Rheumatic musculoskeletal disease (RMD) patients when family planning must consider fertility, disease activity and management from pre-conception to lactation. We have developed, in conjunction with the National Maternity Hospital, Holles St., a dedicated Rheumatology Reproductive service for women with RMD. This service includes a comprehensive multidisciplinary team including a rheumatologist and rheumatology nurse specialist, obstetric and midwifery, maternal medicine, anaesthesia and pharmacy. We identify patients’ emotional and healthcare needs, provide expert advice and aim to achieve maintenance of good disease control and positive reproductive outcomes. To date, ninety-eight women (mean age (range) = 35 years (19-48)) have been managed. The majority of patients (66%) had inflammatory arthritis and a minority connective tissue disease, vasculitis or other diagnosis. Following analysis of these data and literature review we established an evidence-based care pathway for women with RMD. In conclusion, we describe the first evidence-based reproductive care pathway for women with rheumatic musculoskeletal diseases RMDs in a unique rheumatology reproductive health service, RRHS.
The joints of patients with inflammatory arthritis (IA) show a complex microenvironment of neoangiogenesis, immune cell and fibroblast activation leading to inflammation and joint destruction. T cells play a key role in the pathogenesis of both Rheumatoid Arthritis and Psoriatic arthritis, with differential T cell populations associated with both diseases. It has now emerged that T cell subsets can exhibit functional plasticity, particularly, making it difficult to identify discrete T cell subsets on the basis of their cytokine production. Th17 cells appear to be particularly unstable under inflammatory conditions and can become so-called ex-Th17 cells or nonclassical Th1 cells, which start to produce IFN-γ with the eventual loss of IL-17 expression. Interestingly, we have shown enrichment of polyfunctional Th1, Th17 and Ex-Th17 cells in the periphery and synovial fluid of patients with RA and PsA. In addition, the frequency of polyfunctional T cells are associated with disease activity and response to therapy, suggesting they play a key pathogenic role in disease. Regulatory T cells (Tregs) represent an important peripheral tolerance mechanism that serves to prevent autoimmunity, but fails to constrain inflammation in autoimmune diseases such as RA and PsA. Several studies examining Treg phenotype have reported a decrease in the frequency in peripheral blood of patients with RA/PsA compared with healthy control (HCs), however, studies have also demonstrated enrichment of Tregs at the site of inflammation. However, they have reduced suppressive function thus allowing pathogenic polyfunctional CD161+ cells to further potentiate inflammation. In this study, we investigated the regulation of effector T cells taken from the RA SF by Tregs. The reduced suppression was in part mediated by the CD161+ Th cells, which exhibited enhanced pathogenicity which were resistant to Treg suppression.
In Rheumatology Reproductive Medicine clinic, RA and PsA patients wishing to achieve pregnancy are assessed when they present with active arthritis and intervention is designed to induce remission before conception. Patients are then followed and closely monitored during pregnancy and post-partum to assess disease activity and possible flare. Studies have shown increased frequency and function of Treg cells that are protective in RA patients who are pregnant, however little is known about polyfunctional T cells.
The present study will investigate effector T cells polyfunctionality and Treg cell function in patients with inflammatory arthritis who are pregnant in (i) remission; (ii) during disease flare, if it occurs; and (iii) post-partum.
RA is a complex autoimmune disease resulting from apparently stochastic interactions between genetic and environmental factors. Important environmental factors include smoking, especially heavy smoking, which is the greatest lifestyle risk factor for the development of RA. Environmental factors implicated in addition to smoking include education/social class, breastfeeding, body fat, vitamin D levels, and caffeine and alcohol consumption. According to the WHO, worldwide obesity has nearly tripled since 1975. In parallel with its increase in the general population, obesity has become increasingly common in RA patients.
BMI has been the obesity measure of choice in many previous studies in inflammatory arthritis. However, it has been shown that BMI is not an accurate anthropometric method to diagnose obesity, especially in individuals with altered body compositions (such as inflammatory arthritis patients) due to its inability to discriminate between lean mass and fat mass. Waist circumference has been shown to be superior to BMI in its correlation with visceral fat and has become the preferred measure for abdominal obesity.Central obesity is defined as having a waist circumference of ≥94 cm in men and ≥80 cm in women The pro-inflammatory nature of fat tissue is now well established. These effects are mediated through the secretion of numerous pro-inflammatory cytokines by adipose tissue, coined adipokines. It is suggested that increased adiposity may have a role in the pathogenesis of inflammatory diseases, however the evidence is conflicting. Numerous studies have demonstrated a positive correlation between BMI and the risk of developing RA. An association between obesity and disease activity in RA has been reported in several previous studies. The Better Anti‐Rheumatic Farmacotherapy observational (BARFOT) study demonstrated that obese patients had higher disease activity and lower rates of remission). Obesity has also been associated with a reduced response to TNF-inhibitors (TNFi).
The aim of this study was to evaluate body composition in seropositive and seronegative rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients and assess associations with disease characteristics and baseline synovial arthroscopic findings. We will also access the effect of Obesity on immune cell responses.
The Centre for Arthritis and Rheumatic diseases (SVUH, UCD) and Molecular Rheumatology (TCD) have developed a number of industry partnerships around drug discovery and translational research. These studies utilize the ex vivo whole tissue synovial explant model, sorted synovial cells and multiplex protein assays, transcriptomics and a systems biology approach to establish pre-clinical drug development studies of novel biotherapeutics and small molecular weight candidates.
RA disability stems from structural damage of cartilage and bone due to erosions in synovial joints, if not treated early and aggressively. Treatment guidelines are based on clinical factors such as rheumatoid factor (RF), and more recently, presence of the autoantibodies anti-citrullinated peptide antibodies (ACPA), which may provide improved prediction of outcome in RA. The association with ACPA appears to be highly specific to RA, indeed these antibodies may be present before the onset of clinical arthritis, in some cases several years before, suggesting that autoimmunity precedes inflammation. Autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. This implies a direct link between autoantibody response and structural bone damage in RA. In this study we propose to improve the early diagnosis and prognosis of RA patients by examining the role of ACPA positivity on immune cell function and synovial invasiveness. Specifically, we are stratifying pre-RA and RA patients using ACPA positivity, erosive status and immunopathology of synovial T and B cells in high-risk, poor outcome or good prognosis groups. Phenotype and functional characterisation of T cells and B cells isolated from the site of inflammation in ACPA+ vs ACPA- patients, and their reciprocal interactions and subsequent effect on synovial invasive mechanisms are being examined. Finally, a functional genomics and systems biology approach for disease onset, progression and response is being utilised. Combining clinical status, immunopathology, immune function and transcriptomics analysis from ACPA+ vs ACPA- patients will provide valuable insight into the diagnosis and prognosis of patients with RA at an earlier stage of disease than is currently possible and this will allow selection of treatment for specific patients based on a sound, scientific rationale.
Mitochondrial respiration is the main source of metabolic energy in cells by generating adenosine-triphosphate (ATP) in an oxygen-dependent manner. Environmental cues such as the availability of nutrients and oxygen are sensed by mTOR, AMPK and HIF-1α together with inflammatory cell activation signals to determine the outcome of cell activation and differentiation. We have previously demonstrated that efficiency of oxygen supply to the synovium is poor due to the highly dysregulated synovial microvasculature. This, along with the increased energy demands of activated infiltrating immune cells and inflamed resident cells, leads to an hypoxic microenvironment and mitochondrial dysfunction. This favours an increase in reactive oxygen species, leading to oxidative damage which further promotes inflammation. In this adverse microenvironment synovial cells adapt and rapidly produce ATP to maintain cell activation/function and switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This allows them to produce essential building blocks to support their proliferation. Therefore, metabolic-reprogramming of synovial cells may provide novel therapeutic strategies for treatment of inflammatory arthritis. However, the inflamed synovial tissue is composed of many different cell types including macrophages, T-and B-cells, dendritic cells, endothelial cells and synovial fibroblasts which through cell-cell interactions drive synovial invasiveness, thus making the understanding of these pathways very complex. Therefore, our research programme aims to define the metabolic profile and signalling pathways in specific cell types isolated from the joint and in ex vivo organotypic synovial explant tissue from patients with IA. We have demonstrated distinct metabolic profiles and transcriptional signatures in specific cell types isolated from the joint. Furthermore, we have identified distinct subsets within specific cell types that differ in their metabolic profile, an effect that impacts on whether the cell is pro-inflammatory or pro-resolution. Finally, we have identified that these changes occur very early in disease and can even be present pre-disease onset. Our ongoing work examines the therapeutic potential of targeting metabolic pathways using in-vitro, ex-vivo and in-vivo models.