Periodic Reporting for period 6 - RTCure (Rheuma Tolerance for Cure)
Reporting period: 2022-09-01 to 2023-08-31
The problem: 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 modulatory treatment. A preferred remedy is to enable prevention and treatments that lead to remission of the disease and ultimately cure. It is known that treatment initiated very early in the disease has a better chance to lead to these results. Due to recent progress in prevention of RA with immunomodulating drugs as well as with lifestyle changes, prevention is within reach for many individuals provided individuals at risk for disease are identified early and offered an appropriate intervention. Similarly, very early diagnosis of arthritis increases the chance of curative treatment. One major problem at the onset of RTCure was the lack of enough knowledge about how to identify individuals at risk for RA, and how to stratify these individuals in subsets where degree of risk can help to select interventions. There was also a lack of biomarkers able to both predict risk for RA and inform about biological processes involved in the progression towards RA.
A second major challenge at the beginning of RTCure was to better understand which immune reactions are driving the disease, and in particular understand how immune reactions evolve from a stage of immunity preceding arthritis towards arthritis in some but not all individuals with pre-existing autoimmunity. Such understanding would form the basis for the development of the next generation of therapies for RA, i.e targeting disease-inducing immunity while sparing other parts of specific immune reactions.
Addressing these two major challenges in the field of RA, i.e. prevention and development of tolerizing therapies for prevention and treatment, remain the two most important tasks for research in RA. Any progress towards resolving these challenges will thus be of major importance for patients with RA and for individuals at risk for RA, as well as for society and economy at large.
The RTCure project has aimed to address both these major challenges for RA. (1) Members of our project have produced knowledge and tools that enable identification of individuals at risk for disease by means of screening for symptoms, by use of biomarkers, in particular autoantibody patterns and features, and by producing algorithms able to stratify individuals according to magnitude of risk. Standard Operating procedures (SOPs) for how to perform these analysis and use such algorithms have been developed and made broadly available; (2) Members of the consortium have also produced new knowledge on what immune reactions may contribute to development of RA, and used such knowledge both to better understand disease development and chronicity, and as a basis for development of the next generation of therapies, i.e. induction of tolerance against potentially pathogenic immunity. We have also developed SOPs assays used to monitor effects of immune interventions, including tolerizing therapies, in currently ongoing and forthcoming clinical trials in RA. The same SOPs are and will be used in clinical trials for prevention in individuals at high risk for RA.
Members of the consortium have pioneered testing of therapies able to prevent development of disease via completion of three innovative and groundbreaking prevention trials. Taken together, these accomplishments within the frame of RTCure have opened a new era of handling the RA disease, where prevention becomes a reality.
A second major challenge at the beginning of RTCure was to better understand which immune reactions are driving the disease, and in particular understand how immune reactions evolve from a stage of immunity preceding arthritis towards arthritis in some but not all individuals with pre-existing autoimmunity. Such understanding would form the basis for the development of the next generation of therapies for RA, i.e targeting disease-inducing immunity while sparing other parts of specific immune reactions.
Addressing these two major challenges in the field of RA, i.e. prevention and development of tolerizing therapies for prevention and treatment, remain the two most important tasks for research in RA. Any progress towards resolving these challenges will thus be of major importance for patients with RA and for individuals at risk for RA, as well as for society and economy at large.
The RTCure project has aimed to address both these major challenges for RA. (1) Members of our project have produced knowledge and tools that enable identification of individuals at risk for disease by means of screening for symptoms, by use of biomarkers, in particular autoantibody patterns and features, and by producing algorithms able to stratify individuals according to magnitude of risk. Standard Operating procedures (SOPs) for how to perform these analysis and use such algorithms have been developed and made broadly available; (2) Members of the consortium have also produced new knowledge on what immune reactions may contribute to development of RA, and used such knowledge both to better understand disease development and chronicity, and as a basis for development of the next generation of therapies, i.e. induction of tolerance against potentially pathogenic immunity. We have also developed SOPs assays used to monitor effects of immune interventions, including tolerizing therapies, in currently ongoing and forthcoming clinical trials in RA. The same SOPs are and will be used in clinical trials for prevention in individuals at high risk for RA.
Members of the consortium have pioneered testing of therapies able to prevent development of disease via completion of three innovative and groundbreaking prevention trials. Taken together, these accomplishments within the frame of RTCure have opened a new era of handling the RA disease, where prevention becomes a reality.
The RTCure project has aimed to address the two major challenges for RA described above, i.e. demonstrate ability to prevent onset of disease and how to accomplish a more specific and ultimately curative tolerizing therapy for the disease. Major progress has been made towards prevention, and important basic work has also been done to enable future development of tolerizing and curative therapies:
(1) Members of our consortium have produced knowledge and tools that enable identification of individuals at risk for disease by means of screening for symptoms, by use of biomarkers, in particular autoantibody patterns and features, and by producing algorithms able to stratify individuals in different strata according to magnitude of risk. Standard Operating procedures (SOPs) for how to perform these analyses and use such algorithms have been developed and made broadly available.
(2) Members of the consortium have also produced new knowledge on what immune reactions may contribute to development of RA, and used such knowledge both for better understanding of disease development and chronicity and as a basis for development of the next generation of therapies, i.e. induction of tolerance against potentially pathogenic immunity. We have also developed standard operating procedures (SOPs) for assays used to monitor effects of immune interventions, including tolerizing therapies in currently ongoing and forthcoming clinical trials in RA. The same SOPs are and will be used in clinical trials for prevention in individuals at high risk for RA.
Specific for the final year of the project has been efforts to ensure sustainability of the results of RTCure. We have established structures retaining information from RTCure in project-independent databases with different partners of RTCure, where these partners are able to make data available both for previous members and non-members of the consortium and based on templates of legal agreements developed in RTCure.
We have also ensured contributions from all partners, including patient research partners in the final conclusion and dissemination of progress from RTCure which was concluded at our final annual meeting in May 2023.
(1) Members of our consortium have produced knowledge and tools that enable identification of individuals at risk for disease by means of screening for symptoms, by use of biomarkers, in particular autoantibody patterns and features, and by producing algorithms able to stratify individuals in different strata according to magnitude of risk. Standard Operating procedures (SOPs) for how to perform these analyses and use such algorithms have been developed and made broadly available.
(2) Members of the consortium have also produced new knowledge on what immune reactions may contribute to development of RA, and used such knowledge both for better understanding of disease development and chronicity and as a basis for development of the next generation of therapies, i.e. induction of tolerance against potentially pathogenic immunity. We have also developed standard operating procedures (SOPs) for assays used to monitor effects of immune interventions, including tolerizing therapies in currently ongoing and forthcoming clinical trials in RA. The same SOPs are and will be used in clinical trials for prevention in individuals at high risk for RA.
Specific for the final year of the project has been efforts to ensure sustainability of the results of RTCure. We have established structures retaining information from RTCure in project-independent databases with different partners of RTCure, where these partners are able to make data available both for previous members and non-members of the consortium and based on templates of legal agreements developed in RTCure.
We have also ensured contributions from all partners, including patient research partners in the final conclusion and dissemination of progress from RTCure which was concluded at our final annual meeting in May 2023.
The RTCure project has been the most extensive and ambitious project in the world aiming to enable prevention and more specific and ultimately tolerizing therapy for treatment and prevention of RA. Following this ambition, several results are far beyond the state of art at the beginning of the project. Most notable are:
• A new understanding of the longitudinal evolution of seropositive RA from triggering of immunity outside joints, often at mucosal surfaces until development of arthritis in some but not all individuals identified as being at risk for the disease. The understanding that has been gained provides a basis for risk stratification, for choice of potential therapies for prevention and for development of novel therapies for prevention as well as for early treatment options.
• Pioneering and successfully completed clinical trials that for the first time demonstrate that prevention of RA is feasible. These results provide the basis for future development and clinical implementation of prevention as a new modality for treatment a disease acutely and preventing the chronic RA disease state.
• A fundamentally improved understanding of specificity and regulation of immune reactions that are associated with antibody-positive RA. These data provide a basis for further clinical trials for tolerance disease.
In summary we claim that we have successfully addressed the big challenges for RA that were identified as starting points for the RTCure consortium. Results of RTCure will provide a basis for the future realization and implementation of prevention and better and ultimately tolerizing therapies for patients with established RA.
• A new understanding of the longitudinal evolution of seropositive RA from triggering of immunity outside joints, often at mucosal surfaces until development of arthritis in some but not all individuals identified as being at risk for the disease. The understanding that has been gained provides a basis for risk stratification, for choice of potential therapies for prevention and for development of novel therapies for prevention as well as for early treatment options.
• Pioneering and successfully completed clinical trials that for the first time demonstrate that prevention of RA is feasible. These results provide the basis for future development and clinical implementation of prevention as a new modality for treatment a disease acutely and preventing the chronic RA disease state.
• A fundamentally improved understanding of specificity and regulation of immune reactions that are associated with antibody-positive RA. These data provide a basis for further clinical trials for tolerance disease.
In summary we claim that we have successfully addressed the big challenges for RA that were identified as starting points for the RTCure consortium. Results of RTCure will provide a basis for the future realization and implementation of prevention and better and ultimately tolerizing therapies for patients with established RA.