Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy

TLDR: It is concluded that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.

Abstract: Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood–CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natal...

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Year:2013
CerebrospinaluidparametersofBcell-relatedactivityinpatientswith
activediseaseduringnatalizumabtherapy
Harrer,A;Tumani,H;Niendorf,S;Lauda,F;Geis,C;Weishaupt,A;Kleinschnitz,C;Rauer,S;
Kuhle,J;Stangel,M;Weber,F;Uhr,M;Linnebank,M;Wildemann,B;Jarius,S;Guger,M;
Ayzenberg,I;Chan,A;Zettl,U;Wiendl,H;Pilz,G;Hitzl,W;Weber,J;Kraus,J
Abstract:Recently,thedisappearanceofoligoclonalbands(OCBs)fromthecerebrospinaluid(CSF)ofa
fewnatalizumab-treatedpatientswithmultiplesclerosis(MS)hasbeenreported.Thisisinterestingsince
CSF-restrictedOCBarebelievedtopersistinMS.WepooledCSFdatafrom14MScenterstoobtainan
adequatesamplesizeforinvestigatingthesuspectedchangesincentralnervoussystem(CNS)-restricted
humoralimmuneactivitiesinthecontextofnatalizumabtherapy.Inaretrospectivechartanalysis,CSF
parametersofblood-CSFbarrierintegrityandintrathecalIgGproductionfrom73natalizumab-treated
MSpatientsrequiringadiagnosticpunctureforexclusionofprogressivemultifocalleukoencephalopathy
werecomparedwithCSFdataobtainedearlierinthecourseofdiseasebeforenatalizumabtherapy. At
thetimeofrepeatlumbarpuncture,localIgGproduction(accordingtoReibergram)wassignicantly
reduced(p<0.0001)andOCBhaddisappearedin16%ofthepatients.Wethereforeconcludethat
natalizumabtherapyinterfereswithintrathecalantibodyproductionatleastinasignicantnumberof
patients.
DOI:https://doi.org/10.1177/1352458512463483
PostedattheZurichOpenRepositoryandArchive,UniversityofZurich
ZORAURL:https://doi.org/10.5167/uzh-67158
JournalArticle
AcceptedVersion
Originallypublishedat:
Harrer,A;Tumani,H;Niendorf,S;Lauda,F;Geis,C;Weishaupt,A;Kleinschnitz,C;Rauer,S;Kuhle,J;
Stangel,M;Weber,F;Uhr,M;Linnebank,M;Wildemann,B;Jarius,S;Guger,M;Ayzenberg,I;Chan,
A;Zettl,U;Wiendl,H;Pilz,G;Hitzl,W;Weber,J;Kraus,J(2013).Cerebrospinaluidparameters
ofBcell-relatedactivityinpatientswithactivediseaseduringnatalizumabtherapy.MultipleSclerosis
Journal,19(9):1209-1212.
DOI:https://doi.org/10.1177/1352458512463483

1
SHORT REPORT for resubmission to Multiple Sclerosis Journal
Cerebrospinal fluid parameters of B cell-related activity in patients
with active disease during natalizumab therapy
Andrea Harrer
1
, Hayrettin Tumani
2
, Simonetta Niendorf
2
, Florian Lauda
2
, Christian Geis
3
, Andreas
Weishaupt
3
, Christoph Kleinschnitz
3
, Sebastian Rauer
4
, Jens Kuhle
5
, Martin Stangel
6
, Frank Weber
7
,
Manfred Uhr
7
, Michael Linnebank
8
, Brigitte Wildemann
9
, Sven Jarius
9
, Michael Guger
10
, Ilya
Ayzenberg
11
, Andrew Chan
11
, Uwe Zettl
12
, Heinz Wiendl
13
, Georg Pilz
1
, Wolfgang Hitzl
14
, Jörg R.
Weber
15
, and Jörg Kraus
1
1
Department of Neurology, Christian-Doppler-Klinik, Paracelsus Medical University, Salzburg, Austria
2
Department of Neurology, University Ulm, Germany
3
Department of Neurology, University Würzburg, Germany
4
Department of Neurology, Albert Ludwigs University Freiburg, Germany
5
Departments of Neurology and Biomedicine, University Basel, Switzerland
6
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School,
Germany
7
Research Group Inflammatory Disorders of the Central Nervous System, Max Planck Institute of Psychiatry,
Munich, Germany
8
Department of Neurology, University Zurich, Switzerland
9
Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Germany
10
Departments of Neurology and Psychiatry, AKH Linz, Austria
11
Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany
12
Department of Neurology, University Rostock, Germany
13
Inflammatory Disorders of the Nervous System and Neurooncology, Department of Neurology, University
Münster, Germany
14
Research Office, Biostatistics, Paracelsus Medical University, Salzburg, Austria
15
Department of Neurology, Klinikum Klagenfurt, Austria
Keywords: natalizumab; multiple sclerosis; oligoclonal bands; intrathecal IgG; cerebrospinal
fluid
word count: 1.126
references: 10
Table: 1
Corresponding author:
Andrea Harrer, Department of Neurology, Christian-Doppler-Klinik, Paracelsus Medical
University, Ignaz-Harrer-Strasse 79, A-5020 Salzburg, Austria. e-mail:
a.harrer@salk.at

2
ABSTRACT
Recently, disappearance of oligoclonal bands (OCB) from the CSF of a few natalizumab-treated patients with
MS has been reported. This is interesting since CSF-restricted OCB are considered to persists in MS.
Since lumbar punctures during natalizumab therapy are infrequent we pooled CSF data from fourteen MS
centers to obtain a suitable patient cohort for furhter investigations about the suspected impact of
natalizumab on CNS-restricted humoral immune activities.
In a retrospective chart analysis CSF parameters of blood-CSF barrier integrity and intrathecal IgG production
from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive
multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before
natalizumab therapy.

3
Introduction
Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing- remitting multiple
sclerosis (RRMS) and interferes with immune cell migration into the CNS by binding to the adhesion molecule
very late activation antigen-4 (VLA-4).
1
The result is a pronounced and sustained reduction of immune cell
numbers in the CSF.
2
Less knowledge exists about natalizumab interfering with intrathecal humoral immune
activities. Recently, disappearance of oligoclonal bands (OCB) during natalizumab therapy in
4 out of 6 patients was reported from von Glehn et al.
3
This is very interesting and
substantiates the importance of investigating intrathecal antibody production in response to
natalizumab treatment because, in contrast to other CNS diseases including neuromyelitis
optica
4
, CSF-restricted OCB have been reported to persist in MS.
5,6
Since CSF data from patients during natalizumab therapy is scarce, we collected CSF data
from several specialized MS centers to obtain an appropriate sample size for determining
significant changes in CNS-restricted humoral immune activity attributable to natalizumab
therapy.

4
Patients and methods
Patients
CSF parameters from 73 patients (mean age 37.0, range 17-65) with RRMS were collected retrospectively at
fourteen German, Swiss, and Austrian hospitals. Lumbar punctures were performed (i) at first diagnosis of MS
and/or other routine diagnostic purposes before natalizumab therapy, and ii) for diagnostic purposes after an
average of 30 months (SD 17.9) on natalizumab therapy, in particular, to rule out progressive multifocal
leukoencephalopathy (PML). In 7 patients (10%) presence of PML was confirmed by the detection of JC virus
DNA by PCR. In 16 patients natalizumab therapy was terminated or paused leading to intervals of >8 weeks
between the last natalizumab infusion and lumbar puncture.
CSF parameters
CSF data were obtained from MS centers whose laboratories participate at interlaboratory
testing and/or are certified by the German Society of CSF Diagnostics and Clinical
Neurochemistry (Deutsche Gesellschaft für Liquordiagnostik und klinische Neurochemie,
DGLN). IgG and albumin concentrations of CSF and serum samples were measured by
immunonephelometry and used to calculate the CSF/serum quotients for IgG and albumin
(QIgG, QAlb). Blood-CSF barrier integrity was assessed by QAlb with the upper reference
limit of the age-dependent QAlb calculated according to Reiber et al.
7
Intrathecal IgG
synthesis was quantified as the relative intrathecal IgG fraction (IgG
IF
) using the CSF/serum
quotient diagrams according to Reiber
6
. Since quantitative data were not available in several
cases IgG
IF
and QAlb were dichotomized into normal or pathologic for statistical analysis.
Detection of OCB was performed by isoelectric focusing and presence or absence of OCB in
the CSF but not in serum was evaluated qualitatively.
Statistics
McNemar's test was used to compare differences in CSF parameters from the two lumbar
punctures. Person-Cloppers values were used to compute 95% confidence intervals (CI) for