Automated multi-scale computational pathotyping (AMSCP) of inflamed synovial tissue.

Rheumatoid arthritis (RA) is a complex immune-mediated inflammatory disorder in which patients suffer from inflammatory-erosive arthritis. Recent advances on histopathology heterogeneity of RA synovial tissue revealed three distinct phenotypes based on cellular composition (pauci-immune, diffuse and lymphoid), suggesting that distinct etiologies warrant specific targeted therapy which motivates a need for cost effective phenotyping tools in preclinical and clinical settings. To this end, we developed an automated multi-scale computational pathotyping (AMSCP) pipeline for both human and mouse synovial tissue with two distinct components that can be leveraged together or independently: (1) segmentation of different tissue types to characterize tissue-level changes, and (2) cell type classification within each tissue compartment that assesses change across disease states.

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation.

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis.

Machine Learning Reveals Synovial Fibroblast Genes Associated with Pain Affect Sensory Nerve Growth in Rheumatoid Arthritis.

Unlabelled: It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We identified a module of 815 genes associated with pain, using a novel machine learning approach, Graph-based Gene expression Module Identification (GbGMI), in samples from patients with longstanding RA, but limited synovial inflammation at arthroplasty, and validated this finding in an independent cohort of synovial biopsy samples from early, untreated RA patients. Single-cell RNA-seq analyses indicated these genes were most robustly expressed by lining layer fibroblasts and receptor-ligand interaction analysis predicted robust lining layer fibroblast crosstalk with pain sensitive CGRP+ dorsal root ganglion sensory neurons.

Computer Vision Analysis of Rheumatoid Arthritis Synovium Reveals Lymphocytic Inflammation Is Associated With Immunoglobulin Skewing in Blood.

Objective: We sought to develop computer vision methods to quantify aggregates of cells in synovial tissue and compare these with clinical and gene expression parameters.

Methods: We assembled a computer vision pipeline to quantify five features encompassing synovial cell density and aggregates and compared these with pathologist scores, disease classification, autoantibody status, and RNA expression in a cohort of 156 patients with rheumatoid arthritis (RA) and 149 patients with osteoarthritis (OA).

Results: All five features were associated with pathologist scores of synovial lymphocytic inflammation (P < 0.

Machine learning identification of thresholds to discriminate osteoarthritis and rheumatoid arthritis synovial inflammation.

Background: We sought to identify features that distinguish osteoarthritis (OA) and rheumatoid arthritis (RA) hematoxylin and eosin (H&E)-stained synovial tissue samples.

Methods: We compared fourteen pathologist-scored histology features and computer vision-quantified cell density (147 OA and 60 RA patients) in H&E-stained synovial tissue samples from total knee replacement (TKR) explants. A random forest model was trained using disease state (OA vs RA) as a classifier and histology features and/or computer vision-quantified cell density as inputs.

Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis.

Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15HLADR and CD48S100A2 monocytes, recently identified in inflamed RA synovia and blood of those with RA flares.

Factors Associated With Increasing Length of Stay for Rheumatoid Arthritis Patients Undergoing Total Hip Arthroplasty and Total Knee Arthroplasty.

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are cost-effective procedures that decrease pain and improve health-related quality of life for patients with advanced symptomatic arthritis, including rheumatoid arthritis (RA). Patients with RA have a longer length of stay (LOS) after THA or TKA than patients with osteoarthritis, yet the factors contributing to LOS have not been investigated. : We sought to identify the factors contributing to LOS for patients with RA undergoing THA and TKA at a single tertiary care orthopedic specialty hospital.

Dynamic spectrum of ectopic lymphoid B cell activation and hypermutation in the RA synovium characterized by NR4A nuclear receptor expression.

Ectopic lymphoid structures (ELS) can develop in rheumatoid arthritis (RA) synovial tissue, but the precise pathways of B cell activation and selection are not well understood. Here, we identify a synovial B cell population characterized by co-expression of a family of orphan nuclear receptors (NR4A1-3), which is highly enriched in RA synovial tissue. A transcriptomic profile of NR4A synovial B cells significantly overlaps with germinal center light zone B cells and an accrual of somatic hypermutation that correlates with loss of naive B cell state.

Rheumatoid Arthritis Synovial Inflammation Quantification Using Computer Vision.

Objective: We quantified inflammatory burden in rheumatoid arthritis (RA) synovial tissue by using computer vision to automate the process of counting individual nuclei in hematoxylin and eosin images.

Methods: We adapted and applied computer vision algorithms to quantify nuclei density (count of nuclei per unit area of tissue) on synovial tissue from arthroplasty samples. A pathologist validated algorithm results by labeling nuclei in synovial images that were mislabeled or missed by the algorithm.

DRUL for school: Opening Pre-K with safe, simple, sensitive saliva testing for SARS-CoV-2.

To address the need for simple, safe, sensitive, and scalable SARS-CoV-2 tests, we validated and implemented a PCR test that uses a saliva collection kit use at home. Individuals self-collected 300 μl saliva in vials containing Darnell Rockefeller University Laboratory (DRUL) buffer and extracted RNA was assayed by RT-PCR (the DRUL saliva assay). The limit of detection was confirmed to be 1 viral copy/μl in 20 of 20 replicate extractions.

Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement.

Objective: We sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma).

Methods: Fifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in two clinical trials. Histologic/immunophenotypic assessments of global severity, alpha-smooth muscle actin (aSMA), CD34, collagen, inflammatory infiltrate, follicles and thickness were compared with gene expression and clinical data.

RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.

Background: Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown.

Methods: We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq).

Tranexamic Acid Does Not Reduce the Risk of Transfusion in Rheumatoid Arthritis Patients Undergoing Total Joint Arthroplasty.

Background: Patients with rheumatoid arthritis (RA) receive transfusions more often than patients with osteoarthritis following lower extremity total joint arthroplasty (TJA), but mitigating factors are not described. Tranexamic acid (TXA) is widely used to reduce blood loss in patients undergoing TJA, but its effect on transfusion rates in patients with RA has not been studied.

Methods: We retrospectively reviewed data from a prospectively collected cohort of patients with RA undergoing TJA.

Rheumatoid Arthritis Morning Stiffness Is Associated With Synovial Fibrin and Neutrophils.

Objective: Morning stiffness is a hallmark symptom of rheumatoid arthritis (RA), but its etiology is poorly understood. This study was undertaken to determine whether any histologic features of synovium are associated with this symptom.

Methods: Data on patient-reported morning stiffness duration and severity, and Disease Activity Score in 28 joints (DAS28) were collected from 176 patients with RA undergoing arthroplasty.

Rheumatoid Arthritis Flares After Total Hip and Total Knee Arthroplasty: Outcomes at One Year.

Objective: Most patients with rheumatoid arthritis (RA) undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) have active RA and report postoperative flares; whether RA disease activity or flares increase the risk of worse pain and function scores 1 year later is unknown.

Methods: Patients with RA were enrolled before THA/TKA. Patient-reported outcomes, including the Hip disability and Osteoarthritis Outcome Score (HOOS)/Knee Injury and Osteoarthritis Outcome Score (KOOS) and physician assessments of disease characteristics and activity (Disease Activity Score in 28 joints [DAS28] and Clinical Disease Activity Index), were collected before surgery.