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DEPARTMENT OF NEUROLOGY · THE NEUROSCIENCE CENTRE · COPENHAGEN UNIVERSITY HOSPITAL · RIGSHOSPITALET · COPENHAGEN, DENMARK · WWW.MS-RESEARCH.DK Danish Multiple Sclerosis Center Annual Report 2014 DMSC missions and aims The mission of Rigshospitalet is to be the leading hospital in Denmark for patients in need of highly specialized treatment The missions of the Danish Multiple Sclerosis Center (DMSC) are: o be the leading multiple sclerosis (MS) center T in Denmark o be at the forefront of highly specialized T management of MS carry out research and development in MS To at an advanced international level collaborate scientifically and exchange To knowledge in MS research educate staff to a highly specialized level in To their relevant fields o contribute with professional advice on MS T to the healthcare community meet people with MS at their terms with To openness and respect The aims of the DMSC are: o provide the optimal interdisciplinary patient T care to all MS patients in the region and to patients from other regions in need of highly specialized therapy o carry out high quality research in MS with T focus on clinical research, new therapies, MS genetics, neuroimmunology and MS pathology o teach undergraduate students and PhDT students and stimulate their interest in MS research o educate post docs, MS physicians, nurses, T secretaries and other professionals to a high level of knowledge of MS in their relevant expert fields lead the national research in Denmark in To partnership with other Danish researchers and to establish a broad international collaboration with MS research groups in Europe and from overseas. DMSC staff seminar i Liseleje 2014 2 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 Table of contents 2 DMSC missions and aims 4 A short review of 2014 in the Danish Multiple Sclerosis Center 6 About the Danish Multiple Sclerosis Center 10 Organization diagram 12 Research activities 2014 14 Clinical and epidemiological research 17 Neuro Imaging 18 Neurogenetics 20 Neuroimmunology 22 Routine analyses in Neuroimmunology Laboratory 24 Scientific publications 2013-2014 29 Prizes and honorary offices 30 Scientific collaboration 31 Collaboration with pharmaceutical companies 31 Acknowledgements Annual Report 2014 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 3 PROFESSOR PER SOELBERG SØRENSEN, MD, DMSc Director of the Danish Multiple Sclerosis Center (DMSC) A short review of 2014 in the Danish Multiple Sclerosis Center The most epoch-making event in 2014 was the announcement that Rigshospitalet and Glostrup Hospital were going to merge into one hospital by January 1st 2015. The message started many speculations about the fate of the Danish Multiple Sclerosis Center (DMSC) in the setting of the new large common hospital that would be named Rigshospitalet. The merging of the two neurological departments at Rigshospitalet and Glostrup Hospital, each harboring a large multiple sclerosis clinic, would be combined with the appointment of a new common chairperson, who would be the current chairperson of the Department of Neurology at Glostrup Hospital, Allan Andersen. It is now a fact that the two MS clinics will be joined but it is still uncertain whether the new MS clinic will be placed at the current Rigshospitalet, at Glostrup Hospital or even at both locations. During this turbulent time, the activities at the Danish Multiple Sclerosis Center have continued 4 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 with care for the same number of patients with multiple sclerosis. A large number of the patients in the MS Clinic have started oral treatments, and we have increasingly used the new very effective treatment with the monoclonal antibody Lemtrada. The Danish National Board of Health has decided that treatment with Lemtrada should be confined to a few university departments, and currently Rigshospitalet is the department at which most patients have received this new therapy. As a result of a rearrangement of the geographical area that each hospital in the capital region is going to serve, approximately 15% of the patients in the Danish Multiple Sclerosis Center should have been transferred to other hospitals, provided that the patients would comply with this decision. However, only very few of the patients have decided to continue therapy at other hospitals, and the vast majority of patients have remained Scientific symposium for professor Per Soelberg Sørensen under care in the MS Clinic at the Danish Multiple Sclerosis Center. Also the research activities have continued to increase. We completed the study of erythropoietin (EPO) in patients with progressive MS and the results were presented at the ECTRIMS/ACTRIMS congress in Boston, September 2014. Unfortunately the treatment had no beneficial effect on patients. We finalized collection of stools from more than 200 multiple sclerosis patients from DMSC in a study of the role of altered gut bacteria flora in the pathogenesis of multiple sclerosis that is carried out in collaboration with the Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics at University of Copenhagen, and currently the genetic profile of the gut microbiota is being investigated. A study of methylprednisolone given as monthly oral courses to patients with progressive MS was completed. The treatment did not have a significant effect on molecules in the cerebrospinal fluid but there were some trends towards slight improvement in patients. We almost finalized the recruitment of patients to our study of mesenchymal stem cells and have taken the lead in patient recruitment in the large international collaborative study. Melinda Magyari defended her Ph.d.-thesis: “Gender differences in multiple sclerosis epidemiology and treatment response” in May 2014. Another Ph.d.-thesis by Rikke Ratzer “Progressive multiple sclerosis: Studies on immunology and treatment in the progressive phase of multiple sclerosis” was defended in October 2014. Other ongoing Ph.d. studies comprise the influence on children of having a parent with multiple sclerosis, the interaction between genes and environmental factors of importance for MS in natalizumab treated MS patients, and the relationship between smoking, immune activation and disease progression in MS. From October 2014 senior consultant Morten Blinkenberg became chief operating executive of the MS clinic and member of the MS team leadership. In March 2014, the ECTRIMS congress 2013 in Copenhagen, and Per Soelberg Sørensen, was awarded the prize as Congress Host of the Year 2013 at Copenhagen Congress & Event Award. The award was presented at the Town Hall of Copenhagen by the Lord Mayor Frank Jensen. In December 2014 the founder of Danish Multiple Sclerosis Center, professor Per Soelberg Sørensen reached the age of seventy, and in February 2015 the news was broken that he would step down as leader of DMSC and let over the leadership to professor Finn Sellebjerg in April 2015. Hence, this will be my last annual report as director of the Danish Multiple Sclerosis Center. I hope that you will enjoy reading the 2014 annual report of DMSC. Per Soelberg Sørensen DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 5 About The Danish Multiple Sclerosis Center 6 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 7 The Danish Multiple Sclerosis Center About the Danish Multiple Sclerosis Center The Danish Multiple Sclerosis Center (DMSC) is the leading centre for treatment and research in multiple sclerosis in Denmark and provides multidisciplinary care for more than 2,000 MS patients, offering both basic and highly specialized therapy. We serve patients from the Copenhagen capital region and many patients from neighboring regions, and from all over Zealand, are referred for regional and highly specialized therapy. DMSC is composed of a MS Clinic and a MS Research Unit. The MS Clinic is located at the 8th floor of the main complex of Rigshospitalet where the offices of professors and consultants are located. The MS Clinic contains the reception desk, the secretary offices, the nurse offices, as well as the outpatient consultation rooms, facilities for intravenous infusion-therapy with disease modifying drugs, and rooms for invasive procedures. ACTIVE PATIENTS IN DMSC 2,400 2,200 2,000 1,800 1,600 1,400 1,200 1,000 800 600 400 200 0 8 1994 2004 2008 2012 2013 2014 2015 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 We have been designated highly specialized function in providing therapy with strong immunosuppressants and experimental medications. From 2011 we have been offering immunoablative therapy followed by autologous stem cell transplantation to patients with very active MS and accumulation of disability despite immunomodulatory or immunosuppressive therapy. DMSC is the centre in Eastern Denmark for treatment of children and adolescence with MS and has a highly specialized function in treating neuromyelitis optica. DMSC also offers treatment of severe spasticity with an intrathecal baclofen pump, not only to patients with MS but also to other patients with diseases or traumatic injuries causing severe spasticity. It is the aim of the MS Clinic to provide highquality multi-disciplinary care for all our patients with openness and respect. The staff comprises two professors, one associate professor, 4 consultants, 1 staff neurologist and several external consultants working part time in the MS Clinic. There is one leading nurse and 10 MS specialist nurses, 4 secretaries, a neuropsychologist, a physiotherapist and a medical social counsellor. The MS Research Unit is located partly in the proximity of the MS Clinic, where most patientrelated clinical research takes place and where the offices of 2 research nurses and 1 research secretary are embedded. The remaining part of the MS Research Unit is located on the first floor in the Michaelsen Building 63 and in the basement of building 93. These facilities contain the Neuroimmunology Laboratory and offices for the research staff. The laboratory is equipped with an 8-colour flow cytometer and facilities for doing real-time polymerase chain reaction (PCR). Further, the facilities contain the MS Biobank and the neurogenetics laboratory for DNA preparation, and facilities for making routine laboratory tests. The focus of the research in DMSC is clinical research, neuroimmunology, neurogenetics and, in particular, translational research aiming at implementing the findings in neurogenetics and immunology into new therapies of MS. DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 9 Organization Danish Multiple Sclerosis Research Center Director: Professor Per Soelberg Sørensen MS clinic MS Research Unit NEUROLOGISTS Professor Per Soelberg Sørensen Professor Finn Sellebjerg Chief operating executive Morten Blinkenberg Ass. professor Annette Oturai Consultant Karen Schreiber Consultant Ana Voldsgaard Consultant Melinda Magyari Consultant Susanne Helweg-Larsen Staff neurologist Henrik Mathiesen Staff neurologist Peter Roos CLINICAL RESEARCH Professor Per Soelberg Sørensen Consultant Karen Schreiber Consultant Ana Voldsgaard Consultant Melinda Magyari Neuropsychologist Lisbet Marstrand PhD student Eva Rosa Petersen PhD student Rikke Ratzer PhD student Julie Maria Hejgaard PhD student Anja Thormann PhD student Cecilie Ammitzbøll PhD student Julie Yoon S. Moberg Research nurses Vibeke Jespersen Sidsel Nielsen Ext. consultant Mikael Lund Ext. Consultant Tina Dysgaard Ext. consultant Cecilia Rajda Ext. consultant Anna Tsakiri Ext. consultant Birgit Æ. Bundesen Ext. consultant Said Ashna Ext. consultant Marie Norsker Folke Ext. consultant Monika Góra MS NURSES Leading nurse Anne Hansen Dorthe Stauning Rasmussen Anette Husted Pedersen Lene Almind Louise Nathalie Christiansen Rie Forsberg Pedersen Sidsel Nielsen Karina Jørgensen Mette Grønkjær Nielsen PhD student PhD student Julie Yoon S. Moberg PhD student Anja Thormann Research secretaries Annette Larsen Pia Maria Sandstød Ibsen NEUROIMAGING RESEARCH Chief operating executive Morten Blinkenberg Staff neurologist Henrik Mathiesen GENETIC RESEARCH Ass. Professor Annette Oturai Senior research fellow Helle Bach Søndergaard PhD students Julie Maria Hejgaard SECRETARIES Annette Larsen Malene Møllesøe Pia Maria Sandstød Ibsen Maiken Leth Svane Stine Merser Julie Lind NEUROPSYCHOLOGIST Lisbet Marstrand PHYSIOTHERAPIST Lis Albrechtsen 10 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 NEUROIMMUNOLOGY RESEARCH Professor Finn Sellebjerg Senior research fellow Helle Bach Søndergaard Senior research fellow Marina Rode Von Essen Post doc Lars Börnsen Part-time post doc Jeppe Romme Christensen PhD students Rikke Ratzer Cecilie Ammitzbøll Julie Maria Hejgaard Eva Rosa Petersen Pregraduate students Ditte Jonesco Sophie Buhelt Jacob Talbot NEUROIMMUNOLOGY LABORATORY Head of Laborarory Poul Erik Hyldgaard Jensen Laboratory technicians Leading Laboratory technician Joy Mendel-Hartvig Michael Jensen Vibeke Lindgaard Fuglholt Rikke Larsen Freja Melissa Bekner Betina Gall Professor Per Soelberg Sørensen Professor Finn Sellebjerg Consultant Morten Blinkenberg Ass. professor Annette Oturai Consultant Karen Schreiber Consultant Ana Voldsgaard Consultant Melinda Magyari Staff neurologist Henrik Mathiesen Laboratory leader Poul Erik Hyldgaard Jensen Senior research fellow Helle Bach Søndergaard Senior research fellow Lars Börnsen Senior research fellow Marina Rode Von Essen Leading laboratory technician Joy MendelHartvig Leading nurse Anne Hansen DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 11 Research activities 2014 Clinical research Clinical research Neuroimaging Neurogenetics Neuroimmunology Routine analyses in Neuroimmunology Laboratory 12 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 13 Research activities 2014 Clinical and epidemiological research CLINICAL RESEARCH GROUP: Per Soelberg Sørensen, Morten Blinkenberg, Finn Sellebjerg, Annette Oturai, Ana Voldsgaard, Karen Schreiber, Henrik Mathiesen, Melinda Magyari, Lars Bornsen, Jeppe Romme Christensen, Rikke Ratzer, Julie Maria Hejgaard, Anja Thormann, Julie Yoon S. Moberg, Lisbet Marstrand, Vibeke Jespersen, Sidsel Walther Nielsen, Anne Hansen, Annette Larsen, Pia Maria Sandstød Ibsen. Therapeutic trials of new medicine Previously, most efforts in therapeutic trials of new medicine have been directed towards treatment of patients with relapsing-remitting MS. However, we have recently been performing several single-centre studies in patients with progressive MS in order to try to find treatment options for this phase of the disease that currently lacks effective therapy. These studies are performed in collaboration with the MRI Department, Hvidovre Hospital. We published the results of a proof-of-concept phase II open-label study (Neurology 2014) of the effects of treatment with natalizumab 300 mg 14 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 every 4 weeks for 60 weeks in patients with progressive MS. Compared with baseline findings natalizumab significantly reduced inflammatory molecules in the cerebrospinal fluid, and also markers of axonal damage (neurofilament light) decreased significantly. In addition, we showed a reduction in disability (mean EDSS), reduction in grey matter atrophy on MRI and increase in magnetization transfer ratio (MTR). The findings suggest a role of systemic inflammation in progressive MS, and natalizumab treatment may have favorable clinical effect in progressive MS patients. We also finalized a study in 24 progressive MS patients in a pilot study of methylprednisolone administered orally in a monthly course of 500 mg for 3 days. The primary endpoint was the changes in inflammatory molecules in the cerebrospinal fluid (osteopontin, CXCL13 and matrix metalloproteinase-9), but also markers of axonal damage (neurofilament light) and demyelination (myelin basic protein) were studied. In addition, we used conventional and non-conventional MRI markers (magnetization transfer ratio and diffusion tensor imaging) as well as reduction in disability as secondary endpoints. The results of the study were reported at the ECTRIMS/ACTRIMS congress in September 2014 by Rikke Ratzer, who won the prize as best young investigator oral presentation. Another clinical trial finalized in 2014 was the study of the effect of erythropoietin (EPO) on disability in patients with progressive MS in a randomized double-blind trial. In all, 56 patients with primary or secondary progressive MS had been included and treated with either EPO or placebo for 24 weeks. Unfortunately, neither the primary outcome measure, the change from baseline to 24 weeks in a composite measure of maximum gait distance, a test of hand dexterity, and a neuropsychological test, nor any of the secondary endpoints including clinical relapses, disability, and several MRI measures were beneficial influenced by EPO. The results were presented at the ECTRIMS/ACTRIMS congress in September 2014. In collaboration with the Stem Cell Unit at the Department of Clinical Immunology, Rigshospitalet and the MRI Department, Hvidovre Hospital, we have initiated a trial of intravenous therapy with autologous mesenchymal stem cells in MS patients. The primary objective of the study is to assess the safety and the activity in terms of reduction in the total number of contrast-enhancing lesions on MRI over 24 weeks as compared to placebo. The secondary objectives of the study are to gather preliminary information on the efficacy of the experimental treatment in terms of clinical efficacy measures and immunological markers. The study is a randomized double-blind study comparing treatment with autologous mesenchymal stem cells vs suspension media at 24 weeks. After 24 weeks patients initially assigned to suspension media treatment will be shifted to the treatment with mesenchymal stem cells, and a secondary analysis will compare the number of adverse events and gadolinium-enhancing lesions in weeks 0-24 and 24-48 in these patients. The study is a part of an international collaboration between centres in Spain, England, Sweden, Denmark, France, Germany, Iran, and Canada comprising in all 160 patients, of whom 25 patients will be Danish. We almost completed enrolment in 2014. A Ph.d. study investigates the consequences for young people being brought up by a parent with MS. The project comprises an interview study and a register study to elucidate the psychosocial effects and the impact on educational and financial status. Currently, we take part in an EU supported study, ABIRISK (Immunogenicity: assessing the clinical relevance and risk minimization of antibodies to DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 15 Research activities 2014 pharmaceuticals). The project aims to provide an integrated approach to anti-drug immunization, bringing together, in an extensive and coordinated manner, a large network of clinicians from various specialties with broad experience in the care of patients, biologists and scientists specialized in the mechanisms of immunogenicity, and, in addition, collaboration with a large network of private pharmaceutical industries. In addition to these investigator-driven therapeutic trials, DMSC are taking part in clinical trials of new drugs sponsored and driven by the pharmaceutical industry. We are currently involved in trials of new indications for treatment with natalizumab, subcutaneous injections of natalizumab and in the development of three new monoclonal antibodies, alemtuzumab, daclizumab and ofatumumab, with strong effects on disease activity. Epidemiological research group: In 2014, using data from the Danish Multiple Sclerosis Registry, we published the results of a nationwide study comprising 1,403 MS patients aged 15-55 at clinical onset between 2000 and 2004. We showed that childbirths within five years before clinical onset reduced the risk of MS onset in women, but not in men. Considering the possibility of reversed causation, which was not supported by the data, pregnancy could exert a certain protection against MS on a biological basis, lasting up to five years. We did not identify any physical or social environmental factors which could explain the gender discrepancy in the incidence increase. 16 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 Currently, we are studying the effect of environmental factors, such as smoking habits and vitamin D intake on the susceptibility to MS. Vitamin D that seems to yield some protection against encountering MS may also influence the disease activity in established MS, and we have completed a study exploring the role of vitamin D on clinical disease activity in MS. Currently two ongoing ph.d studies are conducted using data from the MS Registry. One study explores the occurrence of co-morbidity in MS patients and the impact of co-morbidity on disease activity and social parameters. The other ph.d. study investigates socioeconomical differences as educational level, income, marital status, etc. between children who have parents with MS and children who have not. Pediatric research group: Pediatric MS carries a relatively higher mortality and morbidity rate than adult MS. Pediatric MS symptoms and paraclinical findings at the first demyelinating event have never been characterized in a Danish setting and therefore we aimed at comparing onset symptoms in pediatric MS with those of an adult MS population. In 2014, we published a study with Magnus Spangsberg Boesen, showing that onset symptoms were comparable between pediatric and adult MS. Further studies are ongoing, investigating the nationwide incidence of pediatric MS in Denmark. Neuro Imaging NEUROIMAGING RESEARCH GROUP: Morten Blinkenberg, Henrik Mathiesen, Per Soelberg Sørensen Multiple sclerosis (MS) is a multifocal disease in the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss. Although MRI is highly sensitive in detecting MS lesions, it lacks histopathological specificity. The current MRI marker for acute CNS inflammation is gadolinium, visualizing blood–brain barrier leakage, as a result of inflammation, but not inflammation itself. The inflammation induces microglia activation, leading to expression of the 18-kDa translocator protein TP-18, which is part of the so-called peripheral benzodiazepine receptor complex. This can be recognized by synthetic ligands and is used in positron emission tomography (PET), visualizing activated microglia and ongoing disease process in MS. The methodological approach in PET is expensive and time consuming, and a more feasible approach could be single photon emission tomography (SPECT) measurements of [123I]-CLINDE, which is a new radioiodinated imidazopyridine-3-acetamide ligand for the study of peripheral benzodiazepine binding sites. In this way it is possible to evaluate larger samples of MS patients with regard to disease progression and treatment effect. In 2014 we examined four patients with MS and studies are ongoing. The figure below illustrates an MS patient before and after high dose chemotherapy and hemopoietic stem cell transplantation, showing reduced CLINDE activity post treatment, as a result of disease remission. Studies on resting-state fMRI, assessing functional brain connectivity, were continued in 2014 in collaboration with Danish Research Centre for Magnetic Resonance, PhD Anne-Marie Dogonowski. Our studies have so far shown, that worsening of disability in MS results in increased coupling and better integrity between regions of importance to motor function, as a possible neural adaption to disease progression. The latest of Anne-Marie Dogonowskis studies was finalized in 2014, and addresses recovery of the motor system from an acute MS relapse. This was examined by prospectively assessing functional brain connectivity with resting-state functional magnetic resonance imaging during the acute motor relapse. The results from the 12 examined MS patients show, that motor resting-state connectivity decreased in the supplementary motor area extending into the mesial primary motor cortex in proportion to individual motor improvement, and indicate a normalisation of connectivity patterns with recovery. An imaging study with quite a different focus than the brain was also finalized in 2014. Corticosteroids are widely used in the treatment of MS, for both acute relapses and as add on treatment to interferon-beta. A rare side effect of corticosteroids is avascular osteonecrosis characterized by focal necrosis of bone tissue and followed by collapse of architectural bony structure. A former study has reported a high prevalence of osteonecrosis in MS patients (15.2%) receiving a high cumulated dose of methylprednisolone, although this has never been confirmed. Therefore we studied 40 patients from the interferon beta-1a i.m (MECOMBIN) study, where 22 patients had received high dose methylprednisolone and 18 placebo. Bilateral femoral MRI was performed in order to determine the presence of avascular osteonecrosis, which was found in one MS patient from the methylprednisolone group. We conclude that the risk of osteonecrosis is low in MS patients treated with high doses of MP, which does not corroborate previous findings. DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 17 Research activities 2014 Neurogenetics NEUROGENETICS RESEARCH GROUP: Annette Bang Oturai, Helle Bach Søndergaard, Julie Hejgaard, Eva Rosa Petersen, Anna Olsson, Stefan Gustavsen, Nanna Larsen, Per Soelberg Sørensen, Finn Sellebjerg. Gene-environment interactions and treatment response in MS Epidemiological studies suggest a complex interplay between genetic and environmental triggering factors in MS. The HLA locus has long been known to increase the MS risk by a factor 3-4, also among Danish patients. Recently we have participated in genome-wide association studies that identified several genes outside this locus, in particular immunologically relevant genes, supporting the proposed immunopathogenesis of the disease. A low 30% concordance rate among monozygotic twins strongly suggests a dominant contribution of environmental factors such as smoking, diet, low sunlight, vitamin D deficiency, infectious agents, toxins and geographical location. It is still unclear how such environmental factors may influence the disease and treatment response. The overall aim for us is to firmly establish genetic and environmental risk factors in MS and study their interactions and influence on treatment response, with the longterm goal of using such information for personalized medicine. Chip studies Gene chip technology with the study of single nucleotide polymorphisms (SNPs) has made genome wide association studies (GWAS) possible. As a member of the International Multiple Sclerosis Genetic Consortium (IMSGC) and member of the steering committee, we have recently been involved in the world’s largest MS genetic studies, altogether identifying 110 MS genetic risk gene variations. In total 2,000 Danish MS patients and 2000 Danish controls are on either the GWAS chip, the Immunochip or the ongoing MS replication chip. The Immunochip is a custom genotyping chip with 162,000 SNPs, most of them located in 184 densely mapped regions around loci established as risk loci for autoimmune diseases. The MS chip contains around 18 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 100,000 SNPs, including all established MS risk SNPs as well as many SNPs with weaker evidence of association to MS. Finally, we will have access to 250,000 rare SNPs in genome-wide exomes. Most genetic variations revealed today are linked to molecules related to the immune system, including 2 related to vitamin D metabolism. The MS chip project will be completed in 2015, thus data from all chip studies will be available to the scientific community, including the Nordic MS Genetics Group, with whom we have collaborated for more than 20 years. Patients and controls Patient materials for the different studies are available from the Danish MS Biobank, where we store DNA, RNA and serum samples. Prospectively collected clinical information will be obtained from the Danish Multiple Sclerosis Treatment Registry, which prospectively collects data from all MS patients on disease-modifying therapy. An environmental and lifestyle questionnaire with more than 100 questions, adapted from a questionnaire developed by the Department of Clinical Neuroscience at Karolinska Institute in Sweden, address the following topics; smoking, alcohol, mononucleosis, BMI, diet, sun exposure, infections, vaccination, social and educational factors, work exposures, comorbidity and geographical factors. In the Danish Biobank we have blood from >2,500 patients and 5,000 healthy donor controls, questionnaires are available from the majority of the patients and all 5,000 donor controls. Genetic influence on oligoclonal band status and JC-Virus Within our Nordic collaboration we have participated in large studies showing that: - SNPs from the HLA complex and six other loci were associated with oligoclonal band (OCB) status. The study confirmed both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicated different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS patients with possible implications for patient management (J Neuroimmunol. 2014). - Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JC-virus (JCV) infection. Alleles within the DQB1*06:03 haplotype showed an opposite association. These associations between JC virus antibody response and HLA molecules support the notion that CD4+ T cells are crucial in the immune defense against JCV and lays the ground for risk stratification for PML and development of therapy and prevention. JCV carriers with a compromised immune system, such as in HIV, or subjects on immunosuppressive therapies, such as anti VLA-4 therapy (natalizumab) may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain (PLoS Pathog. 2014). The influence of genetic and environmental factors on treatment and clinical outcome Among Danish patients we have found that: - Pretreatment relapse rate and clinical disease activity during the first 2 years of treatment on interferon-beta (IFN-β) may be associated with disease progression in MS patients, but genetic analysis of single nucleotide polymorphisms (SNPs) in the genes encoding interferon response factor (IRF)-5, IRF-8 and glypican-5 (GPC5) were not associated with risk of relapse or disease progression (Acta Neurol Scand. 2014). - A higher disease activity and disease severity was observed in MS patients who smoked before and during treatment with IFN-beta, and furthermore this effect seemed to be by HLA-DRB1*15:01. The previously reported interaction between HLA genes, smoking and MS susceptibility may therefore also affect disease course. - In 1,500 MS patients examined for the association between vitamin D in the blood and six GWAS SNPs, season, age, sex, eye colour, body mass index, vitamin D supplements, smoking, fish intake, sun habits and severity of MS. We found significant effects of both genetic (vitamine D metabolism SNPs) and environmental factors on vitamine D levels in MS patients. Since 25(OH)D might have protective effects in MS, and vitamine D supply is a modifiable factor, it may be important to include this in the MS treatment regimen (Multiple Sclerosis 2014). Ongoing studies further investigate the role of •The study of vitamin D and age at onset •The study of vitamin D on disease activity •Weighted genetic risk score and treatment response •The role of shift work on MS risk in Danish MS patients •The role of alcohol intake and MS risk in Danish MS patients •The role of passive smoking and MS risk in Danish MS patients. DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 19 Research activities 2014 Neuroimmunology NEUROIMMUNOLOGY RESEARCH GROUP: Finn Sellebjerg, Cecilie Ammitzbøll, Sophie Buhelt, Lars Börnsen, Marina Rode von Essen, Poul Erik Hyldgaard Jensen, Ditte Jonesco, Annette Bang Oturai, Eva Rosa Petersen, Rikke Ratzer, Birgitte Romme Nielsen, Jeppe Romme Christensen, Helle Bach Søndergaard, Jacob Talbot, Per Soelberg Sørensen. Neuroimmunology of MS Inflammation, demyelination and axonal damage or neurodegeneration are central elements in the pathogenesis of MS, but the relationship between them is incompletely understood. Treatments that target systemic immune activation or migration of immune cells to the brain and spinal cord prevent relapses in MS, and it is widely accepted that relapsing-remitting MS is an immune-mediated disease. The relationship between immune activation and slowly progressive disease is, however, controversial. Elucidating the pathogenesis of progressive forms of MS is crucial since there are still no efficacious therapies for this course of the disease, which is the major cause of disability in MS. The aim of our research is to investigate the relationship between systemic immune activation, 20 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 intrathecal immune activation, demyelination and axonal damage. We study the activation of immune cells in blood by a panel of different immunological methods, study measures of immune activation and tissue damage in the brain and spinal cord by studying samples of cerebrospinal fluid (CSF), and compare these measures with clinical and magnetic resonance imaging studies of the impact of the disease. We compare patients with relapsing-remitting, primary and secondary progressive MS, and study how treatment alters these factors. In addition, we study how immune activation and disease activity is influenced by genetic, environmental and lifestyle factors associated with the risk of developing MS. Molecular biology studies In molecular biology studies we investigate mRNA and protein expression and measure the expression and function of microRNAs, which are small, non-coding RNA molecules that regulate the degradation and translation of mRNA. We previously reported that patients with MS show differential expression of miRNA in blood cells, and some of these microRNA changes can also be detected in serum or plasma samples. We have also identified differentially expressed microRNAs in blood cells from pregnant MS patients. This is an intriguing finding since it is well known that pregnancy is associated with reduced disease activity in MS. Ongoing studies further investigate the role of microRNAs in MS and investigate how MS-associated genetic variants influence gene expression and immune cell functions in MS. These studies include: •Studies of microRNA in pregnant MS patients: identification of the cellular sources of differentially expressed microRNA and their immunological effects •Studies of serum microRNA as diagnostic and prognostic biomarkers in patients with newly diagnosed MS •Studies of microRNA effects of treatment with interferon-beta and glatiramer acetate •Studies of the effects of an MS-associated genetic variant in the gene encoding the interleukin-2 receptor alfa-chain in patients with MS and healthy control subjects •Studies of the effects of MS-associated genetic variants on the expression of pro-inflammatory and immunoregulatory cytokines. Immune activation in MS We previously used microarray studies of gene expression and a broad panel of flow cytometry analyses to map immune activation in circulating blood cells in patients with MS. These studies implicated several subtypes of T lymphocytes in the pathogenesis of MS, and identified potentially important differences between patients with relapsing-remitting, primary and secondary progressive MS. In addition, we have recently identified an activation phenotype with increased coexpression of specific chemokine receptors in patients with MS. Furthermore, we have identified two novel genes that are expressed at increased levels in healthy control subjects and MS patients who smoke. We are continuing studies of: •Activation of naïve, memory and effector T cells in MS •The effect of smoking and other exogenous risk factors on immune activation in MS •The effect of genetic risk factors on immune activation in MS •Immune activation and autoreactive T cells in relapsing-remitting MS •Immune activation and autoreactive T cells in progressive MS. Effects of MS therapy and biomarkers We have pursued the identification of biomarkers that can be used as surrogate outcomes in clinical trials and as prognostic biomarkers in newly diagnosed patients with MS. In addition, we try to identify biomarkers for the response to treatment in relapsing-remitting MS. We have previously reported that the molecules osteopontin and neurofilament light chain in cerebrospoinal fluid may be useful surrogate outcomes in progressive MS treatment trials. In a recent study we used these biomarkers to show that treatment with methylprednisolone has no consistent effect in patients with progressive MS, and we reported the immunological effects of this treatment on circulating blood cells in a separate study. We also conducted studies showing that another molecule, chitanase-3-like-1 may be even better suited as a prognostic and surrogate cerebrospinal fluid biomarker. Finally, we published a study which, unfortunately, could not confirm previous reports of an association between specific genetic variants and response to treatment with interferon-beta. We are currently investigating a broad panel of cerebrospinal fluid biomarkers in patients with MS and Huntington disease as a neurodegenerative disease control group. Other ongoing studies investigate the effects of treatment with mesenchymal stem cells. These are conducted partly as studies of the ex vivo effects of stem cells, partly studies of the in vivo effects in patients participating in an ongoing multicentre phase 2 study. Furthermore, we continue our studies of the response to various MS therapies. These studies investigate: •Effects of mesenchymal stem cell treatment on immune activation and autoreactive T cells •Immune activation and autoreactive T cells in MS patients treated with natalizumab, fingolimod, alemtuzumab, dimethyl fumarate, and teriflunomide •Chemokines and gene expression in patients treated with interferon-beta •Gene expression and disease activity in patients treated with glatiramer acetate. DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 21 Research activities 2014 Routine analyses in the Neuroimmunology Laboratory NEUROIMMUNOLOGY LABORATORY RESEARCH GROUP: Poul Erik H. Jensen, laboratory technicians: Joy Mendel-Hartvig, Michael Kolbjørn Jensen, Vibeke L. Fuglholt, Freja Melissa Bekner. Diagnostic evaluation The presence of oligoclonal IgG-bands in CSF is of interest in the diagnosis of Multiple Sclerosis (MS). In 2014 we have analyzed 1,444 patient samples, using isoelectric focusing of CSF and corresponding plasma samples for the characterization of IgG bands. In the autoimmune disease myasthenia gravis (MG), autoantibodies against the acetylcholine receptor (AChR) may cause a diminished binding of ACh on muscular surfaces and thereby a reduced impulse transmission to the postsynaptic membrane of the neuromuscular endplate occurs. For diagnostic and therapeutic purposes, we measure the concentrations of these autoantibodies from patient serum samples, using a radio-immunoassay kit, and in year 2014 we analyzed 1,039 patient samples. 22 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 Measurement of neutralizing antibodies Subgroups of MS patients, treated with IFN-β or Tysabri, generate neutralizing antibodies, which diminish the therapeutic effects. IFN-β molecules bind to leucocytes and a specific up-regulation of MxA mRNA in the cells occur. Neutralizing antibodies may abolish this effect, and therefore we measure the neutralization of IFN-β by antibodies in a cell-culture assay based on luciferase-induced expression, and further by the MxA mRNA-expression as a biological response to treatment with IFNß. In 2014 we have analyzed 853 patient samples for neutralizing antibodies, and 35 patient samples for MxA mRNA expression. The action of Tysabri differs from IFN-β, since it blocks mononuclear cell binding to endothelial cells. In this way Tysabri inhibits mononuclear cells from entering the central nervous system. The generation of neutralizing antibodies to Tysabri in MS patients blocks the biological effects of Tysabri. In 2014 we analyzed 570 blood samples for the presence of antibodies to Tysabri by ELISA. The measurements of the concentrations of antibodies against aquaporin-4, which are used for the diagnosis of neuromyelitis optica (NMO) increased in number of samples analyzed to 192 patient samples in 2014. DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 23 Scientific publications, prizes, collaboration, acknowledgements Scientific publications 2013-2014 Prizes Honorary offices Scientific collaboration Acknowledgements Scientific publications Publications 2013-2014 Peer reviewed original papers International Multiple Sclerosis Genetics Consortium,Sorensen PS. Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls. American Journal of Human Genetics. 2013 jun 6;92(6):854-65. International Multiple Sclerosis Genetics Consortium (IMSGC). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45:1353-1360. Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C et al. Analysis of immunerelated loci identifies 48 new susceptibility variants for multiple sclerosis. Nature Genetics. 2013 ov;45(11):1353-60. Blinkenberg M, Sellebjerg F, Leffers AM, Madsen CG, Sorensen PS. Clinically silent PML and prolonged immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab. Multiple sclerosis (Houndmills, Basingstoke, England). 2013 aug;19(9):1226-9. Comi G, Cook SD, Giovannoni G, Rammohan K, Rieckmann P, Sorensen PS et al. MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study. Journal of Neurology. 2013;260(4):1136-46. Dogonowski A-M, Siebner HR, Sorensen PS, Wu X, Biswal B, Paulson OB et al. Expanded functional coupling of subcortical nuclei with the motor restingstate network in multiple sclerosis. Multiple Sclerosis. 2013 apr;19(5):559566. Dogonowski A-M, Andersen KW, Madsen KH, Sorensen PS, Paulson OB, Blinkenberg M et al. Multiple sclerosis impairs regional functional connectivity in the cerebellum. NeuroImage. Clinical. 2013 nov 27;4:130-8. Dogonowski A-M, Siebner HR, Sorensen PS, Paulson OB, Dyrby TB, Blinkenberg M et al. Resting-state connectivity of pre-motor cortex reflects disability in multiple sclerosis. Acta Neurologica Scandinavica. 2013 mar 6;128(5):328–335. Hegen H, Millonig A, Albrecht N, Bertolotto A, Comabella M, Giovannoni G, Guger M, Hoelzl M, Khalil M, Lindberg R, Polman CH, Rudzki D, Schautzer F, Sellebjerg F, Skrobal A, Sorensen PS, Deisenhammer F. Earlydetection of neutralizing antibodies to interferon-beta in multiple sclerosis patients. Mult Scler [E-pub ahead of print]. Leone MA, Barizzone N, Esposito F, Lucenti A, Harbo HF, Goris A, Kockum I, Oturai AB, Celius EG, Mero IL, Dubois B, Olsson T, Sondergaard HB, Cusi D, Lupoli S, 26 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 Andreassen BK; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2, Myhr KM, Guerini FR; PROGEMUS Group; PROGRESSO Group, Comi G, Martinelli-Boneschi F, D’Alfonso S. Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients. PLoS One. 2013 Jun 13;8(6):e64408. doi: 10.1371/journal. pone.0064408. Print 2013. PMID: 23785401 [PubMed – in process] Lund H, Krakauer M, Skimminge A, Sellebjerg F, Garde E, Siebner HR et al. Blood-brain barrier permeability of normal appearing white matter in relapsing-remitting multiple sclerosis. P L o S One. 2013;8(2):e56375. Magyari M, Koch-Henriksen NI, Pfleger CC, Sorensen PS. Reproduction and the risk of multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2013 okt;19(12):1604-9. Magyari M, Sondergaard HB, Sellebjerg F, Sorensen PS. Preserved in vivo response to interferon-α in multiple sclerosis patients with neutralising antibodies against interferon-β (REPAIR study). MSARD 2013; 2: 141-146. Mathiesen HK, Sorensen PS. Prolonged-release fampridine improves walking in a proportion of patients with multiple sclerosis. Expert review of neurotherapeutics. 2013 dec;13(12):1309-17. Mechelli R, Umeton R, Policano C, Annibali V, Coarelli G, Ricigliano VAG et al. A “candidate-interactome”aggregate analysis of genome-wide association data in multiple sclerosis. P L o S One. 2013;8(5):e63300. Mero I-L, Gustavsen MW, Sather HS, Flam ST, BergHansen P, Sondergaard HB et al. Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles. P L o S One. 2013;8(3):e58352. Modvig S, Degn M, Horwitz H, Cramer SP, Larsson HBW, Wanscher B et al. Relationship between cerebrospinal fluid biomarkers for inflammation, demyelination and neurodegeneration in acute optic neuritis. P L o S One. 2013;8(10):e77163. Moller M, Sondergaard HB, Koch-Henriksen N, Sorensen PS, Sellebjerg F, Oturai AB. The chemokine receptor CCR5 Δ32 allele in natalizumab-treated multiple sclerosis. Acta Neurol Scand [E-pub ahead of print]. Olsson T, Achiron A, Alfredsson L, Berger T, Brassat D, Chan A et al. Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort. Multiple sclerosis (Houndmills, Basingstoke, England). 2013 okt;19(11):1533-8. 2013 2014 Paulson OB, Sorensen PS. Neuroonkologi. I Paulson OB, Thage O, Waldemar G, red., Neurologi i 100 ar: beretninger fra Rigshospitalets neurologiske afdeling. [Nationalt Videnscenter for Demens]. 2013. s. 112-115. Pedersen EG, Hallas J, Hansen K, Jensen PEH, Gaist D. Late-onset myasthenia not on the increase: a nationwide register study in Denmark, 1996-2009. European Journal of Neurology. 2013;20(2):309-14. Pedersen EG, Pottegard A, Hallas J, Friis S, Hansen K, Jensen PEH et al. Use of azathioprine for non-thymoma myasthenia and risk of cancer: a nationwide casecontrol study in Denmark. European journal of neurology: the official journal of the European Federation of Neurological Societies. 2013 jun;20(6):942-8. Ratzer R, Sondergaard HB, Christensen JR, Bornsen L, Borup R, Sorensen PS et al. Gene expression analysis of relapsing-remitting, primary progressive and secondary progressive multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2013 dec;19(14):1841-8. Romme Christensen J, Bornsen L, Khademi M, Olsson T, Jensen PE, Sorensen PS et al. CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis. Multiple Sclerosis. 2013;19(7):877-84. Romme Christensen J, Bornsen L, Ratzer R, Piehl F, Khademi M, Olsson T et al. Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. P L o S One. 2013;8(3):e57820. Schreiber K, Voldsgaard A, Sorensen PS. Der er begraenset effekt af interferonbeta til behandling af sekundaer progressive multipel sklerose - en gennemgang af et Cochranereview. Ugeskrift for laeger. 2013 maj 6;175(19):1342-4. Sellebjerg F, Hesse D, Limborg S, Lund H, Sondergaard HB, Krakauer M et al. Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2013 feb;19(2):179-87. Svenningsson A, Falk E, Celius EG, Fuchs S, Schreiber K, Berko S et al. Natalizumab treatment reduces fatigue in multiple sclerosis. Results from the TYNERGY trial; a study in the real life setting. P L o S One. 2013;8(3):e58643. Sondergaard HB, Hesse D, Krakauer M, Sorensen PS, Sellebjerg F. Differential microRNA expression in blood in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2013 dec;19(14):1849-57. Sondergaard HB, Hesse D, Krakauer M, Sorensen PS, Sellebjerg F. Differential expression of microRNA in multiple sclerosis. Mult Scler 2013; 19: 1849-1857. Sorensen PS. Multipel sklerose. I Paulson OB, Thage O, Waldemar G, red., Neurologi i 100 ar: beretninger fra Rigshospitalets neurologiske afdeling. [Nationalt Videnscenter for Demens]. 2013. s. 72-80. Theibich A, Dreyer L, Magyari M, Locht H. Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic: description of six cases. Clinical rheumatology. 2013 nov 8. Boesen MS, Sellebjerg F, Blinkenberg M. Onset symptoms in paediatric multiple sclerosis. Danish Medical Bulletin (Online). 2014 apr;61(4):A4800. Damotte V, Guillot-Noel L, Patsopoulos NA, Madireddy L, El Behi M, Ban M et al. A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility. Genes and Immunity. 2014 jan 16;15:126-32. De Stefano N, Airas L, Grigoriadis N, Mattle HP, O’Riordan J, Oreja-Guevara C et al. Clinical relevance of brain volume measures in multiple sclerosis. C N S Drugs. 2014 feb;28(2):147-56. Dessau R, Bangsborg JM, Hansen K, Lebech A-M, Sellebjerg FT, Skarphedinsson S et al Lyme Borreliose: Klinik, diagnostik og behandling i Danmark [Online] 2014. Enevold C, Kjær L, Nielsen CH, Voss A, Jacobsen RS, From Hermansen M-L et al. Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes. Rheumatology International. 2014 okt;34(10):1401-8. Gustavsen MW, Viken MK, Celius EG, Berge T, Mero I-L, Berg-Hansen P et al. Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general. Journal of Neuroimmunology. 2014 sep 15;274(1-2):1749. Hegen H, Millonig A, Bertolotto A, Comabella M, Giovanonni G, Guger M et al. Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development. Multiple sclerosis (Houndmills, Basingstoke, England). 2014 apr;20(5):577-87. Kerrn-Jespersen BM, Lindelof M, Illes Z, Blaabjerg M, Lund EL, Klausen C et al. CLIPPERS among patients diagnosed DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 27 Scientific publications with non-specific CNS neuroinflammatory diseases. Journal of the neurological sciences. 2014 aug 15;343(12):224-7. Liu Y, Carlsson NR, Comabella M, Wang J, Kosicki M, Carrion B et al. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nature Medicine. 2014 mar;20(3):272-82. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014 maj 28;83(3):278-86. Lyksborg M, Siebner HR, Sørensen PS, Blinkenberg M, Parker GJM, Dogonowski A-M et al. Secondary progressive and relapsing remitting multiple sclerosis leads to motor-related decreased anatomical connectivity. P L o S One. 2014;9(4):e95540. Magyari M, Koch-Henriksen N, Pfleger CC, Sørensen PS. Gender and autoimmune comorbidity in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2014 feb 5;20(9):1244-51. Magyari M, Koch-Henriksen N, Laursen B, Sørensen PS. Gender effects on treatment response to interferon-beta in multiple sclerosis. Acta Neurologica Scandinavica. 2014 dec;130(6):374-9. Mathiesen HK, Sørensen PS. The background for the use of fampridine, the indications, contraindications, side effects, and recommendations for Danish patients with multiple sclerosis are reviewed. Ugeskrift for læger [online]. Møller M, Søndergaard HB, Koch-Henriksen NI, Sorensen PS, Sellebjerg F, Oturai AB. The chemokine receptor CCR5 Δ32 allele in natalizumab-treated multiple sclerosis. Acta Neurologica Scandinavica. 2014 jan;129(1):27-31. Pedersen EG, Pottegård A, Hallas J, Friis S, Hansen K, Jensen PEH et al. Risk of non-melanoma skin cancer in myasthenia patients treated with azathioprine. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2014;21(3):454-58. Pedersen EG, Pottegård A, Hallas J, Friis S, Hansen K, Jensen PEH et al. Myasthenia and risk of cancer: a population-based case-control study. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2014 maj;21(5):773-8. 28 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 Ratzer R, Romme Christensen J, Romme Nielsen B, Sørensen PS, Börnsen L, Sellebjerg F. Immunological effects of methylprednisolone pulse treatment in progressive multiple sclerosis. Journal of Neuroimmunology. 2014 nov 15;276(1-2):195-201. Romme Christensen J, Ratzer R, Börnsen L, Lyksborg M, Garde E, Dyrby TB et al. Natalizumab in progressive MS: results of an open-label, phase 2A, proof-of-concept trial. Neurology. 2014 apr 29;82(17):1499-507. Schytz HW, Ashina M, Magyari M, Larsen VA, Olesen J, Iversen HK. Acute headache and persistent headache attributed to cervical artery dissection: Field testing of ICHD-III beta. Cephalalgia : an international journal of headache. 2014 feb 5;34(9):712-716. Sellebjerg F, Søndergaard HB, Koch-Henriksen N, Sørensen PS, Oturai AB. Prediction of response to interferon therapy in multiple sclerosis. Acta Neurologica Scandinavica. 2014 okt;130(4):268-75. Sorensen PS. New management algorithms in multiple sclerosis. Current Opinion in Neurology. 2014 jun;27(3):24659. Sorensen PS, Koch-Henriksen N, Petersen T, Ravnborg M, Oturai A, Sellebjerg F. Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients. Journal of Neurology. 2014 jun;261(6):1170-7. Sorensen PS. Effects of fingolimod in relapsing-remitting multiple sclerosis. Lancet neurology. 2014 jun;13(6):5267. Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014 feb 18;82(7):573-81. Sundqvist E, Buck D, Warnke C, Albrecht E, Gieger C, Khademi M et al. JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants. P L o S Pathogens (Online). 2014 apr;10(4):e1004084. Vollmer TL, Sorensen PS, Selmaj K, Zipp F, Havrdova E, Cohen JA et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. Journal of Neurology. 2014 apr;261(4):773-83. Wu X, Hanson LG, Skimminge A, Sorensen PS, Paulson OB, Mathiesen HK et al. Cortical N-acetyl aspartate is a predictor of long-term clinical disability in multiple sclerosis. Neurological Research. 2014 aug;36(8):701-08. Prizes and honorary offices Prizes RIKKE RATZER Young Investigator Award for Best Oral Presentation at the ACTRIMS/ECTRIMS Congress in Boston. PER SOELBERG SØRENSEN Received in March 2014 the international MonradKrohn Award in Oslo for his research in multiple sclerosis during the last 20 years and for his latest research in new biomarkers of disease activity and treatment effect in multiple sclerosis. Honorary offices A: National ANNETTE BANG OTURAI: Chairman of the Danish Society for Research in Multiple Sclerosis (DAREMUS) Board member of the Torben Fogh and Erik Trier foundation. 2006 FINN SELLEBJERG: Chairman of the Research Committee of the Danish Multiple Sclerosis Society Board member of the Gangsted Foundation Board member of the Karen A. Tolstrup Foundation Member of the Research Board, Rigshospitalet, University of Copenhagen Member of the Scientific Committee of the Board of Application of Expensive Therapies in Denmark MORTEN BLINKENBERG: Board member of the Danish Society for Research in Multiple Sclerosis (DAREMUS) Board member of the Research Committee of the Danish Multiple Sclerosis Society PER SOELBERG SØRENSEN: Chairman of the Danish Multiple Sclerosis Group Chairman of the Foundation for Neurological Research Board member of the Johnsen Legacy for Research in Multiple Sclerosis Chairman of the Scientific Committee of the Board of Application of Expenses Therapies in Denmark B: International ANNETTE BANG OTURAI: Danish member of the Strategy Group within the Multiple Sclerosis Genetics Consortium (IMSGC). Danish leader of the Nordic Multiple Sclerosis Genetic Group. PER SOELBERG SØRENSEN AND THE ECTRIMS CONGRESS Received in March 2014 the Prize as Congress Host of the Year in 2013 at the Copenhagen Congress & Event Award. The award was presented at the City Hall by the Lord Mayor of Copenhagen, Frank Jensen. PER SOELBERG SØRENSEN Received in November 2014 the Multiple Sclerosis Reward. This prize is awarded with intervals of several years by the Danish Multiple Sclerosis Society to individuals who have accomplished an outstanding effort to the benefit of people with multiple sclerosis. FINN SELLEBJERG: Member of the Multiple Sclerosis International Federation (MSIF), International Medical and Scientific Board Member of the European Academy of Neurology Subspecialty Panel Multiple Sclerosis Secretary of the Teaching Course Committee, European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Member of the Editorial Board, Multiple Sclerosis and Related Disorders PER SOELBERG SØRENSEN: Member of the Editorial Board, European Journal of Neurology, 2003 – Member of the Editorial Board, Multiple Sclerosis Journal, 2010 – Member of the Editorial Board, Therapeutic Advances in Neurological Diseases, 2005 – Member of the Editorial Board, Multiple Sclerosis and Demyelinating Disorders Executive board member of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 2010 – Member of the medical advisory board of the International Federation of Multiple Sclerosis Society, 2010 – Member of the International Advisory Committee on Clinical Trials on MS under the sponsorship of the US National MS Society and ECTRIMS, 2010 – Chairman of the Teaching Course Committee, European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 2010 – Member of the Congress Organizing Committee for the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 2010 – Secretary General of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 2014Executive board member of the European Academy of Neurology (EAN), 2013 DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 29 Scientific collaboration Scientific collaboration National The Danish Multiple Sclerosis Register, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (Nils Koch-Henriksen, MD) Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Denmark (Peter Garred, Jacob Larsen MD, Lars Ryder , Klaus Rieneck, MD, Hans O. Madsen, MD) Institute for Inflammation Research, Copenhagen University Hospital, Rigshospitalet, Denmark (Claus Nielsen, MD, PhD) Department of Human Genetics, Aarhus University, Denmark (Bjørn Andersen Nexø) Institute of Biological Psychiatry, Mental Health Center, Sct. Hans, Denmark (Thomas Werge) Department of Clinical Immunology, Rigshospitalet, University of Copenhagen , Denmark (Henrik Ullum) Laboratory of Neuropathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, (Henning Laursen, MD) Danish Research Center for Magnetic Resonance, Hvidovre Hospital, (Professor Olaf Paulsen, Professor Hartwig Siebner, Ellen Garde, MD Faculty of Life Sciences, University of Copenhagen, Denmark (Professor Christian M.O. Kapel, Professor Allan Roepstorff, Professor Stig Milan Thamsborg) Department of Neurology, Ullevål University Hospital, Oslo, Norway (Elisabeth G Celius, MD) Department of Neurology, Haukeland Hospital, Bergen, Norway (Professor Kjell-Morten Myhr) Department of Neurology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden (Professor Jan Hillert, Eva Åkesson, MD, Helena Modin, MD) Department of Clinical Neuroscience and Centrum for Molecular Medicine Karolinska Insitutet at Karolinska University Hospial, Solna 171 76 Stockholm, Sweden (Professor Tomas Olsson, associate Professor Ingrid Kockum) Department of Neurology, Lund University Hospital, Lund, Sweden (Professor Magnhild Sandberg-Wollheim) Department of Neurology, Gothenburg University Hospital, Gothenburg, Sweden (Professor Oluf Andersen) Institute for Molecular Medicine Finland, University of Helsinki, Finland (Janna Saarela) University of Cambridge, Neurology Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom (Stephen Sawcer, MD, Professor Alastair Compston) Cell Therapy Unit, The Blood bank, Department of Clinical Immunology, Rigshospitalet (Anne Fischer-Nielsen, MD, Roberto Oliveri, MD) “International Multiple Sclerosis Genetic Consortium” (IMSG): MS genetic collaboration between 15 countries from Europe, USA, Canada and Australia The MS Clinic, Glostrup Hospital, Glostrup, Denmark (professor Jette Frederiksen, Signe Modvig, MD) Immunochip Consortium: autoimmune diseases genetic collaboration between 20 countries from Europe, USA, Canada and Australia International Nordic MS Genetic Network: Collaboration between the Nordic countries: Sweden (Huddinge, Lund, Gothenburg, Stockholm), Norway (Oslo, Bergen), Finland (Helsinki) and Denmark (Copenhagen) 30 Institute of Immunology, Rikshospitalet, University Hospital, Oslo, Norway (Anne Spurkland, MD, Hanne F. Harbo, MD, professor Frode Vartdal) DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 Sankt Joseph Hospital and Ruhr University, Bochum, Germany (Professor Ralf Gold) Department of Neurology, Turku and University of Turku (Associate Professor Juha-Pekka Eralinna) Department of Neurology, Hopital Henri Mondor, Creteil, France University of Helsinki, Finland (Professor Markus Farkkila) Heinrich-Heine-University, Dusseldorf, Germany (Professor Hans-Peter Hartung) Department of Immunopathology, Brain Research Center, Medical University of Vienna, Vienna, Austria. (Professor Hans Lassmann and Josa Frischer, MD) Ospedale Universitario San Luigi, Torino, Italy (Professor Auturio Bertolotto) Queen Square, London, The United Kingdom (Professor Gavin Giovannoni) Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA (Professor Claudia F. Lucchinetti) Innsbruck Medical University, Innsbruck, Austria (Professor Florian Deisenhammer) VU Medical Centre, Amsterdam, The Netherlands (Professor Chris Polman) General Charles University, Prague, Czech Republic (Professor Eva Havrdova) Utrecht University, Utrecht, The Netherlands (Professor Hub Schellekens) Hospital Universitari Vall d’Hebron, Barcelona, Spain (Professor Xavier Montalban) Collaboration with pharmaceutical companies on clinical trials Collaboration with pharmaceutical companies on clinical trials Novartis, Denmark Merck Serono Nordic, Denmark, Norway and Sweden Biogen idec, Denmark and USA Teva/Aventis, Israel and Denmark Sanofi-aventis, Denmark Bayer Schering, Germany Genzyme, Holland Glaxo Smith-Kline Ovamed, Germany Swedish Orphan, Sweden Forward Pharma, Denmark MedDay Pharmaceuticals, France Lundbeck Foundation Center of Medical Genomics The Novo Nordisk Foundation Center For Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen, Denmark Acknowledgements Danish MS Society Warwara Larsen Foundation Rigshospitalets Scientific Board The Johnsen Memorial Foundation Fondsbørsvekselerer Henry Hansen og Hustrus Legat Danish Medical Research Council EU Sixth Framework Programme Brdr. Rojne Holding Jeppe Juel Memorial Legacy RoFar Foundation Roche Denmark The Danish Strategic Research Council The Lounkar Foundation Biogen idec Sanofi-aventis Merck Serono Ejner Jonasson og Hustrus mindelegat Publisher: Danish Multiple Sclerosis Center Photos: Dorthe S. Rasmussen, Morten Blinkenberg, Cecilie Ammitzbøll Editor: Morten Blinkenberg Proofreading: Karen Schreiber Authors: Per Soelberg Sørensen, Morten Blinkenberg, Finn Sellebjerg, Annette Oturai, Helle Bach Søndergaard, Poul Erik H. Jensen Concept, design, graphic production and print: Datagraf Communications St. Kongensgade 72, 1264 København K Tlf. 33 13 73 83, www.datagraf.dk DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014 31