Search

Introduction: In CARE-MS II (NCT00548405), alemtuzumab (12mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved clinical/MRI outcomes vs SC IFNB-1a over 2 years (y) in RRMS patients with inadequate response to prior therapy. Efficacy was maintained in a 4-y extension study (NCT00930553), wherein patients could receive additional 3-day alemtuzumab courses (⩾12 months apart) as needed for disease activity or receive other disease-modifying therapy (DMT) per investigator discretion. Further follow-up was available in an additional 5-y extension, TOPAZ (NCT02255656). Aims: To evaluate the efficacy and safety of alemtuzumab in CARE-MS II patients over 9y. Methods: At investigator discretion, patients in TOPAZ can receive additional as-needed alemtuzumab (⩾12 months apart; no criteria) or receive other DMT (at any time). Results: From core study baseline through Y9, 288/435 (66%) CARE-MS II alemtuzumab-treated patients remained on study; 41% received neither additional alemtuzumab nor another DMT through Y9. At Y9, annualised relapse rate was 0.13. From core study baseline through Y9, 68% of patients had stable/improved EDSS scores, and mean change in EDSS was +0.32. Over 9y, 60% of patients were free of 6-month confirmed disability worsening, and 49% achieved 6-month confirmed disability improvement. In Y9, 72% of patients were free of MRI disease activity, 88% were free of new gadolinium-enhancing lesions, and 73% were free of new/enlarging T2 hyperintense lesions. From core study baseline through Y9, median percent cumulative brain volume loss (BVL) was -1.22%; median annual BVL was ⩽0.19% each year over Y3-9. Alemtuzumab had a consistent safety profile over 9y, with the incidence of overall adverse events (AEs) and infections declining through Y9; of patients who received ⩾1 dose of alemtuzumab, cumulative thyroid AE incidence was 44% and immune thrombocytopenia (ITP) incidence was 4%. In Y9, 1 case of ITP (14 months after the 4th course of alemtuzumab) and no new cases of nephropathy were reported. Efficacy and safety in SC IFNB-1a-treated patients from the core study who switched to alemtuzumab in the extension were consistent with those treated with alemtuzumab both in the core and extension. Conclusions: Efficacy of alemtuzumab on clinical, MRI, and BVL outcomes was maintained over 9y in CARE-MS II patients, with 66% remaining on study and 41% receiving no further treatment through Y9. Safety remained consistent and manageable over 9y.

ObjectiveTo compare the clinical effectiveness of high- and low-efficacy treatments in patients with recently active and inactive secondary progressive multiple sclerosis (SPMS) after accounting for therapeutic lag.MethodsPatients treated with high-efficacy (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, fingolimod) or low-efficacy (interferon beta, glatiramer acetate, teriflunomide) therapies after SPMS onset were selected from MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP), 2 large observational cohorts. Therapeutic lag was estimated for each patient from their demographic and clinical characteristics. Propensity score was used to match patients treated with high- and low-efficacy therapies. Outcomes after the period of therapeutic lag was disregarded were compared in paired, pairwise-censored analyses.ResultsOne thousand patients were included in the primary analysis. Patients with active SPMS treated with high-efficacy therapy experienced less frequent relapses than those on low-efficacy therapy (hazard ratio [HR] 0.7,p= 0.006). In patients with inactive SPMS, there was no evidence for a difference in relapse frequency between groups (HR 0.8,p= 0.39). No evidence for a difference in the risk of disability progression was observed.ConclusionIn treated patients with SPMS, high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active but not those with inactive SPMS. However, more potent therapies do not offer an advantage in reducing disability progression in this patient group.Classification of EvidenceThis study provides Class III evidence that high-efficacy therapy is superior to low-efficacy therapy in reducing relapses in patients with active SPMS, although we did not find a difference in disability progression between patients treated with high- and low-efficacy therapy.

Background: There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. Aim: We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. Methods: Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. Results: Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10−15), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10−15), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was −0.50% (IQR = −0.96, −0.16) and was predicted by the baseline IgM index (B = −0.37; p = 0.003). Conclusions: Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment.

ObjectiveTo describe the dynamics of brain volume loss (BVL) at different stages of relapsing-remitting multiple sclerosis (RRMS), to describe the association between BVL and clinical measures, and to investigate an effect of treatment escalation on the rate of BVL.MethodsTogether, 1903 patients predominantly with RRMS from the Avonex-Steroids-Azathioprine cohort (N = 166), the study of early IFN-β1a treatment cohort (N = 180), and the quantitative MRI cohort (N = 1,557) with ≥2 MRI scans and ≥1-year of follow-up were included. Brain MRI scans (N = 7,203) were performed using a single 1.5-T machine. Relationships between age or disease duration and global and tissue-specific BVL rates were analyzed using mixed models.ResultsAge was not associated with the rate of BVL (β = −0.003; Cohen f2 = 0.0005; adjusted p = 0.39). Although disease duration was associated with the rate of BVL, its effect on the BVL rate was minimal (β = −0.012; Cohen f2 = 0.004; adjusted p = 4 × 10−5). Analysis of association between tissue-specific brain volume changes and age (β = −0.019 to −0.011; adjusted p = 0.028–1.00) or disease duration (β = −0.028 to −0.008; adjusted p = 0.16–0.96) confirmed these results. Although increase in the relapse rate (β = 0.10; adjusted p = 9 × 10−9), Expanded Disability Status Scale (EDSS; β = 0.17; adjusted p = 8 × 10−5), and EDSS change (β = 0.15; adjusted p = 2 × 10−5) were associated with accelerated rate of BVL, their effect on the rate of BVL was minimal (all Cohen f2 ≤ 0.007). In 94 patients who escalated therapy, the rate of BVL decreased following treatment escalation by 0.29% (β = −0.29; Cohen f2 = 0.133; p = 5.5 × 10−8).ConclusionsThe rate of BVL is relatively stable throughout the course of RRMS. The accelerated BVL is weakly associated with concurrent higher disease activity, and timely escalation to high-efficacy immunotherapy helps decrease the rate of BVL.