Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis

The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix ‘pre-RA with:’ could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites

The expression of creativity in learning how to read and write : a case study

O presente artigo tem por objetivo destacar as formas em que a criatividade se expressa na aprendizagem da leitura e da escrita da criança. Assume-se como referencial teórico a concepção de aprendizagem criativa desenvolvida por Mitjáns Martínez. Segundo essa concepção, os processos criativos emergem nos contextos de ação do sujeito, mediante recursos subjetivos constituídos historicamente e que se organizam no momento da ação concreta. A expressão desse tipo de aprendizagem tem se configurado pela personalização da informação, confrontação com o dado e pela geração, produção de ideias novas que vão além do que está posto. Adota-se como eixo norteador a pesquisa qualitativa, apoiada nos princípios da epistemologia qualitativa desenvolvida por González Rey, com opção pelo estudo de caso utilizando instrumentos abertos e semiabertos, tais como: dinâmicas conversacionais, observações, entrevistas como processo e diário de ideias. A investigação foi desenvolvida em uma escola da rede pública, com alunos dos primeiros e segundos anos do ensino fundamental, na qual acompanhamos os aprendizes por dois anos consecutivos. Como conclusão, considera-se que a expressão da criatividade na aprendizagem da leitura e da escrita foi significativamente apresentada pelas características destacadas por Mitjáns Martínez, bem como pela relação lúdica da criança com sua aprendizagem.This paper has the purpose of highlighting the ways through which creativity is expressed in the child´s learning of how to read and write. The theoretical assumption taken is the concept of creative learning developed by Mitjáns Martínez. According to such conception, the creative processes emerge in the context of the individual´s action, through subjective resources that are historically constructed and are organized in the moment of concrete action. The expression of this type of learning has been configured by the personalization of information, confrontation with the data, and by the generation and production of new ideas that go beyond what is taken for granted. The guiding axis adopted is qualitative research, supported by the principles of thequalitative epistemology developed by González Rey, with the option of conducting a case study utilizing open and semi-open tools, such as: conversational dynamics, observations, interviews as a process and a diary of ideas. The investigation took place in a public school, among 1st and 2nd graders, in which we monitored the learners for two years in a row. As a conclusion, we consider that the expression of creativity in learning how to read and write was significantly presented by the characteristics emphasized by the author mentioned above, as well as by the playful relationship of the child with his/her learning