MIRNAS AS BIOMARKERS IN AUTOIMMUNE RHEUMATIC DISEASES

MicroRNAs (miRNAs) are small non-coding single-stranded RNAs of about 22 nucleotides in length that act as post-transcriptional regulators of gene expression. Depending on the complementarity between miRNA and target mRNA, cleavage or destabilization of mRNA or translational suppression occurs within the RISC complex. As gene expression regulators, miRNAs are involved in a variety of biological functions. Dysregulation of miRNAs and their target genes contribute to pathophysiology of many disorders including autoimmune rheumatic diseases. For example, dysregulation of miR-155, miR-146a or miR-203 have been known for a long time to contribute to aggressive behavior of synovial fibroblasts and inflammatory milieu in rheumatoid arthritis. Dysregulation of miR-155 or miR-130b infl uence inflammatory or resident renal tubular cells in systemic lupus erythematosus. MiR-29 appears a key regulator of collagen expression in systemic sclerosis. Many miRNAs have been shown to be of therapeutic potential in in vivo animal models. MiRNAs are also present extracellularly in body fluids. Their incorporation into membrane vesicles or protein complexes with Ago2, HDL or nucleophosmin 1 protects them against RNases. Cell-free miRNAs can be delivered to another cell in vitro and maintain their functional potential. Therefore, miRNAs can be considered mediators of intercellular communication. Remarkable stability of cell-free miRNAs makes them accessible in body fluids. However, their origin, target tissue/organ or mechanism of action at the targeted site remains to be elucidated. We aim to summarize growing pieces of evidence supporting diagnostic and prognostic potential of cell-free miRNAs in autoimmune rheumatic diseases such as rheumatoid arthritis, axial spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies or Sjögren´s syndrome. Acknowledgement: Projects MHCR 023728. References: 1. Filková M, Jüngel A, Gay RE, Gay S. MicroRNAs in rheumatoid arthritis: potential role in diagnosis and therapy. BioDrugs. 2012 Jun 1;26(3):131–41

MIRNAS AS BIOMARKERS IN AUTOIMMUNE RHEUMATIC DISEASES

MicroRNAs (miRNAs) are small non-coding single-stranded RNAs of about 22 nucleotides in length that act as post-transcriptional regulators of gene expression. Depending on the complementarity between miRNA and target mRNA, cleavage or destabilization of mRNA or translational suppression occurs within the RISC complex. As gene expression regulators, miRNAs are involved in a variety of biological functions. Dysregulation of miRNAs and their target genes contribute to pathophysiology of many disorders including autoimmune rheumatic diseases. For example, dysregulation of miR-155, miR-146a or miR-203 have been known for a long time to contribute to aggressive behavior of synovial fibroblasts and inflammatory milieu in rheumatoid arthritis. Dysregulation of miR-155 or miR-130b infl uence inflammatory or resident renal tubular cells in systemic lupus erythematosus. MiR-29 appears a key regulator of collagen expression in systemic sclerosis. Many miRNAs have been shown to be of therapeutic potential in in vivo animal models. MiRNAs are also present extracellularly in body fluids. Their incorporation into membrane vesicles or protein complexes with Ago2, HDL or nucleophosmin 1 protects them against RNases. Cell-free miRNAs can be delivered to another cell in vitro and maintain their functional potential. Therefore, miRNAs can be considered mediators of intercellular communication. Remarkable stability of cell-free miRNAs makes them accessible in body fluids. However, their origin, target tissue/organ or mechanism of action at the targeted site remains to be elucidated. We aim to summarize growing pieces of evidence supporting diagnostic and prognostic potential of cell-free miRNAs in autoimmune rheumatic diseases such as rheumatoid arthritis, axial spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies or Sjögren´s syndrome. Acknowledgement: Projects MHCR 023728. References: 1. Filková M, Jüngel A, Gay RE, Gay S. MicroRNAs in rheumatoid arthritis: potential role in diagnosis and therapy. BioDrugs. 2012 Jun 1;26(3):131–41

Is there a role of synovial biopsy in drug development?

Rheumatoid arthritis (RA) is an autoimmune disease which causes significant pain, joint deformity, functional disability. The pathological hallmark of RA is inflammation of the synovium characterized by involvement of inflammatory and resident stromal cells, soluble mediators and signalling pathways leading to irreversible joint destruction. The treatment goal in RA has evolved over the last decade towards a target of disease remission that is achieved in less than a third of patients in clinical trials. The lack of therapeutic response to current treatments is suggestive of alternative drivers of RA pathogenesis that might serve as promising therapeutic targets. There are data to justify the use of synovial tissue in early drug development. Synovial tissue represents an appropriate compartment to be studied in patients with inflammatory arthritis and provides information that is distinct from peripheral blood. Modern techniques have made the procedure much more accessible and ultrasound guided biopsies represent a safe and acceptable option. Advances in analytic technologies allowing transcriptomic level of analysis can provide unique inside to target organ/tissue following the exposure to investigational medicinal product. However, there are still caveats with regard to both the choice of technique and analytical methods. Therefore the significance of synovial biopsy remains to be determined in future clinical trials. The aim of the current debate is to explore the potential for accessing and evaluating synovial tissue in early drug development, to summarize lessons we have learned from clinical trials and to discuss the challenges that have arisen so far

Changing clinical patterns in rheumatoid arthritis management over two decades:Sequential observational studies

BACKGROUND: Rheumatoid arthritis (RA) treatment paradigms have shifted over the last two decades. There has been increasing emphasis on combination disease modifying anti-rheumatic drug (DMARD) therapy, newer biologic therapies have become available and there is a greater focus on achieving remission. We have evaluated the impact of treatment changes on disease activity scores for 28 joints (DAS28) and disability measured by the health assessment questionnaire scores (HAQ). METHODS: Four cross-sectional surveys between 1996 and 2014 in two adjacent secondary care rheumatology departments in London evaluated changes in drug therapy, DAS28 and its component parts and HAQ scores (in three surveys). Descriptive statistics used means and standard deviations (SD) or medians and interquartile ranges (IQR) to summarise changes. Spearman’s correlations assessed relationships between assessments. RESULTS: 1324 patients were studied. Gender ratios, age and mean disease duration were similar across all cohorts. There were temporal increases in the use of any DMARDs (rising from 61 % to 87 % of patients from 1996-2014), combination DMARDs (1 % to 41 %) and biologic (0 to 32 %). Mean DAS28 fell (5.2 to 3.7), active disease (DAS28 > 5.1) declined (50 % to 18 %) and DAS28 remission (DAS28 < 2.6) increased (8 % to 28 %). In contrast HAQ scores were unchanged (1.30 to 1.32) and correlations between DAS28 and HAQ weakened (Spearman’s rho fell from 0.56 to 0.44). CONCLUSIONS: Treatment intensity has increased over time, disease activity has fallen and there are more remissions. However, these improvements in controlling synovitis have not resulted in comparable reductions in disability measured by HAQ. As a consequence the relationship between DAS28 and HAQ has become weaker over time. Although the reasons for this divergence between disease activity and disability are uncertain, focussing treatment entirely in suppressing synovitis may be insufficient

Changing clinical patterns in rheumatoid arthritis management over two decades:Sequential observational studies

This article attempts to examine the problem of friendship as it was understood by Seneca in his letters sent to Lucillus. The author scrutinizes the main items in the philosopher’s autobiography to investigate the influence of the events from Seneca’s biography in the shaping of the opinions of the thinker. Lucillus, the addressee of the letters, was actually Seneca’s long-time friend and confidant. The issue of friendship has a long and rich tradition of its own in the antique times. This particular relationship between human beings was of much interest to Plato, Aristotle, Epicurus, Cicero and many others. Seneca does not venture into an attempt at creating a vision for coherent science related to friendship. What he does though is to furnish a vast array of thoughts concerning such questions as: who is worthy of friendship, why is it worth having a friend and what forms the basis for friendship? Strangely enough, these establishments made by Seneca somehow seem to be more close to us than those in which the philosopher constructs the image of a superhuman wise man, a stoic

Polypharmacy and unplanned hospitalizations in patients with rheumatoid arthritis

Objective.Polypharmacy (PP), the prescribing of multiple drugs for an individual, is rising in prevalence. PP associates with an increased risk of adverse drug reactions (ADR) and hospital admissions. We investigated the relationship between PP, characteristics of rheumatoid arthritis (RA), and the risk of unplanned hospital admissions.Methods.Patients from a hospital RA cohort were retrospectively analyzed. Information was collected from electronic medical records. Cox proportional hazards were used to compare hospitalization risk according to levels of PP. Admissions were adjudicated to determine whether an ADR was implicated.Results.The study included 1101 patients; the mean number of all medications was 5. PP correlated with increasing age, disease duration, disease activity, and disability. At least 1 unplanned admission occurred for 16% of patients. Patients taking ≥ 10 medications had an adjusted HR for hospitalization of 3.1 (95% CI 2.1–4.5), compared to those taking 0–5 medications. Corticosteroid use associated with a doubling in adjusted risk of admission of 1.7 (95% CI 1.2–2.4). The most common reason for hospitalization was infection (28%). While in half of all admissions an ADR was a possible contributing factor, only 2% of admissions were found to directly result from an ADR.Conclusion.PP is common in RA and is a prognostic marker associated with increased risk of acute hospitalizations. Our data suggest that PP may be an indicator of comorbidity burden rather than a contributing cause of a drug-related toxicity. PP should be monitored to minimize inappropriate combination of prescribed medications. PP may be a useful predictor of clinical outcomes in epidemiologic studies.</jats:sec

Heterogeneity of Integrin αIIbβ3 Function in Pediatric Immune Thrombocytopenia Revealed by Continuous Flow Cytometry Analysis

Immune thrombocytopenia (ITP) is an autoimmune condition primarily induced by the loss of immune tolerance to the platelet glycoproteins. Here we develop a novel flow cytometry approach to analyze integrin αIIbβ3 functioning in ITP in comparison with Glanzmann thrombasthenia (GT) (negative control) and healthy pediatric donors (positive control). Continuous flow cytometry of Fura-Red-loaded platelets from whole hirudinated blood was used for the characterization of platelet responses to conventional activators. Calcium levels and fibrinogen binding were normalized to ionomycin-induced responses. Ex vivo thrombus formation on collagen was observed in parallel-plate flow chambers. Platelets from all ITP patients had significantly higher cytosolic calcium concentration in the quiescent state compared to healthy donors (15 ± 5 nM vs. 8 ± 5 nM), but calcium increases in response to all activators were normal. Clustering analysis revealed two subpopulations of ITP patients: the subgroup with high fibrinogen binding (HFB), and the subgroup with low fibrinogen binding (LFB) (8% ± 5% for LFB vs. 16% ± 3% for healthy donors in response to ADP). GT platelets had calcium mobilization (81 ± 23 nM), fibrinogen binding (5.1% ± 0.3%) and thrombus growth comparable to the LFB subgroup. Computational modeling suggested phospholipase C-dependent platelet pre-activation for the HFB subgroup and lower levels of functional integrin molecules for the LFB group