26 research outputs found
MIRNAS AS BIOMARKERS IN AUTOIMMUNE RHEUMATIC DISEASES
No full textMicroRNAs (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
Editorial: Osteoarticular-immunological interplay in response to disease and therapy
No full textEditorial on the Research Topic
Osteoarticular-immunological Interplay in Response to Disease and Therap
Is there a role of synovial biopsy in drug development?
No full textRheumatoid 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.</p
Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial
No full textBackground: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. Methods: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). Findings: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. Interpretation: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. Funding: Innovative Medicine Initiative
Comparison of promoted alkaline-earth oxide catalysts prepared through evaporation and sol-gel methods by their catalytic performance in propane oxidative dehydrogenation
No full textNovel de novo pathogenic variant in the <em>GNAI1 </em>gene as a cause of severe disorders of intellectual development
No full text\ua9 2021, The Author(s), under exclusive licence to The Japan Society of Human Genetics.Pathogenic sequence variant in the GNAI1 gene were recently introduced as a cause of novel syndrome with a manifestation of variable developmental delay and autistic features. In our study, we report a case of monozygotic twins with severe intellectual disability and motor delay and developmental dysphasia. Both probands and their parents were examined using multi-step molecular diagnostic algorithm including whole-exome sequencing (WES), resulting in the identification of a novel, de novo pathogenic sequence variant in the GNAI1 gene, NM_002069.6:c.815 A>G, p.(Asp272Gly) in probands. Using WES we also verified the microarray findings of a familial 8q24.23q24.3 duplication and heterozygous 5q13.2 deletion, not associated with clinical symptoms in probands. Our results confirmed the role of the GNAI1 gene in the pathogenesis of syndromic neurodevelopmental disorders. They support trio- or quatro-based WES as a suitable molecular diagnostics method for the simultaneous detection of clinically relevant sequence variants and CNVs in individuals with neurodevelopmental disorders and rare diseases
Polypharmacy and Unplanned Hospitalizations in Patients with Rheumatoid Arthritis
No full textObjective.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
Structural study of the MO–Nd<sub>2</sub>O<sub>3</sub> system obtained by a sol–gel procedure
No full textNeodymium-doped alkaline-earth oxide catalysts for propane oxidative dehydrogenation. Part II. Catalytic properties
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