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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - RTCure (Rheuma Tolerance for Cure)

Teaser

Summary

Rheumatoid arthritis (RA) is characterized by joint inflammation and causes disability and reduced quality of life. By the time of diagnosis, the disease is generally chronic, requiring long-term, usually life-long, immune suppressive treatment. 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 prevent onset of disease. 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 expansion of the pathogenic autoimmune responses underlying RA through immune tolerising treatments 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 major proportion of RA patients and prevention of diseases in individuals at risk for RA.

An important part of our work is to achieve a better understanding of the yet unexplored phase of the disease prior to RA diagnosis. We will develop and validate new methods to identify individuals at risk for RA, tools to monitor disease progress and expand and further develop cohorts suitable for these purposes. Furthermore, we will validate and standardise methods to monitor immune tolerance to be used in clinical trials for RA. Investigator-initiated as well as company-sponsored clinical trials in well stratified groups is performed in collaboration with small-medium enterprises (SMEs) and/or contributing pharma companies and their immune effects studied using the same panel of biomarkers allowing for standardisation across protocols.

Work performed

During the first year of the Rheuma Tolerance for Cure project (RTCure), we focussed on the increased understanding of the specificity and function of autoreactive T and B cells, on the establishment of a common RTCure registry with individuals at risk of developing RA, and on the preparation for clinical trials incorporating the results and technologies developed in RTCure. During the second year, we have continued and expanded the work on B and T cell specificity in RA and produced several seminal papers that demonstrate the reactivity to multiple post-translationally modified proteins and peptides from human monoclonal antibodies derived from B cells and plasma cells from blood, inflamed synovia, lungs as well as servicular fluids. Knowledge on these basic features of the immune response in RA is now being implemented in the development of immunosurveillance methods that are used to monitor the immunological effects of different potentially tolerizing therapies.

We have studied immune processes responsible for the progression from asymptomatic autoimmunity to joint pain and bone loss, and regulatory mechanisms at various phases of RA development. For example, the characteristics of Anti-Citrullinated Protein Antibodies (ACPA) that might be responsible for its pathogenic function have been deeply investigated. We have analysed the occurrence of glycans on Immunoglobulin G (IgG) ACPAs, and compared levels in RA patients and their (ACPA+) first-degree relatives and found that glycosylation of specific regions are associated with future development of RA. We have also looked at different specificities of ACPAs and analysed pathogenic effects of different autoantibodies, using also the human monoclonals described above. To study the mechanisms involved in breach of tolerance, we have developed and during the past year used an antigen specific model of inflammatory arthritis in mice for tolerance studies. With this model we can now assess how the T cells respond to various tolerising regimes, the impact of this on development of arthritis and thus establish the best approaches (treatment, times and locations) to re-establish tolerance in an experimental model.

To allow for future studies of the immune events responsible for the different stages of RA development and to support future clinical studies on tolerising therapies we generated an overview of the cohorts within RTCure, and during year 2 we have organized a new RTCure registry with information on individuals at risk of developing RA. This registry is the first in the world to explore this state of the disease in the multifaceted way we use in RTCure and this registry will also be an important base for recruitment of individuals for clinical trials. Also, a regulatory expert team has been set up and has during year 2 completed an extensive text that will be used to approach regulators with the aim to advance the development of EMA guidelines for the performance of clinical trials in the at risk for RA population. During year 2 we have also continued and extended our interactions with Patient Research Partners and we have appointed a special lead, paid by RTCure for coordination of patient partnersÂ´contributions to the goals of RTCure.

Final results

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, where large medical needs are present, we consider the goals and strategies of our project to be far beyond the current state of the art research in RA. We also need to acknowledge that we in September 2019 arranged a seminar in Washington DC together with the NIH-funded Accelerated Medicines Partnership (AMP) for RA. The AMP project is focused on events in the inflamed joint evaluated with modern single cell technologies, and we concluded after the seminar that the two projects (RTCure and AMP RA) are very complementary, and that the RTCure project has a leading edge concerning the development of therapies, including tolerising therapies that may be used to prevent RA or treat RA very early. If we succeed with this goal, 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 big pharma as well as SMEs in a favorable position to develop products (e-health, diagnostic and therapeutic) for this transformation of care in RA. We also believe that progress in this area for RA may have major dissemination effects into other immune-mediated diseases.