002 Therapeutic lag in relapsing multiple sclerosis

At the time of publication of the most recent National Institute for Health and Care Excellence (NICE) guidance [technology appraisal (TA) 32] in 2002 on beta-interferon (IFN-β) and glatiramer acetate (GA) for multiple sclerosis, there was insufficient evidence of their clinical effectiveness and cost-effectiveness. To undertake (1) systematic reviews of the clinical effectiveness and cost-effectiveness of IFN-β and GA in relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome (CIS) compared with best supportive care (BSC) and each other, investigating annualised relapse rate (ARR) and time to disability progression confirmed at 3 months and 6 months and (2) cost-effectiveness assessments of disease-modifying therapies (DMTs) for CIS and RRMS compared with BSC and each other. Searches were undertaken in January and February 2016 in databases including The Cochrane Library, MEDLINE and the Science Citation Index. We limited some database searches to specific start dates based on previous, relevant systematic reviews. Two reviewers screened titles and abstracts with recourse to a third when needed. The Cochrane tool and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and Philips checklists were used for appraisal. Narrative synthesis and, when possible, random-effects meta-analysis and network meta-analysis (NMA) were performed. Cost-effectiveness analysis used published literature, findings from the Department of Health's risk-sharing scheme (RSS) and expert opinion. A de novo economic model was built for CIS. The base case used updated RSS data, a NHS and Personal Social Services perspective, a 50-year time horizon, 2014/15 prices and a discount rate of 3.5%. Outcomes are reported as incremental cost-effectiveness ratios (ICERs). We undertook probabilistic sensitivity analysis. In total, 6420 publications were identified, of which 63 relating to 35 randomised controlled trials (RCTs) were included. In total, 86% had a high risk of bias. There was very little difference between drugs in reducing moderate or severe relapse rates in RRMS. All were beneficial compared with BSC, giving a pooled rate ratio of 0.65 [95% confidence interval (CI) 0.56 to 0.76] for ARR and a hazard ratio of 0.70 (95% CI, 0.55 to 0.87) for time to disability progression confirmed at 3 months. NMA suggested that 20 mg of GA given subcutaneously had the highest probability of being the best at reducing ARR. Three separate cost-effectiveness searches identified > 2500 publications, with 26 included studies informing the narrative synthesis and model inputs. In the base case using a modified RSS the mean incremental cost was £31,900 for pooled DMTs compared with BSC and the mean incremental quality-adjusted life-years (QALYs) were 0.943, giving an ICER of £33,800 per QALY gained for people with RRMS. In probabilistic sensitivity analysis the ICER was £34,000 per QALY gained. In sensitivity analysis, using the assessment group inputs gave an ICER of £12,800 per QALY gained for pooled DMTs compared with BSC. Pegylated IFN-β-1 (125 µg) was the most cost-effective option of the individual DMTs compared with BSC (ICER £7000 per QALY gained); GA (20 mg) was the most cost-effective treatment for CIS (ICER £16,500 per QALY gained). Although we built a de novo model for CIS that incorporated evidence from our systematic review of clinical effectiveness, our findings relied on a population diagnosed with CIS before implementation of the revised 2010 McDonald criteria. DMTs were clinically effective for RRMS and CIS but cost-effective only for CIS. Both RCT evidence and RSS data are at high risk of bias. Research priorities include comparative studies with longer follow-up and systematic review and meta-synthesis of qualitative studies. This study is registered as PROSPERO CRD42016043278. The National Institute for Health Research Health Technology Assessment programme.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

The silent progression of patients with multiple sclerosis (MS) has been reported. The aim of this study was to investigate the association between brain atrophy rates and disease-modifying drugs (DMDs) in patients with MS during their relapse-free period. Patients with relapsing-remitting MS were classified into two groups on the basis of clinical records, i.e. a first-generation DMD group treated with interferon-beta-1a, interferon-beta-1b or glatiramer acetate and a second-generation DMD group treated with dimethyl fumarate, fingolimod or natalizumab. Brain volume was calculated with SPM12. A total of 45 patients with relapsing-remitting MS were enrolled in the first-generation (n=22) or second-generation (n=23) DMD group. The annualized relapse rate was lower in the first-generation than in the second-generation DMD group (median 0.26 vs. 0.59; P<0.001). The annualized atrophy rate of the normalized brain volume was not different between the first- and second-generation DMD groups after analysis of covariance (median 0.13% vs. 0.59%; P=0.17). The median annualized atrophy rate of normalized brain volume in the first-generation DMD group was similar to the previously reported annual brain atrophy rate of healthy controls, which may suggest that treatment with a first-generation DMD need not be changed when patients with MS are clinically inactive.

BackgroundNew frontline oral therapies for relapsing remitting multiple sclerosis (RRMS) are available. The change to the oral route of administration could increase adherence.1PurposeThe aim was to assess patient adherence to...

We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer acetate (GA) therapies, using propensity score-matched cohorts from observational multiple sclerosis registries. The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity. First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) (p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28-0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58-0.93; p = 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale-time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-β/GA.

Background and importancePharmacists are well positioned to improve clinical outcomes for patients by assisting with individualised patient in the outpatient setting. Given the difficulty of measuring the health outcome of...

BackgroundPatients with highly active relapsing-remitting multiple sclerosis inadequately responding to first-line therapies (interferon-based therapies, glatiramer acetate, dimethyl fumarate, and teriflunomide, known collectively as “BRACETD”) often switch to natalizumab or fingolimod.ObjectiveThe aim was to estimate the comparative effectiveness of switching to natalizumab or fingolimod or within BRACETD using real-world data and to evaluate the cost-effectiveness of switching to natalizumab versus fingolimod using a United Kingdom (UK) third-party payer perspective.MethodsReal-world data were obtained from MSBase for patients relapsing on BRACETD in the year before switching to natalizumab or fingolimod or within BRACETD. Three-way-multinomial-propensity-score–matched cohorts were identified, and comparisons between treatment groups were conducted for annualised relapse rate (ARR) and 6-month–confirmed disability worsening (CDW6M) and improvement (CDI6M). Results were applied in a cost-effectiveness model over a lifetime horizon using a published Markov structure with health states based on the Expanded Disability Status Scale. Other model parameters were obtained from the UK MS Survey 2015, published literature, and publicly available UK sources.ResultsThe MSBase analysis found a significant reduction in ARR (rate ratio [RR] = 0.64; 95% confidence interval [CI] 0.57–0.72; p < 0.001) and an increase in CDI6M (hazard ratio [HR] = 1.67; 95% CI 1.30–2.15; p < 0.001) for switching to natalizumab compared with BRACETD. For switching to fingolimod, the reduction in ARR (RR = 0.91; 95% CI 0.81–1.03; p = 0.133) and increase in CDI6M (HR = 1.30; 95% CI 0.99–1.72; p = 0.058) compared with BRACETD were not significant. Switching to natalizumab was associated with a significant reduction in ARR (RR = 0.70; 95% CI 0.62–0.79; p < 0.001) and an increase in CDI6M (HR = 1.28; 95% CI 1.01–1.62; p = 0.040) compared to switching to fingolimod. No evidence of difference in CDW6M was found between treatment groups. Natalizumab dominated (higher quality-adjusted life-years [QALYs] and lower costs) fingolimod in the base-case cost-effectiveness analysis (0.453 higher QALYs and £20,843 lower costs per patient). Results were consistent across sensitivity analyses.ConclusionsThis novel real-world analysis suggests a clinical benefit for therapy escalation to natalizumab versus fingolimod based on comparative effectiveness results, translating to higher QALYs and lower costs for UK patients inadequately responding to BRACETD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-021-01106-6.

Decreased relapse rate and slower disease progression have been reported with long-term use of immunomodulatory treatments (IMTs, interferon beta or glatiramer acetate) in relapsing-remitting multiple sclerosis. There are, however, patients who do not respond to such treatments, and they can be potential candidates for alternative therapeutic approaches. To identify clinical factors as possible predictors of poor long-term response. A 9-year prospective, continuous follow-up at a single center in Hungary to assess clinical efficacy of IMT. In a patient group of 81 subjects with mean IMT duration of 54 ± 33 months, treatment efficacy expressed as annual relapse rate and change in clinical severity from baseline did not depend on the specific IMT (any of the interferon betas or glatiramer acetate), and on mono- or multifocal features of the initial appearance of the disease. Responders had shorter disease duration and milder clinical signs at the initiation of treatment. Relapse-rate reduction in the initial 2 years of treatment predicted clinical efficacy in subsequent years. Based on these observations, we suggest that a 2-year trial period is sufficient to decide on the efficacy of a specific IMT. For those with insufficient relapse reduction in the first 2 years of treatment, a different IMT or other therapeutic approaches should be recommended.

Efficacy of the Mediterranean diet in the treatment of multiple sclerosis (RRMS): A systematic review and meta-analysis.

Étude observationnelle de la mitoxantrone dans les formes rémittentes actives de sclérose en plaques: suivi à long terme d’une cohorte de 100 patients consécutifs

To investigate whether or not the disparity in disease progression in those with pediatric-onset compared with adult-onset multiple sclerosis (MS) is due to differences in relapse rates. Inception cohort. Mean follow-up times were 3.67 (standard deviation, 1.64) and 3.98 (standard deviation, 1.17) years in the pediatric and adult groups, respectively. Comprehensive MS centers. Patients with relapsing-remitting MS who were seen at the pediatric and adult MS centers at Massachusetts General and Brigham and Women's Hospitals, respectively, 12 months or less from onset of first symptom in July 2001 or later and were followed up for 12 months or longer. One hundred ten patients with adult-onset and 21 patients with pediatric-onset MS were included. Three eligible patients with adult-onset MS were excluded owing to incomplete records. Annualized relapse rates were compared between pediatric-onset and adult-onset patients using the proportional means model. The annualized relapse rate in the pediatric-onset group was significantly higher than that in the adult-onset group (1.13 vs 0.40; P < .001) with an adjusted rate ratio of 2.81 (95% confidence interval, 2.07-3.81). When we controlled for time spent undergoing disease-modifying treatment in the analysis, the difference between the groups remained highly significant (adjusted rate ratio, 2.82; 95% confidence interval, 2.08-3.83; P < .001). When age at disease onset was treated as a continuous variable, a highly significant association between age and relapse rate was observed (P < .001). Relapses are more frequent in patients with pediatric-onset compared with adult-onset MS in the disease-modifying treatment era. This finding suggests that patients with pediatric-onset MS experience a more inflammatory disease course than patients with adult onset of the disease.

In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics.

IntroductionPatients with multiple sclerosis may have a distinct gut microbiota profile. Delayed-release dimethyl fumarate is an orally administered drug for relapsing–remitting multiple sclerosis, which has been associated with gastrointestinal side-effects in some patients.ObjectivesThe purpose of this study was to determine if dimethyl fumarate alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with gastrointestinal side-effects.MethodsThirty-six patients with relapsing–remitting multiple sclerosis received either dimethyl fumarate (n = 27) or an injectable multiple sclerosis disease-modifying therapy (glatiramer acetate or interferons, n = 9) for 12 weeks. Stool samples were collected at baseline, two and 12 weeks. We included 165 healthy individuals as controls.ResultsAt baseline, 16 microbial genera were altered in multiple sclerosis patients compared with healthy controls. In the dimethyl fumarate-treated patients (n = 21) we observed a trend of reduced Actinobacteria (p = 0.03, QFDR = 0.24) at two weeks, mainly driven by Bifidobacterium (p = 0.06, QFDR = 0.69). At 12 weeks, we observed an increased abundance of Firmicutes (p = 0.02, QFDR = 0.09), mostly driven by Faecalibacterium (p = 0.01, QFDR = 0.48).ConclusionsThis pilot study did not detect a major effect of dimethyl fumarate on the gut microbiota composition, but we observed a trend towards normalization of the low abundance of butyrate-producing Faecalibacterium after 12 weeks treatment. The study was underpowered to link microbiota to gastrointestinal symptoms.

Natalizumab is indicated for the treatment of relapsing multiple sclerosis (MS) with insufficient response to first-line disease-modifying therapy (DMT). We studied the efficacy of natalizumab for treatment of MS in a single centre observational design. A retrospective observational study of 146 patients [66% female; mean age 37.4; 72% relapsing remitting MS (RRMS), 28% secondary progressive MS (SPMS)] referred for natalizumab treatment at St. Michael's Hospital MS Clinic between 2007 and August 2009. Data included demographic, clinical (Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR)) and patient self-report measures. The mean duration of treatment was 20 months in those treated with natalizumab and 97% had received prior DMTs. Eighty-three patients (57%) received at least 12 months of natalizumab treatment. In those who received at least 12 months of treatment, baseline ARR and EDSS were 1.6 and 2.7 in RRMS patients versus 1.0 and 5.4 in SPMS with relapses. The ARR decreased with natalizumab treatment to 0.38 (76% reduction, p<0.001) in RRMS versus 0.32 in SPMS patients (68% reduction, p=0.01). There was a treatment associated 11% reduction in EDSS to 2.4 (p=0.04) in RRMS, but no significant change in SPMS. Eighty-five percent of patients reported improved overall quality of life (QOL) and 62% indicated improved energy. There was a major reduction in relapse rate, stabilization in EDSS and improvement in QOL and energy in some patients on natalizumab, all similar to treatment effects in the pivotal trial.

BackgroundAge has been independently associated with higher rates of treatment discontinuation in multiple sclerosis.ObjectiveThe current study examines the impact of age on persistence for all reimbursed DMTs for RRMS in Australia.MethodsThe Pharmaceutical Benefits Scheme (PBS) 10% sample supplied by the Department of Human Services was used in this study. Eligible patients must have received a script for a reimbursed DMT for RRMS between September 2011 and February 2016. Patients were classified into five age-groups (ages 18–30; 31–40; 41–50; 51–60; 61+) and defined as persistent if their DMT script was filled within 4 months. Persistence was derived using the Kaplan-Meier method and hazard ratios (HR) to represent the relative rate of drop-off of different age groups.ResultsPatients aged 18–30 (n=250) had a 44% increased risk of discontinuation (HR 1.44 (95%CI: 1.22–1.72) compared to the ‘all ages’ cohort (n=1,866); no significant difference was observed for any other age group (HRs between 1.08 and 0.92). Patients in this 18–30 age-group had a significantly higher risk of discontinuation on injectable therapy (glatiramer acetate, interferon beta-1a, interferon beta-1b) compared to those on non-injectable therapy (dimethyl fumarate, fingolimod, natalizumab, teriflunomide) (HR 2.42 (95% CI: 1.63–3.61).ConclusionsPatients aged 18–30 were the least persistent age group in this study. Patients aged 18–30 were less persistent on injectable than non-injectable DMTs.