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Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis

Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis
Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis
OBJECTIVE: To investigate if blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of sub-optimal treatment response in relapsing-remitting multiple sclerosis (RRMS).
METHODS: 35 RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the CNS, were scanned with DCE-MRI at 3T prior to treatment and at three and six-months post-treatment. We calculated the influx constant Ki , a measure of BBB permeability, using the Patlak model. Sub-optimal treatment response was defined as loss of no evidence of disease activity (NEDA-3) status after two years of treatment.
RESULTS: Subjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after six months of treatment, compared to subjects with maintained NEDA status (mean difference 0.06 (CI 0.02-0.09) ml/100g/min; p=0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at two years (AUC 0.84, CI 0.70-0.99; p=0.003) and a value above 0.136 ml/100/g/min yielded an odds ratio of 12.4 for sub-optimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.
INTERPRETATION: Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts sub-optimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here.
0364-5134
Cramer, Stig P.
ed3fe479-8e5e-4e38-bc02-bac30263db63
Simonsen, Helle J.
9911a788-79bb-4955-8191-c0045d0f9841
Varatharaj, Aravinthan
33d833af-9459-4b21-8489-ce9c0b6a09e0
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Frederiksen, Jette L.
05f563b8-7656-477e-a253-cdbc63d6f53a
Larsson, Henrik B.W.
e6a4213a-310b-4928-8f07-4e2e53be51ae
Cramer, Stig P.
ed3fe479-8e5e-4e38-bc02-bac30263db63
Simonsen, Helle J.
9911a788-79bb-4955-8191-c0045d0f9841
Varatharaj, Aravinthan
33d833af-9459-4b21-8489-ce9c0b6a09e0
Galea, Ian
66209a2f-f7e6-4d63-afe4-e9299f156f0b
Frederiksen, Jette L.
05f563b8-7656-477e-a253-cdbc63d6f53a
Larsson, Henrik B.W.
e6a4213a-310b-4928-8f07-4e2e53be51ae

Cramer, Stig P., Simonsen, Helle J., Varatharaj, Aravinthan, Galea, Ian, Frederiksen, Jette L. and Larsson, Henrik B.W. (2018) Permeability of the blood-brain barrier predicts no evidence of disease activity at two years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis. Annals of Neurology, 83 (5). (doi:10.1002/ana.25219).

Record type: Article

Abstract

OBJECTIVE: To investigate if blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of sub-optimal treatment response in relapsing-remitting multiple sclerosis (RRMS).
METHODS: 35 RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the CNS, were scanned with DCE-MRI at 3T prior to treatment and at three and six-months post-treatment. We calculated the influx constant Ki , a measure of BBB permeability, using the Patlak model. Sub-optimal treatment response was defined as loss of no evidence of disease activity (NEDA-3) status after two years of treatment.
RESULTS: Subjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after six months of treatment, compared to subjects with maintained NEDA status (mean difference 0.06 (CI 0.02-0.09) ml/100g/min; p=0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at two years (AUC 0.84, CI 0.70-0.99; p=0.003) and a value above 0.136 ml/100/g/min yielded an odds ratio of 12.4 for sub-optimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.
INTERPRETATION: Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts sub-optimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here.

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Cramer_et_al-2017-Annals_of_Neurology - Accepted Manuscript
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Accepted/In Press date: 28 March 2018
e-pub ahead of print date: 31 March 2018
Published date: May 2018

Identifiers

Local EPrints ID: 419288
URI: http://eprints.soton.ac.uk/id/eprint/419288
ISSN: 0364-5134
PURE UUID: a196d86e-3479-49eb-b2e7-f8a8709dece0
ORCID for Aravinthan Varatharaj: ORCID iD orcid.org/0000-0003-1629-5774
ORCID for Ian Galea: ORCID iD orcid.org/0000-0002-1268-5102

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Date deposited: 10 Apr 2018 16:30
Last modified: 26 Nov 2021 06:26

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Contributors

Author: Stig P. Cramer
Author: Helle J. Simonsen
Author: Ian Galea ORCID iD
Author: Jette L. Frederiksen
Author: Henrik B.W. Larsson

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