what we have funded

JAK-inhibitors have evolved into widely used treatments for chronic inflammatory arthritis (IA). However, the ORAL Surveillance study has raised concerns about a potentially increased risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) with JAK-inhibitor treatment. While a wealth of clinical data on this topic have since emerged, the biological mechanisms by which JAK-inhibitors might affect cardiovascular risk remain unclear. We aim to address this by comprehensively studying the effect of JAK-inhibitors and biologics on blood lipid profiles in patients with chronic inflammatory arthritis.

Juvenile dermatomyositis (JDM) is a rare childhood autoimmune disease, presenting with proximal muscle weakness and skin manifestations, characterised by abnormal interferon (IFN)-type-I signalling. There is an urgent need for better treatments, since complications and morbidity remain high. In JDM I have identified abnormal mitochondrial biology and oxidised mitochondrial (oxmt) DNA as potential targets to therapeutically modulate downstream effects of IFN type 1, and have demonstrated three novel druggable targets in this pathway (Wilkinson, 2023). I have now validated a dysregulated mitochondrial gene signature (MGS) detected (37 genes) in monocytes within a new well-powered JDM cohort of treatment-naïve cases, (n=26) compared to age-matched healthy controls (n=19). The MGS represent this mitochondrial abnormality. From the MGS, 17 genes, defined by factor analysis, form a reliable gene-set to measure mitochondrial dysfunction in JDM. Interestingly, the MGS remains dysregulated, even when patients are on treatment and the IFN signature has reduced. I have also shown that the MGS score is highly correlated in CD14+ monocytes compared to matched total PBMC suggesting that the signature could be readily translatable to a clinical test. For this proposal I will test that this novel MGS, measuring mitochondrial dysfunction in autoimmune diseases, predicts disease course for specific patient groups, and could translate into a tool to monitor changes in mitochondrial pathology in clinical trials or stratify treatment to mitochondrial targeted agents.

Sjögren disease (Sjo) is a prototypic systemic autoimmune disease (AID) characterized by lymphoid infiltration of lachrymal and salivary glands leading to xerophtalmia and xerostomia, as well as polyclonal B-cell activation and systemic complications. Sjo is the AID with the highest risk of lymphoma with an increased risk of 10 to 15 fold compared to the general population. Progression from autoimmunity towards B cell lymphoma in Sjo is a multistep process. Our hypothesis is that the occurrence of lymphoma in Sjo results from hyperactivation of B cells, notably of auto-reactive rheumatoid factor (RF) B cells, and from defective immunosurveillance.

People with gout have higher cardiovascular disease risk and recent prior gout flares have been associated with a short-term increase in acute cardiovascular events. Long-term treat-to-target urate-lowering therapy (T2T-ULT) prevents gout flares. Whether lowering serum urate with T2T-ULT will prevent cardiovascular events, likely via flares reduction, has not been investigated. Additionally, whether gout flares are associated with arrhythmias, decompensated heart failure, and complications of acute myocardial infarction is unknown. The purpose of this study is to better understand cardiovascular outcomes associated with gout flares and to ascertain if T2T-ULT and colchicine flare prophylaxis prevent cardiovascular events.

Childhood-onset systemic lupus erythematosus (cSLE) is a rare autoimmune disease with a worse prognosis than adult-onset SLE, yet it remains understudied, leading to a lack of evidence-based therapeutic strategies. Most treatment approaches for cSLE draw from adult SLE research, making it difficult to determine optimal treatment strategies while minimizing damage. A collaborative international initiative, supported by several organizations including PReS and CARRA, aims to validate pediatric-specific treatment targets for cSLE. Recent collaborative work mapped data fields across the three largest cSLE cohorts, creating the largest cSLE dataset globally. A task force led by Dr. Eve Smith has developed consensus-based definitions for lupus low disease activity and clinical remission, requiring clinical validation. Leveraging successful collaboration and existing infrastructures, the initiative aims to validate cSLE treatment targets and assess their impact on patient outcomes through a prospective trial. The study will explore personalized predictions of target attainment using both conventional statistical methods and machine learning approaches

Joint involvement is common in systemic sclerosis (SSc), but remains unexplored. In our first exploratory study, 8 of 9 SSc synovial biopsies were characterized by a non-inflammatory pauci-immune pathotype, whereas this pathotype was only observed in 50% of rheumatoid arthritis (RA) biopsies. In single-cell RNA sequencing, activated signaling pathways were largely different between SSc and RA synovial fibroblasts (SFs) with enrichment in TGFβ and interferon pathways in SSc. We now aim to further decipher SSc-synovium at cellular, molecular and functional levels and to open therapeutic avenues.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune inflammatory disease that mainly affects the joints leading to irreversible disability. RA has been associated with a significantly increased risk of cardiovascular (CV) mortality, only partially explained by traditional CV risk factors. Despite the similarities in pathophysiological mechanisms between synovial and arterial wall inflammation, research focused on the specific mechanisms of RA-induced atherosclerosis is limited. The aim of the present proposal is to investigate how chronic inflammatory pressure in RA imprints a pro-inflammatory signature in hematopoietic stem and progenitor cells (HSPCs) generating circulating monocytes with increased atherogenic potential. In this context, we will perform both human and mouse studies. Firstly, we will assess the effect of lipoproteins commonly found in the inflamed arterial wall in the transcriptome, metabolism, epigenetic regulation and function (transmigration capacity, differentiation into foam cells) of monocytes from RA patients with different inflammatory burden or disease’s stage. Since “Clonal Haematopoiesis of Indeterminate Potential (CHIP)” promotes myelopoiesis, exacerbates atherosclerosis and was also reported in RA, we will investigate whether CHIP-related mutations in RA have an additive effect in the atherogenicity of circulating myeloid cells. As inflammation-adapted HSPCs could contribute to different myeloid cell-driven inflammatory diseases by acquiring a long-term pro-inflammatory phenotype, we will investigate the contribution of medullary and extramedullary myelopoiesis in the development and regression of atherosclerosis in chronic and transient mouse models of experimental arthritis. The final aim of the proposal is to provide novel insights focused in the proatherogenic fingerprint of myeloid cells in RA, which could be used as a therapeutic target to improve the management of both arthritis and RA-associated atherosclerosis.

There is a knowledge gap in the understanding of mechanisms and predictors of flare in remission RA. Based on our preliminary data, we hypothesize that synovial tissue in disease remission exhibit heterogeneity in cellular and molecular pathways, and this determines clinical outcome after treatment tapering/cessation (remission maintenance or flare). Dissecting this heterogeneity will provide: (i) biomarkers to develop testable machine-learning (ML) models that accurate predict disease flares, and uncover (ii) cellular mechanisms responsible for maintenance of remission or flare. To test this hypothesis, we will establish a comprehensive cellular and molecular synovial tissue atlas of remission RA, achieved with different therapeutics. This will aid discovery of (a) cell clusters/pathways driving flare or sustaining remission, and (b) provide an evidence-base to develop ML tools to predict flares. We will test the performance of this ML-derived algorithm on longitudinal remission RA cohort in a biopsy-driven clinical study. To test the functional roles of distinct cell clusters that distinguish synovium of those who flared from those who maintained in remission, we will investigate their pathogenic or inflammation resolving functions using human synovial organoid system. In summary, this project will uncover tissue biomarkers of flare that will help in management of patients’ flares with current therapeutics and provide novel targets for therapeutic intervention to enhance the resolution/repair processes that could transform remission into long-term state.

The optimisation of diagnostic and stratification tools, as well as a better understanding of disease pathogenesis and standardized therapeutic strategy in interstitial lung diseases (ILD) associated to rheumatoid arthritis (RA) and systemic sclerosis (SSc), represent an important translational and clinical unmet need in the field of Rheumatology. This project aims at identifying myeloid epigenetic signatures associated with RA-ILD and SSc-ILD, studying their role on myeloid phenotypes and tissue infiltration in disease, and identification of myeloid biomarkers for early stratification of patients with RA. By addressing this knowledge gap in the field of RA- and SSC-ILD, we believe that this work will facilitate the identification of new therapeutic targets and early biomarkers; which together will facilitate patients’ stratification, clinical trials and clinical management.

Accumulating evidence demonstrates that pathogenic changes at the gut-site, such as dysbiosis of the gut-microbiota, drives inflammation in the synovium of patients with autoimmune arthritis. However, the exact nature of the gut-derived signals that condition the pro-arthritogenic potential of inflammatory cells are yet to be clarified. Here, using juvenile idiopathic arthritis (JIA) as a model, I will investigate whether, and how, specific gut-derived metabolites, whose production is controlled by the gut-microbiota and/or diet, impact B-cell pathogenicity in JIA. Significantly, there is a strong association between gut and joint/eye inflammation in JIA and the use of samples from childhood disease provides an opportunity to investigate the gut-joint axis in a subset of patients where inflammation is less confounded by accumulating lifestyle choices. This proposal builds on my previously published data that the gut-microbiota and microbiota-derived metabolites control the balance between antibody-producing and regulatory B-cell responses in experimental arthritis, and my new data establishing that pathways controlling gut-derived metabolite production are altered in the gut-microbiome of JIA patients with inflamed joints. The findings from this proposal will generate new insights into the mechanisms controlling the gut-joint axis in childhood arthritides.

Background – Sjӧgren Syndrome (SS) is a systemic autoimmune disease characterized by inflammation of lacrimal and salivary glands (SG), with progressive loss of secretory function. To date, SS has no effective treatment. SG epithelial cells (SGEC) play a key role in sustaining inflammation in SS, which is indeed often termed an ‘autoimmune epitelitis’. However, the mechanisms responsible for the inflammatory activation of SGEC remain largely undetermined.

Our line of research indicates that SGECs in SS exhibit profound changes in cell energy metabolism (eg, increased autophagy, glycolysis, and TCA cycle activation), as well as downstream upregulation of adhesion molecules and increased cytokine production (eg, IL-6). Based on these findings, we hypothesize that altered cell energy metabolism of SGEC is a central and targetable driver of SG inflammation in SS.

Systemic rheumatic and musculoskeletal diseases (RMDs) are complex multiorgan diseases with a high disease burden. Pulmonary involvement with interstitial lung disease (ILD) is frequent in many RMDs and is associated with reduced survival. The disease course of ILD varies, from stable to rapidly progressive disease, with a progressive period doubling mortality. Often, the disease progresses without being immediately recognized by the patients. This is often first detected at the next regular hospital visit, leading to a delay in appropriate management, and irreversible damage to the lungs. This limitation can be addressed by implementation of home monitoring with tight control of lung function and respiratory symptoms by E-health, to identify disease progression as it occurs.

JAK inhibitors (JAKi) are small molecules that inhibit several cytokines signaling. They are approved for the treatment of rheumatoid arthritis (RA). In a post authorization, open label, randomized, trial in RA patient, of tofacitinib a JAKi acting on JAK1, 2 and 3, the risk of malignancies was higher in tofacitinib was higher than with anti-TNF with a HR of 1.48 (1.04-2.09)(1). This led our team to study the effect of several JAKi on cancer immunosurveillance by NK cells(2). However, macrophages are the most frequent immune cells in the tumor microenvironment (3-6) and our team has the expertise of studying this cell subset in RA(8,9). The cytokines inhibited by JAKi have a key role in the polarization of monocyte into macrophages. Thus, itaconate, a metabolite acting as a JAK1i leads to a defect of polarization into anti-inflammatory macrophage potentially promoting anti-tumor effects(10). In this project we aim to investigate the role of JAKi on polarization and cancer immunosurveillance by monocyte derived macrophages (MDMs).

The WiSDom project aims to address the complex underlying pathogenetic mechanisms of Sjogren’s disease (SD), a prevalent systemic autoimmune rheumatic disease characterized by chronic inflammation of epithelial structures and increased risk of lymphoma development. Through a multi-faceted approach, WiSDom seeks to characterize both circulating and tissue infiltrating double negative (CD27-, IgD-) B cells (DN B cells) in SD patients, investigating their extended immunophenotype, gene expression profile, and functional role in disease pathogenesis. Recent research has identified this subset of B cells, as prominently involved in SD tissue biopsies. Leveraging, unique patient cohorts and biospecimens along with cutting-edge techniques such as Spectral Flow Cytometry, Imaging Mass Cytometry, mRNA Sequencing, and functional assays, this project endeavors to elucidate the role of DN B cell-mediated tissue damage in SD. The findings of WiSDom have the potential to uncover prognostic biomarkers and novel therapeutic targets offering personalized treatment strategies for SD, ultimately improving the prognosis and quality of life for affected individuals.

Iron is an essential nutrient critical for many cellular processes, but its regulation is crucial to prevent harmful effects from either deficiency or excess. Labile iron (Fe(II)), a potent oxidant, can induce inflammation, cellular aging, and fibrosis by promoting the transformation of fibroblasts and endothelial cells into myofibroblasts, as observed in conditions like hemochromatosis. Experiments have shown that mice with iron overload can spontaneously develop fibrosis in organs such as the lungs, kidneys, and heart. However, the role of tissue iron in systemic sclerosis (SSc), a disease characterized by vascular damage, immune activation, and fibrosis, is not well understood. Early stages of SSc show microvascular damage and bleeding that could lead to significant iron deposition in tissues, considering that erythrocytes, which contain about 70% of the body’s iron, are the source of the bleed. Preliminary studies have found evidence of labile iron in the skin of SSc patients, correlating with inflammatory and fibrotic gene expression, and MRI imaging has revealed iron deposits in the hands and hearts of SSc patients, even before visible fibrosis appears. The research aims to further explore how iron contributes to the fibrosis seen in SSc, using a combination of in vitro experiments, spatial phenotyping, and MRI T2* mapping to track iron in the body. Should this hypothesis prove true, iron chelators could represent a new therapeutic approach for managing early-stage SSc by targeting the fibrotic process.

Spondyloarthritis (SpA) and rheumatoid arthritis (RA) are chronic immune-mediated inflammatorydiseases, primarily affecting joints and potentially causing irreversible damage and disability.These diseases seem to home more to certain joints than others and which we previouslyuncovered to be explained by mechanical loading-induced inflammation. Herein, mechanical loadappears to initiate joint inflammation and to influence the interplay between myeloid cells andsynovial fibroblasts which are thought to act as primary sensors of mechanical stimulation.MONARCH proposes a proof-of-concept study to investigate the mechanical loading-inducedmonocyte-responsive signature as gateway for drug-delivery to monocytes to target this viciouscircle of fibroblast-myeloid crosstalk. Thus, MONARCH project aims to pave the path towardsnovel anti-inflammatory nanomedicine drugs in arthritic diseases by focusing onmechanoinfammation in monocytes and macrophages using a translational medicine approach.

The VISION project seeks to investigate the pathobiology of axial spondyloarthritis (axSpA)-associated acute anterior uveitis (AAU) by using translational proteomics and single-cell transcriptomics analyses to advance in the diagnostic and therapeutic strategies in axSpA, particularly by reducing diagnostic delay and improving patient identification. We will perform proteomics analyses of aqueous humour, tear fluid and serum to identify specific immune signatures and biomarker candidates for early detection of axSpA in AAU patients from: 1) prospectively recruited patients with axSpA-associated AAU and controls with idiopathic AAU and without autoimmune disease (work package WP1); 2) already collected longitudinal biosamples from the Uveitis arm of GESPIC (German Spondyloarthritis Inception Cohort) – comprising AAU patients with and without concomitant (ax)SpA (WP2). Single-cell transcriptomics of activated peripheral immune cells from axSpA-associated AAU patients and controls will be conducted to characterize disease-specific immune cell subsets and their activation states (WP3). The analyses of these data will be combined using established artificial intelligence (AI) models to decipher local and systemic inflammation in axSpA-associated AAU compared to idiopathic AAU, axSpA without AAU, and controls without autoimmune diseases. We will use AI to identify diagnostic biomarkers for concomitant axSpA in AAU patients and validate these findings in the prospective cohort of WP1. Furthermore, the impact of concomitant SpA in patients with AAU will be examined using the three-year longitudinal data from the GESPIC-Uveitis cohort, in which 56% of the subjects had concomitant SpA at baseline. In parallel, we will assess the impact of AAU on patients with axSpA using the 10-year data from the GESPIC-core and GESPIC-AS cohorts (WP4). The engagement and contribution of the patient research partners (PRP) will be essential to disseminate the findings of VISION to the broader public (WP5).

Muscle fatigue severely debilitates the quality of life for patients with established RA despite effective anti-inflammatory medication. Muscle fatigue is the inability of the muscle to maintain a defined force over a defined period of time and may be the results of impaired mitochondrial respiration due to inflammatory mediators. This study investigates whether inflammation-related remodeling of mitochondrial respiration (IRRMR) contributes to muscle fatigue in patients with

established rheumatoid arthritis (RA). The research will assess muscle fatigue in association with muscle mitochondrial respiration and the concentration of systemic elevated inflammatory mediators in the blood of established RA patients compared to healthy controls. These patient assessments are followed-up by in-vitro studies in muscle cells (myotubes) to establish which inflammatory mediators and under what conditions relevant to established RA patients lead to

IRRMR. A validated human in-vitro 3D muscle model will subsequently allow to confirm that this indeed leads to muscle fatigue. Anticipated outcomes include evidence for IRRMR-induced muscle fatigue in RA patients, and insights in the underlying pathogenesis. Ultimately this project will enhance knowledge and awareness of the clinical problem of muscle fatigue in RA patients and gives leads to follow-up studies for development of treatment strategies.

Concurrently with the growing complexity of healthcare, it is predicted that socio-economic (SE) inequities in health outcomes will further increase. Health literacy (HL) constitutes a link between SE disparity and health outcomes that we can act upon. While there is evidence that persons with limited HL can effectively be supported in maximizing their health, healthcare professionals find it challenging to uncover and understand the (often) situational needs of patients. To support health professionals in their efforts to be more responsive to patients’ needs, in this project we aim to develop and evaluate the early implementation of a conversation tool (the CHAT-iRD), and design an educational programme to support healthcare professionals in using this tool. State of the art methods to co-create interventions and develop educational materials will be applied.

No contract yet

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a loss of immune tolerance which leads to unregulated tissue inflammation and organ damage. SLE patients are also burdened by elevated cardiovascular risk responsible for high morbidity and mortality, and which is incompletely explained by traditional cardiovascular risk factors. We, and other have identified that blood platelets link the immune and the hemostasis systems in SLE, and represents a potential therapeutic target.

ANCA-associated vasculitides (AAV) are characterized by recurrent, chronic small vessel inflammation and deleterious organ damage. Early disease control by targeted treatment has improved considerably, but the most important clinical challenge now is the recognition and control of flares. This project aims to delineate the immunological basis of disease flares and disease persistence in AAV patients. We have observed that individual AAV patients (in contrast to healthy individuals) can harbour large populations of B cells expressing IgM-ANCA, and that IgM-ANCA can strongly activate complement. Based on this preparatory work, we hypothesize that auto-reactive B cell responses reflect a so far undetermined layer of immunological disease activity in AAV, with IgM B cell responses driving flares. To test this novel hypothesis, the project unites three AAV expert centres that combine unique expertise and technology in autoreactive B cell biology, well-defined cohorts with longitudinal follow-up and biological samples, and patient representatives experienced in supporting translational research. The expected end-product is an immunological definition of (imminent) disease flares in AAV and a novel measure of disease activity. This addresses directly the scope of the call and will be crucial to guide future trials aiming at testing strategies for optimal control of disease.

Sustained drug-free remission (SDFR) is achievable in up to 50% of patients with rheumatoid arthritis (RA) in drug-induced remission. However, methods to predict SDFR, its immunological basis, and its impact from a patient perspective remain unknown. The goal of this proposal is to address these unmet needs in three distinct yet complementary work packages (WPs), combining our large patient cohorts and biobanks across three EULAR Centres of Excellence with an industrial partner (Genentech). In WP1, we aim to validate our prototype cytokine biomarker of SDFR using our existing sample biobanks. In WP2, we aim to explore and understand specific mechanisms that potentiate SDFR as implicated by our pilot data, namely: the abundance, phenotype and function of CD4+ Tregs and ACPA-expressing B cell subsets; and markers of regulatory macrophage and intestinal barrier function. In WP3, we aim to understand the impact of living with SDFR from a patient perspective using qualitative methodology. Patient research partners (PRPs) will play an integral role in project design, delivery and dissemination. If successful, our project will support a future clinical efficacy trial of biomarker-driven drug cessation in RA remission, a paradigm shift in the management of RA. Furthermore, new insights into the immunobiology of SDFR could identify novel approaches to treat and prevent RA flare, and understanding the lived experience of SDFR will help to guide patient-clinician discussions around drug cessation.

Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis (SSc). A significant challenge in managing SSc-ILD patients is the high molecular heterogeneity, which varies not only between patients but also spatially within the lungs of an individual. A deep molecular understanding of these lung tissue changes in each patient is crucial to initiate precise and targeted treatment. Current diagnostic tools inadequately address this need.

Radiomic analysis of routinely performed high-resolution CT scans offers a non-invasive way to assess this molecular heterogeneity across the entire lung. Our project aims to integrate spatially resolved radiomic profiles with matched molecular data derived from single-nuclei RNA sequencing (snRNA-seq) to decipher the cellular programs underlying the spatial heterogeneity in SSc-ILD and how they are reflected in the radiomic phenotype. Specifically, utilising a unique collection of 15 systemically processed whole explant lungs from SSc-ILD and 5 healthy donors, we will analyse by snRNA-seq how cellular composition, and molecular pathways vary spatially in the lungs, and integrate these findings with spatially-matched radiomic profiles to derive noninvasive radiomic signatures for cell state profiles and pathway activations on the tissue level. The identified radiomic patterns will be independently validated and mapped to the microscopic context with multiplexed immunofluorescence. Finally, we will associate the identified radiomic cell state/pathway signatures with patient characteristics and outcome, including lung disease progression and treatment response in retrospective SSc-ILD patient cohorts. This will pave the way for the non-invasive assessment of pathophysiological cell states on the tissue level and hence precision medicine in SSc-ILD. Beyond its clinical significance, this project will also significantly advance our understanding of the cellular mechanisms underlying the spatial heterogeneity in SSc-ILD, thus informing drug discovery and therapeutic innovation.

Advances in the field of emerging rheumatoid arthritis (RA) paved the way for studies aiming to prevent RA development. Individuals at risk for RA can be identified with a combination of symptoms while clinical arthritis is still absent (Clinically Suspect Arthralgia, CSA). Recent proof-of-concept prevention trials showed delay or disease modification, but no prevention of RA development. Apparently, key mechanisms for chronicity are not specifically affected by anti-CD20 and methotrexate. With the ultimate aim to achieve targeted prevention, I propose to start research into subclinical inflamed tissue to gain insight on key mechanisms underlying progression from CSA to RA.

SLE and many rheumatic autoimmune diseases are characterized by autoantibodies, which are produced when B cells derange and recognize self-tissue as foreign. This is referred to as tolerance breakthrough. The tolerance checkpoints regulating B cell activation and terminal plasma cell differentiation are ill defined and understood.

I aim to identify the immunological mechanisms underlying the breach of tolerance checkpoints that lead to autoantibody production. I will take a unique approach by studying tolerance checkpoints in the cutaneous B cell response in SLE compared to chronic cutaneous lupus erythematosus (CCLE). Most patients with CCLE have skin involvement and no autoantibodies, but some subsequently develop SLE with loss of tolerance and systemic B cell autoimmunity.

Thus, this approach provides an exceptional opportunity to delineate tolerance checkpoints at the local site where B cell activation and break of tolerance occurs.