Symptom complexes in patients with seropositive arthralgia and in patients newly diagnosed with rheumatoid arthritis: a qualitative exploration of symptom development

Objective: The aim of this study was to explore symptoms and symptom development during the earliest phases of rheumatoid arthritis (RA) in patients with seropositive arthralgia and patients newly diagnosed with RA

T cell subsets: An immunological biomarker to predict progression to clinical arthritis in ACPA-positive individuals

Objectives Anticitrullinated protein antibody (ACPA)+ individuals with non-specific musculoskeletal symptoms are at risk of inflammatory arthritis (IA). This study aims to demonstrate the predictive value of T cell subset quantification for progression towards IA and compare it with previously identified clinical predictors of progression. Methods 103 ACPA+ individuals without clinical synovitis were observed 3-monthly for 12 months and then as clinically indicated. The end point was the development of IA. Naïve, regulatory T cells (Treg) and inflammation related cells (IRCs) were quantified by flow cytometry. Areas under the ROC curve (AUC) were calculated. Adjusted logistic regressions and Cox proportional hazards models for time to progression to IA were constructed. Results Compared with healthy controls (age adjusted where appropriate), ACPA+ individuals demonstrated reduced naïve (22.1% of subjects) and Treg (35.8%) frequencies and elevated IRC (29.5%). Of the 103 subjects, 48(46.6%) progressed. Individually, T cell subsets were weakly predictive (AUC between 0.63 and 0.66), although the presence of 2 T cell abnormalities had high specificity. Three models were compared: model-1 used T cell subsets only, model-2 used previously published clinical parameters, model-3 combined clinical data and T cell data. Model-3 performed the best (AUC 0.79 (95% CI 0.70 to 0.89)) compared with model-1 (0.75 (0.65 to 0.86)) and particularly with model-2 (0.62 (0.54 to 0.76)) demonstrating the added value of T cell subsets. Time to progression differed significantly between high-risk, moderate-risk and low-risk groups from model-3 (p=0.001, median 15.4 months, 25.8 months and 63.4 months, respectively). Conclusions T cell subset dysregulation in ACPA+ individuals predates the onset of IA, predicts the risk and faster progression to IA, with added value over previously published clinical predictors of progression

Anomalous spin-splitting of two-dimensional electrons in an AlAs Quantum Well

We measure the effective Lande g-factor of high-mobility two-dimensional electrons in a modulation-doped AlAs quantum well by tilting the sample in a magnetic field and monitoring the evolution of the magnetoresistance oscillations. The data reveal that |g| = 9.0, which is much enhanced with respect to the reported bulk value of 1.9. Surprisingly, in a large range of magnetic field and Landau level fillings, the value of the enhanced g-factor appears to be constant.Comment: 4 pages, 3 figure

Profiling microRNAs in individuals at risk of progression to rheumatoid arthritis

Background: Individuals at risk of rheumatoid arthritis (RA) demonstrate systemic autoimmunity in the form of anti-citrullinated peptide antibodies (ACPA). MicroRNAs (miRNAs) are implicated in established RA. This study aimed to (1) compare miRNA expression between healthy individuals and those at risk of and those that develop RA, (2) evaluate the change in expression of miRNA from "at-risk" to early RA and (3) explore whether these miRNAs could inform a signature predictive of progression from "at-risk" to RA. Methods: We performed global profiling of 754 miRNAs per patient on a matched serum sample cohort of 12 anti-cyclic citrullinated peptide (CCP) + "at-risk" individuals that progressed to RA. Each individual had a serum sample from baseline and at time of detection of synovitis, forming the matched element. Healthy controls were also studied. miRNAs with a fold difference/fold change of four in expression level met our primary criterion for selection as candidate miRNAs. Validation of the miRNAs of interest was conducted using custom miRNA array cards on matched samples (baseline and follow up) in 24 CCP+ individuals; 12 RA progressors and 12 RA non-progressors. Results: We report on the first study to use matched serum samples and a comprehensive miRNA array approach to identify in particular, three miRNAs (miR-22, miR-486-3p, and miR-382) associated with progression from systemic autoimmunity to RA inflammation. MiR-22 demonstrated significant fold difference between progressors and non-progressors indicating a potential biomarker role for at-risk individuals. Conclusions: This first study using a cohort with matched serum samples provides important mechanistic insights in the transition from systemic autoimmunity to inflammatory disease for future investigation, and with further evaluation, might also serve as a predictive biomarker

Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively - coincidence within one family

<p>Abstract</p> <p>Background</p> <p>Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Heterozygous <it>LEMD3 </it>gene mutations were shown to be the primary cause of the disease <abbrgrp><abbr bid="B2">2</abbr></abbrgrp>. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones <abbrgrp><abbr bid="B4">4</abbr><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr></abbrgrp>. However, not all MRO affected individuals carry germ-line <it>LEMD3 </it>mutations <abbrgrp><abbr bid="B7">7</abbr></abbrgrp>. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous <it>LEMD3 </it>mutation coincides with a novel mutation in <it>EXT1</it>, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both <it>LEMD3 </it>and <it>EXT1 </it>gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group.</p> <p>Methods</p> <p>We investigated <it>LEMD3 </it>and <it>EXT1 </it>in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses.</p> <p>Results</p> <p>We found a novel c.2203C > T (p.R735X) mutation in exon 9 of <it>LEMD3</it>, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in <it>EXT1 </it>gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the <it>EXT1 </it>gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated.</p> <p>Conclusions</p> <p>We identified a new mutation in <it>LEMD3 </it>gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel <it>EXT1 </it>gene mutations. One of them A598T co-incided with the <it>LEMD3 </it>mutation. Co-incidence of <it>LEMD3 </it>and <it>EXT1 </it>gene mutations was not associated with a more severe skeletal phenotype in those patients.</p

The MLL recombinome of acute leukemias in 2017

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients

The KMT2A recombinome of acute leukemias in 2023

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.publishedVersionPeer reviewe

Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1–12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis

D-Penicillamine Metabolism in an In-Vivo Model of Inflamed Synovium

Oxidation to disulphides is the chief metabolic transformation of D-penicillamine (D-pen) in patients with rheumatoid arthritis. Oxidation also occurs in many biological fluids in-vitro. Reduction of oxygen species may accompany the oxidation of D-pen under appropriate conditions and may mediate the anti-rheumatic action of D-pen. The transformation of D-pen therefore was examined in an in-vivo model of inflamed synovium. Subcutaneous air-pouches of groups of rats were treated with saline, 10% serum or 10% zymosan activated serum (ZAS). The transformation of D-pen to low molecular weight (LMW) metabolites and protein conjugates within the pouch was then assessed. The concentrations of total protein were significantly higher in the serum and ZAS-treated groups than in the saline-treated group and the inflammatory cell counts were significantly higher in the ZAS-treated group than in either of the other groups, as expected. D-pen oxidised rapidly to LMW metabolites and smaller amounts of D-pen-protein conjugate (D-pen-protein) in the air pouches of all animals. The rates of oxidation to LMW metabolites were greater in the ZAS-treated animals than the saline-treated group (p less than 0.005). The concentrations of D-pen-protein conjugate were also greater for the serum-treated and ZAS-treated animals than for the saline controls (p less than 0.005 in each case) at all times. Oxidation of D-pen therefore occurs at this site of inflammation and is influenced by local conditions. This may be important to understanding the forms in which D-pen exists in inflamed synovial joints and the way it may exert its antirheumatic activity