Pathophysiology and treatment of rheumatic diseases

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Rheumatology.

Aim and focus

Rheumatic disorders develop insidiously and have a heterogeneous disease course with pain and loss of function. The overall aim of the department is to integrate patient care and research to increase understanding of rheumatic diseases and thereby improving patient care. To this end patient care has been organized in cohorts with structured follow-up including imaging, immunomonitoring, biobanking and outcome measures. For the main diseases, dedicated groups have been formed which consist of at least a medical specialist, an epidemiological/outcome expert and a translational/basic researcher. In this way optimal interaction between basic research/laboratory and epidemiological methodology is secured and firmly embedded in a clinical setting with well-organized data management.The department focusses on recent onset inflammatory arthritis (the early arthritis cohort and arthralgia cohorts), recent-onset spondyloarthritis (SpA) (the SPACE-cohort) as well as hand osteoarthritis (OA) (HOSTAS cohort). Likewise, we have structured cohorts on the “orphan diseases”  neuropsychological SLE and systemic sclerosis where the department functions as an expert center for the Netherlands and as last clinical resort.
The focus of our laboratory research is on inflammation. Given the fact that autoantibodies are the best known risk factor for development of RA and future damage, autoantibody formation and B-cell biology is a strong focus of our laboratory research. The role of innate immunity and the balance between destruction and repair, including resolution of inflammation, are the focus in OA laboratory research.  
The integration between clinic and basic/translational research is exemplified by our early arthritis clinic. Starting in 1993, over 4000 patients are followed longitudinally for diagnosis, disease activity, function, and destruction as measured by imaging techniques, serologic and cellular parameters. These parameters have been studied in relation to genetic markers.
The aim is to increase the knowledge and understanding of risk factors for development of the disease, to develop diagnostic and prognostic algorithms and to improve the effectiveness of therapeutic strategies.  The studies employing this cohort are performed by clinicians, immunologists, biologists, epidemiologists and are supported by research nurses and a data manager. Likewise, in these cohorts we have performed medication intervention studies to unveil which therapeutic strategies lead to the best outcome. Also these studies were linked to translational studies in the laboratory.
We have a tradition of collaboration with private practise rheumatologists to include similar patients as in our cohorts to enhance patient recruitment in time and number. The intervention studies in early RA pioneered by our department are now implemented in most rheumatology clinics in the Netherlands and world-wide as more aggressive treatments are now routinely given in (very) early disease. Our current clinical efforts are aiming to treat patients even earlier (Treat Earlier Study). These studies aim to reach the next barrier in rheumatology patient care by achieving long lasting drug free remission (i.e. cure) as endpoint.  The TREAT EARLIER study is a placebo-controlled trail including patients with Clinically Suspect Arthralgia (i.e. patients without clinical arthritis) who also have displayed an abnormal MRI-profile of the hands, suspect of reflecting inflammation. Treatment of these patients is double-blind placebo-controlled with oral methotrexate and a single intramuscular injection with methylprednisolone. We have now also embedded within our outpatient clinic a “quick-walk in“ screening clinic to allow detection of patients in the phase before arthritis. Our clinical suspect arthralgia cohort represents the largest cohort world-wide with a patient population at risk for arthritis that display a substantial probability to develop RA (35% conversion rate to RA in 6 months).
In 1999 research in OA was started. As in arthritis, well-characterized cohorts including over 1000 patients with hand, knee and hip OA have been set-up, collecting patient-reported outcomes, structural abnormalities as assessed by radiography, ultrasonography and MR imaging, and serological, genetic, cellular and histological parameters. A close collaboration exists with the department of Clinical Epidemiology in the NEO study (Netherlands Obesity study), including  over 6000 participants. The focus is twofold: first to unravel the underlying pathways in development and progression of OA, and second the search for instruments to measure clinical burden and progression. Clinical and imaging data from our patient studies have demonstrated the importance of inflammation in OA development and progression. The basic research is well connected with the clinic; it is focussing on the factors driving resolution/persistency of inflammation and destruction, with special attention for fatty acids and lipid mediators. Poly-unsaturated fatty acids and lipid mediators can be detected in joint fluid and appears to be involved in resolution pathways in OA. In international collaborations outcome measures for hand OA research have been optimized. Currently, we are investigating whether targeting inflammation in patients with inflammatory hand OA results in benefit for the patient. The HOPE study is a double-blind placebo-controlled trial that aims to decrease synovial inflammation and alleviate symptoms in hand OA by treatment with prednisolone. Both patient-reported outcomes and extensive imaging and laboratory outcomes are evaluated.  
The research on auto-immunity is performed in the framework of autoimmune rheumatic diseases (ARDs). Focus is given to the evolving phenotype of auto-antibody responses and auto-reactive B-cells from pre-disease to disease as this might help to develop strategies for prevention, also given the fact that many ARDs can still not be cured or prevented, but are responsive to therapeutic targeting of B-cells. The latter  indicates that B-cells are intimately involved in pathogenesis and chronicity of ARDs. Because of the close link between auto-reactive B-cells and disease pathogenesis, visualization of phenotype and behaviour of these cells and their products may also represent the most direct and specific way to develop an etiology-based classification of rheumatic disease, including the differentiation into molecularly defined disease subsets. The research into the evolving auto-immune response is not only performed in the context of RA, but also in the context of SLE and scleroderma to further strengthen the “top-referral care” profile of the department.

Position in international context

Position in international content The department is recognized as a Center of Excellence by EULAR (European League Against Rheumatism). The department works in 3 main areas of disease, RA, SpA and OA.

  • For Rheumatoid Arthritis, 3 staff members are considered to be among the top 1% of experts (Van der Heijde, Huizinga and Toes, website Expertscape). The department of Rheumatology of Leiden University ranked highest in the world (website CWUR). 
  • In the area of SpA, Prof Van der Heijde scores 2nd in the category “world experts”, university of Leiden as 7th institution (website Expertscape).  
  • In the field of OA, Prof Kloppenburg is considered to be among the top 1% of the field. Likewise, recognition in the field of ARDs is also visible by the awarding of several IMI projects to the department, both in the field of RA- and OA-research. In two of these projects, BT-CURE and RT-Cure, prof Huizinga is in the leadership. The Integrated project in the 7th EU- framework Masterswitch was led by prof Huizinga. Recognition in the field of pathogenesis of arthritis is illustrated by the awarding of a VICI-grant and TOP-grant to prof Toes. Both prof Van der Helm and dr Trouw received an ERC consolidator grant in 2017, after having received a VIDI-fellowship in 2012. Two other (younger) staff members received a VENI-fellowship in 2017 (dr Van der Woude and dr Scherer). The intervention studies have obtained worldwide attention.
    The prominent place of prof Huizinga and Van der Heijde in design of international trials for the pharmaceutical industry reflects the leading position of the department as well. The TREAT EARLIER study further enhances our mission to achieve drug-free remission. With regard to SpA prof Van der Heijde has a strong alliance with groups all over the world (Italy, Norway, Sweden) who follow the SPACE-organisation of inception cohorts and there are mutual projects with the French DESIR cohort. Prof Kloppenburg’s position in hand osteoarthritis is reflected by her leadership of the EULAR committees that are designing the criteria for hand osteoarthritis and recommendations for hand OA management, her leadership in the OMERACT hand OA working group developing outcome measures in hand OA and her membership of the board of directors of the Osteoarthritis Research Society International (OARSI). The OA research is financially supported by the Dutch Arthritis Foundation, TI Pharma, and the European Union (IMI-APPROACH).

Content / highlights / achievements

The department has discovered the third genetic risk factor for RA (the C5-TRAF region) and has discovered novel autoantibody system in RA, the anti-carbamylated antibodies. As mentioned, dr Trouw received a VIDI award and an ERC-grant  to study this system in more detail. To enhance his position as an independent PI, and following the advice of the midterm review regarding coaching of human talent, he moved in 2017 to the IHB department allowing him to grow on the basis received in the department of rheumatology.  Recently the department discovered that anti-citrullinated antibodies exhibit abundant Fab-glycosylation, providing unique structural data on this important autoantibody system in RA. Another highlight is that we are now able to visualize ACPA-producing B-cells by tetramer technology, allowing, for the first time, to study this auto-reactive human B cell population in detail. This work is, amongst others, embedded in a clinical setting through a clinical fellowship awarded to dr Scherer. The department has been at the forefront by identifying factors that predict development of RA vs remission from the pre-RA-disease phase. This research has led to prediction models of which subsequently the underlying biology has been formulated which are supported by a VIDI grant as well as an ERC grant  to prof. Van der Helm. Within her research the largest data set of MRIs in the preclinical phase of RA and subsequent follow-up in the world has been established to determine the diagnostic value of MRI. The concept of Clinical Suspect Arthralgia and the subsequent EULAR definition was developed by Van der Helm. Within the OA group, it was found that next to inflammation obesity is a clear risk factor for hand OA. In knee OA obesity was recognized as a risk factor via it’s mechanical loading, however in hand OA the metabolic aspects appeared to be important. This has led to basic studies exploring  the mechanism between fat tissue and joint biology where the role of lipid mediators is currently being unravelled; this work is taking place in the context of the ”gravity” consortium (Institute for Chemical Immunology), which dedicated funding for exploring how lipid mediators influence inflammation. Moreover, it was discovered that inflammation contributed to symptoms and progression of structural damage in OA. This has given the basis for a, unique, internationally double-blind placebo-controlled intervention study with anti-TNF in erosive OA, that has demonstrated that structural damage in OA can be inhibited by anti-inflammatory treatment. International collaborations within OMERACT have improved outcome measures in hand OA clinical research, resulting in sets of outcome measures for clinical trials and newly developed scoring system for thumb base OA. Within the SpA a modified algorithm was developed that improved diagnostic performance considerably as compared to the original algorithms. This modified algorithm is now the diagnostic algorithm in the official guidelines. Finally the recent implementation of low-dose CT scanning as a sensitive method for the assessment of new or growing syndesmophytes will allow better understanding of the structural damage in SpA.

Future themes

  • The next and ultimate goal of research within the rheumatic disease area is to cure and/or prevent disease. It is our ambition to meet this goal and to prevent and cure ARDs with an emphasis on RA. 
  • Spondyloarthritis: our unique longitudinal data will allow determining the relation between inflammation and structural damage as well as determination of risk factors for disease onset and progression. Clinically we expect to identify risk factors for disease precipitation and progression that will be subsequently used as the basis for predictive models
  • Osteoarthritis: within the OA group the theme will be to develop disease modifying treatments for OA. Our focus is thereby on research in local and systemic factors contributing to inflammation in OA
  • Scleroderma and SLE: new initiatives will be developed implementing the established know-how and expertise in the field of auto-antibodies and auto-reactive B cells to these diseases with the aim to better characterize these auto-immune responses in relation to clinical outcome in these diseases.

Cohesion within LUMC

The department is strongly embedded within the LUMC research lines Genetics, Immunology and transplantation, Haematology, translational research and Epidemiology.