Summary Background High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis, but can be inconvenient and expensive. We aimed to assess ...whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration. Methods We did this multicentre, double-blind, randomised, controlled, non-inferiority trial at 13 centres for multiple sclerosis in France. We enrolled patients aged 18–55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale. With use of a computer-generated randomisation list and in blocks of four, we randomly assigned (1:1) patients to either oral or intravenous methylprednisolone, 1000 mg, once a day for 3 days. Patients, treating physicians and nurses, and data and outcome assessors were all masked to treatment allocation, which was achieved with the use of saline solution and placebo capsules. The primary endpoint was the proportion of patients who had improved by day 28 (decrease of at least one point in most affected score on Kurtzke Functional System Scale), without need for retreatment with corticosteroids, in the per-protocol population. The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15%. This trial is registered with ClinicalTrials.gov , number NCT00984984. Findings Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7·0 days (SD 3·6) and 7·4 days (3·9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment difference 0·5%, 90% CI −9·5 to 10·4). Rates of adverse events were similar, but insomnia was more frequently reported in the oral group (77 77%) than in the intravenous group (63 64%). Interpretation Oral administration of high-dose methylprednisolone for 3 days was not inferior to intravenous administration for improvement of disability scores 1 month after treatment and had a similar safety profile. This finding could have implications for access to treatment, patient comfort, and cost, but indication should always be properly considered by clinicians. Funding French Health Ministry, Ligue Française contre la SEP, Teva.
The concept of induction treatment followed by long-term maintenance treatment in multiple sclerosis (MS) has attracted considerable attention. The combination of mitoxantrone as the induction ...therapy followed by an immunomodulatory drug (e.g., interferon beta or glatiramer acetate) as the maintenance therapy is of particular interest. This approach is suitable for patients with particularly aggressive disease, characterised by frequent relapses with incomplete recovery and the accumulation of focal lesions visible on magnetic resonance imaging. A long-term study has shown that a short (6 month) course of mitoxantrone followed by maintenance therapy with an immunomodulatory drug brings about a rapid reduction in disease activity and subsequent sustained disease control for at least 5 years. Furthermore, randomised studies have demonstrated that induction with mitoxantrone followed by maintenance treatment affords better disease control than monotherapy with an interferon beta. Natalizumab is also effective in patients with very active MS, but has a propensity to result in rebound inflammatory disease activity on withdrawal. More recently, a mere 5-day course of 12-mg intravenous perfusions of alemtuzumab was found to bring long-term clinical benefits in early relapsing MS patients at risk of developing severe systemic autoimmune disease within the space of a few years.
Background:
Multiple sclerosis (MS) is usually diagnosed between 20-40 years old, when women often plan to have children.
Objective:
Our objectives were to estimate pregnancy incidence rates in women ...with multiple sclerosis (MS), and to describe the use of disease-modifying therapies (DMTs) before conception and during pregnancy, and pregnancy outcomes.
Methods:
This retrospective cohort study included all 15- to 49-year-old women with MS in the French national health insurance database over 2010–2015. A pregnancy was exposed if a DMT reimbursement claim occurred during pregnancy or in the 14 preceding days. We used zero-inflated negative binomial (ZINB) regression models to estimate incidence rates and ordinal and multinomial regression models to estimate DMT exposure and pregnancy outcomes.
Results:
The pregnancy incidence rate was 4.5 per 100 person-years. The probability of having a DMT-exposed pregnancy increased from 0.22 in 2010 to 0.30 in 2015. The probability of live birth was 0.72 (95% CI = 0.70–0.74) for exposed pregnancies (varied considerably among DMTs), 0.77 (95% CI = 0.76–0.79) without treatment, and 0.81 (95% CI = 0.79–0.83) if treatment was stopped within the previous year.
Conclusion:
In this population-based study, we showed an increase of exposed pregnancies over time, beta-interferon and glatiramer acetate being the most used DMTs and associated with the highest probabilities of live birth. Interrupted exposed pregnancies may reflect undesired pregnancies or fear of an adverse outcome, while recent DMT stop probably reflects pregnancy planning.
Background:
Changes in relapse activity during secondary progressive multiple sclerosis (SPMS) need to be accurately characterized in order to identify patients who might benefit from continuing ...disease-modifying therapies.
Objective:
To describe relapse occurrence in patients with SPMS during long-term follow-up and assess its impact on disability worsening.
Methods:
This retrospective cohort study included 506 patients. We assessed the influence of relapses on time from SPMS onset to an Expanded Disability Status Scale score of 6 (EDSS 6), and on irreversible worsening of EDSS scores across different periods.
Results:
The annualized relapse rate (ARR) decreased with patient’s age (mean reduction of 43% per decade) and SPMS duration (mean reduction of 46% every 5 years). Post-progression relapses were associated with shorter time from secondary progressive (SP) phase onset to EDSS 6 (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = (1.01, 1.64)). Relapse occurrence during the first 3 years and 3–5 years after SP onset was associated with an increased risk of irreversible EDSS worsening (OR = 3.12 (1.54, 6.31) and 2.04 (1.16, 3.58)). This association was no longer significant after 5 years.
Conclusion:
The occurrence of relapses was a marker of short-term disability progression during early SPMS, but did not have decisive impact in later SPMS.
Background:
A recent controlled trial suggested that high-dose biotin supplementation reverses disability progression in patients with progressive multiple sclerosis.
Objective:
To analyze the impact ...of high-dose biotin in routine clinical practice on disability progression at 12 months.
Methods:
Progressive multiple sclerosis patients who started high-dose biotin at Nantes or Rennes Hospital between 3 June 2015 and 15 September 2017 were included in this prospective study. Disability outcome measures, patient-reported outcome measures, relapses, magnetic resonance imaging (MRI) data, and adverse events were collected at baseline, 6, and 12 months.
Results:
A total of 178 patients were included. At baseline, patients were 52.0 ± 9.4 years old, mean Expanded Disability Status Scale (EDSS) score was 6.1 ± 1.3, mean disease duration was 16.9 ± 9.5 years. At 12 months, 3.8% of the patients had an improved EDSS score. Regarding the other disability scales, scores either remained stable or increased significantly. In total, 47.4% of the patients described stability, 27.6% felt an improvement, and 25% described a worsening. Four patients (2.2%) had a relapse. Of the 74 patients (41.6%) who underwent an MRI, 20 (27.0%) had new T2 lesions, 8 (10.8%) had gadolinium-enhancing lesions. Twenty-five (14%) reported adverse event.
Conclusion:
In this study, high-dose biotin did not seem to be associated with a clear improvement in disability.
Many studies have investigated pregnancy in women with multiple sclerosis (MS). However, no study has measured prenatal healthcare utilization in women with MS or adherence to follow-up ...recommendations to improve antenatal care quality. A better knowledge of the quality of antenatal care in women with MS would help identify and better support women with insufficient follow-up. Our objective was to measure the level of compliance to prenatal care recommendations in women with MS using data from the French National Health Insurance Database.
This retrospective cohort study included all pregnant women with MS who gave live birth in France between 2010 and 2015. Using the French National Health Insurance Database, follow-up visits with gynecologists, midwives, and general practitioners (GPs) were identified, as well as ultrasound exams and laboratory tests. Based on the Adequacy of Prenatal Care Use and Content and Timing of care in Pregnancy indices, a new tool adapted to the French recommendations was developed to measure and classify the antenatal care trajectory (adequate or inadequate). Explicative factors were identified using multivariate logistic regression models. A random effect was included because women may have had more than one pregnancy during the study period.
In total, 4,804 women with MS (
= 5,448 pregnancies ending in live births) were included. When considering only visits with gynecologists/midwives, 2,277 pregnancies (41.8%) were considered adequate. When adding visits with GP, their number increased to 3,646 (66.9%). Multivariate models showed that multiple pregnancy and higher medical density were associated with better adherence to follow-up recommendations. Conversely, adherence was lower in 25-29-year-old and >40-year-old women, in women with very low income, and agricultural and self-employed workers. No visits, ultrasound exams, and laboratory tests were recorded in 87 pregnancies (1.6%). In 50% of pregnancies, women had at least one visit with a neurologist during the pregnancy, and women restarted disease-modifying therapy (DMT) within 6 months after delivery in 45.9% of pregnancies.
Many women consulted their GP during pregnancy. This could be linked to a low density of gynecologists but may also reflect the preferences of women. Our findings can help adapt recommendations and healthcare providers' practices according to the women's profiles.
Our study aimed to describe safety and neurological impact of alemtuzumab as last-line rescue therapy in aggressive multiple sclerosis (MS) patients, previously treated by Mitoxantrone (MITOX). ...Between June 2004 and October 2013, 13 patients received alemtuzumab at 20 mg/day and 3 at 12 mg/day for 5 days. EDSS, relapses, secondary progression were prospectively assessed 12 and 6 months before treatment, at baseline and every 3 months. Mean follow-up was 6.2 years 1–10. Mean age at alemtuzumab start was 40 years 26–49 for 8 Secondary Progressive (SP) and 30 years 26–35 for 8 Relapsing-Remitting (RR) patients. MS duration was 13.7 (±3) and 8.3 (±4) years, respectively. During the 12 months before alemtuzumab, annual relapse rate was 0.75 and 3.14, respectively and the 16 patients accumulated 2–30 new gadolinium enhancing lesions. 4 patients (suboptimal responders) received alemtuzumab during MITOX and 12 patients 1–7.8 years after MITOX. Out of 8 SPMS, 2 were disease free up to last visit (4.7 and 8 years), 5 improved or stabilized but only transiently and 1 worsened. Out of 8 RRMS, 1 remained stable up to last visit (8.7 years) despite 1 relapse and active MRI at 18 months and 7 improved (1–4 point EDSS): 4 remained disease free up to last visit (12, 24, 38 months and 7 years), 2 were successfully retreated at 25 and 33 months and 1 worsened progressively 24 months after alemtuzumab. 2 patients developed Grave’s disease and 1 hypothyroidism. Alemtuzumab controls aggressive RRMS despite previous use of MITOX.
Background:
Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy.
Objective:
To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with ...nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo.
Methods:
POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo.
Results:
Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58–1.39), placebo = 0.97 (0.63–1.50) (p = 0.79)).
Conclusion:
POPARTMUS failed showing efficacy of a NOMAc–E2 combination in preventing post-partum relapses.
After more than 2 decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable interest in the use of high-efficacy ...therapies in the early stage of the disease. Early intervention with induction/high-efficacy disease-modifying therapy may have the best risk-benefit profile for patients with relapsing-remitting multiple sclerosis who are young and have active disease, numerous focal T2 lesions on spinal and brain magnetic resonance imaging, and no irreversible disability. Although we have no curative treatment, at least seven classes of high-efficacy drugs are available, with two main strategies. The first strategy involves the use of high-efficacy drugs (e.g., natalizumab, sphingosine 1-phosphate receptor modulators, or anti-CD20 drugs) to achieve sustained immunosuppression. These can be used as a first-line therapy in many countries. The second strategy entails the use of one of the induction drugs (short-term use of mitoxantrone, alemtuzumab, cladribine, or autologous hematopoietic stem cell transplant) that are mainly recommended as a second-line or third-line treatment in patients with very active or aggressive multiple sclerosis disease. Early sustained immunosuppression exposes patients to heightened risks of infection and cancer proportionate to cumulative exposure, and induction drugs expose patients to similar risks during the initial post-treatment period, although these risks decrease over time. Their initial potential safety risks should now be revisited, taking account of long-term data and some major changes in their regimens: natalizumab with the long-term monitoring of John Cunningham virus; use of monthly courses of mitoxantrone with maximum cumulative doses of 36–72 mg/m
2
, followed by a safer disease-modifying drug; cladribine with only 2-weekly treatment courses required in years 1 and 2 and no systematic treatment for the following 2 years; alemtuzumab, whose safety and clinical impacts have now been documented for more than 6 years after the last infusion; and autologous haematopoietic stem cell transplant, which dramatically reduces transplantation-related mortality with a new regimen and guidelines. Escalation and induction/high-efficacy treatments need rigorous magnetic resonance imaging monitoring. Monitoring over the first few years, using the MAGNIMS score or American Academy of Neurology guidelines, considerably improves prediction accuracy and facilitates the selection of patients with relapsing-remitting multiple sclerosis requiring aggressive treatment.
Automatic tools for detecting new lesions in patients with MS between two MRI scans are now available to clinicians. They have been assessed from the radiologist's point of view, but their impact on ...the therapeutic strategies that neurologists offer their patients has not yet been documented.
To compare neurologist's decisions according to whether a lesion detection support system had been used and describe variability between neurologists on decision-making for the same clinical cases.
We submitted 28 clinical cases associated with pairs of MRI images and radiological reports (produced by the same radiologist without vs. with the help of a system to detect new lesions) to 10 neurologists who regularly follow patients with MS. They examined each clinical case twice (without vs. with support system) in two sessions several weeks apart, and their patient management decisions were recorded.
There was considerable variability between neurologists on decision-making (both with and without support system). When the support system had been used, neurologists more often made changes to patient management (75 % vs. 68 % of cases, p = 0.01) and spent significantly less time analyzing the clinical cases (249 s vs. 216 s, p == 3.10-4).
The use of a lesion detection support system has an impact not only on radiologists' reports, but also on neurologists' subsequent decision-making. This observation constitutes another strong argument for promoting the wider use of such systems in clinical routine. However, despite their use, there is still considerable variability in decision-making across neurologists, which should encourage us to refine the guidelines.
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