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 17 Hot Topics in Multiple Sclerosis [March 2018] that, once reached EDSS 3.0 (i.e., a disability milestone that marks the entry in the progressive disease phase) the impact of anti-inflammatory therapies on neurodegeneration becomes less pronounced and might be not significant. This further suggests the importance of early therapeutic intervention with second-line drugs in patients with poor response to first line therapies. Alemtuzumab . As above described, in patients with RRMS treated with alemtuzumab in the CARE-MS-I RCT, the mean percentage of BPF loss after two years was −0.87 against −1.49 of the patients treated with high-dose high frequency sub-cutis IFN. At the end of the extension study (core study + extension = six years) the BPF loss was −1.43 percent, corresponding to a mean loss of −0.23 percent/year, comparable to the mean loss observed in normal individuals. This extraordinary result was confirmed in the CARE-MS-II RCT. After two years, the mean percentage of BPF loss was −0.62 percent in alemtuzumab-treated patients and −0.82 in IFN-treated patients. At the end of the extension study, alemtuzumab- treated patients lost a mean percentage of BPF of −0.95, corresponding to a mean annual loss of −0.16 percent. 113 Daclizumab . In a retrospective analysis aimed at determining the effect of daclizumab on brain atrophy, 26 MS patients treated for a median period of 4.3 years with daclizumab were compared to a control group of 44 patients treated with other DMD (predominantly IFN). Supratentorial brain volume declined by 5.17mL per year (95% confidence limits: 3.58–6.77) in the DMD group and by 3.72mL (p=0.01) in the daclizumab group. The rate of ventricular enlargement decreased from 1.26 to 0.42mL per year (p <0.001). Focused analysis suggested that reduction in the rate of GM atrophy could explain the results. 114 Ocrelizumab . In the trial ORATORIO the effect of ocrelizumab (anti-CD20 humanized antibody) on disability progression (primary endpoint) was analyzed in PPMS. Among the secondary MRI endpoints, the adjusted mean PBVC from Week 24 to Week 120 (fourth secondary endpoint) was lower with ocrelizumab than with placebo (−0.90 vs. –1.09) and the difference reached the significance (p=0.02). 115 In the OPERA I and OPERA II trials (ocrelizumab vs. high-dose, high frequency sub-cutis IFNβ1a in RRMS), despite the extraordinary effects of the drugs on clinical and MRI-inflammatory endpoints, the differences in the %PBVC from Week 24 to Week 96 between the ocrelizumab group and the IFN group were non-confirmatory in the OPERA I trial (nominal p=0.004) and non- significant in the OPERA II trial (nominal p=0.09). 116 Although the findings were non-confirmatory as a result of failure of the hierarchical analysis, the percentages of patients who had no evidence of disease activity were higher with ocrelizumab than with IFNβ1a in both trials. Cladribine . An exploratory analysis on the cladribine tablets treating multiple sclerosis orally (CLARITY) study (Phase 3, double-blind, placebo-controlled, multicenter trial in patients with RMS assessing the effects of cladribine tablets given annually over two years) 117 disclosed that cladribine significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates. 118 Indeed, compared with placebo (−0.70% ±0.79), the annualized percentage brain volume change (PBVC/y) was reduced in patients treated with cladribine tablets 3.5mg/ kg (−0.56% ±0.68, p=0.010) and 5.25 mg/kg (−0.57% ±0.72, p=0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI=0.571, 0.787; p <0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at two years and vice versa. Since cladribine crosses the blood brain barrier, it might be hypothesized that this drug acts not only on focal WM inflammation but also on the diffuse brain, including cortical, tissue damage and neurodegeneration in RRMS. CONCLUSION This review highlights that 1) compared to no treatment, all DMDs reduce the rate of brain volume loss and/or GM atrophy in RRMS, 2) the early treatment generally shows a FIGURE 1. Percent changes in brain volume in multiple sclerosis patients under treatment for two or three years with disease modifying drugs in Phase III Randomized Clinical Trials or observational studies. The estimated ranges of brain volume loss for healthy individuals and relapsing remitting multiple sclerosis are indicated with different shades of grey.

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