TY - JOUR

T1 - Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe

T2 - A descriptive study of test results

AU - Link, Jenny

AU - Ramanujam, Ryan

AU - Auer, Michael

AU - Ryner, Malin

AU - Hässler, Signe

AU - Bachelet, Delphine

AU - Mbogning, Cyprien

AU - Warnke, Clemens

AU - Buck, Dorothea

AU - Hyldgaard Jensen, Poul Erik

AU - Sievers, Claudia

AU - Ingenhoven, Kathleen

AU - Fissolo, Nicolas

AU - Lindberg, Raija

AU - Grummel, Verena

AU - Donnellan, Naoimh

AU - Comabella, Manuel

AU - Montalban, Xavier

AU - Kieseier, Bernd

AU - Soelberg Sørensen, Per

AU - Hartung, Hans-Peter

AU - Derfuss, Tobias

AU - Lawton, Andy

AU - Sikkema, Dan

AU - Pallardy, Marc

AU - Hemmer, Bernhard

AU - Deisenhammer, Florian

AU - Broët, Philippe

AU - Dönnes, Pierre

AU - Davidson, Julie

AU - Fogdell-Hahn, Anna

AU - ABIRISK Consortium

PY - 2017/2

Y1 - 2017/2

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Age Factors

KW - Aged

KW - Aged, 80 and over

KW - Antibodies/immunology

KW - Child

KW - Child, Preschool

KW - Europe

KW - Female

KW - Humans

KW - Immunologic Factors/adverse effects

KW - Infant

KW - Infant, Newborn

KW - Interferon-beta/adverse effects

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis/drug therapy

KW - Natalizumab/adverse effects

KW - Retrospective Studies

KW - Sex Factors

KW - Time Factors

KW - Young Adult

U2 - 10.1371/journal.pone.0170395

DO - 10.1371/journal.pone.0170395

M3 - Journal article

C2 - 28170401

VL - 12

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 2

M1 - e0170395

ER -