JAK inhibitors and modulation of B cell immune responses in rheumatoid arthritis

Copyright © 2021 Moura and Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC BY). The use,distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use,distribution or reproduction is permitted which does not comply with these termsRheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disease that can lead to joint destruction, functional disability and substantial comorbidity due to the involvement of multiple organs and systems. B cells have several important roles in RA pathogenesis, namely through autoantibody production, antigen presentation, T cell activation, cytokine release and ectopic lymphoid neogenesis. The success of B cell depletion therapy with rituximab, a monoclonal antibody directed against CD20 expressed by B cells, has further supported B cell intervention in RA development. Despite the efficacy of synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs) in the treatment of RA, few patients reach sustained remission and refractory disease is a concern that needs critical evaluation and close monitoring. Janus kinase (JAK) inhibitors or JAKi are a new class of oral medications recently approved for the treatment of RA. JAK inhibitors suppress the activity of one or more of the JAK family of tyrosine kinases, thus interfering with the JAK-Signal Transducer and Activator of Transcription (STAT) signaling pathway. To date, there are five JAK inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib) approved in the USA, Europe and/ or Japan for RA treatment. Evidence from the literature indicates that JAK inhibitors interfere with B cell functions. In this review, the main results obtained in clinical trials, pharmacokinetic, in vitro and in vivo studies concerning the effects of JAK inhibitors on B cell immune responses in RA are summarized.info:eu-repo/semantics/publishedVersio

B cells on the stage of inflammation in juvenile idiopathic arthritis: leading or supporting actors in disease pathogenesis?

Copyright © 2022 Moura and Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Juvenile idiopathic arthritis (JIA) is a term that collectively refers to a group of chronic childhood arthritides, which together constitute the most common rheumatic condition in children. The International League of Associations for Rheumatology (ILAR) criteria define seven categories of JIA: oligoarticular, polyarticular rheumatoid factor (RF) negative (RF-), polyarticular RF positive (RF+), systemic, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. The ILAR classification includes persistent and extended oligoarthritis as subcategories of oligoarticular JIA, but not as distinct categories. JIA is characterized by a chronic inflammatory process affecting the synovia that begins before the age of 16 and persists at least 6 weeks. If not treated, JIA can cause significant disability and loss of quality of life. Treatment of JIA is adjusted according to the severity of the disease as combinations of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and/ or biological disease modifying anti-rheumatic drugs (DMARDs). Although the disease etiology is unknown, disturbances in innate and adaptive immune responses have been implicated in JIA development. B cells may have important roles in JIA pathogenesis through autoantibody production, antigen presentation, cytokine release and/ or T cell activation. The study of B cells has not been extensively explored in JIA, but evidence from the literature suggests that B cells might have indeed a relevant role in JIA pathophysiology. The detection of autoantibodies such as antinuclear antibodies (ANA), RF and anti-citrullinated protein antibodies (ACPA) in JIA patients supports a breakdown in B cell tolerance. Furthermore, alterations in B cell subpopulations have been documented in peripheral blood and synovial fluid from JIA patients. In fact, altered B cell homeostasis, B cell differentiation and B cell hyperactivity have been described in JIA. Of note, B cell depletion therapy with rituximab has been shown to be an effective and well-tolerated treatment in children with JIA, which further supports B cell intervention in disease development.The authors would like to acknowledge Sociedade Portuguesa de Reumatologia (SPR) for funding.info:eu-repo/semantics/publishedVersio

Disease mechanisms in preclinical rheumatoid arthritis: a narrative review

Copyright © 2022 Romão and Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.In the last decades, the concept of preclinical rheumatoid arthritis (RA) has become established. In fact, the discovery that disease mechanisms start years before the onset of clinical RA has been one of the major recent insights in the understanding of RA pathogenesis. In accordance with the complex nature of the disease, preclinical events extend over several sequential phases. In a genetically predisposed host, environmental factors will further increase susceptibility for incident RA. In the initial steps of preclinical disease, immune disturbance mechanisms take place outside the joint compartment, namely in mucosal surfaces, such as the lung, gums or gut. Herein, the persistent immunologic response to altered antigens will lead to breach of tolerance and trigger autoimmunity. In a second phase, the immune response matures and is amplified at a systemic level, with epitope spreading and widening of the autoantibody repertoire. Finally, the synovial and bone compartment are targeted by specific autoantibodies against modified antigens, initiating a local inflammatory response that will eventually culminate in clinically evident synovitis. In this review, we discuss the elaborate disease mechanisms in place during preclinical RA, providing a broad perspective in the light of current evidence.VCR work was funded by Fundação para a Ciência e Tecnologia (Interno Doutorando Bursary reference SFRH/SINTD/95030/2013); European League Against Rheumatism (EULAR Scientific Training Bursary 2014); and Sociedade Portuguesa de Reumatologia (Fundo de Apoio à Investigação da SPR 2015 & 2016 to VCR).info:eu-repo/semantics/publishedVersio

Major challenges in Rheumatology: will we ever treat smarter, instead of just harder?

Copyright © 2019 Romão and Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The field of rheumatology has witnessed astonishing progress in the understanding and management of rheumatic diseases since the second half of the twentieth century. The discovery and introduction of glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) into the therapeutic armamentarium of rheumatologists enabled, for the first time, to effectively change the natural course of disease and improve most clinical outcomes. The new millennium pushed the revolution further at an exponential level with the advent of sophisticated, biologically-engineered drugs—the so-called biologicals or bDMARDs—that targeted specific molecules in key pathogenic pathways and dramatically modified the prognosis of most patients with immune-mediated rheumatic diseases.VR's work was partially supported by Fundação para a Ciência e Tecnologia (Interno Doutorando Bursary reference SFRH/SINTD/95030/2013).info:eu-repo/semantics/publishedVersio

Osteoblasts and bone formation

© 2007 Sociedade Portuguesa de ReumatologiaBone is constantly being remodelled in a dynamic process where osteoblasts are responsible for bone formation and osteoclasts for its resorption. Osteoblasts are specialized mesenchymal cells that undergo a process of maturation where genes like core-binding factor α1 (Cbfa1) and osterix (Osx) play a very important role. Moreover, it was found recently that the Wnt/β-catenin pathway plays a part on osteoblast differentiation and proliferation. In fact, mutations on some of the proteins involved in this pathway, like the low-density lipoprotein receptor related protein 5/6 (LRP5/6), lead to bone diseases. Osteoblasts have also a role in the regulation of bone resorption through receptor activator of nuclear factor-κB (RANK) ligand (RANKL), that links to its receptor, RANK, on the surface of pre-osteoclast cells, inducing their differentiation and fusion. On the other hand, osteoblasts secrete a soluble decoy receptor (osteoprotegerin, OPG) that blocks RANK/RANKL interaction by binding to RANKL and, thus, prevents osteoclast differentiation and activation. Therefore, the balance between RANKL and OPG determines the formation and activity of osteoclasts. Another factor that influences bone mass is leptin, a hormone produced by adipocytes that have a dual effect. It can act through the central nervous system and diminish osteoblasts activity, or can have an osteogenic effect by binding directly to its receptors on the surface of osteoblast cells.info:eu-repo/semantics/publishedVersio

Editorial: Synovial tissue: turning the page to precision medicine in arthritis?

Copyright © 2021 Orr, Humby and Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.It is with great pleasure that we present in this article collection, a timely overview of the rapidly developing field of synovial tissue analysis. Some of the most prominent protagonists in the field have contributed, and the collection walks the reader through everything from the history of the field’s development, to technical aspects of sampling, providing an update on the science and clinical applications, as well as discussing potential future perspectives. A broad consensus exists amongst clinicians and scientists, that a patient-centred, precision medicine approach holds the most promise to improve patient outcomes. The relevance of synovial biopsies in achieving this end is a major theme of this article collection. We are currently at an exciting juncture in this important field. This collection not only discusses the enormous potential of synovial tissue as a research and clinical tool, but also the many challenges in advancing its role in translational and clinical applications. Several key advancements concerning synovial biopsies over the last number of years have together contributed to the rheumatology community discussing in earnest how such sampling can contribute to precision medicine in arthritis.info:eu-repo/semantics/publishedVersio

Editorial: Risk factors for Rheumatoid Arthritis and pre-Rheumatoid Arthritis

No abstract availabl

Uma arquitectura para a composição dinâmica de serviços dependentes do contexto

A difusão das ligações sem fios nos locais de trabalho, de lazer e mesmo em casa, juntamente com a proliferação dos dispositivos móveis abrem novos cenários para o fornecimento de serviços aos utilizadores. Além dos serviços tradicionais de Internet devem por isso, ser disponibilizados novos serviços que de uma forma transparente se adeqúem e se adaptem ao contexto do utilizador. Os utilizadores teriam ainda mais flexibilidade e escolha se, para além do fornecimento de destes serviços, lhes fosse dada a possibilidade de eles próprios comporem novos serviços com base em serviços já existentes. Este artigo discute os componentes essenciais de um sistema context-aware que permite a composição dinâmica de serviços sensíveis ao contexto e propõe uma arquitectura possível para implementação desses serviços

A service-oriented middleware for composing context aware mobile services

Recent advances in wireless networks and mobile devices have brought about new scenes for the provision of services to end-users. Besides traditional services, new ones may be provided that transparently adjust and adapt to the user context. The user would have more choice and flexibility if, besides using the services, he could also compose his own services in an ad-hoc way. This paper presents iCas, an architecture to create context-aware services on the fly and discusses its main components. Also an application scenario is briefly described

A systematic review with network meta-analysis of the available biologic therapies for psoriatic disease domains

Copyright © 2021 Torres, Barcelos, Filipe and Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction: Several new treatments have been developed for psoriatic disease, an inflammatory condition that involves skin and joints. Notwithstanding, few studies have made direct comparisons between treatments and therefore it is difficult to select the ideal treatment for an individual patient. The aim of this systematic review with network meta-analysis (NMA) was to analyze available and approved biologic therapies for each domain of psoriatic disease: skin, peripheral arthritis, axial arthritis, enthesitis, dactylitis, and nail involvement. Methods: Data from randomized clinical trials (RCTs) were included. A systematic review was performed using the MEDLINE database (July 2020) using PICO criteria. Bayesian NMA was conducted to compare the clinical efficacy of biological therapy in terms of the American College of Rheumatology criteria (ACR, 24 weeks) and Psoriasis Area and Severity Index (PASI, 10-16 weeks). Results: Fifty-four RCTs were included in the systematic review. Due to the design of the RCTs, namely, outcomes and time points, network meta-analysis was performed for skin and peripheral arthritis domains. For the skin domain, 30 studies reporting PASI100 were included. The peripheral arthritis domain was analyzed through ACR70 in 12 studies. From the therapies approved for both domains, secukinumab and ixekizumab were the ones with the highest probability of reaching the proposed outcomes. There is a lack of outcome uniformization in the dactylitis, enthesitis, and nail domains, and therefore, an objective comparison of the studies was not feasible. Nevertheless, secukinumab was the treatment with the best compromise between the number of studies in each domain and the results obtained in the different outcomes. Conclusion: Secukinumab and ixekizumab were the treatments with the highest probability of reaching both PASI100 and ACR70 outcomes. Due to the lack of a standard evaluation of outcomes of the other psoriatic disease domains, a network meta-analysis for all the domains was not possible to perform.info:eu-repo/semantics/publishedVersio