NordPerMed: NORA-Personalized medicine in RA by combining genomics, biomarkers, clinical & patient-derived data from the Nordic countries

Rheumatoid arthritis (RA) is an inflammatory disease including joints and tendons. If not treated, it may cause serious damage. It is large individual differences in disease progression as well as efficacy of medication. Emerging data suggest that RA is not one disease but comprised by subsets with distinct aetiologies, which may explain the difficulties in predicting disease course, treatment response, and long-term outcomes. So far, we treat by tradition and try different treatments in a rather random fashion and often too late, despite the increasing number of effective medicines that have become available in routine care. This is the background for the NORA study, where we wanted to explore and develop prediction tools that can help to give the patient the optimal medication. The goal of the NORA study was by use of modern knowledge regarding genetics, biomarkers, new ways of using clinical and patient-reported data as well as use of registrars, to develop methods that on a patient level can help to identify the correct choice of medication. The studies are based on collaboration between strong scientific centres in the Nordic countries, including groups with high expertise on laboratory work and digital competence. The study has been led by the Karolinska Institute in Stockholm. The NORA study is comprehensive and we included several existing patient cohorts in the Nordic countries, where large amounts of clinical data and biological material have been collected, and where advanced technical and digital analyses could be used to develop methods for personalized medicine. Effective medication for RA patients is expensive and may cause side effects. Thus, development of personalized medicine would be of high importance for both patients and the society. The results of the NORA study include several abstracts that have been accepted at different international rheumatological congresses. From the Norwegian group, we have a study under second revision in Scand J Clin Lab Invest. The study explores two different methods for assessing the inflammatory marker calprotectin in plasma (ELISA and FEIA) from early or established RA. We found the two methods to give similar results, supporting the robustness of assessing calprotectin. Thus, this inflammatory marker could be included in the repertoire of tests in clinical routine laboratories. In another paper we are working on the potential for calprotectin and the commonly used inflammatory markers CRP and ESR to predict clinical and ultrasound responses during medical treatment. The study includes both early and established RA patients. Preliminary data suggest that calprotectin may be the best predictor of the three. The NORA collaboration is divided into 8 work packages (WP). The Norwegian group have participated in most of the packages. However, we are in charge of WP5, where results from other WPs shall be validated. We plan to validate the predictors (genetical, laboratory, imaging, patient reported) found in the NORA study using the two randomized studies NORDSTAR and DANACT (which includes patients with early RA). However, it has taken a relatively long time to discuss and to get all the papers in order, but we have now settled a good collaboration with the steering committees for the NORDSTAR and DANACT studies. Plasma samples from most of the patients in the NORSTAR trial have recently been sent to Sweden for several new examination in the NORA study. The DANACT study is recently finalized, but it will take some time till we are given access to the blood samples and clinical data to perform the planned examinations as part of NORA. However, we will soon be able to explore relevant predictors for response in the two cohorts. Thus, even if not all the planned studies in NORA are finalized, the work will go on until we have all the results planned from this study.

NORA-prosjektet har resultert i oppbyggingen av en av verdens største, mest detaljerte og best harmoniserte behandlingskohorter innen RA. I tillegg har vi organisert en teknisk infrastruktur for å håndtere og analysere disse dataene. NORA prosjektets overgripende målsetning har vært å utvikle forbedrede biomarkører for RA sykdomsaktivitet og prediktive algoritmer for å kunne gi persontilpasset medikamentell behandling og dermed få et bedre sykdomsforløp. Dataene som er samlet er bakgrunn for en rekke basale og kliniske forskningsresultater publisert i internasjonale tidsskrifter. Vi vil fortsatt arbeide med dataene, og flere publikasjoner er forventet.

Rheumatoid arthritis (RA, life-time risk around 2%) entails a considerable burden for affected individuals (pain, reduced life-span, reduced function, reduced quality of life), and delayed or ineffective treatment leads to joint destruction, co-morbidities, and increased mortality. RA demonstrates a striking heterogeneity in terms of clinical presentation, response to treatment, and clinical outcomes, with emerging data suggesting RA to be a subsets with distinct etiologies. So far we treat by tradition and try different treatments in a rather random fashion and often too late. The goal of this project is to develop a personalized medicine approach to the management of Rheumatoid Arthritis (RA), both by the development of new prediction tools and by digital tools to bring these now insights to patients and to health-care. Our approach builds on our strong collaboration within Nordic Rheumatology including work with data sharing across the Nordic countries, and a complementary public-private partner constellation that spans all the necessary competences and infrastructures. The novelty in our approach includes the availability and analyses of data across different domains (genomics, biomarkers, clinical data, patient-reported data, register-linkage data) that so far have not been analyzed together, new biomarker assays, the inclusion of patient-centric outcomes (e.g., pain) rather than composite and insensitive outcome metrics. In addition, our constellation of partners will also develop, validate and disseminate these new insights into improvement of therapy directly to patients and health care via the development of digital tools. The anticipated outcomes of our approach is better and earlier treatment of RA paired with the development of products (diagnostics and digital companion tools) that can be used for cost-efficient improvement of treatment results for patients, and thus become attractive commercial products as well.