Exogenous sexual steroids together with pregnancy have been shown to influence the risk of relapses in multiple sclerosis (MS). Treatments used during assisted reproductive techniques may ...consequently influence the short term evolution of MS by modifying the hormonal status of the patient. The objective of this study was to determine if there was an increased risk of developing exacerbations in women with MS after in vitro fertilisation (IVF).
MS and IVF data were either automatically extracted from 13 French university hospital databases or obtained from referring neurologists. After matching databases, patient clinical files were systematically reviewed to collect information about MS and the treatments used for IVF. The association between IVF and the occurrence of MS relapses was analysed in detail using univariate and multivariate statistical tests.
During the 11 year study period, 32 women with MS had undergone 70 IVF treatments, 48 using gonadotrophin releasing hormone (GnRH) agonists and 19 using GnRH antagonists. A significant increase in the annualised relapse rate (ARR) was observed during the 3 month period following IVF (mean ARR 1.60, median ARR 0) compared with the same period just before IVF (mean ARR 0.80, median ARR 0) and to a control period 1 year before IVF (mean ARR 0.68, median ARR 0). The significant increase in relapses was associated with the use of GnRH agonists (Wilcoxon paired test, p=0.025) as well as IVF failure (Wilcoxon paired test, p=0.019).
An increased relapse rate was observed in this study after IVF in patients with MS and may be partly related both to IVF failure and the use of GnRH agonists.
Objective:
To evaluate the effectiveness and tolerance of mycophenolate mofetil (MMF) as a first-line treatment in neuromyelitis optica spectrum disorder (NMOSD).
Methods:
In all, 67 NMOSD patients ...treated by MMF as first-line therapy, from the NOMADMUS cohort were included. A total of 65 fulfilled 2015 NMOSD criteria, and 5 were myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) positive. Effectiveness was evaluated on percentage of patients continuing MMF, percentage of patients free of relapse, pre- and post-treatment change in the annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS).
Results:
Among 67 patients, 40 (59.7%) continued treatment till last follow-up. A total of 33 (49.3%) were relapse-free. The median ARR decreased from one pre-treatment to zero post-treatment. Of 53 patients with complete EDSS data, the score improved or stabilized in 44 (83%; p < 0.05). Effectiveness was observed in aquaporin-4 (AQP4)-IgG (57.8% continued treatment, 46.7% relapse-free), MOG-IgG (3/5 continued treatment, 4/5 relapse-free), and seronegative NMOSD (64.7% continued treatment, 61.3% relapse-free). In 16 patients with associated steroids, 13 (81.2%) continued MMF till last follow-up versus 15 of 28 (53.6%) in the non-steroid group. Nine patients discontinued treatment for tolerability purpose.
Conclusion:
MMF showed effectiveness and good tolerability as a first-line therapy in NMOSD, whatever the AQP4-IgG status. Concomitant use of oral steroids at start could limit the risk of treatment failure.
There is growing evidence of a preventive effect of Rituximab (RTX) in neuromyelitis optica spectrum disorders (NMO-SD). This monoclonal antibody against CD20 is becoming the most widely used ...preventive therapy in NMO-SD, as a first-line therapy or as a rescue therapy. Nevertheless, considerable heterogeneity still exists concerning the pre-treatment work-up, the vaccinations required before and under treatment, the number and dosage of infusions, prevention of the risk of infusion-related reactions, prevention of infections under treatment, and frequency of therapeutic cycles. Thanks to a collaborative work among NMO-SD experts belonging to the NOMADMUS project, we provide here recommendations for all these topics concerning RTX use in NMO-SD.
Background
No specific treatment has demonstrated its effectiveness to prevent post-partum relapses for multiple sclerosis (MS) women.
Objective
To assess the effectiveness of preventive high-dose ...corticosteroids in the post-partum period by comparing two strategies: (1) no preventive treatment and (2) standardized preventive treatment.
Methods
We selected five French Multiple Sclerosis centers using the same post-partum strategy for their patients—either high-dose steroids (treating centers TC) or no treatment (non-treating centers NTC). We included relapsing–remitting multiple sclerosis women who delivered between January 2007 and January 2017. Our primary outcomes were the time from delivery to first relapse, EDSS progression and MRI activity between patients of treating centers and non-treating centers, after propensity-score weighting.
Results
350 patients were included (116 from treating centers, 234 from non-treating centers). For both groups, the annualized relapse rate decreased during pregnancy (0.28 in treating centers and 0.34 in non-treating centers during the third trimester) and increased during the first post-partum trimester (0.45 and 0.69, respectively) with 11% and 14% (NS) of patients facing at least one relapse, respectively. Our primary outcomes were not statistically different between both groups.
Conclusion
This study provides class III evidence that systematic high-dose corticosteroids are not associated with a reduced inflammatory activity during the post-partum period in multiple sclerosis patients.
Objective
Multiple sclerosis (MS) is a multifactorial disease with increasingly complicated management. Our objective is to use on‐demand computational power to address the challenges of dynamically ...managing MS.
Methods
A phase 3 clinical trial data (NCT00906399) were used to contextualize the medication efficacy of peg‐interferon beta‐1a vs placebo on patients with relapsing–remitting MS (RRMS). Using a set of reference patients (PORs), selected based on adequate features similar to those of an individual patient, we visualize disease activity by measuring the percentage of relapses, accumulation of new T2 lesions on MRI, and worsening EDSS during the clinical trial.
Results
We developed MS Vista, a functional prototype of clinical decision support system (CDSS), with a user‐centered design and distributed infrastructure. MS Vista shows the medication efficacy of peginterferon beta‐1a versus placebo for each individual patient with RRMS. In addition, MS Vista initiated the integration of a longitudinal magnetic resonance imaging (MRI) viewer and interactive dual physician‐patient data display to facilitate communication.
Interpretation
The pioneer use of PORs for each individual patient enables personalized analytics sustaining the dialog between neurologists, patients and caregivers with quantified evidence.
Neuromyelitis optica spectrum disorder (NMOSD) attacks require an urgent probabilistic anti-inflammatory therapeutic strategy. As inadequately treated attacks result in disability, there is a need to ...identify the optimal attack-treatment regimen. Our study aimed to identify predictors of outcome after a first attack in patients with an NMOSD presentation and propose the best treatment strategy.
We performed a retrospective cohort study on the French national NMOSD registry (NOMADMUS), a nested cohort of the French multiple sclerosis observatory (OFSEP) recruiting patients with NMOSD presentations in France. We studied the first attack for any independent locations of clinical core characteristic of NMOSD, in treatment-naïve patients. The primary outcome was the evolution of the Expanded Disability Status Scale (EDSS) score at 6 months, stratified in two ways to account for recovery (return to baseline EDSS score) and treatment response (classified as "good" if the EDSS score decreased by ≥ 1 point after a nadir EDSS score ≤ 3, or by ≥ 2 points after a nadir EDSS score > 3). We used ordinal logistic regression to infer statistical associations with the outcome.
We included 211 attacks among 183 patients (104 with anti-AQP4 antibodies, 60 with anti-MOG antibodies, and 19 double seronegative). Attack treatment regimens comprised corticosteroids (n = 196), plasma exchanges (PE; n = 72) and intravenous immunoglobulins (n = 6). Complete recovery was reached in 40 attacks (19%) at 6 months. The treatment response was "good" in 134 attacks (63.5%). There was no improvement in EDSS score in 50 attacks (23.7%). MOG-antibody seropositivity and short delays to PE were significantly and independently associated with better recovery and treatment response.
We identified two prognostic factors: serostatus (with better outcomes among MOG-Ab-positive patients) and the delay to PE. We, therefore, argue for a more aggressive anti-inflammatory management of the first attacks suggesting an NMOSD presentation, with the early combination of PE with corticosteroids.
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective ...treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages.
SummaryBackground 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
Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment ...strategies for POMS still lack consensus.
To assess the real-world association of HET as an index treatment compared with MET with disease activity.
This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.
HET or MET at treatment initiation.
The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.
Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean SD age, 16.0 1.8 years; 364 female 68.7%) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio HR, 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio OR, 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).
Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.
Significant alterations in the transmigration capacity of peripheral blood T‐lymphocytes found as a feature in multiple sclerosis.
Mechanisms of T lymphocyte trafficking in the brain remain unclear ...in MS. We hypothesized that MS is associated with increased CD4+ and CD8+ T lymphocyte trafficking across the BBB. To test this hypothesis, we calculated the frequency of PSGL‐1+/CD4+ and PSGL‐1+CD8+ or LFA‐1+/CD4+/CD8+ T cells in the PBMC of 27 patients with a RR‐MS (21 untreated and six IFN‐β‐treated) and 18 HI. Next, we measured their ex vivo TR across resting and TNF‐α‐activated human BBB‐derived hCMEC/D3 endothelial layers under static conditions. The frequency of PSGL‐1+CD4+ T lymphocytes was significantly higher in treated or untreated MS patients than HI. Furthermore, resting hCMEC/D3 TR of CD4+ lymphocytes (purified or in PBMC) from treated or untreated MS patients were significantly higher than those of HI and associated with significant enrichments of CD4+PSGL+ or CD4+PSGL‐1+CD45RO+ T cells in their transmigrating fractions. The TR of CD4+ and CD8+ from MS patients across TNF‐α‐activated hCMEC/D3 were also significantly higher than that observed in HI. Resting hCMEC/D3 transmigration was blocked significantly by anti‐PSGL‐1/anti‐LFA‐1 in all groups, and anti‐VLA‐4 inhibited transmigration of MS T cells specifically. Purified PSGL‐1‐negative CD4+ lymphocytes transmigrated resting hCMEC/D3 with <10% of transmigrating cells re‐expressing PSGL‐1, suggesting PSGL‐1‐independent transmigration mechanisms. The frequency of PSGL‐1 was unchanged in CD8+ cells from MS patients, whereas CD8+LFA‐1high were reduced significantly in IFN‐β‐treated patients specifically. Collectively, MS is associated with an expanding pool of PSGL‐1+CD4+ T lymphocytes able to transmigrate the BBB endothelium in vitro and possibly contributing to brain pathology.
PDF
