13 research outputs found

    RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

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    Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

    Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 r4ra randomized trial

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    Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients

    A pilot project informing the design of a web-based dynamic nomogram in order to predict survival one year after hip fracture surgery

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    BACKGROUND: Hip fracture is associated with high mortality. Identification of individual risk informs anesthetic and surgical decision-making and can reduce the risk of death. However, interpreting mathematical models and applying them in clinical practice can be difficult. There is a need to simplify risk indices for clinicians and laypeople alike. OBJECTIVE: Our primary objective was to develop a web-based nomogram for prediction of survival up to 365 days after hip fracture surgery. METHODS: We collected data from 329 patients. Our variables included sex; age; BMI; white cell count; levels of lactate, creatinine, hemoglobin, and C-reactive protein; physical status according to the American Society of Anesthesiologists Physical Status Classification System; socioeconomic status; duration of surgery; total time in the operating room; side of surgery; and procedure urgency. Thereafter, we internally calibrated and validated a Cox proportional hazards model of survival 365 days after hip fracture surgery; logistic regression models of survival 30, 120, and 365 days after surgery; and a binomial model. To present the models on a laptop, tablet, or mobile phone in a user-friendly way, we built an app using Shiny (RStudio). The app showed a drop-down box for model selection and horizontal sliders for data entry, model summaries, and prediction and survival plots. A slider represented patient follow-up over 365 days. RESULTS: Of the 329 patients, 24 (7.3%) died within 30 days of surgery, 65 (19.8%) within 120 days, and 94 (28.6%) within 365 days. In all models, the independent predictors of mortality were age, BMI, creatinine level, and lactate level. The logistic model also incorporated white cell count as a predictor. The Cox proportional hazards model showed that mortality differed as follows: age 80 vs 60 years had a hazard ratio (HR) of 0.6 (95% CI 0.3-1.1), a plasma lactate level of 2 vs 1 mmol/L had an HR of 2.4 (95% CI 1.5-3.9), and a plasma creatinine level of 60 vs 90 mol/L had an HR of 2.3 (95% CI 1.3-3.9). CONCLUSIONS: In conclusion, we provide an easy-to-read web-based nomogram that predicts survival up to 365 days after hip fracture. The Cox proportional hazards model and logistic models showed good discrimination, with concordance index values of 0.732 and 0.781, respectively

    nestedcv:an R package for fast implementation of nested cross-validation with embedded feature selection designed for transcriptomics and high-dimensional data

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    MOTIVATION: Although machine learning models are commonly used in medical research, many analyses implement a simple partition into training data and hold-out test data, with cross-validation (CV) for tuning of model hyperparameters. Nested CV with embedded feature selection is especially suited to biomedical data where the sample size is frequently limited, but the number of predictors may be significantly larger (P ≫ n). RESULTS: The nestedcv R package implements fully nested k × l-fold CV for lasso and elastic-net regularized linear models via the glmnet package and supports a large array of other machine learning models via the caret framework. Inner CV is used to tune models and outer CV is used to determine model performance without bias. Fast filter functions for feature selection are provided and the package ensures that filters are nested within the outer CV loop to avoid information leakage from performance test sets. Measurement of performance by outer CV is also used to implement Bayesian linear and logistic regression models using the horseshoe prior over parameters to encourage a sparse model and determine unbiased model accuracy. AVAILABILITY AND IMPLEMENTATION: The R package nestedcv is available from CRAN: https://CRAN.R-project.org/package=nestedcv

    Axl and MerTK regulate synovial inflammation and are modulated by IL-6 inhibition in rheumatoid arthritis

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    International audienceThe TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment
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