Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development

H Hegen; A Millonig; A Bertolotto; M Comabella; G Giovanonni; M Guger; M Hoelzl; M Khalil; J Killestein; R Lindberg; S Malucchi; M Mehling; X Montalban; C H Polman; D Rudzki; F Schautzer; F Sellebjerg; P S Sørensen; F Deisenhammer

doi:10.1177/1352458513503597

Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development

H Hegen, A Millonig, A Bertolotto, M Comabella, G Giovanonni, M Guger, M Hoelzl, M Khalil, J Killestein, R Lindberg, S Malucchi, M Mehling, X Montalban, C H Polman, D Rudzki, F Schautzer, F Sellebjerg, P S Sørensen, F Deisenhammer

Department of Clinical Medicine

36 Citations (Scopus)

Abstract

Background: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis(MS) patients. NAbs evolve in up to 44% of treated patients, usually between 618 months on therapy. Objectives: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. Methods: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment inthis prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.Results: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b reatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers>400 predicted NAb evolutionwith a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the Ab/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAbnegative amples, respectively, were also diminished compared to BAb/NAb-negative samples. onclusions: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its brogation by anti-IFN-b antibodies.

Original language	English
Journal	Multiple Sclerosis
Volume	20
Issue number	5
Pages (from-to)	577-587
Number of pages	11
ISSN	1352-4585
DOIs	https://doi.org/10.1177/1352458513503597
Publication status	Published - Apr 2014

Keywords

Adult
Antibodies, Neutralizing
Biological Markers
Chemokine CXCL10
Demyelinating Diseases
Early Diagnosis
Europe
Female
Humans
Immunologic Factors
Interferon-beta
Male
Middle Aged
Multiple Sclerosis, Relapsing-Remitting
Myxovirus Resistance Proteins
Predictive Value of Tests
Prospective Studies
TNF-Related Apoptosis-Inducing Ligand
Time Factors
Treatment Outcome

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Hegen, H., Millonig, A., Bertolotto, A., Comabella, M., Giovanonni, G., Guger, M., Hoelzl, M., Khalil, M., Killestein, J., Lindberg, R., Malucchi, S., Mehling, M., Montalban, X., Polman, C. H., Rudzki, D., Schautzer, F., Sellebjerg, F., Sørensen, P. S., & Deisenhammer, F. (2014). Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development. Multiple Sclerosis, 20(5), 577-587. https://doi.org/10.1177/1352458513503597

Hegen, H, Millonig, A, Bertolotto, A, Comabella, M, Giovanonni, G, Guger, M, Hoelzl, M, Khalil, M, Killestein, J, Lindberg, R, Malucchi, S, Mehling, M, Montalban, X, Polman, CH, Rudzki, D, Schautzer, F, Sellebjerg, F , Sørensen, PS & Deisenhammer, F 2014, 'Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development', Multiple Sclerosis, vol. 20, no. 5, pp. 577-587. https://doi.org/10.1177/1352458513503597

@article{e0f7cd7d5e7a4cfcad9398190b8a1098,

title = "Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development",

abstract = "Background: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis(MS) patients. NAbs evolve in up to 44% of treated patients, usually between 618 months on therapy. Objectives: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. Methods: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment inthis prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.Results: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b reatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers>400 predicted NAb evolutionwith a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the Ab/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAbnegative amples, respectively, were also diminished compared to BAb/NAb-negative samples. onclusions: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its brogation by anti-IFN-b antibodies.",

keywords = "Adult, Antibodies, Neutralizing, Biological Markers, Chemokine CXCL10, Demyelinating Diseases, Early Diagnosis, Europe, Female, Humans, Immunologic Factors, Interferon-beta, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting, Myxovirus Resistance Proteins, Predictive Value of Tests, Prospective Studies, TNF-Related Apoptosis-Inducing Ligand, Time Factors, Treatment Outcome",

author = "H Hegen and A Millonig and A Bertolotto and M Comabella and G Giovanonni and M Guger and M Hoelzl and M Khalil and J Killestein and R Lindberg and S Malucchi and M Mehling and X Montalban and Polman, {C H} and D Rudzki and F Schautzer and F Sellebjerg and S{\o}rensen, {P S} and F Deisenhammer",

year = "2014",

month = apr,

doi = "10.1177/1352458513503597",

language = "English",

volume = "20",

pages = "577--587",

journal = "Multiple Sclerosis Journal",

issn = "1352-4585",

publisher = "SAGE Publications",

number = "5",

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TY - JOUR

T1 - Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients

T2 - binding antibodies predict neutralizing antibody development

AU - Hegen, H

AU - Millonig, A

AU - Bertolotto, A

AU - Comabella, M

AU - Giovanonni, G

AU - Guger, M

AU - Hoelzl, M

AU - Khalil, M

AU - Killestein, J

AU - Lindberg, R

AU - Malucchi, S

AU - Mehling, M

AU - Montalban, X

AU - Polman, C H

AU - Rudzki, D

AU - Schautzer, F

AU - Sellebjerg, F

AU - Sørensen, P S

AU - Deisenhammer, F

PY - 2014/4

Y1 - 2014/4

N2 - Background: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis(MS) patients. NAbs evolve in up to 44% of treated patients, usually between 618 months on therapy. Objectives: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. Methods: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment inthis prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.Results: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b reatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers>400 predicted NAb evolutionwith a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the Ab/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAbnegative amples, respectively, were also diminished compared to BAb/NAb-negative samples. onclusions: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its brogation by anti-IFN-b antibodies.

AB - Background: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis(MS) patients. NAbs evolve in up to 44% of treated patients, usually between 618 months on therapy. Objectives: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. Methods: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment inthis prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2.Results: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b reatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers>400 predicted NAb evolutionwith a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the Ab/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAbnegative amples, respectively, were also diminished compared to BAb/NAb-negative samples. onclusions: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its brogation by anti-IFN-b antibodies.

KW - Adult

KW - Antibodies, Neutralizing

KW - Biological Markers

KW - Chemokine CXCL10

KW - Demyelinating Diseases

KW - Early Diagnosis

KW - Europe

KW - Female

KW - Humans

KW - Immunologic Factors

KW - Interferon-beta

KW - Male

KW - Middle Aged

KW - Multiple Sclerosis, Relapsing-Remitting

KW - Myxovirus Resistance Proteins

KW - Predictive Value of Tests

KW - Prospective Studies

KW - TNF-Related Apoptosis-Inducing Ligand

KW - Time Factors

KW - Treatment Outcome

U2 - 10.1177/1352458513503597

DO - 10.1177/1352458513503597

M3 - Journal article

C2 - 24009164

SN - 1352-4585

VL - 20

SP - 577

EP - 587

JO - Multiple Sclerosis Journal

JF - Multiple Sclerosis Journal

IS - 5

ER -

Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development

Abstract

Keywords

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