Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results.
Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jenny
J
Link
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.|KTH - Royal Institute of Technology, Stockholm, Sweden.
Ryan
R
Ramanujam
Innsbruck Medical University, Innsbruck, Austria.
Michael
M
Auer
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Malin
M
Ryner
CESP, Université Paris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
Signe
S
Hässler
CESP, Université Paris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
Delphine
D
Bachelet
CESP, Université Paris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.
Cyprien
C
Mbogning
Medical Faculty, Department of Neurology University of Düsseldorf, Düsseldorf, Germany.
Clemens
C
Warnke
Department of Neurology, Technische Universität München, Munich, Germany.
Dorothea
D
Buck
Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Poul Erik
PE
Hyldgaard Jensen
University Hospital Basel, Basel, Switzerland.
Claudia
C
Sievers
Medical Faculty, Department of Neurology University of Düsseldorf, Düsseldorf, Germany.
Kathleen
K
Ingenhoven
Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Nicolas
N
Fissolo
University Hospital Basel, Basel, Switzerland.
Raija
R
Lindberg
Department of Neurology, Technische Universität München, Munich, Germany.
Verena
V
Grummel
Ipsen Biopharm Ltd, Berkshire, United Kingdom.
Naoimh
N
Donnellan
Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Manuel
M
Comabella
Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Xavier
X
Montalban
Medical Faculty, Department of Neurology University of Düsseldorf, Düsseldorf, Germany.
Bernd
B
Kieseier
Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Per
P
Soelberg Sørensen
Medical Faculty, Department of Neurology University of Düsseldorf, Düsseldorf, Germany.
Hans-Peter
HP
Hartung
University Hospital Basel, Basel, Switzerland.
Tobias
T
Derfuss
GlaxoSmithKline R&D, Uxbridge, Middlesex, United Kingdom.
Andy
A
Lawton
GlaxoSmithKline R&D, Uxbridge, Middlesex, United Kingdom.
Dan
D
Sikkema
INSERM UMR 996, Univ. Paris-Sud, Faculty of Pharmacy, Université Paris-Saclay, Châtenay-Malabry, France.
Marc
M
Pallardy
Department of Neurology, Technische Universität München, Munich, Germany.
Bernhard
B
Hemmer
Innsbruck Medical University, Innsbruck, Austria.
Florian
F
Deisenhammer
CESP, Université Paris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.|Assistance Publique - Hôpitaux de Paris, Hôpital Paul Brousse, Villejuif, France.
Philippe
P
Broët
SciCross AB, Skövde, Sweden.
Pierre
P
Dönnes
GlaxoSmithKline R&D, Uxbridge, Middlesex, United Kingdom.
Julie
J
Davidson
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Anna
A
Fogdell-Hahn
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D016899:Interferon-beta / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology*; D000069442:Natalizumab / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D012189:Retrospective Studies; D012737:Sex Factors; D013997:Time Factors; D055815:Young Adult
D000906:Antibodies; D007155:Immunologic Factors; D000069442:Natalizumab; D016899:Interferon-beta