TY - JOUR
T1 - Permeability of the blood–brain barrier predicts no evidence of disease activity at 2 years after natalizumab or fingolimod treatment in relapsing–remitting multiple sclerosis
AU - Cramer, Stig P.
AU - Simonsen, Helle J.
AU - Varatharaj, Aravinthan
AU - Galea, Ian
AU - Frederiksen, Jette L.
AU - Larsson, Henrik B.W.
PY - 2018
Y1 - 2018
N2 - Objective: To investigate whether blood–brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of suboptimal treatment response in relapsing–remitting multiple sclerosis (RRMS). Methods: Thirty-five RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the central nervous system, were scanned with DCE-MRI at 3T prior to treatment and at 3 and 6 months posttreatment. We calculated the influx constant Ki, a measure of BBB permeability, using the Patlak model. Suboptimal treatment response was defined as loss of no evidence of disease activity (NEDA) status after 2 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 6 months of treatment, compared to subjects with maintained NEDA status (mean difference = 0.06ml/100g/min, 95% confidence interval [CI] = 0.02–0.09, p = 0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at 2 years (area under the curve = 0.84, 95% CI = 0.70–0.99, p = 0.003), and a value above 0.136ml/100/g/min yielded an odds ratio of 12.4 for suboptimal 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 suboptimal 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. Ann Neurol 2018;83:902–914.
AB - Objective: To investigate whether blood–brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of suboptimal treatment response in relapsing–remitting multiple sclerosis (RRMS). Methods: Thirty-five RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the central nervous system, were scanned with DCE-MRI at 3T prior to treatment and at 3 and 6 months posttreatment. We calculated the influx constant Ki, a measure of BBB permeability, using the Patlak model. Suboptimal treatment response was defined as loss of no evidence of disease activity (NEDA) status after 2 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 6 months of treatment, compared to subjects with maintained NEDA status (mean difference = 0.06ml/100g/min, 95% confidence interval [CI] = 0.02–0.09, p = 0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at 2 years (area under the curve = 0.84, 95% CI = 0.70–0.99, p = 0.003), and a value above 0.136ml/100/g/min yielded an odds ratio of 12.4 for suboptimal 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 suboptimal 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. Ann Neurol 2018;83:902–914.
U2 - 10.1002/ana.25219
DO - 10.1002/ana.25219
M3 - Journal article
C2 - 29604233
AN - SCOPUS:85049007026
SN - 0364-5134
VL - 83
SP - 902
EP - 914
JO - Annals of Neurology
JF - Annals of Neurology
IS - 5
ER -