Download Danish Multiple Sclerosis Center Annual Report 2014

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
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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
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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
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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
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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,
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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
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DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014
Table of contents
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DMSC missions and aims
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A short review of 2014 in the Danish Multiple Sclerosis Center
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About the Danish Multiple Sclerosis Center
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Organization diagram
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Research activities 2014
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Clinical and epidemiological research
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Neuro Imaging
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Neurogenetics
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Neuroimmunology
22
Routine analyses in Neuroimmunology Laboratory
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Scientific publications 2013-2014
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Prizes and honorary offices
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Scientific collaboration
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Collaboration with pharmaceutical companies
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Acknowledgements
Annual
Report
2014
DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014
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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
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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
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About
The Danish Multiple
Sclerosis Center
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DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014
DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014
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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
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200
0
8
1994
2004
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2012
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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
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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
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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
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Research
activities 2014
Clinical research
Clinical research
Neuroimaging
Neurogenetics
Neuroimmunology
Routine analyses in Neuroimmunology Laboratory
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DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014
DANISH MULTIPLE SCLEROSIS CENTER ANNUAL REPORT 2014
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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
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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
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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.
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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.
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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
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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