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THE CHALLENGE OF RHEUMATOLOGICAL EDUCATION IN EUROPE

H. Bijlsma.Chairman, EULAR Standing Committee on Education and Training

Education program: It is the task of the EULAR Standing Committee on Education and Training (ESCET) to formulate and promote education and training opportunities in rheumatology in Europe (however, most of these activities are also open for people from other areas). The committee has been responsible for training and educational activities for physicians and rheumatologists, while the tasks on education and training of Allied Health Professionals and Patients was part of the task of their separate Standing Committees. For operational and educational purposes, our target population will be classified into the following groups: undergraduate students, general practitioners, young rheumatologists and experienced rheumatologists. Young rheumatologists are those in training to become rheumatologists and those registered as a rheumatologist within the last 5 years. For practical reasons, this group will have an age limit of 40 years. Experienced rheumatologists are those that finished their training for over 5 years.

Education instruments: The following educational instruments and/or events are, or will shortly be available within the structure of EULAR.

  1. EULAR annual congress

  2. EULAR post-graduate course

  3. EULAR courses and Eular Scientific Meetings

  4. EULAR patronage of meetings

  5. EULAR webcourse on line

  6. EULAR update on rheumatic diseases

  7. EULAR learning tools for undergraduate students and general practitioners

  8. Other activities

This list is not exhaustive and will be adapted regularly.

1. Annual EULAR congress: The EULAR annual congress is organised by a dedicated scientific committee, appointed by the executive committee of EULAR. The chairman of ESCET is ex officio member of this scientific committee. The role of the ESCET with regard to the EULAR annual congress is limited in giving advice with regard to the educational content and structure of the congress. ESCET is especially interested to see a balanced number of “state of the art”, “educational hands-on”, “basic science explained” sessions. ESCET is also committed to evaluate whether all relevant topics within the field of rheumatology are covered within the context of the congress at least once every 3 years. ESCET is involved in two special educational issues within the Annual Congress: A young rheumatologists track, including educational lectures specifically designed for trainees and fellows, where in a safe atmosphere “stupid questions” can be asked. The second activity is the organisation of a “Meet the Standing Committee session” dedicated to an educational topic for trainees and trainers, such as assessment, how to write a paper, how to get most out of your congress, and so on.

2. Post-graduate course: Every second year EULAR organise the post-graduate course targeted to young rheumatologists, in particular trainees in the last 2 years of their training and rheumatologists within the first 5 years after registration. The aim is not only to teach high standards of rheumatology science and clinical practice, but also to promote interaction of young rheumatologists from different countries from Europe among themselves and with the experts in the field. The last postgraduate course was held in Warsaw, October 22–28, 2006.

3. EULAR courses and EULAR scientific meetings: These courses/meetings are meant to cover topics which are not sufficiently covered by the EULAR congress or other educational events. These courses should cover topics that are specific for the field of rheumatology, such as cappillaroscopy, crystal examination, ultrasound, assessment of rheumatic diseases, etc. EULAR also feels commitment to education on infrequent rheumatic diseases. Courses on issues common to other specialities, such as evidence based medicine, are not a priority as they are available in many countries in different settings. It is the goal of EULAR to make an overall structure for these courses 3 years in advance. In September 06 the EULAR Executive ratified the program that will cover the years 2007–2009. Special rules apply for these courses (see EULAR website) and EULAR will take responsibility for the logistic and financial management of these courses/meetings. Application to host and organise these courses are announced on the EULAR website and potential organisers will be stimulated to submit proposals.

4. EULAR scientific patronage of meetings: Courses/meetings in the field of rheumatology, which are not organised by EULAR itself, may apply for the scientific sponsoring of EULAR. Rules for this purpose have been formulated (see EULAR website). EULAR considers these important topics in the field of rheumatology, but does not take responsibility in the organisation of these courses/meetings.

5. EULAR on line course: This educational course is under development; a pilot is running from September 2006 to January 2007 and the definite course will start in April 2007. The course will be totally run through the web and is designed to last for two years. It will be composed of 42 modules; each of these modules is dedicated to a specific topic. In 4 of the modules participants will be allowed to choose between 3 optional topics. Each module corresponds to approximately 5 hours working schedule for the student, totalling around 210 hours of educational training. The participant will have to answer correctly questions regarding the specific topic before he can continue with the next topic. At the end there will be an on line examination that will, if successfully performed, lead to a certificate of completion of the EULAR on-line-course on rheumatic diseases. This course will have the level of what rheumatologists should know at the end of their training, but the course will be open to all rheumatologists as part of their continuous medical education.

6. EULAR book EULAR update on rheumatic diseases: As a side product of the EULAR on line course on rheumatic diseases the updated version of each chapter will become part of the book: EULAR update on rheumatic diseases. Probably the electronic version of this book will be updated yearly, while the printed version will be updated every 2 to 3 years. The first version will be available when the last module of the online course is finalised (December 08)

7. EULAR learning tools for undergraduate students and general practitioners: A new task EULAR started thinking about is supplying learning tools for undergraduate students and general practitioners. Rheumatologists in Europe are involved in the training of medical students and general practitioners. It is not the task of EULAR to take over these activities, but EULAR could help these rheumatologists by developing good quality learning tools, such as books, interactive DVDs, online course and so on. The EULAR has started a task-group on this subject. Good quality undergraduate training of medical students and GPs will have a positive effect on future rheumatology in Europe.

8. Bursaries/sponsorship: The EULAR is involved in the selection of training and travel bursaries, the visiting professor program and different awards and prizes.

9. Other activities: The chairman of EULAR is ex officio member of the European Board for Rheumatology, UEMS, and involved in developing and assessing training programs. Also liaison with the paediatric rheumatology in this sense has been arranged.

Please sent all comments and suggestions to: j.w.j.bijlsma{at}umcutrecht.nl

EDUCATIONAL CHALLENGES FOR RHEUMATOLOGY IN THE UNITED STATES

J. Kay.Rheumatology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

The major challenge faced when providing post-graduate education in rheumatology in the United States is to provide programs that meet the needs of a diverse target audience. The majority of rheumatologists in the United States provide patient care directly in a clinical setting. However, others are involved primarily in basic or clinical research at academic centers or within the pharmaceutical industry. The American College of Rheumatology (ACR) Annual Scientific Meeting is designed to meet the educational needs of this varied audience, providing each attendee with the most current information relevant to his or her area of interest. Other smaller meetings, such as the State-of-the-Art Clinical Symposium, the Winter Rheumatology Symposium, and the Innovative Therapies in Autoimmune Diseases Meeting, provide opportunities for those with specific interests to gather and discuss relevant topics. Rheumatologists in the United States are certified by the American Board of Internal Medicine. To maintain board certification, physicians must complete Medical Knowledge Self-Assessment and Practice Improvement Modules and must take a recertification examination, every 10 years. The ACR provides those rheumatologists who are preparing for recertification with a course, in which the various topics are reviewed, and has developed a Rheumatology Self-Assessment Program and Practice Improvement Modules. As the constraints of busy professional and personal lives limit the ability of rheumatologists to travel to face-to-face meetings, alternative strategies have been developed to deliver post-graduate education to rheumatologists. Webcasts of selected sessions provide meeting content to those who are unable to travel to the site of the meeting. Highlights of the ACR Annual Scientific Meeting can be viewed on the internet at the ACR website (www.rheumatology.org). Case studies and images also may be disseminated via the internet to reach a much larger audience. The new millennium has brought with it new challenges in delivering post-graduate education to rheumatologists. However, new technologies allow the rapid and efficient dissemination of information to a global audience, benefiting both physicians and patients with rheumatic diseases in many countries.

THE FUTURE OF EULAR IN EUROPE

F. C. Breedveld.Leiden University Medical Center, Leiden, The Netherlands

The aims of EULAR are to reduce the impact of rheumatic diseases on the individual and society and to improve the social position of people with rheumatic diseases in Europe. Therefore EULAR shall stimulate, promote and support the research, prevention, treatment and rehabilitation of rheumatic diseases. Given the large changes in the rheumatological community the EULAR executive committee will initiate in 2007 a discussion on the EULAR strategy of the next decade. The goal is to obtain a shared vision among all EULAR stakeholders about the direction EULAR should move towards; the nature of programs reflecting this direction and to review the current structure and governance model supporting these programs effectively. This activity should set the base for the strategy becoming a cornerstone of EULAR’s thinking and working.

IMMUNOLOGICAL TOLERANCE AND AUTOIMMUNITY

S. Romagnani.University of Florence, Italy

Immunological tolerance is a complex series of mechanisms that impair the immune system to mount responses against self antigens. Central tolerance occurs when immature lymphocytes encounter self antigens in the primary lymphoid organs and consequently they die or become unreactive. Peripheral tolerance occurs when mature lymphocytes, escaped to negative selection during ontogeny, encounter self antigens in secondary lymphoid organs and undergo anergy, deletion or suppression. A heterogenous family of T regulatory cells has recently been identified, which have been found to play an important role in suppressing immune responses against self. Failure or breakdown of immunological tolerance result in autoimmunity and autoimmune diseases. Such events are related to both genetic and environmental factors, the latter being mainly represented by infections. Infectious agents can indeed promote autoimmune responses either by inducing tissue inflammation and therefore by-stander activation of autoreactive T effector cells or by promoting T cell responses against self peptides which cross-react with microbial epitopes. For many years, T effector cells specific for autoantigens have been thought to be type 1 T helper (Th1) cells. Very recently, however, the possible pathogenic role in autoimmune disorders of a new subset of T effector cells, named as type 17 Th (Th17), has been emphasized.

TARGETING FIBROSIS IN SCLERODERMA/SYSTEMIC SCLEROSIS

J. Varga.Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Systemic sclerosis (SSc), a chronic autoimmune connective tissue disease of unknown etiology, is associated with high mortality, and to date has no effective therapy. The hallmark of the diseases is progressive parenchymal and perivascular fibrosis of the skin and multiple internal organs. Most frequently affected are the lungs, GI tract, kidneys, heart and the exocrine glands; in contrast, the liver and CNS are generally spared. Interstitial lung disease and pulmonary hypertension, the leading causes of death in SSc, are both caused by fibrosis. While late-stage SSc is characterized by widespread fibrosis, in early SSc vascular injury, endothelial cell activation and inflammation of multiple tissues is prominent. This constellation of findings has led to the hypothesis that vascular injury, possibly the initial lesion of SSc, leads to inflammatory cell infiltration of target tissues, skewing of the immune response toward Th2 pattern, and activation of resident fibroblasts. Transforming growth factor-β secreted in lesional tissue by infiltrating monocyte/macrophages, or released in situ from its matrix-bound latent form, plays a key role in initiating and sustaining fibroblast activation and transdifferentiation into myofibroblasts. Emerging evidence indicates that excessive autocrine signaling by TGF-ß, coupled with abnormalities in signaling pathways intrinsic to SSc fibroblasts, contributes to inappropriate fibrotic signaling. Smad-mediated TGF-β signal transduction has been shown to be deregulated in SSc. Additional signaling pathways and transcriptional regulatory proteins, including Sp1, Egr-1, the histone acetyltransferase coactivator p300, and c-Abl tyrosine kinase, and suppressors such as Fli1 and peroxisome proliferators activated receptor-gamma (PPAR-gamma), are also deregulated in SSc fibroblasts. An imbalance between positively and negatively acting regulators of matrix gene expression and myofibroblast differentiation in SSc fibroblasts appears to contribute to the development or progression of fibrosis. Mice with targeted deletion of Smad3, or Egr-1, show attenuation of bleomycin-induced fibrosis, a murine model of scleroderma. Targeting the Smad pathways, and additional TGF-β signaling pathways, using small molecules represents a potential approach to the therapy of fibrosis in SSc.

PENTRAXIN 3, A SOLUBLE PATTERN RECOGNITION RECEPTOR: THE HUMORAL ARM OF INNATE IMMUNITY

C. Garlanda.Istituto Clinico Humanitas, Rozzano, Milano, Italy

Pentraxins are a superfamily of proteins conserved in evolution characterized by a structural motif, the pentraxin domain. Short pentraxins, C reactive protein (CRP) in man and serum amyloid P component (SAP) in mouse, are produced by the liver in response to inflammatory stimuli as IL-6. PTX3 was the first long pentraxin identified as an IL-1β inducible gene in endothelial cells. A variety of cell types produce PTX3 in response to pro-inflammatory stimuli as endothelial cells, smooth muscle cells, adypocytes, fibroblasts, mononuclear phagocytes, dendritic cells and granulosa cells. PTX3 binds selected ligands as C1q, specific micro-organisms and microbial moieties, activating an amplification loop of the innate immune response, possibly through complement activation. Studies in vivo with PTX3 deficient mice unveiled the non-redundant role played by PTX3 in innate resistance towards selected pathogens, and in inflammation. In humans, increased levels of PTX3 are found in diverse human pathological conditions, in particular in different infectious diseases including sepsis, A. fumigatus infections, tuberculosis and dengue. In some of these, PTX3 levels correlated with disease activity or severity. Increased levels of PTX3 have also been observed in a restricted set of autoimmune disorders (e.g. in the blood in small vessel vasculitis, in the synovial fluid in rheumatoid arthritis). In small vessel vasculitis, PTX3 levels correlate with clinical activity of the disease and represent a candidate marker for monitoring the disease. Finally, increased levels of PTX3 have been observed in inflammatory conditions reflecting in particular the involvement of the vascular bed, as in acute myocardial infarction, in atherosclerotic lesions and in pre-eclampsia. Being rapidly produced by the inflamed tissue, PTX3, unlike CRP (made in the liver and induced primarily by IL-6), may represent a rapid marker for primary local activation of innate immunity and inflammation.

TIM FAMILY OF GENES: ROLE IN T CELL DIFFERENTIATION, AUTOIMMUNITY AND TOLERANCE

V. K. Kuchroo.Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

CD4+ T helper lymphocytes can be divided into two subsets of effector cells, known as Th1 and Th2 cells, based upon their functional properties and the cytokines they produce. While much is known about the functional properties of these subsets, there are few known surface molecules that distinguish between them. We have recently identified and characterized a novel transmembrane protein, TIM-3, which contains an immunoglobulin (Ig)-like and a mucin-like domain and is expressed only on differentiated Th1 cells. In vivo administration of soluble Tim3.Ig fusion protein induces hyperproliferation of Th1 responses, abrogates tolerance induction and enhances the clinical and pathologic severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease. These data suggest that Tim-3 may be an inhibitory molecule and blockade of Tim-3: Tim3L pathway by Tim3.Ig fusion protein results in the enhancement of Th1 response. Emerging data suggest that Tim.3 ligand (Tim.3L) is a critical molecule which regulates expansion and function of Th1 cells. Using the Tim3.Ig fusion protein, we have biochemically purified the Tim3L and identified it as galectin-9. Galectin-9 induces death in Th1 cells in Tim-3 dependent manner. In vivo administration of Tim3.L during an ongoing immune response results in selective loss of IFN-g but not IL-4 or IL-10 producing cells. These data demonstrate that Tim3: TIM-3.L pathway has evolved to ensure effective termination of effector pro-inflammatory Th1 immunity. To identify cytokines and transcription factors that control Tim 3 expression, we analyzed Tim-3 expression in a panel of genetic mutant cytokine, cytokine receptor and transcription factor transgenic mice. Our experiments demonstrate that Tim-3 expression is regulated by the Th1-specific transcription factor T-bet, as well as by the IL-12/STAT-4 signaling axis, which is known to stabilize and reinforce Th1 commitment. This introduces a novel paradigm in that the transcription factors responsible for effector cell differentiation of Th1 cells also simultaneously increase the expression of a specific counter-regulatory molecule to ensure appropriate termination of an immune response. Recent data suggests that Tim-3 is also expressed on Th17 cells and the effect of Tim-3:Tim-3L interaction on the development of Th17 is being studied. Tim-3, along with two other family members (Tim-1 and Tim-2), is located on Chromosome 11 in mice and 5q33 in humans, an interval that has shown linkage to a number of autoimmune and allergic diseases. Polymorphic alleles of Tim-1 and Tim-3 have been identified that differ between resistant and susceptible strains of mice. The role of this gene family in regulating effector functions of Th1 and Th2 cells and regulating autoimmune and allergic diseases will be discussed.

MOLECULAR MECHANISMS OF BONE DESTRUCTION

G. Schett.University of Erlangen-Nuremberg, Germany

Chronic joint disease leads to a remodeling of the architecture of the affected joint. In rheumatoid arthritis profound destruction of the joints occurs as a consequence of bone erosion. Other joint disease build up new bone and appears as bone nodules like osteophytes and spondylophytes. Some of the joint diseases, like psoriatic arthritis, show a combination of these two joint patterns and exhibit erosions and signs of bone formation in the same joint. In arthritis, proinflammatory cytokines shift the balance between bone formation and bone resorption and, as a consequence, affect the joint architecture. TNF, Il-1 and IL-17 are potent inducers of osteoclast formation, either by direct stimulation of these cells or by inducing their differentiation by inducing the expression of RANKL. Osteoclasts resorb bone and lead to a destabilization of the joint. Effective pharmacological blockade of RANKL, however, inhibits bone erosion and thus protects the joints from degradation. This suggests that RANKL is a critical mediator for bone resorption in arthritis. On the other hand, joints have a natural “response to stress” mechanism and build up osteophytes, which are bony appositions and attempt to bridge joints. This reaction is abundant in spondylarthropathies but also found in psoriatic arthritis, but it is virtually absent in rheumatoid arthritis. We recently discovered Wnt signaling as a key inducer of osteophytes and identified a negative regulator of Wnt, Dickkopf-1 (DKK), as a master regulator of joint remodeling in arthritis. Cytokines such as TNF can induce DKK-1, which in turn down regulates bone anabolic responses and prevents the formation of osteophytes. These data suggest that the changes of joint architecture observed in various forms of arthritis are under a tight regulation of molecules critically involved in bone metabolism.

Question 1:

  • Tumor necrosis factor inhibits osteoclast and osteoblast formation

  • Tumor necrosis factor inhibits osteoclast and enhances osteoblast formation

  • Tumor necrosis factor inhibits osteoblast and enhances osteoclast formation

  • Tumor necrosis factor enhances osteoclast and osteoblast formation

Question 2:

  • RANKL is expressed on activated T cells and induces osteoclast formation

  • RANKL is expressed on macrophages and induces osteoclast formation

  • Dickkopf proteins are inhibitors of Wnt signaling and induce bone formation

  • Dickkopf proteins are inducers of Wnt signaling and inhibit bone formation

EPIGENETIC MODULATIONS LEADING TO FIBROBLAST ACTIVATION IN RHEUMATOID ARTHRITIS

S. Gay, M. Neidhart, E. Karouzakis, A. Jungel, H. Hemmatazad, L. Huber, J. Stanczyk, F. Brentano, M. Pierer, D. Kyburz, R. E. Gay.WHO Collaborating Center for Molecular Biology and Novel Strategies for the Treatment of Rheumatic Diseases, Dept Rheumatology, University Hospital, Zurich, Switzerland

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by a progressive destruction of the affected joints. Despite the major progress in the treatment with powerful biologicals, we cannot cure the disease yet. The latter fact is attributed to the activated synovial fibroblast (SF). In our laboratory we search for the cause(s) of the endogenous activation of these cells. Based on most recent observations that gene expression is tightly regulated by epigenetic modifications, we study the states of acetylation, methylation and microRNA in RA-SF. We could show that the histone deacetylase (HDAC) inhibitor Trichostatin A, a compound recently used in cancer therapy, induces apoptosis in RA-SF. Moreover, we could demonstrate that RA-SF are hypomethylated leading to the induction of specific galectins and the MAPK p38delta. It is thought that the inflammatory milieu produced by RA-SF through the production of proinflammatory chemokines, including MCP-2, IP-10 and Rantes, induced by the Toll-like receptors (TLR) 2, 3 and 4 facilitates the process of hypomethylation in these cells. Gene transfer is utilized to study the epigenetic modulation of gene expression in RA-SF to design novel strategies for the treatment of RA.

CLINICAL TRIALS: WHICH IS THE TARGET POPULATION?

P. Emery.Academic Unit of Musculoskelatal Disease, Department of Rehabilitation, University of Leeds, UK

The therapy for rheumatoid arthritis has made enormous advances in recent times. The efficacy of TNF blocking agents particularly on structure has been striking. Therefore, why should there by any discussion about clinical trials? However, a number of issues have arisen which threaten the long-term management of therapies.

Problems: Poor recruitment in populations from Western Europe is seen because patients are required to have high levels of disease activity. However, there is already evidence showing this produces irreversible damage and few patients now attend clinic with this level of inflammation. The problem is compounded by the availability of many active therapies so that there is a reluctance to try experimental therapy. Also wrong populations are being recruited. Remission should be the aim of therapy. Furthermore the unmet need is for patients failing existing therapies. Neither of these are represented in clinical trials. Other problems are the insistence on placebo during which time patients deteriorate leading to only short term studies or studies undertaken where optimal therapy is not available. Finally there is still a requirement showing structural benefit on x-ray requiring large populations.

Solutions: The overriding issue is to redesign clinical trials to reflect clinical practice. There are a number of general measures that can improve things including phenotyping patients to ensure homogeneity and the use of sensitive outcome measures, both of which lead to more efficient studies. Proof of concept/amount of action studies which currently produce answers with studies of increased power. Furthermore there is the redesign of clinical trials for remission and relapse, and treatment to end-point rather than the difference between therapies. A number of mode of action studies have recently been performed which exemplify this.

SHOULD CLINICAL TRIALS IN RHEUMATOID ARTHRITIS BE MORE LIKE STANDARD CLINICAL CARE AND VICE VERSA?

T. Pincus.Vanderbilt University Medical Center, Nashville, USA

Background: Major advances in quantitative assessment of rheumatoid arthritis (RA) have been seen over the last 3 decades. These advances have led to improved standardization in clinical trials and clinical research. However, clinical trials have many limitations, including short time frame and patient selection; indeed, only a small fraction of patients seen in standard clinical care are eligible. Furthermore, most standard rheumatology care continues to be conducted largely according to qualitative “gestalt” impressions, as formal joint counts and patient questionnaires are not used at most visits by most rheumatologists. The only quantitative measures in most standard care are laboratory tests, which usually are not available at the time of the visit, and often give false positive and false negative information. Therefore, 99% of quantitative RA assessment is applied to less than 1% of patients.

Purpose: To suggest methods whereby clinical trials could be more like standard clinical care, and standard clinical care may include more quantitative measurement.

Methods: Patients seen in standard clinical care were analyzed according to inclusion criteria of clinical trials. Adaptations of measures used in clinical research have been developed for standard clinical care.

Results: Fewer than 10% of patients seen in standard clinical care, at least in certain clinical settings in the United States and elsewhere, meet inclusion criteria for most clinical trials of anti-TNF agents. A traditional 66/68 joint count has been adapted to 28 joints, which is as informative as a 66/68 joint count in clinical trials and in the prognosis of 5–20 year mortality. The disease activity score, which requires a calculator or website, has been adapted to a simplified disease activity index (SDAI) and clinical disease activity index (CDAI), which can be calculated directly by the treating physician. The health assessment questionnaire (HAQ) has been simplified to a multidimensional HAQ (MDHAQ), with 10 activities in lieu of 20, pain and global estimate visual analog scales (VAS) in 21 circles rather than a 10 cm line, a rheumatoid arthritis disease activity index (RADAI) self-report joint count. Also included on one side of one page on the MDHAQ are 0–10 scoring templates for physical function and self-report joint count, and routine assessment of patient index data (RAPID) indices, including RAPID 3 composed of the core data set measures—physical function, pain and global status, RAPID 4 which adds the RADAI joint count, and RAPID 5 which adds a physician global assessment. RAPID scores are correlated significantly with DAS and CDAI scores in the clinic and clinical trials and perform as effectively to distinguish active from control treatment in 7 clinical trials studied to date. Categories of RAPID 0–1  =  near remission, 1.01–2  =  low severity, 2.01–4  =  moderate severity, 4–10  =  high severity, are correlated with high kappa levels with DAS and CDAI categories of remission, low, moderate and high disease activity.

Conclusion: It is possible to improve clinical trials with less restrictive inclusion and exclusion criteria, and to facilitate quantitative assessment in standard clinical care using measures such as CDAI and MHDAQ, which may also be used in clinical trials.

META-ANALYSIS: ADDED VALUE OR MODERN ALCHEMY?

J. Fransen.Department of Rheumatology, Radboud University, Nijmegen Medical Centre, The Netherlands

In meta-analysis a set of similar studies with the same hypothesis is pooled to provide an aggregate measure of effect. Most meta-analyses combine randomised controlled trials with an outlook to learn about treatment effects. Pooling of trial data has the major advantage that a treatment effect can be estimated with larger precision, as well as the possibility to study whether a treatment effect is different for specific subgroups of patients. A major disadvantage of meta-analysis is that, even if randomised controlled trials are pooled, the meta-analysis itself is not a large randomised trial but an observational study (of randomised trials). The pooling of heterogenous studies, the impeded control of bias and more generally the loss of sight of what is going on in the mixture may lead to a view of meta-analysis as a modern form of alchemy (inherently unscientific). Alchemy is known today for the use of heterogenous poorly identified mixtures with the aim to convert it into something better (say, gold). In this lecture it is outlined how a meta-analysis can be performed to have added value in acquiring scientific knowledge.

OUTCOME MEASURES IN CLINICAL TRIALS: ARE THEY FOR US OR FOR THE PATIENT?

J. Smolen.Chairman, Division of Rheumatology, Internal Medicine III, Medical University of Vienna, and Chairman, 2nd Department of Medicine, Center for Rheumatic Diseases, Lainz Hospital, Vienna, Austria

Outcome can be measured by assessing individual items or composite indices on the one hand, and can be patient-centred or use correlates of the biological processes on the other hand. Outcome of rheumatoid arthritis (RA) therapy can be evaluated in terms of disease activity (as the underlying process), joint damage (as the consequence of this process) and disability as the consequence of both. Composite indices are more reliable instruments than individual items of clinical or laboratory features, joint damage is best reflected by x-ray progression and disability, for example by HAQ, comprises both. There exist many composite disease activity scores, among them the DAS28, the SDAI and the CDAI. The latter two allow assessing disease activity without the use of a calculator. Their construction makes it easy to be understood also by the patients. The CDAI, in contrast to the SDAI, also does not require an acute phase response measure and can, therefore, be calculated right at the visit of the patient without the need to send the patient to the laboratory before or after that visit or wait for the result. It has high validity and reliability and allows the patient to speak the same language as the physician. The CDAI informs the doctor on the actual disease activity and its change, enabling to adhere to tight control strategies and novel therapeutic algorithms. “Know your CDAI!” is a message to the patient that may lead to better compliance and better patient–doctor relations and thus benefit long-term outcome.

MINING THE TREASURE OF NEGATIVE TRIALS

J. R. Seibold.Professor & Director, University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA

The pathogenesis of systemic sclerosis remains poorly understood although there frequently emerges sufficient specific knowledge to form the basis for rational therapeutics. Effective translational research is further impaired by the remarkable heterogeneity of the clinical syndrome. Recent years have seen performance of a large number of robust randomized clinical trials including use of non-specific antifibrotics (D-penicillamine, recombinant human relaxin, α-interferon); non-specific anti-immune strategies (methotrexate, cyclophosphamide, immunoablation with reconstitution) and highly specific agents of narrow biologic effect (MAb toTGFβ, endothelin receptor antagonists) as well as other less plausible therapies (minocycline, rituximab, anti-TNF agents). The available therapies have demonstrated either equivalence to placebo or small effects of uncertain clinical meaningfulness. Oral cyclophosphamide is associated with transient stabilization of FVC (2%) and oral bosentan reduces the occurrence of new digital ulcers by 30–50% yet has an inconsistent effect on pain and function. A Markoff decision analysis suggests that one year of oral cyclophosphamide results in a marginal effect on quality adjusted life years (2.59 vs 2.54 on no treatment). Nonetheless, robust standardized data have become available that permit analysis of the metrics of multiple clinical domains of systemic sclerosis including skin involvement, functional status, quality of life, measures of pulmonary function and intervals of event free survival. In one exercise, the standard template of clinical outcome measures was utilized from 645 early diffuse scleroderma trial subjects in an individual patient data meta-analysis. Skin was shown to improve 12–15% per year and FVC and DLCO were remarkably static over two years of follow up. Regression towards the mean is the dominant trend—improvement/worsening are inversely related to severity of disease at entry. Correlative analysis of measures combined with parallel Delphi exercises has led to the core elements of a composite measure of outcome and new trial design parameters based on disease severity. Application of the OMERACT filter including analysis of face, content and construct validity as well as reliability and sensitivity to change has led to nearly complete validation of outcome measures. We now have the tools and ability to measure effect of novel new candidate therapies.

INFLAMMATION AND ANGIOGENESIS AS TARGETS IN ONCOLOGY AND IN RHEUMATOLOGY

A. Albini.Polo Scientifico e Tecnologico. Settore Ricerca Oncologica IRCCS Multimedica – Milano, Italy

Many degenerative diseases are based on the chronic activation of those physiological responses linked to tissue defense and repair. Paradoxically, this attempt to restore a functional organ ends up with its almost total deterioration. A similar mechanism is also found in other pathologies such as cancer, where growing scientific evidence points to the microenvironment as a key element in tumor onset and progression. The tight interplay between immune and endothelial cells is not casual, as both share common embryonic origin. While in some experimental settings angiogenesis can be triggered without a manifest inflammation (resembling what happens in embryogenesis), it is almost impossible to imagine an inflammatory response without vascular activation and recruitment. The coordinated dialogue between endothelium and leucocytes is mediated by several soluble factors: cytokines, growth factors and chemokines are able to stimulate both cell populations and, as such, represent putative therapeutic targets to control degenerative diseases. Clinical trials have shown that angiogenesis inhibition is a promising, but also an elusive, target. To date, only those strategies directed against a specific angiogenic factor, VEGF, have shown positive responses. The disruption of VEGF signaling is active on incompletely formed vessels, causing localized endothelial cell death. While this approach can have an adjuvant role in standard cancer therapy, it has no application per-se and the same idea of applying an anti-angiogenic strategy against a long-term established pathogenesis is misleading, as most vessels have already been formed. An alternative, valuable approach should contemporarily target the endothelium and inflammatory cells at the beginning of the pathologic process, and should be continued chronically, which necessitates limited collateral effects and cost. We identified “Angioprevention”, the chemoprevention of angiogenesis, as one possible concrete strategy. Several molecules share the ability to inhibit inflammatory and angiogenic processes; many of them are already approved for clinic use, or dietary components. We have shown that several flavonoids, antioxidants and retinoids act on the tumor micro-environment to inhibit enrollment and activation of endothelial cells and innate immune cells. N-acetyl-cysteine, the green tea flavonoid epigallocatechin-3-gallate (EGCG), the chalchone Xanthomol and the rotenoid Deguelin all prevent angiogenesis in vivo and inhibit the growth of angiogenic tumors in nude mice. The synthetic retinoid 4-hydroxyfenretinide (4HPR) also harbors anti-angiogenic effects. Affymetrix GeneChip array functional genomics analyses of gene expression regulation by some of these compounds in primary endothelial cells (HUVEC) in vitro identified overlapping sets of genes regulated by the anti-oxidants. In contrast, the ROS-producing 4HPR induced members of the TGFβ-ligand superfamily, which, at least in part, explain its anti-angiogenic activity. NAC and the flavonoids all suppressed the IkB/NF-kB signaling pathway, even in the presence of TNF-alpha, and reduced expression of many NF-kB target genes. Repression of the NF-kB pathway suggests anti-inflammatory effects for the anti-oxidant compounds that may also represent an indirect role in angiogenesis inhibition. The green tea flavonoid EGCG does target inflammatory cells, mostly neutrophils, and inhibits inflammation-associated angiogenesis. The other angiopreventive molecules are turning out to be effective modulators of phagocyte recruitment and activation, further linking inflammation and vascularization to tumor onset and progression and providing a key target for angiogenesis prevention.

Questions:

  • a) Which among the following molecules has been the most promising target for specific anti-angiogenic strategies?

    1. TNF-alpha

    2. IL-8

    3. VEGF

    4. PlGF

  • b) Epigallocatechin-3-gallate (EGCG) shows (multiple answers):

    1. Anti-angiogenic properties

    2. Anti-inflammatory properties

    3. Anti-viral properties

    4. Anti-tumor properties

  • c) A common target of anti-oxidant angioprevention compounds is:

    1. the NF-kB pathway

    2. the MET pathway

    3. the P53 pathway

    4. the Rb-1 pathway