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Rheuma Tolerance for Cure

Periodic Reporting for period 4 - RTCure (Rheuma Tolerance for Cure)

Reporting period: 2020-09-01 to 2021-08-31

Today’s treatment of Rheumatoid Arthritis (RA) remains unsatisfactory. By the time of diagnosis, the disease is generally chronic, requiring long-term, usually life-long, immune suppressive treatment. To prevent onset of disease, treatment of RA by inhibiting the pathogenic autoimmune responses in early stages of joint inflammation, or even before onset of joint inflammation, when patients have arthralgia and/or bone loss or sub-clinical stages of joint inflammation would be preferable. Today, no drugs are approved to intervene in these early phases of RA, where symptoms such as pain and fatigue are clearly apparent. In line with the Innovative Medicine Initiative 2 (IMI2) goals for improved therapies and precision medicine, the overarching goal of our project is to prevent RA development or its progression. We aim to accomplish this by inhibiting or modifying the pathogenic autoimmune responses underlying RA through immune tolerising treatments or other targeted therapies in subjects at the earliest stage of their disease. This approach could result in a specific and long-lasting therapeutic effect (ultimately a cure) for a majority of RA patients and preferentially also prevent disease onset for individuals at risk for RA.

An important part of our work is to achieve a better understanding of the yet unexplored phases of the disease prior to RA diagnosis. We have developed and validated new methods to identify individuals at risk for RA and developed tools to monitor disease progression. We have also expanded and further developed cohorts suitable for these purposes. Furthermore, we have also developed standard operating procedures (SOPs) for assays that are and will be used to to monitor effects of immune interventions, including tolerizing therapies that are used in clinical trials for RA. The same SOPs are and will be used in clinical trials for prevention in individuals at high risk for RA.

As described above, a major undertaking for the accomplishment of our aim is to initiate and perform clinical trials seeking tolerance induction in patients with RA-associated immunity while these individuals have not yet developed arthritis. Five such trials are ongoing (partly) within the Rheuma Tolerance for Cure project (RTCure), three have finalized recruitment and are currently subject to evaluation of results. We expect that the combined results of novel approaches to understand pathogenic immunity and efforts to modify this immunity will result in a new paradigm for prevention and early treatment of RA.
During the fourth year of the RTCure project, we have continued our work to understand the origins, specificities and effector functions of autoreactive T and B cells in RA patients. This work has involved detailed characterization of specificities, effector functions and multireactivities of human monoclonal antibodies from RA patients as well as description of unique glycosylation patterns for these antibodies. Partners in RTCure have established novel systems for flow cytometric and cytometry by time-of-flight (CyTOF)-based analysis of T and B cells in individuals at risk for RA and patients with established RA and have also performed single cell mRNA sequencing studies of B cells from RA patients, defining the phenotype of antigen-specific and activated B cells from RA patients. Similarly, we have analyzed antigen-specific T cells from blood, synovial fluids and synovial tissue, used single cell technologies to isolate single antigen-specific T cells (identified using MHC class II tetramers) and sequenced and cloned TCRs from these cells. These TCRs have further been re-expressed in cell lines for in vitro studies and introduced in retrogenic mice enabling in vivo studies on their potential pathogenicity as well as for testing of potential tolerizing therapies in RA-relevant humanized murine systems. All these systems were developed to allow coordinated efforts to enable immunomonitoring in observational as well as in interventional randomized controlled trials (RCT) in both RA patients and in individuals at risk for RA .

Furthermore during year 4 of RTCure, detailed studies on immune processes responsible for the progression from asymptomatic autoimmunity to joint pain and bone loss were performed. Regulatory mechanisms at various phases of RA development were studied. To coordinate our efforts, a registry of individuals at risk for RA has been established. This registry is the first of its kind exploring early stages of RA and will be an important tool for recruitment of individuals in upcoming clinical trials.
Additionally, a regulatory expert team has been set up which during year 4 has completed a document which will be used to approach regulators with the aim to advance the development of EMA guidelines for the execution of clinical trials in a population at risk for RA. A first meeting between our task force in RTCure and the Swedish Medical Agency happened in May 2021, resulting in a positive feed-back from the agency and encouragement to continue interactions with regulators concerning advice and guidelines for clinical trials in the at risk for RA phase. We were advised to take this next step after results from the two most imminent clinical trials on RA prevention are publicly available. Interactions with Patient Research Partners have continued and been extended, so was the work with our Patient Research Partner coordinator lead, paid by RTCure for coordination of Patient Research Partners’ contributions to the goals of RTCure.

Some delays in several of the tasks have occurred due to the COVID-19 Pandemic and the closure of laboratories. Also the work with developing an At risk for RA registry in WP2 has been indirectly affected and delayed by the pandemic.
The RTCure project is the most extensive and ambitious project in the world aiming to develop diagnosis, new therapies and immunosurveillance techniques for individuals/patients in very early stages of development of RA, preferentially at stages where no joint inflammation but arthralgia and bone loss is present. As no drugs are developed and approved for this stage of disease, despite a large medical unmet need, we consider the goals and strategies of our project to be far beyond the current state of the art research in RA. If we succeed with these goals, we would transform the therapy and prevention of RA fundamentally to the benefit of patients and society in Europe and beyond. The public private partnership we have developed with use of unique cohorts and registries in Europe that are very difficult to develop in the rest of the world, will also put European companies, including pharmaceutical companies including Small Medium Enterprises (SMEs) in a favorable position to develop products (e-health, diagnostic and therapeutic) for this transformative approach to care in RA. Progress in this area for RA care should have major dissemination effects into other immune-mediated diseases.

We are currently waiting for the first results from interventions with immunomodulatory drugs for prevention of RA, and expect major novel results both concerning clinical outcomes and concerning immunological mechanisms during the coming year.
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