JAK-Inhibitors for the Treatment of Rheumatoid Arthritis : A Focus on the Present and an Outlook on the Future

Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response. The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence. A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected. The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed. Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time. Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy. Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use

Microbial Agents as Putative Inducers of B Cell Lymphoma in Sjögren's Syndrome through an Impaired Epigenetic Control : The State-of-The-Art

Introduction: Understanding the mechanisms underlying the pathogenesis of Sj\uf6gren's syndrome (SS) is crucially important in order to be able to discriminate the steps that lead to B cell transformation and promptly identify the patients at risk of lymphomagenesis. The aim of this narrative review is to describe the evidence concerning the role that infections or dysbiosis plays in the epigenetic control of gene expression in SS patients and their possible involvement in B cell lymphomagenesis. Materials and Methods: We searched the PubMed and Google Scholar databases and selected a total of 92 articles published during the last 25 years that describe experimental and clinical studies of the potential associations of microbiota and epigenetic aberrations with the risk of B cell lymphoma in SS patients. Results and Discussion: The genetic background of SS patients is characterized by the hyperexpression of genes that are mainly involved in regulating the innate and adaptive immune responses and oncogenesis. In addition, salivary gland epithelial cells and lymphocytes both have an altered epigenetic background that enhances the activation of proinflammatory and survival pathways. Dysbiosis or chronic latent infections may tune the immune response and modify the cell epigenetic machinery in such a way as to give B lymphocytes an activated or transformed phenotype. It is also worth noting that transposable integrated retroelements may participate in the pathogenesis of SS and B cell lymphomagenesis by inducing DNA breaks, modulating cell gene expression, or generating aberrant transcripts that chronically stimulate the immune system. Conclusions: Microorganisms may epigenetically modify target cells and induce their transcriptome to generate an activated or transformed phenotype. The occurrence of lymphoma in more than 15% of SS patients may be the end result of a combination of genetics, epigenetics, and dysbiosis or latent infections

Pain in systemic sclerosis

Chronic pain is a healthcare problem that significantly affects the mental health, and the professional and private life of patients. It can complicate many disorders and represents a common symptom of rheumatologic diseases, but the data on its prevalence is still limited. Pain is a ubiquitous problem in systemic sclerosis (SSc). SSc-related pain has been studied on the basis of biomedical models and is considered a symptom caused by the disease activity or previous tissue damage. Effective pain management is a primary goal of the treatment strategy, although this symptom in SSc has not yet been investigated in detail. However, these patients do not all respond adequately to pharmacological pain therapies, therefore in these cases a multimodal approach needs to be adopted

Possible relationship between certolizumab pegol and arrhythmias : Report of two cases

It is still unknown whether there is an association between the use of certolizumab pegol (CZP) in rheumatic patients and the onset of cardiac arrhythmias. We describe the cases of two patients with rheumatoid arthritis (RA) treated with CZP as the first-line biological drug and methotrexate (MTX), who developed an arrhythmic event. The first was a 60-year-old, hypertensive male smoker, the second a 66-year-old dyslipidemic female non-smoker. Both were diagnosed as having RA in 2010, and started treatment with MTX plus CZP. The first patient developed undatable atrial fibrillation, which was resistant to pharmacological treatment and electrical cardioversion. The second patient developed an atrial flutter, which was treated with a betablocker. In both cases, we set a cautious interval between two consecutive administrations of CZP and, in the first case, also reduced the dose of MTX without any worsening of RA activity. Although many studies have shown that tumor necrosis factor (TNF)-alpha plays a pathogenetic role in inducing an arrhythmogenic substrate that is apparently rescued by anti-TNF drugs, there is still a lack of conclusive data. We suggest caution in any patient developing a cardiac event (including rhythm disorders) during treatment with a conventional or biological disease-modifying anti-rheumatic drug

Biomarkers in Rheumatoid Arthritis

Biomarkers are important for guiding the clinical and therapeutic management of all phases of rheumatoid arthritis because they can help to predict disease development in subjects at risk, improve diagnosis by closing the serological gap, provide prognostic information that is useful for making therapeutic choices and assessing treatment responses and outcomes, and allow disease activity and progression to be monitored. Various biomarkers can be used to identify subjects susceptible to the disease and those with pre-clinical rheumatoid arthritis before the onset of symptoms such as rheumatoid factor and anti-citrullinated protein antibodies. They can be correlated with a risk of developing rheumatoid arthritis and can predict more bone erosions and severe disease progression. Biomarkers such as the erythrocyte sedimentation rate and C-reactive protein levels provide information about disease activity, while predictive biomarkers allow clinicians to assess the probability of a treatment response before starting a particular therapy particularly in the era of biological drugs. This move from traditional approaches to patient stratification and targeted treatment should greatly improve patient care and reduce medical costs

The Role of TH9 Lymphocytes in Rheumatoid Arthritis

Background: Th9 cells are IL-9-secreting Th lymphocytes that are involved in the immunological responses underlying parasitic infections and allergic diseases. In the case of autoimmune diseases, Th9 cells seem to be involved in the pathogenesis of experimental autoimmune encephalomyelitis. No study has yet evaluated the effects of Th9 responses in rheumatic diseases such as rheumatoid arthritis (RA). Objectives: The aim of this study was determine the prevalence of Th9 lymphocytes in RA patients and identify their possible association with the discontinuation of biological treatment with infliximab (IFX). Methods: We enrolled 55 consecutive RA outpatients: 15 not receiving any immunosuppressive drug; 20 responders to IFX treatment; and 20 who had discontinued IFX because of adverse events or inefficacy and were being treated with other biological agents (ABA, TCZ, ETN or CTZ) and traditional immunosuppressive drugs. The matched control group consisted of 10 healthy subjects. After giving their informed consent, the subjects underwent blood sampling for the isolation of peripheral blood mononuclear cells (PBMCs). The PBMCs were cultured with/without IFX 50 mg/L for 18 hours, and the percentage of Th9 cells was assessed by means of flow cytometry. Th9 lymphocytes were identified as IFN\u3b3-, IL4-, IL17-, IL9-secreting CD4+ T cells. Results: Cytometric analysis revealed no significant decrease in the percentage of Th9 cells after IFX exposure in any of the groups, but there were significantly fewer cells in the healthy controls than the RA patients both before and after the IFX stimulation assay (Fig.1). The higher frequency of Th9 cells in the patients was not associated with higher levels of anti-nucleus autoantibodies or other auto-antibody subsets, or with a higher likelihood of experiencing an adverse event or lack of efficacy on IFX treatment. Conclusions IL-9 levels are increased in RA patients, in whom it plays a crucial role. Th9 cells are the major producers of IL-9, and their prevalence is higher in RA patients than in healthy subjects, although they do not seem to affect the outcome of biological therapies