FcγRIIIa Expression on Monocytes in Rheumatoid Arthritis: Role in Immune-Complex Stimulated TNF Production and Non-Response to Methotrexate Therapy

OBJECTIVE:The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. METHODS:FcγRIIIa/CD16 expression on CD14(low) and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. RESULTS:Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. CONCLUSION:Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

Genome-wide Association Study of Response to Methotrexate in Early Rheumatoid Arthritis Patients

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10‾⁷ for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous

A study of the roles of microfilaments and calcium transients during epiboly in zebrafish embryos

The basic body plan of teleost embryos emerges during the gastrula period when a series of extensive cell movements and rearrangements - epiboly, involution, convergence and extension - lead to the formation of the three germ layers as well as the dorsoventral and anterioposterior body axes. Starting towards the end of the blastula period, epiboly consists of the thinning and spreading of both the blastoderm and the yolk syncytial layer (YSL) over the large (~600 μm diameter) yolk cell toward the vegetal pole until, by the end of the gastrula period, the yolk is completed encompassed. The characterisation of microfilaments in zebrafish embryos from the earliest stages of development to around 50% epiboly has been previously described, thus the goal of my project was to complete this study up until the end of epiboly. Here in my thesis, I described four striking new actin-based structures: a punctate actin band in the external yolk syncytial layer (E-YSL); continuous rings of actin at the leading margins of both the enveloping layer (EVL) cells and deep cells (DCs); as well as a dense actin mat located at the vegetal pole (VP). Of these four structures, only one, the vegetal actin mat, is present throughout epiboly. The other three, the punctate actin band and the two marginal actin rings, only appear after the equator of the yolk cell has been crossed by the spreading blastoderm layers. It is suggested, therefore, that these structures are specific for the second half of epiboly and appear in response to the changing geometry of the embryo with respect to the spreading cell layers. With regards to function, the punctate actin band appears to be associated with a region of macropinocytosis that acts to internalise the yolk cell membrane (YCM) in front of the advancing blastoderm margins. It is proposed that this actin-based contractile activity also generates force that helps to draw the E-YSL and attached EVL toward the VP. It is suggested that the EVL and DC marginal actin rings act as contractile purse-strings and thus help to bring together the margins of the EVL and DCs as they approach the VP. Finally, it is proposed that the vegetal actin mat acts as major component of the yolk cell cytoskeleton, maintaining structural integrity during epiboly. I also present evidence to show that Ca2+ may play a key role in the formation and function of these actin-based structures. Treatment with the Ca2+ chelator dibromo-BAPTA (DBB) results in the disruption of the various actin-based structures and leads to the slowing or immediate arrest of epiboly, resulting in a failure of yolk cell occlusion followed by the eventual lysis of the embryo through the vegetal pole region. I also present data whereby embryos were loaded with f-aequorin (a Ca2+-sensitive bioluminescent reporter) at the single cell stage and then treated with either cytochalasin B or DBB during epiboly and the resulting Ca2+ signalling patterns visualised using a Photon Imaging Microscope system. The possible roles of, and interactions between, microfilaments and Ca2+ signalling during late epiboly will be discussed

The Intersection of Perceptions of Classroom Openness With Civic Engagement Among Young Urban Adolescents in Science Classroom

This study examined the extent to which student perceptions of classroom openness and personal characteristics were associated with civic engagement. Survey data including student perceptions of classroom openness, which indicates perceived levels of social and political discussions in the classroom, and personal characteristics such as gender, science engagement, and English Learner (EL) status were collected in 6th-grade science classrooms in an urban intermediate school. Civic engagement was measured using the personally responsible and participatory types of citizenship. Results from hierarchical linear regressions showed that student perceptions of classroom openness uniquely predicted the personally responsible citizen but not participatory citizen after controlling for personal characteristics. Science engagement and gender were significant predictors of both citizenship types. Implications for civic education for middle school science classrooms were discussed

Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib:a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis

OBJECTIVES: To update a previous systematic review assessing the efficacy of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA). METHODS: Two systematic reviews of the literature using PubMed, Embase and the Cochrane library were performed from 2009 until January 2013 to assess the efficacy of csDMARDs (as monotherapy or combination therapy) in adults with RA, and the efficacy of glucocorticoids in early RA. A third systematic review was performed until March 2013 to assess the efficacy of tofacitinib by meta-analysis. RESULTS: For glucocorticoids, of 222 hits, five publications relating to four new trials were analysed for efficacy, confirming that initial treatment of RA with low-dose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone. For csDMARDs, of 498 studies, only two new studies were randomised controlled trials comparing MTX monotherapy with MTX in combination with another csDMARD without differences in glucocorticoid usage. Using tight control principles, clinical outcomes were no better with immediate triple therapy than with ‘step-up’ therapy. For tofacitinib, the pooled analysis of 10 trials showed that tofacitinib was more efficacious on signs and symptoms, disability and appeared to be more efficacious on structural damage than control treatment with placebo (OR (95% CI)—American College of Rheumatology 20% (ACR20) response: 2.44 (1.97 to 3.02)) or treatment with MTX (ACR20 response: 2.38 (1.66 to 3.43)). CONCLUSIONS: Addition of low-dose glucocorticoids to csDMARD therapy produces benefits in early RA. Under tight control conditions, combination therapy with csDMARDs is no better than MTX monotherapy. Tofacitinib is a new DMARD with proven efficacy

Orthographic facilitation in upper elementary students: does attention to morphology of complex words enhance the effects?

The current study aimed to investigate whether exposure to spellings would boost memory of meanings and spellings of morphologically complex words, and when spellings are present, whether drawing attention to the morphology of derivative words would activate morphological analysis and therefore enhance word learning. Participants were 36 fourth and fifth graders (20 Spanish speakers, and 16 English speakers) from an elementary school in the Southeastern U.S. students were randomly assigned to one of the two groups: (a) group A, simple spelling exposure group; and (b) group B, drawing attention to morphology group. Each group learned 12 low-frequency morphologically complex words (e.g., odorous) in two orthographic conditions: with the presence of spelling (1) and with the absence of spelling (2). Three learning trials and three test trials were interweaved. After each learning trial, students were prompted to meaning and spelling recall for each target word. Results have extended the evidence of orthographic facilitation effect to morphologically complex words. Students with both higher and lower word reading skills benefitted from spelling presence. Drawing attention to morphology did not enhance the memory of meanings and spellings of morphologically complex words, in comparison to spelling exposure only condition. Implications for vocabulary learning theories and instruction for linguistically diverse students were discussed

Comorbidities in Anti-Cyclic Citrullinated Peptide Positive At-Risk Individuals Do Not Differ from Those Patients with Early Inflammatory Arthritis

ObjectivesTo compare comorbidities in a cohort of cyclic citrullinated peptide (CCP) antibody positive patients without or prior to onset of inflammatory arthritis (IA) to those in patients with early IA.MethodsBaseline data from two established cohorts were used. The first recruited people at risk of IA: CCP antibody positive cases without IA (CCP Cohort, n = 296). The second cohort [the Inflammatory Arthritis CONtinuum study (IACON)] recruited patients with early IA (n = 725). Proportions of patients with given comorbidities were compared between cohorts and then logistic regression was used to determine odds ratios (OR) for the CCP cohort having specific comorbidities, compared to IACON patients. Analyses adjusted for gender, age, smoking status, and body mass index.ResultsPatients from the CCP cohort were younger (mean age 50, compared to 53 years). The proportion of patients with at least one comorbidity was higher in the IACON than the CCP cohort: (40% compared to 24%, respectively). Results of logistic regression analyses suggested the odds of hypertension, taking a lipid-lowering agent, ischemic heart disease, cerebrovascular disease, lung disease, and diabetes were not increased in either cohort. However, patients in the CCP cohort were more likely to be taking an antidepressant (OR = 1.62, 95% CI 1.03, 2.56, p = 0.037).ConclusionThere was no significant difference in comorbidities among people with CCP antibodies but without IA, compared to those of patients with established IA