Innovations In Clinical Neuroscience

HOTTOP Multiple Sclerosis MAR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 15 Hot Topics in Multiple Sclerosis [March 2018] p=0.02), with a treatment effect of 28 percent. Mean PBVC in early GA treated patients ranged between −0.41 in the first year and −0.50 in the fifth year, i.e., values only slightly higher compared to PBVC observed in healthy subjects. 91 These findings are particularly interesting since a previous multicenter, randomized, double blind, placebo- controlled study in RRMS patients having longer disease duration failed to demonstrate any impact of GA on brain atrophy. 92 This apparent discrepancy further points out the importance of early treatment. However, other possible explanations of these findings might be the short duration of the follow-up and the application of a not normalized, semi-automated MRI technique (OLD) to analyze brain atrophy. Indeed, a subsequent reanalysis of the same data by means of the fully automated, normalized SIENA method, 93 while disclosing similar PBVC average value for both OLD and SIENA techniques, disclosed standard deviations much lower with SIENA. These observations highlight the risk for low reproducibility of not normalized and semi-automated MRI measures for the assessment of brain atrophy and suggest caution when interpreting brain atrophy data. More recently, in a three-year study aimed at analyzing efficacy and safety of 40mg GA three-times weekly in RRMS, patients that were early treated with GA showed significantly smaller changes in GM volume (p=0.015) compared to patients that were treated with placebo for one year before starting active treatment. 94 Interferon beta . RRMS patients treated for two years with once weekly intramuscular interferon beta (IFN) in the MSCRG phase III trial showed significantly less GM atrophy compared to placebo, during Year 2 after treatment initiation. 45 No change in WM atrophy was observed. In this study, the risk of sustained disability progression in IFN-treated patients was significantly associated with GM, but not WM, atrophy. 95 Data about the effects of high- dose high-frequency interferon beta 1a (IFNβ1a) on brain parenchymal fraction (BPF) loss can be deduced from the CARE-MS-I and CARE-MS-II trials. In the study CARE-MS-I (alemtuzumab vs. IFNβ1a as first-line treatment for RRMS), the effect of alemtuzumab on BPF was compared to that of high-dose, high- frequency sub-cutis IFNbβ1a. Median brain volume loss during the two years of the core study was −1.49 in the IFNb 1a cohort (−0.94 in the first year) and −0.87 in the alemtuzumab cohort (−0.59 in the first year). 96 In the CARE MS-II study (a randomized, controlled, two- year study on alemtuzumab for patients with RRMS after unsuccessful disease- modifying therapy), 97 the effect of both drugs in slowing down brain volume loss was more pronounced. Indeed, patients treated with high-dose, high-frequency IFNbβ1a had a − 0.81 percent reduction in BPF (−0.54 in the first year) versus −0.61 percent of alemtuzumab treated patients. Thus, only in the CARE-MS-II IFNβ1a was found to positively impact brain atrophy. The differences observed between these two studies can be explained with the substantial differences in clinical and demographic characteristics of the patient populations. To reduce the confounding effect of pseudo-atrophy phenomenon in the evaluation of brain atrophy, in a four- year longitudinal study, we investigated the progression of cortical atrophy in RRMS patients treated with IFNβ1a or GA. Although both drugs were found to decrease the rate of cortical atrophy, a trend in favor of high-dose, high- frequency sub-cutis IFNβ1a was noticed. 98 In a study conducted in a small number of RRMS patients, IFNβ1a 44μg SC three times weekly determined a reduction in whole brain and GM tissue volume during the first three months of therapy (mean change; −0.95%; p=0.030, −1.52%; p=0.004, respectively), suggesting a short-term treatment- induced pseudoatrophy effect, further confirming that the pseudoatrophy effect appears very early as the result of the resolution of inflammation following treatment initiation with IFN 1a 44μg SC three times weekly. 99 More recently, we have further investigated the effect of IFNβ1a on cortical thickness (CTh) in RRMS patients. We performed a four-year follow-up study of CTh in a group of 30 IFNβ1a (high-dose high-frequency)- responders RRMS patients (19 females, 11 males) treated for a mean period of four years with low and stable degrees of disability (mean EDSS = 1.5 ±1.0) and very low annualized relapse rate (mean 0.2 ± 0.47 year) before study entry. MRI was done at enrollment and then yearly for four years. CTh was measured by means of Freesurfer on 3D–T1-MPRAGE images. The mean loss of global CTh at the end of the four-year follow-up was 1.06 ± 2.05 percent, a value equal to that observed in age-matched normal control individuals, thus confirming that a significant slow-down in cortical GM loss can be observed in patients having a good clinical (anti-inflammatory) response to high-dose, high-frequency IFNβ1a. 100 Teriflunomide . Patients with RRMS treated with teriflunomide in the TEMSO Study 101 showed a significant decrease in %BPF compared to placebo, independently from prior DMD treatments, with no significant pseudoatrophy effect. Indeed, after two years of therapy, teriflunomide-treated naïve patients lost 0.93 percent BPF against 1.12 percent of placebo-treated subjects (p=0.01), while patients coming from previous DMD therapies lost 0.73 percent versus 1.51 percent (p=0.001). In a subsequent blinded independent analysis of TEMSO MRI data, the median annualized PBVC from baseline to Week 48 was calculated by means of SIENA. PBVC was lower for both teriflunomide groups versus placebo at Month 12 (reductions of 34.4% with teriflunomide 7mg, p=0.0011, and 36.9% with teriflunomide 14mg, p=0.0001) and Month 24 (reductions of 27.6% with teriflunomide 7mg, p=0.0019, and 30.6% with teriflunomide 14mg, p=0.0001), 102 thus confirming a significant effect of this drug in slowing down PBVC loss. These findings are particularly interesting considering the relative modest effect

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