Danish Multiple Sclerosis Center Annual Report 2012

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1 Department of Neurology THE Neuroscience Centre Copenhagen University Hospital Rigshospitalet Copenhagen, Denmark Danish Multiple Sclerosis Center Annual Report 2012

2 DMSC staff seminar DANISH Multiple sclerosis CENTER annual report 2012

3 Table of contents Annual Report A short review of 2012 in the Danish Multiple Sclerosis Center DMSC missions and aims About the Danish Multiple Sclerosis Center Organization diagram Research activities 2012 Clinical research Neuro Imaging Neurogenetics Neuroimmunology Routine analyses in Neuroimmunology Laboratory Scientific publications Peer reviewed original papers 2012 Peer reviewed original papers 2011 Honorary offices Scientific collaboration Collaboration with pharmaceutical companies Acknowledgements DANISH Multiple sclerosis CENTER annual report

4 Publisher: Danish Multiple Sclerosis Center Editor: Morten Blinkenberg Authors: Per Soelberg Sørensen Morten Blinkenberg Finn Sellebjerg Annette Oturai Helle Bach Søndergaard Poul Erik H. Jensen Photos: Morten Blinkenberg Dorthe Stauning Rasmussen Proofreading: Karen Schreiber Concept, design, graphic production and print: Datagraf Communications St. Kongensgade København K Tlf DANISH Multiple sclerosis CENTER annual report 2012

5 Professor Per Soelberg Sørensen, MD, DMSc Director of the Danish Multiple Sclerosis Center (DMSC) A short review of 2012 in the Danish Multiple Sclerosis Center In 2012 treatment with Tysabri and Gilenya was allocated to all regions of Denmark, and, in addition, more accommodating criteria for treatment were issued for use of these treatments. The result has been an increased number of patients referred to treatment with Tysabri and Gilenya, and, hence, more than 50% of patients in the Danish Multiple Sclerosis Center (DMSC) are currently treated with Tysabri or Gilenya. In 2012 we began the refurbishment of the MS Clinic that will be completed in May The infusion facilities have been improved with more space and comfort for our patients and better working conditions for the staff. We have completed new therapeutic studies showing that treatment of patients with progressive forms of MS with Tysabri had significant impact on molecules in the cerebrospinal fluid indicative of inflammation and tissue damage. A large multicenter trial conducted from the DMSC showed that add-on therapy with minocycline to interferon did not have any beneficial effect. Current research activities in the MS Research Unit comprise studies of oral methylprednisolone courses for treatment of progressive MS forms and study of EPO as neuroprotective agent in patients with progressive MS. Recently, we have initiated a study of mesenchymal stem cells for treatment of relapsingremitting MS as a part of a large international collaborative investigator driven study. Other research activities comprise molecular biology studies on immune activation in progressive MS, studies of the interaction between genes and environmental factors of importance for MS with focus on vitamin D and vitamin D metabolism, and studies of several aspects of MS in women. The Neuroimmunology Laboratory has developed a new analysis for aquaporin-4 antibodies of importance for the diagnosis of neuromyelitis optica. In November 2012, following nomination by DMSC, the Swedish MS researcher, professor Tomas Olsson, Karolinska Institute, Stockholm received Rigshospitalet s international KFJ Research Prize, awarded to a leading MS researcher that collaborates with a strong research group at Rigshospitalet. The prize of 1.5 million DKK will be used to strengthen the collaboration between MS researchers at Karolinska Institute and DMSC. I 2013 the international ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) Congress will take place in Copenhagen, and preparations for the congress have been a major issue and several colleagues at DMSC have been involved as members of the local organizing committee. I hope you will enjoy reading the annual report of DMSC. Per Soelberg Sørensen DANISH Multiple sclerosis CENTER annual report

6 DMSC missions and aims The mission of Rigs hospitalet 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: The aims of the DMSC are: to be the leading multiple sclerosis (MS) center in Denmark to be at the forefront of highly specialized management of MS to carry out research and development in MS at an advanced international level to collaborate scientifically and exchange knowledge in MS research to educate staff to a highly specialized level in their relevant fields to contribute with professional advice on MS to the healthcare community to meet people with MS at their terms with openness and respect to provide the optimal interdisciplinary patient care to all MS patients in the region and to patients from other regions in need of highly specialized therapy to carryout high quality research in MS with focus on clinical research, new therapies, MS genetics, neuroimmunology and MS pathology to teach undergraduate students and PhDstudents and stimulate their interest in MS research to educate post docs, MS physicians, nurses, secretaries and other professionals to a high level of knowledge of MS in their relevant expert fields to lead the national research in Denmark in partnership with other Danish researchers and to establish a broad international collaboration with MS research groups in Europe and from overseas. 6 DANISH Multiple sclerosis CENTER annual report 2012

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8 About The Danish Multiple Sclerosis Center

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10 The Danish Multiple Sclerosis Center About the Danish Multiple Sclerosis Center ACtive patients in DMSC 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 2000 MS patients, offering both basic and highly specialized therapy. We produce the majority of clinical and translational MS research in Denmark in collaboration with other Danish researchers and MS scientists from all over the world. 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 the professor and consultants are located. In 2012 we began refurbishment of the outpatient clinic to get more spacious rooms for our patients and the staff working in the clinic. The renovation includes 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. The National Board of Health has appointed DMSC to have the regional function for treatment with the second generation of MS therapies, Tysabri and Gilenya tablets. 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 Eastern Danish centre for treatment of children and adolescents with MS and has a highly specialized function in treating neuromyelitis optica, once thought to be a variant of MS, but now considered to be a separate disease entity. 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 a professor (from May 2013 two professors), 5 consultants, 2 staff neurologist and several external consultants working part time in the MS Clinic. There is one leading nurse and 9 MS specialist nurses, 4 secretaries, a neuropsychologist, a physiotherapist and a medical social counsellor. We serve patients from the Copenhagen capital region and many patients from neighbouring regions and from all over Zealand are referred for regional and highly specialized therapy. 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 3 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. 10 DANISH Multiple sclerosis CENTER annual report 2012

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12 Organization Danish Multiple Sclerosis Research Center Director: Professor Per Soelberg Sørensen MS clinic MS Research Unit Neurologists Professor Per Soelberg Sørensen Ass. professor Finn Sellebjerg Consultant Morten Blinkenberg Consultant Annette Oturai Consultant Karen Schreiber Consultant Ana Voldsgaard Staff neurologist Melinda Magyari Staff neurologist Henrik Mathiesen PhD Lars Börnsen PhD student Jeppe Romme Christensen PhD student Rikke Ratzer PhD student Julie Maria Hejgaard Ext. consultant Kristin Sjølie Thygesen Ext. consultant Mikael Lund Ext. consultant Mikkel Anthonisen Ext. consultant Cecilia Rajda Ext. consultant Sarah Taudorf Ext. consultant Stephan Bramow Ext. consultant Janus Kaufmann Ext. consultant Lars-Henrik Krarup Ext. consultant Eva Rosa Petersen Ext. consultant Tina Dysgaard MS nurses Leading nurse Anne Hansen Dorthe Stauning Rasmussen Anette Husted Pedersen Lene Almind Julie Yoon S. Moberg Louise Nathalie Christiansen Rie Forsberg Pedersen Sidsel Nielsen Anne Lene Ipsen Mette Olesen Secretaries Annette Larsen Malene Møllesøe Pia Maria Sandstød Ibsen Maiken Leth Svane Neuropsychologist Agnete Jønsson Physiotherapist Lis Albrechtsen Medical social counselor Keld Nissen Clinical research Professor Per Soelberg Sørensen Consultant Karen Schreiber Consultant Ana Voldsgaard Neuropsycologist Agnete Jønsson PhD student Melinda Magyari Research nurses Vibeke Jespersen Joan Pietraszek Sidsel Nielsen Research secretary Annette Larsen Neuroimaging research Consultant Morten Blinkenberg Staff neurologist Henrik Mathiesen Genetic research Consultant Annette Oturai Senior research fellow Helle Bach Søndergaard PhD students Julie Maria Hejgaard Eva Rosa Petersen Neuroimmunology research Ass. professor Finn Sellebjerg Senior research fellow Helle Bach Søndergaard Senior research fellow Lars Börnsen PhD students Jeppe Romme Christensen Rikke Ratzer Cecilie Ammitzbøll Neuroimmunology Laboratory Head of Laboratory Poul Erik Hyldgaard Jensen Laboratory technicians Leading Laboratory technician Joy Mendel-Hartvig Michael Kolbjørn Jensen Vibeke Lindgaard Fuglholt Rikke Larsen 12 DANISH Multiple sclerosis CENTER annual report 2012

13 Professor Per Soelberg Sørensen Ass. professor Finn Sellebjerg Consultant Morten Blinkenberg Consultant Annette Oturai Consultant Karen Schreiber Consultant Ana Voldsgaard Staff neurologist Henrik Mathiesen Staff neurologist Melinda Magyari Laboratory leader Poul Erik Hyldgaard Jensen Senior research fellow Helle Bach Søndergaard Senior research fellow Lars Börnsen Leading laboratory technician Joy Mendel- Hartvig Leading nurse Anne Hansen DANISH Multiple sclerosis CENTER annual report

14 Research activities 2012 Clinical research Clinical research Neuroimaging Neurogenetics Neuroimmunology Routine analyses in Neuroimmunology Laboratory

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16 Research activities 2012 Clinical research Clinical research group: Per Soelberg Sørensen, Morten Blinkenberg, Finn Sellebjerg, Annette Oturai, Ana Voldsgaard, Karen Schreiber, Henrik Mathiesen, Melinda Magyari, Lars Börnsen, Jeppe Romme Christensen, Rikke Ratzer, Julie Maria Hejgaard, Agnete Jonsson, Vibeke Jespersen, Joan Pietraszek, Sidsel Walther Nielsen, Anne Hansen, Annette Larsen. Therapeutic trials of new medicine Minocycline Study In 2012 we presented the results of the RECYCLINE study, which is an International Multi-centre Study directed from DMSC and conducted in 54 MS Centres in Denmark, Norway, Sweden, Finland, France and Switzerland. The study investigated minocycline as add-on therapy to interferon-beta (IFN-beta) in de novo treated patients with relapsing-remitting MS. We randomised 304 patients to minocycline or placebo as add-on to subcutaneous IFN-beta- 1a. Unfortunately, we did not find any statistical significant difference in the primary outcome measure (the time to first documented relapse) or in any of the secondary outcome measures (annual relapse rate, mean number of new and/or enlarging T2 lesions or change in brain atrophy on MRI). No unexpected adverse events were seen. In conclusion, minocycline did not show any beneficial effect as add-on therapy to subcutaneous IFN-beta-1a. However, it is a question whether the study was well powered for the primary endpoint. A trend towards a beneficial effect of add-on of minocycline was observed in some primary and secondary endpoints. Trichuris Suis Eggs for MS In April 2012 at the American Academy of Neurology Meeting in New Orleans, we presented the results of a small safety study with eggs of the pig whipworm (Trichuris suis) taken orally every 2 weeks. Unfortunately, we could not show any beneficial effects of treatment with Trichuris suis eggs, neither as add- on to interferon-beta therapy or as mono-therapy. Hence, in the light of the negative results we have abandoned the start of a larger phase II trial with inclusion of 80 patients. Natalizumab for Progressive MS In a proof-of-concept phase II open-label study of 12 secondary and 12 primary progressive MS patients, reported at the ECTRIMS congress in Lyon October 2012, we demonstrated that treatment with natalizumab 300 mg every 4 weeks 16 DANISH Multiple sclerosis CENTER annual report 2012

17 for 60 weeks significantly reduced inflammatory molecules in the cerebrospinal fluid (osteopontin, CXCL13 and matrix metalloproteinase-9) compared with baseline values.also markers of axonal damage (neurofilament light) and demyelination (myelin basic protein) was decreased significantly. In addition, we showed a reduction in disability (EDSS) and in grey matter atrophy on MRI. The findings suggest a role of systemic inflammation in progressive MS, and natalizumab treatment may have a favourable clinical effect in progressive MS patients. Interferon-alpha treatment in MS We have completed a small study investigating the in vivo biological response to interferon-alpha in MS patients, who have developed neutralizing antibodies against interferon-beta. We have been able to demonstrate that a number of genes, which usually respond to injection of interferon-beta, could be elicited by injection of interferon-alpha, although the patients no longer had a response to interferon-beta. Hence, interferon-alpha could be a therapeutic option in these patients. Current studies of MS therapy We are currently 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. In this regard we study 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 have been included and treated with either recombinant human erythropoietin or placebo for 24 weeks. The primary outcome measure is the change from baseline to 24 weeks in a composite measure of maximum gait distance, a test of hand dexterity, and a neuropsychological test. Secondary endpoints include clinical relapses, disability, and several MRI measures. The results will be available in summer We also finalized inclusion of 24 progressive MS patients, 12 patients with secondary and 12 patients with primary progressive MS, in a pilot study of methylprednisolone administered orally in monthly course of 500 mg for 3 days. The primary endpoint is 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) will be studied. In addition, we use 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 will be available in summer Stem cell therapy In collaboration with the Stem Cell Unit at the Department of Clinical Immunology, the Blood Bank, 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 as compared to placebo in the total number of contrast-enhancing lesions on MRI over 24 weeks. The secondary objectives of the study are to gather preliminary information of the efficacy of the experimental treatment in terms of combined MRI activity, clinical efficacy measures and immunological markers. The study is a randomized double-blind study comparing treatment with DANISH Multiple sclerosis CENTER annual report

18 Research activities 2012 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 gadoliniumenhancing lesions in weeks 0-23 and in these patients. The study is a part of an international collaboration between centres in Spain, England, Sweden, Denmark, France, Germany and Canada comprising in all 160 patients, of whom 25 will be Danish. Patient recruitment has started December Industry sponsored clinical trials In addition to these investigator-driven therapeutic trials, DMSC is 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, and in the development of three new monoclonal antibodies, alemtuzumab, daclizumab and ofatumumab, with strong effects on disease activity, and we take part in the assessment of fampridine, a drug that improves gait function,. Other clinical research MS epidemiology In collaboration with the Danish MS Register we performed a study of changes in prevalence, incidence, and sex-ratio through the last decades and observed increased incidence rates, apparently confined to women, and demonstrated the dismissal of a true latitudinal gradient on the northern hemisphere. The collaboration has continued and currently we are performing extensive analyses of possible factors that might have contributed to the increase of MS in women. At the American Academy of Neurology Meeting in April 2013, we presented the results of a nationwide study from the Danish Multiple Sclerosis Registry comprising 1403 MS patients aged at clinical onset between 2000 and 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. The studies in women with MS continue with exploration of demographic factors, such as changes in working conditions, marital status, smoking habits and vitamin D intake. Vitamin D Vitamin D seems to yield some protection against encountering MS and may also influence the disease activity in established MS. In 2010 we initiated a study exploring the role of vitamin D on clinical disease activity in MS. Neutralizing antibodies DMSC is among the leading centres in the world regarding studies of antibodies against biological agents. We have published an array of studies on neutralizing antibodies to interferon-beta, and more recently, we have published the results of an international study of the frequency of occurrence of antibodies against natalizumab together with MS centres in Sweden, Norway and Germany. We have also shown that the propensity to develop antibodies against interferon-beta does not carry an excess risk of developing antibodies against natalizumab. We have concluded a study of titres of antibodies against natalizumab and have demonstrated that the titres already 3 months after start of natalizumab therapy predict if a patient will develop permanent antibodies against natalizumab and, therefore, would have to stop natalizumab therapy. Currently, we take part in an EU supported study ABIRISK (Immunogenicity: assessing the clinical relevance and risk minimization of antibodies to 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. 18 DANISH Multiple sclerosis CENTER annual report 2012

19 Neuro Imaging 2012 Neuroimaging research group: Morten Blinkenberg, Henrik Mathiesen, Per Soelberg Sørensen PET In 2012 our studies on positron emission tomography (PET) and quantitative magnetic resonance spectroscopy (MRS), reflecting neuronal deterioration in the early phase of MS, was published. We aimed at exploring if changes in PET, which is the gold standard for measuring brain activation, reflected changes in MRS (N-acetyl-aspartate) measuring neuronal dysfunction and loss, as a consequence of the progressive disease. Our results showed that reduction in brain activation is associated with reduction in brain N-acetyl-aspartate, and in this way there seem to be a relationship between these two different measures of cerebral neuronal integrity in MS. Our findings may have implication for the further use of MRS in clinical trials as well as in the clinical evaluation of patients with MS. CCSVI Our studies on chronic cerebrospinal venous insufficiency (CCSVI), the recently proposed alternative hypothesis explaining the pathogenesis of MS, was also finished in It had been claimed that there is an association between MS and extracranial venous stenoses, and that the use of extracranial high-resolution echo-colour doppler and transcranial colour doppler sonography could discriminate MS patients from controls with 100% accuracy. We therefore investigated Danish MS patients and matched healthy control subjects, to look for characteristic CCSVI changes, and furthermore compare these changes, with changes in MRI measures of flow and morphology. Our results showed very little evidence for anatomic or hemodynamic abnormalities in cervical venous drainage of MS patients and there was no difference between MS patients and controls. In this way we found no evidence for a causative role of CSSVI in MS, which is in line with reports from the majority of international researchers in this field, concluding that CCSVI seem to be clinically irrelevant in MS. Resting state fmri Further studies on resting-state functional MRI (fmri), assessing functional brain connectivity, by measuring the synchronous fluctuation in the blood-oxygen-level dependent signal between remote brain regions at rest, was carried out in In collaboration with Danish research Centre for Magnetic Resonance, PhD-student Anne-Marie Dogonowski uses this method to study motor restingstate connectivity in MS. One study examines how MS affects the inter-regional motor resting-state connectivity and another study examines motor resting-state connectivity with increasing clinical disability in MS, while two ongoing studies are looking at the changes in local connectivity in MS and the longitudinal changes in resting-state motor connectivity during the recovery from an acute motor relapse. Preliminary results show, increased coupling between premotor cortex and the motor network, which might reflect an adaptive mechanism to maintain motor function with increasing clinical disability. Furthermore, MS subjects are characterized by more widespread motor connectivity in the basal ganglia while cortical motor resting-state connectivity is preserved. Our data provide a better understanding of the functional reorganization of distinct brain networks in MS patients, which may find use in current and future rehabilitation programs. DANISH Multiple sclerosis CENTER annual report

20 Research activities 2012 Neurogenetics Neurogenetics research group: Annette Bang Oturai, Helle Bach Søndergaard, Julie Hejgaard, Eva Petersen, Finn Sellebjerg, Per Soelberg Sørensen An unfortunate combination of environmental factors in genetically predisposed individuals is considered to be the cause of the pathogenic immune activation in multiple sclerosis (MS). It is well known that genes play a role for the risk of MS, where HLA-DRB1*15 is the most significant, increasing the risk of MS by a factor of 3-4. Primarily based on results from a genome-wide association study (GWAS) within the International Multiple Sclerosis Genetics Consortium (IMSGC), of which we are part, there is present knowledge of more than 60 genetic variations associated with MS. Environmental studies show that smoking, vitamin D and Epstein Barr virus infection are the best documented factors in MS. Gene-environment interaction We are presently involved in several international large scale genetic projects within the IMSGC. Among these the Immuno-chip project (study of common autoimmune disease genes), Exome-chip project (study of rare single nucleotide polymorphisms (SNPs) in the genomic coding regions) and recently the so-called MS-chip project (replication and fine-mapping of all known MS genes). Locally our group focus on the investigation of gene-environment interaction and the impact on MS risk, age at disease onset, disease course, treatment response and the biological effect assessed by functional studies of gene expression. Our MS patients are selected from the Danish MS Biobank and clinical data are obtained from the Multiple Sclerosis Treatment Register. From all patients we have files with more than 100 questions on lifestyle and environmental factors (smoking, alcohol, mononucleosis, BMI, sun habits, geographical upbringing etc.). In a recent collaboration with the Blood Bank at Rigshospitalet, we have collected blood samples and environmental data from more than 3500 blood donors. Genetic influence on primary progressive MS The role played by genetic factors in the clinical course of multiple sclerosis is not yet well established. We participated in an international collaboration aiming to identify genetic variants associated with progressive MS. The study confirmed the established association with the HLA region and found suggestive evidence for association with a novel locus on chromosome 7q35 which maps within a human endogenous retroviral element. Genetic influence on oligoclonal band status The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in MS. In a Scandinavian collaboration, genetic differences in MS relating to OCB status were studied. Data from earlier GWAS were compared in 1367 OCB positive and 161 OCB negative MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. Results showed that SNPs from the HLA complex and six other loci were associated to OCB status. The study confirmed both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management. Importance of vitamin D Denmark is geographically situated in an area with limited sunlight resulting in reduced vitamin D level in the blood. Vitamin D is known to be strongly immunomodulatory and prospective studies have shown up to 51% lower MS risk between high versus low vitamin D levels. In a PhD study we are investigating the clinical and immunological effects of different vitamin D levels in MS patients and the importance of the same parameters when vitamin D levels after vitamin D3 substitution are normalized. Moreover we analyse whether the polymorphisms in vitamin D metabolism are important for vitamin D levels, immune activation and clinical disease activity. 20 DANISH Multiple sclerosis CENTER annual report 2012

21 Neuroimmunology Neuroimmunology research group: Finn Sellebjerg, Helle Bach Søndergaard, Poul Erik Hyldgaard Jensen, Jeppe Romme Christensen, Lars Börnsen, Cecilie Ammitzbøll, Rikke Ratzer, Annette Bang Oturai, Per Soelberg Sørensen Neuroimmunology of MS Neuroimmunology research in MS aims at understanding how immune activation causes damage to nerve fibers and nerve cells in the brain and spinal cord. It is generally accepted that the pathogenic immune activation in MS is initiated by environmental factors in genetically susceptible individuals. This is especially well documented in patients with the relapsing-remitting form of the disease (RRMS), which is the most common onset form of MS. In RRMS the pathogenic processes are targeted by numerous treatments that all decrease the number of relapses and ensuing damage to the nervous system. The relationship between immune activation and disease activity is less obvious in patients with a slowly progressive disease course. This may either be in the form of primary progressive MS (PPMS), a less common onset form of the disease, or secondary progressive MS, where the progressive course evolves after years of an RRMS disease course. Progressive MS is often considered to be due to neurodegenerative processes, but recent studies indicate that the immune system plays a major role even in PPMS and SPMS. However, therapeutic options for progressive MS are scarce. Neuroimmunology research at DMSC aims at identifying immune activation processes that drive the disease evolution in MS and at understanding the difference between the different subtypes of MS, understanding the effects of MS treatment on the immune system, and understanding how genetic and environmental factors that increase the risk of MS influence immune reactivity. Molecular biology studies Activation of the immune system involves massive changes in gene expression in immune cells. In the past decade it has been discovered that the expression of mrna and the translation of mrna into protein in the cell is regulated by small RNA molecules called micro-rna (mirna). In 2012 we have conducted studies of mrna in blood cells from patients with RRMS, PPMS and SPMS. These studies have revealed that the immune activation DANISH Multiple sclerosis CENTER annual report

22 Research activities 2012 pattern is surprisingly similar in patients with all subtypes of MS. We have also conducted studies comparing the expression of mirna in blood cells and blood plasma in RRMS and healthy controls, and have identified one specific mirna, which may be developed as a diagnostic test for MS as patients with RRMS have much higher concentrations of this mirna in blood than do healthy control subjects. We participated in a major international study, published in 2011 in Nature, which identified more than 60 genetic variations that all influence the risk of developing MS. In 2012 we initiated a series of studies aimed at understanding how some of these influence immune activation pathways thought to play key roles in the pathogenesis of MS. These studies will be completed in 2013, and will provide new insights into how genetic factors increase the risk of developing MS. Immune activation in progressive MS An important result in 2012 was the completion of our proof-of-concept study of natalizumab treatment in progressive MS, described elsewhere in this report. Natalizumab is a monoclonal antibody that blocks the migration of immune cells into the brain and spinal cord. The effect of natalizumab observed in our study proves that circulating immune cells are still of pathogenic importance in progressive MS. In 2012 we also published the results of a study conducted in collaboration with colleagues from Karolinska Hospital in Sweden. This study shows that immune activation in the cerebrospinal fluid can still be detected in progressive MS, that it is comparable in PPMS and SPMS, and that it correlates with measures of damage to the brain and spinal cord. Another study, published in 2013, addressed the important issue of the role of specific, circulating immune cells in disease evolution in the different subtypes of MS. The study identified immune activation patterns that appeared to be more important in some disease courses than others, and suggested an especially important role for a recently identified subtype of immune cells (follicular helper cells) in the evolution of SPMS. Another ongoing study, which will be completed in 2013, investigates the effect of monthly pulse treatment with methylprednisolone in patients with progressive MS. This study will use the same outcome measures as our natalizumab study, but includes a slightly higher number of patients and also includes a detailed assessment of the effect of treatment on circulating immune cells. Effects of MS therapy and biomarkers The term biomarker is generally used for any measure that can be used to identify patients, predict prognosis or predict response to treatment. Examples of biomarkers already in use in the MS field are measures of immunoglobulin G synthesis in cerebrospinal fluid, specific autoantibodies for the diagnosis of neuromyelitis optica, and antibodies reactive with interferon-beta and natalizumab, which impede their therapeutic effect in MS. In 2012 we published several papers on the effect of treatment with interferon-beta and glatiramer acetate on circulating immune cells in RRMS. We identified effects that correlated with risk of disease activity on treatment. However, the measurement of these variables requires access to complex immunological analyses which hampers the routine use of these markers. We therefore continue work on identifying immunological and genetic biomarkers that may be useful for predicting the response to treatment with MS. One example is a mutation in the gene encoding for the chemokine receptor CCR5, which we have analyzed in patients treated with natalizumab and interferon-beta. Unfortunately, whereas this mutation may be associated with disease activity in untreated MS patients, we have not found effect on disease activity in treated patients. In 2012 we also published a detailed analysis of circulating immune cells in patients treated with natalizumab. This study confirmed that treatment with natalizumab results in the retention of specific subtypes of immune cells in the circulation as the antibody blocks the recruitment of cells to the brain and spinal cord. We did, however, also identify a previously unknown effect on immune cells which may contribute to the efficacy of natalizumab treatment by inhibiting the activation of other immune cells. 22 DANISH Multiple sclerosis CENTER annual report 2012

23 Routine analyses in the Neuroimmunology Laboratory Neuroimmunology Laboratory research group: Poul Erik H. Jensen, laboratory technicians: Joy Mendel-Hartvig, Michael Kolbjørn Jensen, Vibeke Fuglholt, Rikke Larsen Diagnostic evaluation The presence in CSF of oligoclonal IgG-bands is of interest in the diagnosis of MS. In 2012 we have analyzed 1013 patient samples, using isoelectric focusing of CSF and corresponding plasma samples for the characterization of IgG bands. In the autoimmune disease myasthenia gravis, 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 2012 we analyzed 963 patient samples. In 2012 we introduced a new analysis measuring concentrations of antibodies against aquaporin-4, which is used for the diagnosis of neuromyelitis optica (NMO) and analyzed 75 patient samples. Measurement of neutralizing antibodies Subgroups of MS patients, treated with IFN-beta or Tysabri, generate neutralizing antibodies, which diminish the therapeutic effects. IFN-beta 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-beta 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 IFN-beta. In 2012 we have analyzed 1159 patient samples for neutralizing antibodies, and 66 patient samples for MxA mrna expression. The action of Tysabri differs from IFN-beta, 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 2012 we analyzed 589 blood samples for the presence of antibodies to Tysabri by ELISA. DANISH Multiple sclerosis CENTER annual report

24 Scientific publications, prizes, collaboration, acknowledgements Scientific publications Prizes Honorary offices Scientific collaboration Acknowledgements

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26 Scientific publications Publications 2012 Peer reviewed original papers Ali S, Paracha N, Cook S, Giovannoni G, Comi G, Rammohan K et al. Reduction in Healthcare and Societal Resource Utilization Associated with Cladribine Tablets in Patients with Relapsing-Remitting Multiple Sclerosis: Analysis of Economic Data from the CLARITY Study. Clinical Drug Investigation. 2012;32(1): Blinkenberg M, Mathiesen HK, Tscherning T, Jønsson A, Svarer C, Holm S et al. Cerebral metabolism, magnetic resonance spectroscopy and cognitive dysfunction in early multiple sclerosis: an exploratory study. Neurological Research jan;34(1):52-8. Blinkenberg M, Akeson P, Sillesen H, Lövgaard S, Sellebjerg F, Paulson OB et al. Chronic cerebrospinal venous insufficiency and venous stenoses in multiple sclerosis. Acta Neurologica Scandinavica. Supplementum dec;126(6): Braendstrup P, Langkilde A, Schreiber K, Ravnborg M, Sellebjerg F, Vindeløv L. Progression and CSF Inflammation after Eradication of Oligoclonal Bands in an MS Patient Treated with Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma. Case Reports in Neurology. 2012;4(2): Brambilla P, Esposito F, Lindstrom E, Sorosina M, Giacalone G, Clarelli F et al. Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans. Neuroscience Letters. Supplement. 2012;530(2): Börnsen L, Christensen JR, Ratzer R, Oturai AB, Sørensen PS, Søndergaard HB et al. Effect of Natalizumab on Circulating CD4(+) T-Cells in Multiple Sclerosis. P L o S One. 2012;7(11):e Cohen JA, Reingold SC, Polman CH, Wolinsky JS, International Advisory Committee on Clinical Trials in Multiple Sclerosis, Sørensen PS. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet Neurology Network. 2012;11(5): Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856): Comi G, Cook SD, Giovannoni G, Rammohan K, Rieckmann P, Sørensen PS et al. MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study. Journal of Neurology. Supplement Dogonowski A-M, Siebner HR, Sørensen PS, Wu X, Biswal B, Paulson OB et al. Expanded functional coupling of subcortical nuclei with the motor resting-state network in multiple sclerosis. Multiple Sclerosis Jensen PEH, Koch-Henriksen N, Sellebjerg F, Sørensen PS. Prediction of antibody persistency from antibody titres to natalizumab. Multiple Sclerosis. 2012;18(10): Jensen PEH, Sellebjerg F, Søndergaard HB, Sørensen PS. Correlation between anti-interferon-β binding and neutralizing antibodies in interferon-β-treated multiple sclerosis patients. European Journal of Neurology. 2012;19(10): Kondziella D, Hansen K, Gonzalez T, Gideon P, Christiansen I, Sellebjerg F. Antithyroideaantistof hos to patienter med subakut dementiel udvikling, ataksi og myoklonus. Ugeskrift for Laeger. 2012;174(9): Lund H, Jønsson A, Andresen JG, Rostrup E, Paulson OB, Sørensen PS. Cognitive deficits in multiple sclerosis: correlations with T2 changes in normal appearing brain tissue. Acta Neurologica Scandinavica. Supplementum. 2012;125(5): Lyksborg M, Larsen R, Sørensen PS, Blinkenberg MB, Garde E, Siebner HR et al. Segmenting Multiple Sclerosis Lesions Using a Spatially Constrained K-Nearest Neighbour Approach. Campilho A, Kamel M, red. I: ICIAR 12 Proceedings of the 9th international conference on Image Analysis and Recognition - Volume Part II. Springer s Martinelli-Boneschi F, Esposito F, Brambilla P, Lindström E, Lavorgna G, Stankovich J et al. A genome-wide association study in progressive multiple sclerosis. Multiple Sclerosis. 2012;18(10): Romme Christensen J, Börnsen L, Khademi M, Olsson T, Jensen PE, Sørensen PS et al. CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis. Multiple Sclerosis Romme Christensen J, Börnsen L, Hesse D, Krakauer M, Sørensen PS, Søndergaard HB et al. Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis. Journal of Neuroinflammation. 2012;9:215. Sellebjerg F, Hedegaard CH, Krakauer M, Hesse D, Lund H, Nielsen CH, Søndergaard HB, Sørensen PS. Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis. Mult Scler 2012; 18: DANISH Multiple sclerosis CENTER annual report 2012

27 Sellebjerg F, Krakauer M, Limborg S, Hesse D, Lund H, Langkilde A et al. Endogenous and recombinant type I interferons and disease activity in multiple sclerosis. P L o S One. 2012;7(6):e Sellebjerg F, Hesse D, Limborg S, Lund H, Søndergaard HB, Krakauer M et al. Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis. Multiple Sclerosis feb;19(2): Sellebjerg F, Krakauer M, Khademi M, Olsson T, Sørensen PS. FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4(+) CD25(high) T cells in multiple sclerosis. Clinical and Experimental Immunology. Supplement. 2012;170(2): Sørensen PS, Bertolotto A, Edan G, Giovannoni G, Gold R, Havrdova E et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Multiple Sclerosis. 2012;18(2): Sørensen PS. Effects of neutralizing antibodies to interferon beta in multiple sclerosis: a logical paradox. Multiple Sclerosis. 2012;18(2): Sørensen PS. Deaths and disability from natalizumab are no longer tolerable: No - (they can be avoided). Multiple Sclerosis. 2012;18(8): Sørensen PS. Dødsfald i forbindelse med tvangsfastholdelse af svært agiterede personer bør kunne undgås. Ugeskrift for laeger. 2012;174(40):2367. Thirup P, Koch-Henriksen N, Sørensen PS. Sclerosebehand lingsregistret. Ugeskrift for laeger. 2012;174(42):2537. Bo Baslund, Ulla Feldt-Rasmussen, Jens Kastrup, Per Soelberg Sørensen (editors). Textbook of Medicine (Lærebog i Medicin). FADLS Forlag, Copenhagen Author of several chapters. Publications 2011 International Multiple Sclerosis Genetics Consortium, Oturai A, Søndergaard HB, Sørensen PS. The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study. P L o S One. 2011;6(4):e Börnsen L, Khademi M, Olsson T, Sørensen PS, Sellebjerg F. Osteopontin concentrations are increased in cerebrospinal fluid during attacks of multiple sclerosis. Multiple Sclerosis. 2011;17(1): de Sa JCC, Airas L, Bartholome E, Grigoriadis N, Mattle H, Oreja-Guevara C et al. Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice. Therapeutic Advances in Neurological Disorders. 2011;4(3): Freedman MS, Bar-Or A, Oger J, Traboulsee A, Patry D, Young C, Olsson T et al.; MAESTRO-01 Investigators. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology. 2011;77(16): Giovannoni G, Cook S, Rammohan K, Rieckmann P, Sørensen PS, Vermersch P et al. Sustained diseaseactivity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurology. 2011;10(4): Hartung H, Montalban X, Sorensen PS, Vermersch P, Olsson T. Principles of a new treatment algorithm in multiple sclerosis. Expert Review of Neurotherapeutics. 2011;11(3): Hedegaard CJ, Enevold C, Sellebjerg F, Bendtzen K, Nielsen CH. Variation in NOD2 augments Th2- and Th17 responses to myelin basic protein in multiple sclerosis. P L o S One. 2011;6(5):e Hedegaard CJ, Sellebjerg F, Krakauer M, Hesse D, Bendtzen K, Nielsen CH. Interferon-beta increases systemic BAFF levels in multiple sclerosis without increasing autoantibody production. Multiple Sclerosis maj 1;17(5): DANISH Multiple sclerosis CENTER annual report

28 Scientific publications Hesse D, Krakauer M, Lund H, Søndergaard HB, Limborg SJW, Sørensen PS et al. Disease protection and interleukin-10 induction by endogenous interferon-β in multiple sclerosis?. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2011;18(2): Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N et al. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurology. 2011;10(8): Khademi M, Kockum I, Andersson ML, Iacobaeus E, Brundin L, Sellebjerg F et al. Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Multiple Sclerosis. 2011;17(3): Koch-Henriksen N, Sorensen PS. Why does the northsouth gradient of incidence of multiple sclerosis seem to have disappeared on the northern hemisphere?. Journal of the Neurological Sciences. 2011;311(1-2): Nexø BA, Christensen T, Frederiksen J, Møller-Larsen A, Oturai AB, Fredsted PV et al. The etiology of multiple sclerosis: genetic evidence for the involvement of the human endogenous retrovirus HERV-Fc1. P L o S One feb 1;6(2):e Pedersen EG, Hallas J, Hansen K, Jensen PEH, Gaist D. Identifying patients with myasthenia for epidemiological research by linkage of automated registers. Neuroepidemiology. 2011;37(2): Sellebjerg FT, Hedegaard C, Krakauer M, Hesse D, Lund H, Nielsen C et al. Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis. Multiple Sclerosis Sorensen PS, Lycke J, Erälinna J, Edland A, Wu X, Frederiksen JL et al. Simvastatin as add-on therapy to interferon β-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurology. 2011;10(8): Søndergaard HB, Sellebjerg F, Hillert J, Olsson T, Kockum I, Lindén M et al. Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs European Journal of Human Genetics. 2011;19(10): Sørensen PS, Jensen PEH, Haghikia A, Lundkvist M, Vedeler C, Sellebjerg F et al. Occurrence of antibodies against natalizumab in relapsing multiple sclerosis patients treated with natalizumab. Multiple Sclerosis. 2011;17(9): Sørensen PS, Koch-Henriksen N, Jensen PEH. Neutralizing antibodies against interferon-β do not predispose antibodies against natalizumab. Neurology. 2011;76(8): Schreiber K, Sørensen PS. Cladribine in the treatment of multiple sclerosis. Clinical Investigation 2011, 1(2): Sawcer S, Hellenthal G, Pirinen M, Spencer CCA, Patsopoulos NA, Moutsianas L et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359): DANISH Multiple sclerosis CENTER annual report 2012

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