Contributions
Abstract: P775
Type: Poster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Early detection of sub-optimal treatment response in relapsing-remitting multiple sclerosis (RRMS) is important for effective treatment escalation. Previously we demonstrated an association between blood-brain barrier (BBB) permeability as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and cerebrospinal fluid cellularity. We hypothesized that DCE-MRI predicts sub-optimal treatment response after two years of treatment with fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the CNS.
Methods: 35 RRMS patients starting on fingolimod or natalizumab were scanned with DCE-MRI at 3T prior to treatment initiation and again 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. Two subjects were excluded due to treatment non-compliance.
Results: 13 out of 33 (39%) subjects lost NEDA status after one year of treatment and 15 out of 33 (45%) lost NEDA status after two years. Subjects who lost NEDA status at two years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after six months of treatment, when compared to the group who maintained NEDA status (p=0.0003), while there was no difference in Ki before treatment initiation or after three months of treatment. We found no such difference for NEDA status at one year. A ROC curve analysis found Ki in NAWM to be a good predictor of loss of NEDA status at two years (AUC 0.84, p=0.003). Values of NAWM Ki at six months above a cut-off of 0.136 ml/100/g/min yielded an odds ratio of 11.5 for loss of NEDA at 2 years (positive and negative predictive values of 73% and 81%, respectively). A one-way repeated measures ANOVA with Ki in NAWM as dependent variable showed a significant treatment effect (p=0.038) only when correcting for baseline methylprednisolone treatment (p=0.0004), days since last relapse (p=0.013), and NEDA status (p=0.045) at two years.
Conclusions: We show that BBB permeability as measured by DCE-MRI is a good predictor of sub-optimal treatment response after treatment with natalizumab or fingolimod. We provide evidence that Ki as a surrogate marker of the state of health of the BBB, with a predictive threshold for disease activity, which is remarkably identical in clinically, isolated syndrome and established RRMS.
Disclosure:
- Dr. Cramer has received research funding from Biogen Idec for this project. Dr, Cramer has received honoraria from Biogen Idec and Genzymes for speaking engagements and funding for travel from Biogen Idec, Merck Serono and Roche. Biogen Idec had no influence on study setup, data analysis, interpretation of results, or publishing decisions and intellectual rights belong to the authors alone.
- Simonsen reports no conflicts of interest for the present study.
- Dr. Galea has received funding for travel and conference attendance from Teva and research funding from Merck Serono. Dr. Galea has served as a scientific advisor to Evgen.
- Dr. Varatharaj has received funding for travel and conference attendance from Teva.
- Dr. Frederiksen 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. Dr. Frederiksen has received speaker honoraria from Biogen Idec, Merck Serono and Teva. She has served as advisor on preclinical development for Takeda.
- Dr. Larsson has received research funding from Biogen Idec for this project.
Abstract: P775
Type: Poster
Abstract Category: Therapy - disease modifying - 30 Tools for detecting therapeutic response
Background: Early detection of sub-optimal treatment response in relapsing-remitting multiple sclerosis (RRMS) is important for effective treatment escalation. Previously we demonstrated an association between blood-brain barrier (BBB) permeability as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and cerebrospinal fluid cellularity. We hypothesized that DCE-MRI predicts sub-optimal treatment response after two years of treatment with fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the CNS.
Methods: 35 RRMS patients starting on fingolimod or natalizumab were scanned with DCE-MRI at 3T prior to treatment initiation and again 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. Two subjects were excluded due to treatment non-compliance.
Results: 13 out of 33 (39%) subjects lost NEDA status after one year of treatment and 15 out of 33 (45%) lost NEDA status after two years. Subjects who lost NEDA status at two years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after six months of treatment, when compared to the group who maintained NEDA status (p=0.0003), while there was no difference in Ki before treatment initiation or after three months of treatment. We found no such difference for NEDA status at one year. A ROC curve analysis found Ki in NAWM to be a good predictor of loss of NEDA status at two years (AUC 0.84, p=0.003). Values of NAWM Ki at six months above a cut-off of 0.136 ml/100/g/min yielded an odds ratio of 11.5 for loss of NEDA at 2 years (positive and negative predictive values of 73% and 81%, respectively). A one-way repeated measures ANOVA with Ki in NAWM as dependent variable showed a significant treatment effect (p=0.038) only when correcting for baseline methylprednisolone treatment (p=0.0004), days since last relapse (p=0.013), and NEDA status (p=0.045) at two years.
Conclusions: We show that BBB permeability as measured by DCE-MRI is a good predictor of sub-optimal treatment response after treatment with natalizumab or fingolimod. We provide evidence that Ki as a surrogate marker of the state of health of the BBB, with a predictive threshold for disease activity, which is remarkably identical in clinically, isolated syndrome and established RRMS.
Disclosure:
- Dr. Cramer has received research funding from Biogen Idec for this project. Dr, Cramer has received honoraria from Biogen Idec and Genzymes for speaking engagements and funding for travel from Biogen Idec, Merck Serono and Roche. Biogen Idec had no influence on study setup, data analysis, interpretation of results, or publishing decisions and intellectual rights belong to the authors alone.
- Simonsen reports no conflicts of interest for the present study.
- Dr. Galea has received funding for travel and conference attendance from Teva and research funding from Merck Serono. Dr. Galea has served as a scientific advisor to Evgen.
- Dr. Varatharaj has received funding for travel and conference attendance from Teva.
- Dr. Frederiksen 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. Dr. Frederiksen has received speaker honoraria from Biogen Idec, Merck Serono and Teva. She has served as advisor on preclinical development for Takeda.
- Dr. Larsson has received research funding from Biogen Idec for this project.