Background

Historically, disease activity diminished during pregnancy in women with relapsing-remitting MS. Today, women with high disease activity are more likely to attempt pregnancy due to the disease control that new therapies offer. But disease activity during pregnancy in the modern day remains understudied.

Objectives

Describe disease activity in a modern pregnancy cohort, grouped by preconception disease-modifying therapy (DMT) class; determine the predictors of relapse during pregnancy.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 were included. DMT were classed by low, moderate and high-efficacy. Annualized relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of relapse during pregnancy were determined using clustered logistic regression.

Results

We included 1640 pregnancies from 1452 women. DMT used in the year before conception were none (n=346), low (n=845), moderate (n=207) and high-efficacy (n=242). Most common DMT in each class was interferon-beta (n=597), fingolimod (n=147) and natalizumab (n=219) for low, moderate and high-efficacy respectively. Conception EDSS ≥2 was more common in higher efficacy DMT groups (high: 41.3%; moderate 28.5%; low 22.4%; none 20.2%). For low-efficacy and no DMT groups, ARR fell through pregnancy. ARR of the moderate-efficacy group increased in the 1^st pregnancy trimester (0.55 [95% CI 0.36-0.80] vs 0.14 [95% CI 0.10-0.21] on low-efficacy), then decreased to a trough in the third. Conversely, ARR steadily increased throughout pregnancy for those on high-efficacy DMT (3^rd trimester: 0.42 [95% CI 0.25-0.66] vs 0.12 [95% CI 0.07-0.19] on low-efficacy). Higher efficacy DMT groups were associated with higher ARR in the early postpartum period (high: 0.84 [95% CI 0.62-1.1]; moderate: 0.90 [95% CI 0.65-1.2]; low: 0.47 [95% CI 0.38-0.58]). Preconception use of high and moderate-efficacy DMT and higher preconception ARR were predictors of relapse in pregnancy. But, continuation of high-efficacy DMT into pregnancy was protective against relapse (odds ratio 0.80 [95% CI 0.68-0.94]). Age ≥35 years was associated with reduced odds of relapse.

Conclusions

Women with RRMS treated with moderate or high-efficacy DMT are at greater risk of relapse during pregnancy. Careful pregnancy management, and use of long-acting high-efficacy DMT preconception, or continuing natalizumab into pregnancy, may prevent relapse in pregnancy.

Background

Similar to other neurodegenerative disorders, the onset of progressive MS is related to age, a factor known to amplify neurodegeneration. Recent studies have shown that exposure of aged mice to a young blood circulation through parabiosis or administration of young blood plasma (plasma from 3-month-old mice) reverses cognitive deficits observed with normal ageing.

Objectives

We aimed to search for soluble factors in the serum of patients with progressive MS that are affected by age and are differentially decreased in patients compared to healthy controls (HC) of similar age.

Methods

Protein levels were determined in serum samples from a cohort of 30 untreated MS patients (15 patients with secondary progressive MS - SPMS - and 15 with primary progressive MS - PPMS) and 25 HC. Progressive MS patients were classified according to age and clinical characteristics into the following three groups (each group containing 10 patients, 5 with SPMS and 5 with PPMS): (i) 40 ± 3 years old, disease duration <10 years, EDSS <4.5; (ii) 50 ± 3 years old, disease duration between 10-20 years, EDSS between 4.5-6; and (iii) 60 ± 3 years old, disease duration >20 years, EDSS >6.5. HC were classified based on age into the following groups (each group containing 5 individuals): 20, 30, 40, 50, and 60 ± 3 years old. To maximize the breadth and depth of serum proteome coverage, the top 70 abundant proteins in serum were depleted. Afterwards, samples were subjected to mass spectrometry.

Results

After depletion of the most abundant proteins in serum, a total of 2,059 molecules were detected in all 55 samples. The maSigPro package (R Bioconductor) was used to identify proteins with significantly divergent expression profiles as a function of time. A quadratic regression model was fit for each molecule and 823 proteins, among the 2059 analyzed, were found differentially expressed (FDR < 0.05) between the MS group and HC. The serum levels of the following proteins were significantly decreased by ageing in progressive MS patients compared with HC and were selected for further studies: PLXDC2, Neudesin, Myostatin, Myocilin, and EMMPRIN.

Conclusions

Protein expression profiling associated with ageing in progressive MS patients and HC lead to the identification of number of promising candidates associated with neurotrophic functions, myelination, and nervous system development. Results obtained by mass spectrometry need to be validated by targeted immunoassays.

Background

Teriflunomide is a once-daily oral immunomodulator approved for treating relapsing multiple sclerosis (RMS) and relapsing-remitting MS, depending on the local label. Efficacy and safety of teriflunomide were established in the phase 2 (NCT01487096) and phase 3 trials of patients with RMS (TEMSO [NCT00134563], TOWER [NCT00751881], TENERE [NCT00883337]) and clinically isolated syndrome (TOPIC [NCT00622700]). In post hoc analysis of TEMSO patients stratified by age, structural image evaluation using normalization of atrophy (SIENA) revealed teriflunomide 14 mg significantly reduced the percentage of brain volume change in patients aged >25 to ≤35 years (48%; P=0.0217) and >45 to ≤55 years (35%; P=0.0092) versus placebo over 2 years.

Objectives

To analyze the effect of teriflunomide treatment on MRI lesion activity in TEMSO study patients with RMS stratified by age.

Methods

In TEMSO, patients were randomized 1:1:1 to receive either placebo or teriflunomide 7 mg or 14 mg for ≤108 weeks (Year 2). Through Year 2, MRI lesion activity (unique combined active lesions [UCAL], contrast-enhancing T1 weighted lesions [CEL], and T2 weighted [T2w] lesions) and safety were assessed in the SIENA analysis subgroup; patients were stratified by age at baseline: ≥18 to ≤25 years (n=97 [10%]); >25 to ≤35 years (n=283 [29%]); >35 to ≤45 years (n=388 [40%]); and >45 to ≤55 years (n=201 [21%]). P values between treatment groups were determined for MRI lesions using a Poisson model.

Results

Of 1086 patients in the TEMSO core study, 969 (89%) had scans appropriate for SIENA analysis. Compared with placebo, teriflunomide 14 mg significantly reduced the number of UCAL (0.31–1.44 vs 0.92–6.11 lesions; P≤0.0013) and CEL (0.10–0.46 vs 0.54–3.42 lesions; P≤0.0001) per scan across all age groups. In all age groups except the >45 to ≤55 years group, teriflunomide 14 mg significantly reduced the number of T2w lesions (0.50–0.93 vs 1.07–2.80 lesions; P≤0.001) per scan versus placebo. Similar effects on MRI lesion activity were seen with teriflunomide 7 mg versus placebo. Incidence of adverse events (AEs) generally increased with age, with no deaths reported through Year 2.

Conclusions

Over 2 years in TEMSO RMS patients, teriflunomide reduced the number of new MRI lesions versus placebo across age groups. Significant treatment effects were seen with teriflunomide 14 mg across all age groups for UCAL and CEL. Age-related increases in AEs were observed through Year 2.

STUDY SUPPORT: Sanofi.

Background

Ocrelizumab is the first drug approved as disease modifying treatment for primary progressive (PP) multiple sclerosis (MS). As a humanized monoclonal antibody targeting CD20 cells, it is widely known that ocrelizumab treatment results in B cells depletion, but less is known about the effects of this drug in other blood leukocyte subsets of PPMS patients.

Objectives

To explore the changes induced by ocrelizumab in blood immune cells of PPMS patients to further understand their effects in the abnormal inflammatory response.

Methods

Multi-centre prospective longitudinal study including fifty‐three PPMS patients who initiated ocrelizumab treatment. Effector, memory, and regulatory cells were analyzed by flow cytometry at baseline and after 6 months of treatment. To assess differences between baseline and after 6 months, Wilcoxon matched paired tests were used and p values were corrected using Bonferroni test.

Results

Ocrelizumab decreased numbers of naïve and memory B cells (p<0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (p<0.0001 in all cases). A reduction of CD20+ T cell numbers (p=0.02) and percentages (p<0.0001) was also observed. We also detected a clear remodelation of the T cell compartment characterized by relative increases of the naïve/effector ratio in CD4+ (p=0.002) and CD8+ (p=0.002) T cells, and relative decreases of CD4+ (p=0.03) and CD8+ (p=0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p=0.002), with no changes in those producing inflammatory cytokines. All these changes resulted in a reduction of serum neurofilament light chain (sNfL) levels (p=0.009).

Conclusions

Effector B cell depletion by ocrelizumab treatment induces changes in the T cell response of PPMS patients towards a low inflammatory profile. This resulted in a decrease of sNfL levels.

Background

Background: Diffusion magnetic resonance imaging can reveal quantitative information about the tissue changes in multiple sclerosis. The recently developed multi-compartment spherical mean technique can map different microscopic properties based only on local diffusion signals, and it may provide specific information on the underlying microstructural modifications that arise in multiple sclerosis.

Objectives

Objective: Given that the lesions in multiple sclerosis may reflect different degrees of damage, we hypothesized that quantitative diffusion maps may help characterize the severity of lesions “in vivo” and correlate these to an individual’s clinical profile.

Methods

Methods: We evaluated a cohort of 59 MS patients (62% female, mean age 44.7 years), for whom demographic and disease information was obtained, and who underwent a comprehensive physical and cognitive evaluation. MRI protocol included conventional sequences to define focal lesions and multi-shell diffusion imaging. Quantitative diffusion properties were used to discriminate distinct types of lesions through a k-means clustering algorithm, and the number and volume of those lesions were correlated with parameters of the disease.

Results

Results: The combination of microscopic and macroscopic diffusion properties differentiated two types of lesions, with a prediction strength of 0.931. The type B lesions had larger diffusion changes compared to the type A lesions, irrespective of their location (P <0.001). The number and volume of type B lesions was related to the severity of disease evolution, clinical disability and cognitive decline (P =0.004, Bonferroni correction). Specifically, more and larger type B lesions were correlated with a worse Multiple Sclerosis Severity Score, cerebellar function and cognitive performance, and a greater need for high-efficacy treatments.

Conclusions

Conclusions: The severity of damage within focal lesions have the potential to permit more specific understanding of the mechanisms that drive disease evolution.

Background

People with MS present disruption of structural brain networks, but the differential characteristics of such changes among MS phenotypes and their clinical impact are not well elucidated.

Objectives

To characterize diffusion-based brain connectivity abnormalities in different MS phenotypes and their relation with disability in a large cohort of patients.

Methods

In this multicenter, retrospective, cross-sectional study, we collected clinical and brain MRI data from 344 patients with MS [median Expanded Disability Status Scale, EDSS 2.0 (range 0-7.0)] and 91 healthy volunteers (HV) from four MAGNIMS centers. Cognition was assessed with the Paced Auditory Serial Addition Test (PASAT) and Symbol Digits Modalities Test (SDMT) in 298 patients. We collected 3D-T1, FLAIR, diffusion-weighted images (DWI) and T2 or field maps acquisitions. FSL and ANTs packages were used to carry out DWI preprocessing and MRtrix software to generate connectivity matrices based on fractional anisotropy values. We computed six network measures (strength, global and local efficiency, clustering coefficient, assortativity and transitivity), and applied the ComBat tool to reduce inter-site variability. We calculated age-adjusted differences in graphs between groups using Mann-Whitney with FDR correction or Kruskal-Wallis with Dunn’s Test when necessary. Associations with clinical features were explored with Spearman’s rank correlation.

Results

Thirty-eight (11%) patients presented a clinically isolated syndrome (CIS), 262 (76%) had relapsing-remitting (RR) and 44 (13%) secondary progressive (SP) MS. CIS patients showed reduced global and local efficiency, clustering coefficient and transitivity compared to HV (corrected p<0.001), whilst RRMS did not differ from CIS patients. Compared with CIS and RRMS, patients with SPMS showed larger changes for the same previous graphs measures (corrected p<0.05), and lower strength than RRMS (corrected p=0.019).

In patients, reduced measures of strength, global and local efficiency, clustering and transitivity correlated with higher EDSS (rho:-0.12–-0.16, corrected p<0.034), lower PASAT (rho:0.26–0.30, corrected p<0.001) and worse SDMT scores (rho:0.28–0.32, corrected p<0.001).

Conclusions

Structural network integrity at the whole brain level is already widely reduced in people with MS from the earliest phases of the disease and becomes more abnormal in SPMS. Network modifications may contribute to the clinical manifestations of the disease.

Background

Interleukin-6 (IL-6) is implicated in the immunopathology of neuromyelitis optica spectrum disorder (NMOSD). Satralizumab, a humanized recycling monoclonal antibody that inhibits the IL-6 receptor, demonstrated a reduction in NMOSD relapse risk in two phase 3 studies: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To evaluate the safety of satralizumab vs placebo in a pooled population of NMOSD patients from the SAkura studies, including the latest data from the open-label extension (OLE) period of the studies.

Methods

SAkuraStar and SAkuraSky are randomized studies comprising a double-blind (DB) period (satralizumab 120mg Q4W vs placebo) followed by an OLE period (satralizumab only). The combined DB and extension period was defined as the overall satralizumab treatment (OST) period (cut-off: 7 Jun 2019). Safety was evaluated in the DB and OST periods and reported as adverse event (AE) rates per 100 patient-years (PY).

Results

The pooled DB population included 178 patients (satralizumab, n=104; placebo, n=74), and 166 patients received satralizumab in the OST. Median duration of safety observation with satralizumab was 96.1 weeks in the DB period and 131.9 weeks in the OST period. Rates of AEs and serious AEs were comparable between satralizumab and placebo groups in the DB period (AEs: 478.49 vs 506.51 events/100PY, respectively; serious AEs: 14.97 vs 17.98 events/100PY, respectively), and were consistent in the OST period. In the DB period, four patients (3.8%) in the satralizumab group and five (6.8%) in the placebo group discontinued treatment due to AEs. Serious infection rates were comparable between the satralizumab and placebo groups in the DB period (4.13 vs 6.99 events/100PY) and remained stable in the OST (3.88 events/100PY). No opportunistic infections were observed in the satralizumab group. The injection-related reaction (IRR) rate was higher with satralizumab vs placebo in the DB period (17.03 vs 8.99 events/100PY); IRRs were mostly mild-to-moderate and did not lead to treatment discontinuation. Laboratory abnormalities were in line with those expected with IL-6 receptor antagonists in the DB and OST period. No deaths or anaphylactic reactions were reported.

Conclusions

In NMOSD patients, satralizumab was well tolerated and showed a favorable safety profile. Results from the OST period were consistent with the DB period.

Background

Cognitive decline is frequent in patients with multiple sclerosis (MS). The cognitive trajectory is not well understood and a global overview throughout the disease course needs to be elucidated. Besides, predictors of future cognitive decline are still needed.

Objectives

We aim to (a) assess the temporal dynamics of cognitive function through disease course, and (b) explore different clinical and MRI predictors of cognitive decline in a large cohort of patients with MS.

Methods

Longitudinal study with 212 MS patients who performed a total of 605 neurological, cognitive and MRI examinations at different times of the disease [examinations per patient: 3 (IQR:2-3); baseline age: 40.2 (IQR:34.5-47.6) years; baseline disease duration: 8.2 (IQR:2.3-13.9) years]. A z-score for global cognition (z-BRB) and for each cognitive domain was obtained from the Rao's Battery, and a 3D-structural MRI was acquired to calculate regional gray matter (GM) volumes. We modelled the dynamics of cognition throughout the MS course using age at MS onset, education and sex adjusted mixed-effects linear spline models with knots at 5 and 15 years. An age and sex adjusted multivariate regression model was performed to determine which factors at the first examination best predict cognitive performance at last follow-up in the entire sample.

Results

In the first 5 years of MS, we detected an increase in z-BRB (β=0.050, p=0.004) and z-attention (β=0.048, p=0.013), followed by a decline in z-BRB (β=-0.029, p=0.005) and z-verbal memory (β=-0.049, p=0.001) between the 5-15 years of the disease. During the 15-30 years of MS course, the cognitive decline was maintained, but also involved z-attention (β=-0.035, p=0.012). Lower education, higher EDSS and volumetric changes at right parahippocampus, left parsorbitalis, left superior, left middle and right inferior temporal, and right superior parietal areas at the first examination were associated with worse z-BRB at the last follow-up (adjR2=0.48, β=-0.652–0.863, p=<0.001–0.024).

Conclusions

In MS, cognition deteriorates after the first 5 years of the disease, with a steady decline over the next 25 years. The verbal memory is affected earlier and more markedly, followed by involvement of attention and information processing speed. Moreover, education, clinical disability and GM volume at baseline are associated with future cognitive outcomes.

Background

Around 50% of patients with multiple sclerosis (MS) present a decline in cognitive behavior that impacts negatively on their autonomy, social and working skills. The benefits of cognitive rehabilitation on cognition and brain plasticity are not well understood due to methodological limitations of most studies, such the use of an inappropriate control group or the small number of patients included.

Objectives

To study the efficacy on attention, processing speed and working memory of a cognitive training program in patients with MS.

Methods

Multi-center, phase II, double-blind and randomized clinical trial to a treatment group (upward intensity training) or control group (low intensity static training). Patients were assessed using Rao's battery before and after 12 weeks of online training with the Guttmann, NeuroPersonalTrainer® (GNPT). The main objective was to demonstrate an improvement in attention and working memory tests (Pasat Auditory Serial Addition Test, PASAT, and Symbol Digit Modalities Test, SDMT) in the treatment group.

Results

The recruitment is still active. In an interim analysis on May 2020, 61 patients had been evaluated, of whom 35 fulfilled the inclusion criteria, and 23 had completed the follow-up period (age 48.8±7.4, disease duration 19.2±9.3 years). Ten patients had been assigned to the treatment group and 13 to the control group. The treatment group showed a significant reduction in z-scores of attention and working memory tests (z-score=-1.68±0.90 at baseline and -1.26±1.05 at follow up) compared to the control group (-1.78±0.63 at baseline and -1.45±1.06 at follow up), p corrected=0.003, and a trend for verbal memory (treatment group z-score -2.19±1.14 and -1.61±1.68 and sham group z-score -1.38±1.32 and -1.34±1.5 at baseline and follow up respectively, corrected p=0.074). There were no significant changes in other cognitive domains (verbal, visual, and fluency memory).

Conclusions

This preliminary analysis shows that intensive rehabilitation focused on attention, information processing speed and working memory can improve these cognitive functions.

Background

Patients with neuromyelitis optica spectrum disorders (NMOSD) experience a spectrum of symptoms negatively impacting on daily living and quality of life. The systematic assessment of patient perspectives has the capacity to provide crucial clinical information that could otherwise be lost when relying on clinical evaluation alone. However, the patient experience living with NMOSD is limited, in particular implementing standardized patient-reported outcomes (PROs).

Objectives

The primary objective of this study protocol is to assess the health-related quality of life and well-being of NMOSD patients.

Methods

A multicenter, non-interventional, cross-sectional study will be conducted with patients diagnosed with NMOSD (2015 Wingerchuk criteria) (PERSPECTIVES-NMO Study). Primary outcomes measures will be the 29-item Multiple Sclerosis Impact Scale and the Satisfaction with Life Scale. Demographic characteristics, clinical and imaging outcomes will be collected, including the number and type of attacks, antibody status, Expanded Disability Status Scale score, Nine-Hole Peg Test, Timed 25-Foot Walk, and Magnetic Resonance Imaging findings. Cognition will be evaluated using the Rao Brief Repeatable Neuropsychological Battery. Additional outcomes from the patient´s perspective (PROs) will be collected, including symptoms severity (SymptoMScreen questionnaire), fatigue (Fatigue Impact Scale for Daily Use), pain (MOS Pain Effects Scale), mood (Beck Depression Inventory-Fast Screen), perception of stigma (8-item Stigma Scale for Chronic Illness), and work-related difficulties (23-item Multiple Sclerosis Work Difficulties Questionnaire).

Results

Patient recruitment began in December 2019 with a planned total sample of 70 patients. The study is currently ongoing.

Conclusions

The study results are expected to provide meaningful insights into the clinical burden of disease. A better understanding of patient experiences may foster the development of patient-centered specific plans and more targeted rehabilitation in clinical practice.

Background

Disease activity has been investigated in pregnant women with RRMS treated with low-efficacy or no therapy. How newer, more efficacious therapies affect relapse and disability progression risk after pregnancy remains understudied.

Objectives

To describe disease activity in a modern pregnancy cohort contrasted with historical cohorts. To determine the predictors of postpartum relapse and the predictors of six-month confirmed disability progression events in a contemporary pregnancy cohort.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 (modern cohort) were compared with those conceived between 2005-2010 and pre-2005. Annualised relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of time-to-relapse postpartum (1^st 3 months) and time to 6-month confirmed disability progression event were determined with clustered Cox regression analyses. Breastfeeding duration and time to DMT reinitiation were modelled as time-varying covariates.

Results

We included 1640 pregnancies from 1452 women (modern cohort). Disease-modifying therapy (DMT) used in the year before conception included interferon-beta (n=597), natalizumab (n=219) and fingolimod (n=147). Continuation of DMT up to conception increased over time (31% pre-2005 vs 54% modern cohort). Preconception ARR decreased across epochs (pre-2005: 0·58 [95% CI 0·49-0·70]; 2005-2010: 0·40 [95% CI 0·36-0·45]; modern: 0·29 [95% CI 0·27-0·32]). In all epochs, ARR decreased during pregnancy to reach similar troughs in the 3^rd trimester, and rebounded in the 1^st 3-months postpartum. Preconception use of high-efficacy DMT predicted early postpartum relapse (hazard ratio (HR) 2.1 [1.4-3.1]); although those on no DMT were also at risk of postpartum relapse, relative to women on low-efficacy DMT (HR 2.7 [1.2-5.9]). Conception EDSS ≥2, higher preconception and in-pregnancy ARR were also risk factors. DMT reinitiation, particularly of high-efficacy DMT (HR 0.17 [0.07-0.38]), was protective against postpartum relapse. Women who breastfed were less likely to relapse (HR 0.63 [0.42-0.94]). 4.5% of modern pregnancies had confirmed disability progression after delivery. This was predicted by higher pregnancy and postpartum ARR, with postpartum ARR remaining independently predictive in multivariable analysis (HR 1.5 [1.2-2.0]).

Conclusions

The early postpartum period remains a period of vulnerability for disease rebound in women with MS in the modern era. Early DMT reinitiation, particularly with high-efficacy treatment, is protective against postpartum relapse. Confirmed disability progression events after pregnnacy are uncommon in the modern era. Relapse activity is the key driver of these events.