Blood-brain barrier permeability changes in the first year after alemtuzumab treatment predict 2-year outcomes in relapsing-remitting multiple sclerosis

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Background: In relapsing-remitting multiple sclerosis (RRMS), early disease control reduces the risk of permanent disability. The blood–brain barrier (BBB) is compromised in MS, and its permeability is a potential biomarker. Objective: To investigate BBB permeability measured by MRI as a marker of alemtuzumab efficacy. Methods: Patients with RRMS initiating alemtuzumab treatment were recruited prospectively. BBB permeability was assessed as the Patlak-derived influx constant (Ki) by dynamic contrast-enhanced MRI before and 6, 12, and 18 months after the first course of alemtuzumab. No Evidence of Disease Activity-3 (NEDA-3) status was ascertained two years after treatment initiation. Results: Patients who maintained NEDA-3 status at two years (n = 7) had a larger decrease in Ki between baseline and six months (-0.029 ml/100 g/min [CI -0.005 − -0.053]) and between baseline and 12 months in normal appearing white matter (0.043 [CI 0.022 – -0.065]), than those who experienced disease activity (n = 8). ROC curve analysis of the Ki change between baseline and 12 months in NAWM predicted a loss of NEDA status at 2 years with 86% sensitivity and 86% specificity (AUC 0.98, p = 0.002). Conclusion: BBB permeability predicted alemtuzumab efficacy at two years, indicating that BBB permeability is a biomarker of treatment response in RRMS.

OriginalsprogEngelsk
Artikelnummer103891
TidsskriftMultiple Sclerosis and Related Disorders
Vol/bind63
ISSN2211-0348
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: M.H. Knudsen, H.B.W. Larsson & S.P. Cramer received funding from Sanofi Genzyme and The Danish Multiple Sclerosis Society. Sanofi Genzyme had no influence on the study design, inclusion of patients, data analysis or interpretation. U. Lindberg, M.B. Vestergaard, H.J. Simonsen & I. Galea have nothing to disclose. J.L. Frederiksen received no funding to support this study. She has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis and Almirall. She has received speaker honoraria from Biogen Idec, Teva and Novartis. She has served as advisor on preclinical development for Takeda. J.L Frederiksen participate in advisory board meetings with Alexion and Chiesi. A. Varatharaj is funded by the National Institute for Health Research (UK), and has received travel funding from Teva. F.T. Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen , Merck, Novartis, Roche and Sanofi Genzyme. M. Blinkenberg reports personal fees from Sanofi Genzyme, personal fees from Biogen, personal fees from Merck, personal fees from Novartis, personal fees from Teva, personal fees from Roche, personal fees from Bristol Myers Squibb, nonfinancial support from Biogen , nonfinancial support from Roche , and nonfinancial support from Genzyme , outside the submitted work.

Funding Information:
The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: M.H. Knudsen, H.B.W. Larsson & S.P. Cramer received funding from Sanofi Genzyme and The Danish Multiple Sclerosis Society. Sanofi Genzyme had no influence on the study design, inclusion of patients, data analysis or interpretation. U. Lindberg, M.B. Vestergaard, H.J. Simonsen & I. Galea have nothing to disclose. J.L. Frederiksen received no funding to support this study. She has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis and Almirall. She has received speaker honoraria from Biogen Idec, Teva and Novartis. She has served as advisor on preclinical development for Takeda. J.L Frederiksen participate in advisory board meetings with Alexion and Chiesi. A. Varatharaj is funded by the National Institute for Health Research (UK), and has received travel funding from Teva. F.T. Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. M. Blinkenberg reports personal fees from Sanofi Genzyme, personal fees from Biogen, personal fees from Merck, personal fees from Novartis, personal fees from Teva, personal fees from Roche, personal fees from Bristol Myers Squibb, nonfinancial support from Biogen, nonfinancial support from Roche, and nonfinancial support from Genzyme, outside the submitted work.This investigator-sponsored study was supported by Sanofi Genzyme [Grant number GZ-2016–11,629] and The Danish Multiple Sclerosis Society [Grant numbers A37989, A40212, A41682]. The funding bodies had no influence on the study design, inclusion of patients, data analysis, interpretation or writing of the final manuscript.The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: M.H. Knudsen, H.B.W. Larsson & S.P. Cramer received funding from Sanofi Genzyme and The Danish Multiple Sclerosis Society. Sanofi Genzyme had no influence on the study design, inclusion of patients, data analysis or interpretation. U. Lindberg, M.B. Vestergaard, H.J. Simonsen & I. Galea have nothing to disclose. J.L. Frederiksen received no funding to support this study. She has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis and Almirall. She has received speaker honoraria from Biogen Idec, Teva and Novartis. She has served as advisor on preclinical development for Takeda. J.L Frederiksen participate in advisory board meetings with Alexion and Chiesi. A. Varatharaj is funded by the National Institute for Health Research (UK), and has received travel funding from Teva. F.T. Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. His-laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. M. Blinkenberg reports personal fees from Sanofi Genzyme, personal fees from Biogen, personal fees from Merck, personal fees from Novartis, personal fees from Teva, personal fees from Roche, personal fees from Bristol Myers Squibb, nonfinancial support from Biogen, nonfinancial support from Roche, and nonfinancial support from Genzyme, outside the submitted work.

Funding Information:
This investigator-sponsored study was supported by Sanofi Genzyme [Grant number GZ-2016–11,629] and The Danish Multiple Sclerosis Society [Grant numbers A37989, A40212, A41682]. The funding bodies had no influence on the study design, inclusion of patients, data analysis, interpretation or writing of the final manuscript.

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