World Arthritis Day 2018 ‐ Perspectives on Rheumatic musculoskeletal diseases

Abstract

Rheumatic and musculoskeletal diseases (RMDs) comprise a plethora (∼200) of immune mediated inflammatory conditions including rheumatoid arthritis (RA), osteoarthritis, psoriatic arthritis and systemic autoimmune diseases such as Sjogren's syndrome, systemic lupus erythematosus and systemic sclerosis. Altogether, RMDs affect up to 20% of the overall European population and it is estimated that around one third of the population will be affected at some point in their lives. To make things worse, due to an ageing population, the percentage of citizens who will have to face one or multiple RMDs is likely to increase even further. Similarly, RMDs are the number one cause of disability in Europe. According to the Global Burden of Disease study, RMDs are responsible for nearly 30% of years lived with disabilities in Europe. Moreover, RMDs pose a further significant risk to the population by virtue of accelerating a number of co-morbidities including increased rates of some cancers, cardiovascular disease, gastrointestinal disease, diabetes and increased rates of mental health disorders. As such RMDs comprise a major part of the rapidly increasing emergence of multi-morbidity whereby people present with more than one chronic illness, each impacting on the treatment and outcome of the other. The field of rheumatology comes from challenging therapeutic times in the past, dominated by rehabilitation and containment and management of substantial disability. As a discipline, however rheumatology has seen arguably the most dramatic progress in medicine as we have witnessed tremendous improvement in its therapeutic armamentarium. One of the best examples is the rapidly changing landscape of treatment perspectives for patients with RA. RA is a chronic autoimmune disease were inflammation of the joints (synovitis) destroys cartilage and bone leading to severe disability. Moreover, RA is associated with an increased prevalence of cardiovascular complications leading to a significant risk of premature mortality. Only two decades ago a substantial number of patients were bound to wheelchairs due to the destruction of joints in hips, knees and feet. In line with this, the majority of RA patients lost their hand function leading to loss of work many of those. The tide was turned initially by the introduction of so-called disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate and sulphasalazine soon to be followed by the discoveries on the role for tumour necrosis factor in RA pathology that laid the foundation for the development of TNFa inhibitors. Especially the combination of MTX with TNFa inhibitors was shown to result in stalling of joint damage which has in turn manifest steep decline of joint replacement across Europe, and almost no RA patients bound to wheelchairs. Currently, the therapeutic armamentarium for patients with RA is enriched with cytokine- and cell-based therapies that are registered for clinical use including those targeting B-cells (anti-CD19, anti-CD20), DC-T cell interaction (CTLA4-Ig) and cytokines like IL-6 and, more recently, intracellular targets like Janus Kinases (JAK inhibitors). Importantly, the diversity of novel targets is rapidly expanding as well as is the spread of these therapeutics to other indications within the field of RMDs. However, despite all these positive developments the field of rheumatology is still not where its needs to be. For instance, we measure response to therapy at levels far from disease in remission; to reach clinical response we most often need life-long use of immune suppressive drugs with all risk coinciding with that and; we are unable to cure and/or to prevent disease. Research and innovation are imperative for closing the gap on the lack of knowledge needed to reach our clinical goals. Research into RMDs, however, while focussing on a few areas quite successfully, is lacking coordination and integration with respect to long-term planning in many major areas. Research in Europe remains dispersed; scientific institutions are willing to cooperate, but depend on short-term project funding, limiting them to collaboration in often rather narrow areas. EU Member States and other European countries are promoting research into these diseases to very different degrees, and without sufficient cooperation, while priorities are often defined in total isolation across distinct states or regions. Scarcity of funding resources, but also the need to foster scientific excellence throughout the continent, leads to the conclusion that strategic coordination for a field as important as RMDs would be of great added value. Furthermore, long-term strategic coordination will provide both the scientific community and funding organisations at international, EU and national levels with orientations for long-term investment – and inspire strategic prioritisation during the next decade. In order to contribute to the development of the strategic coordination, the European League Against Rheumatism (EULAR, www.EULAR.org) has proposed the European Roadmap for Research in Rheumatic and Musculoskeletal Diseases (RheumaMap) initiative. RheumaMap is expected to serve as a foundation for communicating with decision makers, the broad scientific community, funding institutions and key stakeholders on what to prioritise in order to better reduce the burden of RMDs in Europe. EULAR represents scientific societies, patient organisations and health professional associations from all European countries. This document has been developed in close collaboration with all EULAR stakeholders to include the range of relevant perspectives. This document will be further developed and updated in the coming years, thereby serving as a ‘living document’ to best serve the dynamic and emerging needs of people with RMDs. The roadmap identifies unmet needs and main challenges in research and innovation in RMDs, proposing key areas where long-term strategic efforts should focus over the mid/term in order to help reduce the enormous burden of these conditions in Europe. In this sense, the aim of RheumaMap is to guide scientific and policy efforts and investments in order to achieve substantial policy goals, as illustrated herein. World Arthritis Day (WAD) is a global awareness-raising day involving all potential stakeholders in the field of RMDs. EULAR participates by promoting international activities for and on this day: It hosts the WAD website and each year designs activities that create understanding around life with rheumatic and musculoskeletal diseases in Europe. Individuals and organisations everywhere are invited to take ideas presented on the WAD website and develop them into national-level actions. In 2018, WAD is again part of the ‘Don't Delay, Connect Today!’ EULAR Campaign which, for the first time, engages all three EULAR pillars – patient organisations (PARE), health professional associations and scientific communities in a panEuropean and even worldwide public awareness campaign. The EULAR Campaign, Don't Delay, Connect Today, was launched in 2017 and focusses on early recognition and diagnosis of RMDs as early diagnosis is key to preventing further damage. In 2018, EULAR strives to reach out to an ever-increasing audience in Europe. One way to do this is the organization of the EULAR WAD conference in Brussels (October 9th) with the given topic - Bringing chronic diseases to the forefront of health innovation: From the lab to individualised health care. Although some disappointments mark the history of the field of Rheumatology, great successes have been observed and many of those are likely to follow. We have learned from adversity and now represent one of the most exciting areas of medical progress. We have come to a point where we keep most patients out of a wheelchair, in work and in a state of much improved health. We now often reach low disease activity in a substantial number of patients. TO address the outstanding unmet needs we see a rich pipelines of (pre)clinical drug candidates. So, the question is what will be possible in the future? Given the speed of developments in the field of molecular technologies the opportunities to collect high throughput and complex molecular data is unprecedented. Harnessing such amounts of data could potentially progress the field towards primary prevention of disease in individuals at risk or those with the earliest signs and symptoms of disease, prediction of drug responses in those individuals who do develop disease and intercept co-morbidities such as cardiovascular disease, uveitis, or IBD in patients with RA or ankylosing spondylitis, respectively. Although we are not there yet, the sky seems the limit 1. The past few years we have seen more realistic attempts to overcome current hurdles in our field by the use of so-called “big data” approaches. For instance, whole-blood transcriptomics, serum proteomics and immune phenotyping was used in an attempt to quantitatively measure molecular remission in patients with rheumatoid arthritis 2. In two other studies, transcriptome analysis, among other techniques, was harnessed to uncover the molecular networks underlying disease like juvenile idiopathic arthritis and juvenile systemic lupus erythematosus 3, 4. Finally, the clinical applicability of cell phenotyping in defining treatment strategies for patients with psoriatic arthritis is enticing 5. These are just a few examples of studies that use deep molecular phenotyping and computer modelling technologies to aid diagnostic reasoning, treatment decisions and translational research in the search for disease understanding and the identification of novel therapeutic targets. The next steps must look beyond the borders of any individual discipline. RMDs coincide with co-morbidities including cardiovascular risk, cancer development and diseases of other organs such as the eye in HLA-B27 associated uveitis, the gut in SpA-associated IBD, the liver in autoimmune associated immune hepatitis and there are many more to discuss. Another perfect phenomenon that exemplifies the need of cross-disciplinary clinical and research approaches is the appearance of rheumatic-like disease in cancer patients initiating checkpoint inhibitors 6, 7. In contrast to the situation in regular clinics where we will not be able to assess the molecular pathways leading up to disease, in the patients on checkpoint inhibitors that develop rheumatic-like disease, deep molecular characterisation at the start of therapy and during follow-up might reveal many molecular secrets paving the way for biomarker and drug development in the field of RMDs. In addition, it is likely that parts of the patients suffering from these different conditions have a greater molecular overlap than those sharing the same diagnosis underlies the need to depart from our disease classification on the basis of diagnostic criteria. The heterogeneity of each disease, the clinical similarities and differences between different RMDs and the large number of patients that remain without a diagnosis further support the need for a novel taxonomy based on patient specific molecular fingerprints or networks 8. Obviously, such molecular taxonomy will not be limited to RMDs but will need to be extended to other disciplines covering the spectrum of medicine in the never-ending attempt to achieve the best outcomes for patients with RMDs and beyond.