNFi, which may be related to TNFalpha-dependent activation of the T helper cell type 1 pathwa

2016 update of the EULAR recommendations for the management of early arthritis

Objectives: Since the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 EULAR recommendations for management of early arthritis. Methods: In accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 health professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of “management” and selected the research questions. A systematic literature research (SLR) was performed by 2 fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process. Results: The updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research. Conclusion: These recommendations provide rheumatologists, general practitioners, health professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis

The reference site collaborative network of the european innovation partnership on active and healthy ageing

Seventy four Reference Sites of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) have been recognised by the European Commission in 2016 for their commitment to excellence in investing and scaling up innovative solutions for active and healthy ageing. The Reference Site Collaborative Network (RSCN) brings together the EIP on AHA Reference Sites awarded by the European Commission, and Candidate Reference Sites into a single forum. The overarching goals are to promote cooperation, share and transfer good practice and solutions in the development and scaling up of health and care strategies, policies and service delivery models, while at the same time supporting the action groups in their work. The RSCN aspires to be recognized by the EU Commission as the principal forum and authority representing all EIP on AHA Reference Sites. The RSCN will contribute to achieve the goals of the EIP on AHA by improving health and care outcomes for citizens across Europe, and the development of sustainable economic growth and the creation of jobs

Diagnosis, prognosis and classification of early arthritis: results of a systematic review informing the 2016 update of the EULAR recommendations for the management of early arthritis

To update the evidence pertaining to the diagnosis, prognosis and classification of patients with early arthritis (EA), and to inform the 2016 European League Against Rheumatism (EULAR) recommendations for the management of patients with EA. MEDLINE, EMBASE and Cochrane databases were searched up to October 2015. The first part of the systematic literature review (SLR) involved a search for studies investigating the recognition and referral of EA. The second part involved a search for studies to identify the place of laboratory and imaging tests in establishing a diagnosis and a prognosis in patients with EA. Regarding the issue of referral of patients with EA (1643 hits), 4 studies were included. These studies were in support of early referral for patients with EA. Regarding the issue of diagnosis and prognosis of patients with EA (11 435 hits), 88 studies were included, evaluating mainly the value of rheumatoid factor (RF) and anticitrullinated-peptide antibodies (ACPAs). Sensitivity of these antibodies for a RA diagnosis in patients with EA was moderate (40-80%). Specificity was higher, notably for ACPAs (frequently >80%). ACPAs also showed better prognostic performance than RF (negative predictive values around 80%). We confirmed that structural damage on baseline X-rays is predictive of further radiographic progression in patients with EA. Regarding other imaging modalities, data are sparse. This SLR highlights the importance of early referral for patients with EA and confirms that RF and mainly ACPAs as well as a search for structural X-rays changes may help in the diagnosis and prognosis of patients with E

Sodium excretion is higher in patients with rheumatoid arthritis than in matched controls.

It was shown that sodium can promote auto-immunity through the activation of the Th17 pathway. We aimed to compare sodium intake in patients with rheumatoid arthritis (RA) vs. matched controls.This case-control study included 24 patients with RA at diagnosis and 24 controls matched by age, gender and body mass index. Sodium intake was evaluated by 24-hr urinary sodium excretion.Sodium excretion was greater for patients with early RA (2,849±1,350 vs. 2,182±751.7mg/day, p = 0.039) than controls. This difference remained significant after adjustment for smoking and the use of anti-hypertensive and nonsteroidal anti-inflammatory drugs (p = 0.043). Patients with radiographic erosion at the time of diagnosis had a higher sodium excretion than those without (p = 0.028).Patients with early RA showed increased sodium excretion which may have contributed to autoimmunity

Phosphatidylserine Outer Layer Translocation Is Implicated in IL-10 Secretion by Human Regulatory B Cells

<div><p>B cells can have a regulatory role, mainly mediated by interleukin 10 (IL-10). IL-10 producing B cells (B10 cells) cells remain to be better characterized. Annexin V binds phosphatidylserine (PS), which is externalized during apoptosis. Previous works suggested that B10 cells are apoptotic cells since they bind Annexin V. Others showed that Annexin V binding could also be expressed on viable B cells. We aimed to explore if PS exposure can be a marker of B10 cells and if PS exposure has a functional role on B cell IL-10 production in healthy subjects. We found that B10 cells were significantly more often Annexin V⁺ than IL-10 non-producing B cells. After CpG activation, Annexin V⁺ B cells differentiated more often into B10 cells than Annexin V^neg B cells. Cell death and early apoptosis were similar between Annexin V⁺ and Annexin V^neg B cells. PS blockage, using biotinylated AnV and glyburide, decreased B10 cell differentiation. This study showed that B10 cells have an increased PS exposure independently of any apoptotic state. B cells exposing PS differentiate more into B10 cells whereas PS blockage inhibits B10 cells generation. These results strongly suggest a link between PS exposure and B10 cells.</p></div

Annexin V binding is increased in IL-10 producing B cells (B10 cells) compared to IL-10 non-producing B cells and to TNFα producing B cells.

<p>PBMCs were stimulated for 24 hr with CpG/ionomycin/PMA and BFA as described previously and analyzed by FACS for annexin V (AnV) binding and IL-10 and TNFα production in 21 subjects. Cytometry gating is shown in A. Results are presented in percentage of positive cells in B and median of fluorescence (MFI) in C. Wilcoxon’s matched pairs signed rank tests were used. Top of the bar represents the median, and whiskers are IQR 25–75.</p

Annexin V positive B cells are not apoptotic cells.

<p>PBMCs were stained with APC anti-CD19 and FITC conjugated Annexin V, sorted by FACSARIA according to annexin V (AnV) staining: high AnV B cells (AnV^hi); low AnV B cells (AnV^low) and AnV negative B cells (AnV^neg). Cell death was analyzed at 72 hr using DAPI staining for necrosis (A) and DIOC6 (B) for mitochondrial apoptosis (n = 4). Additionally, cell cycle was analyzed using propidium iodide (PI) staining at 72 hr (C), showing the proportion of cells in the subG1 phase (apoptotic cells) and in the S phase (proliferating cells) in AnV+ (AnV^hi and AnV^low) and AnV^neg B cells (n = 5). Data are median (IQR25-75).</p

Annexin V positive B cells differentiate more frequently into B10 cells than Annexin V negative B cells.

<p>PBMCs from 6 healthy subjects were sorted by flow cytometry (FACSARIA) according to annexin V (AnV) staining: AnV positive (AnV⁺) and AnV negative B cells (AnV^neg) after exclusion of dead cells (DAPI⁺)(A). Each B cell subpopulation was then stimulated for B10 generation and analyzed by flow cytometry as previously described (B). (C) shows the % of cytokine-positive cells (IL-10, IL-6, GM-CSF and TNF-a) in AnV⁺ and AnV AnV^neg sorted cells. (D) shows IL-10 and IL-6 concentrations assessed by ELISA in supernatant of AnV⁺ and AnV AnV^neg sorted cells.</p

Annexin V binding is increased among CD5+ and CD24hiCD27+ B10 precursors.

<p>A representative plot is presented (A). PBMCs from 12 subjects were analyzed by FACS for B10 precursors phenotype (i.e CD19+CD5+ (B), CD19+CD24^hiCD27⁺ (C) and CD19+CD24^hiCD38^hi, (D)), and for annexin V binding. Wilcoxon’s matched pairs signed rank tests were used. Data are median (IQR 25–75).</p