Abstract
Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.
Highlights
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease (IMID) affecting approximately 1% of the UK population [1]
When comparing our mouse THY1+ scRNAseq data with human subsets identified by Zhang et al (2019) [42], we found three transcriptionally analogous fibroblasts subsets: 1) CD34+ C3+ MFAP5+ associated with blood vessels in the sub-lining perivascular space, expressing genes related to immunoinflammatory processes and stromal memory and 2) COL1A1+ COL8A1+ MDK+ expressing genes involved in bone, cartilage and extra cellular matrix (ECM) re-modelling
The spatial and temporal cellular heterogeneity of synovial macrophages and fibroblasts sees the emergence of specialized cellular subsets that define specilised synovial tissue niches that support the pathpogenic behavior of immune cells
Summary
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease (IMID) affecting approximately 1% of the UK population [1]. As more biological and targeted synthetic DMARDs are introduced into clinical practice, we are observing the emergence of a population of patients that have failed to respond to multiple drugs This disease state is termed treatment refractory or difficult to treat RA [13, 14] and has recently been defined by a EULAR taskforce as the failure to respond to two bDMARDs of different mechanisms of action [15]. The generation of therapeutics in RA will need to identify and target these cellular drivers of disease persistence, if we are to develop effective therapies for those individuals with treatment refractory RA [20] Tissue resident cells such as synovial fibroblasts and macrophages form the underlying basis of the joint microenvironment and have been shown to contibue to tissue homeostasis, and regulate the timing and duration of local inflammatory responses [21,22,23,24,25,26]. We will focus on important cross-talk which exist between different synovial tissue cells and we will discuss potential new therapeutic strategies that target tissue resident synovial cells which could potentially restore homeostasis following chronic disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
