BACKGROUND: Multiple sclerosis (MS) is an autoimmune, T-cell-dependent, inflammatory, demyelinating disease of the central nervous system, with an unpredictable course. Current MS therapies focus on treating and preventing exacerbations, and avoiding the progression of disability. At present, there is no treatment that is capable of safely and effectively reaching these objectives. Clinical trials suggest that alemtuzumab, a humanized monoclonal antibody, could be a promising option for MS.
OBJECTIVES: To evaluate the benefits and harms of alemtuzumab alone or associated with other treatments in people with any form of MS.
SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 21 June 2022.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) in adults with any subtype of MS comparing alemtuzumab alone or associated with other medications versus placebo; another active drug; or alemtuzumab in another dose, regimen, or duration.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our co-primary outcomes were 1. relapse-free survival, 2. sustained disease progression, and 3. number of participants experiencing at least one adverse event. Our secondary outcomes were 4. participants free of clinical disability, 5. quality of life, 6. change in disability, 7. fatigue, 8. new or enlarging lesions on resonance imaging, and 9. dropouts. We used GRADE to assess certainty of evidence for each outcome.
MAIN RESULTS: We included three RCTs (1713 participants) comparing intravenous alemtuzumab versus subcutaneous interferon beta-1a for relapsing-remitting MS. Participants were treatment-naive (two studies) or had experienced at least one relapse after interferon or glatiramer (one study). Alemtuzumab was given at doses of 12 mg/day or 24 mg/day for five days at months 0 and 12, or 24 mg/day for three days at months 12 and 24. Participants in the interferon beta-1a group received 44 μg three times weekly. Alemtuzumab 12 mg: 1. may improve relapse-free survival at 36 months (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.18 to 0.53; 1 study, 221 participants; low-certainty evidence); 2. may improve sustained disease progression-free survival at 36 months (HR 0.25, 95% CI 0.11 to 0.56; 1 study, 223 participants; low-certainty evidence); 3. may make little to no difference on the proportion of participants with at least one adverse event at 36 months (risk ratio [RR] 1.00, 95% CI 0.98 to 1.02; 1 study, 224 participants; low-certainty evidence), although the proportion of participants with at least one adverse event was high with both drugs; 4. may slightly reduce disability at 36 months (mean difference [MD] -0.70, 95% CI -1.04 to -0.36; 1 study, 223 participants; low-certainty evidence). The evidence is very uncertain regarding the risk of dropouts at 36 months (RR 0.81, 95% CI 0.57 to 1.14; 1 study, 224 participants; very low-certainty evidence). Alemtuzumab 24 mg: 1. may improve relapse-free survival at 36 months (HR 0.21, 95% CI 0.11 to 0.40; 1 study, 221 participants; low-certainty evidence); 2. may improve sustained disease progression-free survival at 36 months (HR 0.33, 95% CI 0.16 to 0.69; 1 study, 221 participants; low-certainty evidence); 3. may make little to no difference on the proportion of participants with at least one adverse event at 36 months (RR 0.99, 95% CI 0.97 to 1.02; 1 study, 215 participants; low-certainty evidence), although the proportion of participants with at least one adverse event was high with both drugs; 4. may slightly reduce disability at 36 months (MD -0.83, 95% CI -1.16 to -0.50; 1 study, 221 participants; low-certainty evidence); 5. may reduce the risk of dropouts at 36 months (RR 0.08, 95% CI 0.01 to 0.57; 1 study, 215 participants; low-certainty evidence). For quality of life, fatigue, and participants free of clinical disease activity, the studies either did not consider these outcomes or they used different measuring tools to those planned in this review.
AUTHORS' CONCLUSIONS: Compared with interferon beta-1a, alemtuzumab may improve relapse-free survival and sustained disease progression-free survival, and make little to no difference on the proportion of participants with at least one adverse event for people with relapsing-remitting MS at 36 months. The certainty of the evidence for these results was very low to low.
OBJECTIVE: To compare the efficacy and compliance of up-to-date disease modifying therapies (DMTs) in patients with remitting-relapsing MS (RRMS).
METHODS: We searched PubMed, EMBASE and Cochrane Library for eligible studies. Annualized relapse rate, discontinuation due to adverse events (AEs) were assessed as primary outcomes. Sensitivity analysis and inconsistency detection were performed to evaluated whether exclusion of high-risk studies affected the validity. Risk of bias was assessed using Cochrane's Risk-of-Bias Tool 2. Surface under the cumulative ranking curve (SUCRA) was used to estimate the rankings among different DMTs.
RESULTS: 21 studies were included for main report. Seven studies were evaluated as "high risk" and were therefore excluded. Exclusion of high-risk studies did not affect the validity of evidence. The risk of relapses for most DMTs except Betaseron 50 μg was significantly lower comparing to placebo. Incompliance in patients treated with DMTs was not significantly increased comparing to placebo. Dimethyl fumarate and ocrelizumab had superiority in improving MRI outcomes. Ocrelizumab and ofatumumab had the largest reduction of risk in disability progression at 3 months. Referring to SUCRA, ofatumumab, alemtuzumab and natalizumab showed the best efficacy and compliance.
CONCLUSION: The present study demonstrated the hierarchy of DMTs treating RRMS. Ofatumumab, alemtuzumab and natalizumab have superiority with respect to effectiveness and compliance. More studies are required to explore the long-term effect of DMTs. Our findings could provide helpful information and contribute to clinical treatment decision-making.
Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results: For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.
BACKGROUND: A broad range of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is available. However, the efficacy and safety of traditional DMTs compared with the recently developed DMTs remain unclear.
OBJECTIVE: Therefore, we have synthesised available evidence of clinical outcomes for DMTs in adults with RRMS.
METHODS: PubMed, Scopus and a manual search were performed. Bayesian network meta-analyses of randomised clinical trials assessing DMTs as monotherapies were conducted. SUCRA and GRADE were used to rank therapies and to assess quality of general evidence, respectively.
RESULTS: Thirty-three studies were included in the meta-analyses. The most effective therapies for the outcome of annualised relapse rate were alemtuzumab (96% probability), natalizumab (96%) and ocrelizumab (85%), compared with all other therapies (hazard ratio versus placebo, 0.31, 0.31 and 0.37, respectively; p < 0.05 for all comparisons) (high-quality evidence). However, no significant differences among these three therapies were found. Discontinuation due to adverse events revealed similarity across all therapies, except for alemtuzumab, which showed less discontinuation when compared with interferon-1a intramuscular (relative risk 0.37; p < 0.05).
CONCLUSION: High-quality evidence shows that alemtuzumab, natalizumab and ocrelizumab present the highest efficacy among DMTs, and other meta-analyses are required regarding adverse events frequency, to better understand the safety of therapies. Based on efficacy profile, guidelines should consider a three-category classification (i.e. high, intermediate and low efficacy).
BACKGROUND: Psychiatric comorbidity is prevalent in persons with multiple sclerosis (MS). Few studies have assessed whether second-generation disease-modifying therapies (DMT) are associated with adverse psychiatric effects.
OBJECTIVE: We aimed to systematically review the literature regarding the APEs associated with natalizumab, fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab in MS. As a secondary objective, we evaluated changes in anxiety or depression scores following treatment with the aforementioned DMTs.
METHODS: We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, PsychINFO, Central Register of Controlled Trials & Cochrane database of systematic reviews for published studies, and clinicaltrials.gov and regulatory documents from the US and Canada for unpublished studies. Data sources were searched from inception to September 2017. Studies reporting adverse psychiatric effects involving any DMT of interest were included. We report the incidence proportions of the adverse psychiatric effects and, where applicable, risk differences between DMT-exposed and unexposed individuals along with the corresponding 95% confidence intervals. We calculated the standardized mean differences (SMD) of changes in anxiety and depression scores if reported as study outcomes, and pooled the data using random effects meta-analysis.
RESULTS: Of 4389 abstracts screened, 78 met the inclusion criteria, including 48 clinical trials, 28 observational studies and 2 case reports. Depression was the most commonly reported adverse psychiatric effect. Incidence proportions for all adverse psychiatric effects ranged from 0 to 24.7%. None of the DMT studied were associated with a statistically significant increased risk of any adverse psychiatric effect (range of risk difference: -7.69% [95%CI: -16.06%, 5.56%] to 6.67 [-8.56, 15.59]). Eighteen studies examined changes in depression or anxiety following fingolimod, natalizumab or dimethyl fumarate treatment; depression symptoms improved in fingolimod-treated groups (SMD [95%CI]: 1.18 [0.17, 2.19]). We did not identify studies examining changes in these outcomes following treatment with any of the other DMTs.
CONCLUSION: The DMTs reviewed were not associated with an increased risk of adverse psychiatric effect in MS, and some may reduce the incidence of depressive symptoms. This may reflect either a positive direct effect (e.g. immune modulation) or an indirect effect arising due to a positive impact on disease activity or course.
OBJECTIVE: To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms.
METHODS: Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used.
RESULTS: Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.
OBJECTIVE: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA+DAT), using systematic literature review (SLR) and network meta-analysis (NMA).
METHODS: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA), and safety.
RESULTS: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < 0.05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab, and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < 0.05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA+DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs.
CONCLUSION: In this first NMA to consider cladribine tablets, ocrelizumab, and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA+DAT populations.
BACKGROUND: Alemtuzumab is a humanised monoclonal antibody that alters the circulating lymphocyte pool, causing prolonged lymphopenia, thus remoulding the immune repertoire that accompanies homeostatic lymphocyte reconstitution. It has been proved more effective than interferon (IFN) 1a for the treatment of relapsing-remitting multiple sclerosis (RRMS).
OBJECTIVES: To compare the efficacy, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS to prevent disease activity.
SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register (1 February 2017) which, among other sources, contains records from CENTRAL, MEDLINE, Embase, CINAHL, LILACS, PEDRO and the trial registry databases Clinical Trials.gov and WHO International Clinical Trials Registry Platform for all prospectively registered and ongoing trials.
SELECTION CRITERIA: All double-blind, randomised, controlled trials comparing intravenous alemtuzumab (12 mg per day or 24 mg per day on five consecutive days during the first month and on three consecutive days at months 12 and 24) versus subcutaneous IFN beta 1a (22 μg or 44 μg three times per week (Rebif) or intramuscular injection 30 μg once a week (Avonex)) in people of any gender and age with RRMS.
DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.
MAIN RESULTS: We included three trials involving 1694 participants. All trials compared alemtuzumab 12 mg per day or 24 mg per day versus IFN beta 1a for treating RRMS. In CAMMS223, participants received either subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab (at a dose of 12 mg per day or 24 mg per day) for 36 months. In CARE-MS I and CARE-MS II, participants received subcutaneous IFN beta 1a 44 μg three times per week or annual intravenous cycles of alemtuzumab 12 mg per day for 24 months. The methodological quality was good for all three studies.In the alemtuzumab 12 mg per day group, the results showed statistically significant difference in reducing relapses (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.52 to 0.70), preventing disease progression (RR 0.60, 95% CI 0.45 to 0.79) and developing new T2 lesions on magnetic resonance imaging (RR 0.75, 95% CI 0.61 to 0.93) after 24 and 36 months' follow-up, but found no statistically significant difference in the changes of Expanded Disability Status Scale (EDSS) score (mean difference (MD) -0.35, 95% CI -0.73 to 0.03). In the alemtuzumab 24 mg per day group, the results showed statistically significant differences in reducing relapses (RR 0.38, 95% CI 0.23 to 0.62), preventing disease progression (RR 0.42, 95% CI 0.21 to 0.84) and the changes of EDSS score (MD -0.83, 95% CI -1.17 to -0.49) after 36 months' follow-up.All three trials reported adverse events and serious adverse events. There was no statistically significant difference in the number of participants with at least one adverse event (RR 1.03, 95% CI 0.97 to 1.08) and the number of participants who experienced serious adverse events (RR 1.03, 95% CI 0.83 to 4.54).
AUTHORS' CONCLUSIONS: There is low- to moderate-quality evidence that annual intravenous cycles of alemtuzumab at a dose of 12 mg per day or 24 mg per day reduces the proportion of participants with relapses, disease progression, change of EDSS score and developing new T2 lesions on MRI over 24 to 36 months in comparison with subcutaneous IFN beta-1a 44 μg three times per week.Alemtuzumab appeared to be relatively well tolerated. The most frequently reported adverse events were infusion-associated reactions, infections and autoimmune events. The use of alemtuzumab requires careful monitoring so that potentially serious adverse effects can be treated early and effectively.
