Evidence of disease activity during pregnancy and post-partum in MS patients treated with high-efficacy therapies.

BACKGROUND: Multiple sclerosis (MS) predominantly affects women of childbearing age. Due to the risk of teratogenicity, women with active multiple sclerosis (MS) who require high-efficacy therapies (HET) may need to discontinue treatment during pregnancy. Fingolimod and Natalizumab withdrawal increases the risk of disease reactivation, a risk not commonly associated with anti-CD20 therapies. However, comparative data are limited during pregnancy and post-partum. Our aim was to compare evidence of disease activity during pregnancy and post-partum in women treated with HET (anti-CD20 therapies, Natalizumab or Fingolimod) before conception, whether or not exposed during pregnancy. METHODS: In this single-center retrospective study, we included consecutive pregnancies of relapsing-remitting MS patients and classified them in three groups according to the last HET used before conception: « anti-CD20 ¼ « Natalizumab (NTZ) ¼ and « Fingolimod (FGD) ¼. The main outcome was annualized relapse rate (ARR) during pregnancy and post-partum. RESULTS: We included 66 pregnancies: 21, 24 and 21 in anti-CD20, NTZ and FGD groups respectively. Overall, mean ARR (SD) increased from 0.36 (0.6) during the preconception year to 0.60 (1.3) during pregnancy and to 1.03 (2.0) in the first 3 months post-partum. Mean ARR in anti-CD20 group (0.09 (0.3)) during pregnancy and the first 3 months post-partum was lower compared with NTZ (0.48 (0.6); p = 0,09) and FGD (1.50 (1.8); p = 0.001) groups. Proportion of pregnancies with radiological activity during pregnancy and post-partum in anti-CD20 group (5.2 %) was lower compared with NTZ (63.1 %; p < 0.001) and FGD (72.2 %; p < 0.001) groups. There was no significant difference in the evolution of EDSS score from conception to post-partum between each group (p = 0.75). CONCLUSION: Evidence of disease activity was significantly lower in patients exposed to anti-CD20 therapies before conception. This study suggests that use of anti-CD20 therapies is an efficient option to prevent disease reactivation during pregnancy and post-partum.

Impact of Immune Checkpoint Inhibitors on the Course of Multiple Sclerosis.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are increasingly used in cancer treatment. Their mechanism of action raises the question of possible exacerbation of preexisting multiple sclerosis (MS). The aim of our study was to assess the risk of increased MS activity, defined by the occurrence of a relapse and/or a new MRI lesion, after ICI initiation. METHODS: This French multicentric study collected retrospective and prospective data on patients with MS treated with ICIs after a cancer diagnosis. RESULTS: We identified 18 patients with a median age of 48 years. Three of them (17%), all aged 50 years or younger, with a relapsing-remitting course, showed clinical and/or radiologic signs of MS activity 3 to 6 months after ICI initiation. They had stopped disease-modifying treatment (DMT) several months earlier, at the time of cancer diagnosis. Only one had both clinical and MRI activity, with mild severity and complete recovery. DISCUSSION: Our study suggests that the overall risk of MS activity under ICI is low and could be mainly driven by DMT discontinuation, as in MS in general. Although larger studies are needed for better risk assessment in younger patients with more active disease, ICI should be considered when needed in patients with MS.

Cancer and multiple sclerosis: 2023 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. OBJECTIVE: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). METHODS: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. RESULTS: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. CONCLUSION: These recommendations propose a strategic approach to managing cancer risk in PwMS.

Recurrence of severe symptomatic late-onset neutropenia on ocrelizumab.

BACKGROUND: Late-onset neutropenia (LON), defined as an absolute neutrophil count (ANC) < 1500/mm3 that develops between 4 weeks and 6 months after the last drug administration, is a rare side effect of anti-CD20 drugs including ocrelizumab. Although continuation of ocrelizumab after LON is not contraindicated, the risk of LON recurrence is not well known. CASES: We report three cases of recurrent symptomatic agranulocytosis (ANC < 500/mm3) occurring under ocrelizumab. CONCLUSION: Given the risk of recurrence of symptomatic agranulocytosis and the availability of other treatments, a therapeutic switch may be discussed after the first episode of LON.

[Neuromyelitis optica]. / Neuromyélite optique.

NEUROMYELITIS OPTICA. Neuromyelitis optica (NMO) or neuromyelitis optica spectrum disorder (NMOSD) includes different inflammatory conditions of the central nervous system distinct from multiple sclerosis. It is characterized by the association of typical clinical manifestations, such as optic neuritis, extensive transverse myelitis, involvement of the area postrema, and by the presence of anti-aquaporin 4 antibodies. It evolves with relapses. These can be lethal and justify emergency treatment with the administration of high dose of intravenous corticosteroids possibly associated with plasma exchange sessions. A disease modifying treatment is then started to prevent the occurrence of a new relapse.

NEUROMYÉLITE OPTIQUE. La neuromyélite optique (NMO), ou neuromyelitis optica spectrum disorder (NMOSD), regroupe différentes affections inflammatoires du système nerveux central distinctes de la sclérose en plaques. Elle se caractérise par l'association d'atteintes cliniques typiques, comme la névrite optique, la myélite transverse étendue, l'atteinte de l'area postrema et par la présence d'anticorps anti-aquaporine 4. Elle évolue par poussées. Celles-ci peuvent engager le pronostic vital et justifient une prise en charge en urgence avec l'administration de bolus de corticoïdes intraveineux à fortes doses éventuellement associés à des séances d'échanges plasmatiques. Un traitement de fond est ensuite débuté pour prévenir la survenue d'une nouvelle poussée.

Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society.

OBJECTIVE: The objective of this study was to develop evidence-based recommendations on pregnancy management for persons with multiple sclerosis (MS). BACKGROUND: MS typically affects young women in their childbearing years. Increasing evidence is available to inform questions raised by MS patients and health professionals about pregnancy issues. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and university databases (January 1975 through June 2021). The RAND/UCLA appropriateness method was developed to synthesise the scientific literature and expert opinions on healthcare topics; it was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 104 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, locoregional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses and disease-modifying treatments. CONCLUSION: The 2022 recommendations of the French MS society should be helpful to harmonise counselling and treatment practice for pregnancy in persons with MS, allowing for better and individualised choices.

Pregnancy and neuromyelitis optica spectrum disorders: 2022 recommendations from the French Multiple Sclerosis Society.

BACKGROUND: In 2020, the French Multiple Sclerosis (MS) Society (SFSEP) decided to develop a national evidence-based consensus on pregnancy in MS. As neuromyelitis optica spectrum disorders (NMOSD) shares a series of commonalities with MS, but also some significant differences, specific recommendations had to be developed. OBJECTIVES: To establish recommendations on pregnancy in women with NMOSD. METHODS: The French Group for Recommendations in Multiple Sclerosis (France4MS) reviewed PubMed and universities databases (January 1975 through June 2021). The RAND/UCLA appropriateness method, which was developed to synthesise the scientific literature and expert opinions on health care topics, was used to reach a formal agreement. Fifty-six MS experts worked on the full-text review and initial wording of recommendations. A sub-group of nine NMOSD experts was dedicated to analysing available data on NMOSD. A group of 62 multidisciplinary healthcare specialists validated the final proposal of summarised evidence. RESULTS: A strong agreement was reached for all 66 proposed recommendations. They cover diverse topics, such as pregnancy planning, follow-up during pregnancy and postpartum, delivery routes, loco-regional analgesia or anaesthesia, prevention of postpartum relapses, breastfeeding, vaccinations, reproductive assistance, management of relapses, and disease-modifying treatments. CONCLUSION: Physicians and patients should be aware of the new and specific evidence-based recommendations of the French MS Society for pregnancy in women with NMOSD. They should help harmonise counselling and treatment practise, allowing for better individualised choices.

The Study to Investigate COVID-19 Infection in People Living in Ireland (SCOPI): A seroprevalence study, June to July 2020.

BackgroundRobust data on SARS-CoV-2 population seroprevalence supplement surveillance data in providing evidence for public health action.AimTo conduct a SARS-CoV-2 population-based seroprevalence survey in Ireland.MethodsUsing a cross-sectional study design, we selected population samples from individuals aged 12-69 years in counties Dublin and Sligo using the Health Service Executive Primary Care Reimbursement Service database as a sampling frame. Samples were selected with probability proportional to the general population age-sex distribution, and by simple random sampling within age-sex strata. Antibodies to SARS-CoV-2 were detected using the Abbott Architect SARS-CoV-2 IgG Assay and confirmed using the Wantai Assay. We estimated the population SARS-CoV-2 seroprevalence weighted for age, sex and geographic area.ResultsParticipation rates were 30% (913/3,043) and 44% (820/1,863) in Dublin and Sligo. Thirty-three specimens had detectable SARS-CoV-2 antibodies (1.9%). We estimated weighted seroprevalences of 3.12% (95% confidence interval (CI): 2.05-4.53) and 0.58% (95% CI: 0.18-1.38) for Dublin and Sligo, and 1.69% (95% CI: 1.13-2.41) nationally. This equates to an estimated 59,482 (95% CI: 39,772-85,176) people aged 12-69 years nationally having had infection with SARS-CoV-2, 3.0 (95% CI: 2.0-4.3) times higher than confirmed notifications. Ten participants reported a previous laboratory-confirmed SARS-CoV-2 -infection; eight of these were antibody-positive. Twenty-five antibody-positive participants had not reported previous laboratory-confirmed infection.ConclusionThe majority of people in Ireland are unlikely to have been infected with SARS-CoV-2 by June-July 2020. Non-pharmaceutical public health measures remained key pending widespread availability of vaccination, and effective treatments.

G protein-coupled receptors can control the Hippo/YAP pathway through Gq signaling.

The Hippo pathway is an evolutionarily conserved kinase cascade involved in the control of tissue homeostasis, cellular differentiation, proliferation, and organ size, and is regulated by cell-cell contact, apical cell polarity, and mechanical signals. Miss-regulation of this pathway can lead to cancer. The Hippo pathway acts through the inhibition of the transcriptional coactivators YAP and TAZ through phosphorylation. Among the various signaling mechanisms controlling the hippo pathway, activation of G12/13 by G protein-coupled receptors (GPCR) recently emerged. Here we show that a GPCR, the ghrelin receptor, that activates several types of G proteins, including G12/13, Gi/o, and Gq, can activate YAP through Gq/11 exclusively, independently of G12/13. We revealed that a strong basal YAP activation results from the high constitutive activity of this receptor, which can be further increased upon agonist activation. Thus, acting on ghrelin receptor allowed to modulate up-and-down YAP activity, as activating the receptor increased YAP activity and blocking constitutive activity reduced YAP activity. Our results demonstrate that GPCRs can be used as molecular switches to finely up- or down-regulate YAP activity through a pure Gq pathway.

Challenges of switching towards anti-CD20 monoclonal antibodies in RR-MS: A monocentric study.

BACKGROUND: Anti-CD20 monoclonal antibodies (mAb) have demonstrated their drastic efficacy in the treatment of active relapsing-remitting multiple sclerosis (RR-MS). This study investigates the management of their initiation after another disease modifying therapy (DMT). The objective of this study was to assess the frequency and the risk factors of relapses during the wash-out period (WP) between cessation of last DMT and initiation of anti-CD20 mAb in RR-MS. METHODS: All non-naive RR-MS patients who initiated a treatment with Rituximab or Ocrelizumab between 2016 and 2019 have been included in this retrospective monocentric study. Univariate and multivariate analysis were conducted to evaluate risk factors of relapses during the WP. RESULTS: 73 patients (mean age 35.3 years, standard deviation (SD): 8.7 years) were included, with a mean number of 3.1 (SD: 1.3) previous DMTs. The DMT most frequently received before the switch was Fingolimod (Fg, 31 patients, 42.5%). 20 patients (27.4%) experienced relapses during the WP. Risk factors were previous treatment by Fg (p = 0.001) and WP duration (p = 0.032). Among patients switching from Fg, the probability of experiencing a relapse was 35% after 1 month of wash-out. CONCLUSION: This study suggests to shorten the WP duration when switching towards anti-CD20 mAb, especially after Fg, to avoid relapses.

A Unified Theoretical Framework of Learning Theories to Inform and Guide Public Health Continuing Medical Education Research and Practice.

ABSTRACT: Continuing medical education (CME) emerged at the start of the 20th century as a means of maintaining clinical competence among health care practitioners. However, evidence indicates that CME is often poorly developed and inappropriately used. Consequently, there has been increasing interest in the literature in evaluating wider contexts at play in CME development and delivery. In this article, the authors present a unified theoretical framework, grounded in learning theories, to explore the role of contextual factors in public health CME for health care practitioners. Discussion with pedagogical experts together with a narrative review of learning theories within medical and social science literature informed the framework's development. The need to consider sociocultural theories of learning within medical education restricted suitable theories to those that recognized contexts beyond the individual learner; adopted a systems approach to evaluate interactions between contexts and learner; and considered learning as more than mere acquisition of knowledge. Through a process of rigorous critical analysis, two theoretical models emerged as contextually appropriate: Biggs principle of constructive alignment and Bronfenbrenner bioecological model of human development. Biggs principle offers theoretical clarity surrounding interactive factors that encourage lifelong learning, whereas the Bronfenbrenner model expands on these factor's roles across multiple system levels. The authors explore how unification into a single framework complements each model while elaborating on its fundamental and practical applications. The unified theoretical framework presented in this article addresses the limitations of isolated frameworks and allows for the exploration of the applicability of wider learning theories in CME research.

Nanobody-Based Quantification of GTP-Bound RHO Conformation Reveals RHOA and RHOC Activation Independent from Their Total Expression in Breast Cancer.

As key regulators of the actin cytoskeleton, RHO GTPase expression and/or activity are deregulated in tumorigenesis and metastatic progression. Nevertheless, the vast majority of experiments supporting this conclusion was conducted on cell lines but not on human tumor samples that were mostly studied at the expression level only. Up to now, the activity of RHO proteins remains poorly investigated in human tumors. In this article, we present the development of a robust nanobody-based ELISA assay, with a high selectivity that allows an accurate quantification of RHO protein GTP-bound state in the nanomolar range (1 nM; 20 µg/L), not only in cell lines after treatment but also in tumor samples. Of note, we present here a fine analysis of RHOA-like and RAC1 active state in tumor samples with the most comprehensive study of RHOA-GTP and RHOC-GTP levels performed on human breast tumor samples. We revealed increased GTP-bound RHOA and RHOC protein activities in tumors compared to normal tissue counterparts, and demonstrated that the RHO active state and RHO expression are two independent parameters among different breast cancer subtypes. Our results further highlight the regulation of RHO protein activation in tumor samples and the relevance of directly studying RHO GTPase activities involvement in molecular pathways.

Interaction between Neurons and the Oligodendroglial Lineage in Multiple Sclerosis and Its Preclinical Models.

Multiple sclerosis (MS) is a complex central nervous system inflammatory disease leading to demyelination and associated functional deficits. Though endogenous remyelination exists, it is only partial and, with time, patients can enter a progressive phase of the disease, with neurodegeneration as a hallmark. Though major therapeutic advances have been made, with immunotherapies reducing relapse rate during the inflammatory phase of MS, there is presently no therapy available which significantly impacts disease progression. Remyelination has been shown to favor neuroprotection, and it is thus of major importance to better understand remyelination mechanisms in order to promote them and hence preserve neurons. A crucial point is how this process is regulated through the neuronal crosstalk with the oligodendroglial lineage. In this review, we present the current knowledge on neuron interaction with the oligodendroglial lineage, in physiological context as well as in MS and its experimental models. We further discuss the therapeutic possibilities resulting from this research field, which might allow to support remyelination and neuroprotection and thus limit MS progression.

Beyond COVID-19: DO MS/NMO-SD patients treated with anti-CD20 therapies develop SARS-CoV2 antibodies?

Since 2019, a new coronavirus infection (COVID-19) due to an agent called SARS-CoV-2 spread rapidly worldwide. Patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMO-SD) are often treated with immunosuppressants. Beyond their effect on the risk of COVID-19 infection, the consequences on the long-term immune response against the coronavirus remain unknown. Among 13 MS or NMOSD patients with confirmed COVID-19 included, all 5 patients treated with anti-CD20 therapies had a negative SARS-CoV-2 serology. To date, maximal precautions to prevent coronavirus infection should be maintained in MS/NMOSD patients already exposed to COVID-19 during anti-CD20 therapy.

Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.

PURPOSE: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). METHODS: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. RESULTS: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects. CONCLUSION: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities. Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity. Design, Setting, and Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020. Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms. Main Outcomes and Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes. Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01). Conclusions and Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.

Revisit ligand-receptor interaction at the human vasopressin V2 receptor: A kinetic perspective.

The vasopressin V2 receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target for water balance disorders such as polycystic kidney disease. Traditionally, the discovery of novel agents for the vasopressin V2 receptor has been guided by evaluating their receptor affinity, largely ignoring the binding kinetics. However, the latter is receiving increasing attention in the drug research community and has been proved to be a more complete descriptor of the dynamic process of ligand-receptor interaction. Herein we aim to revisit the molecular basis of ligand-vasopressin V2 receptor interaction from the less-investigated kinetic perspective. A homogenous time-resolved fluorescence resonance energy transfer (TR-FRET) assay was set up and optimized, which enabled accurate kinetic profiling of unlabeled vasopressin V2 receptor ligands. Receptor occupancy profiles of two representative antagonists with distinct target residence time were simulated. Their functional effects were further explored in cAMP assays. Our results showed that the antagonist with longer receptor residence time (lixivaptan) displayed sustained target occupancy than the antagonist with shorter receptor residence time (mozavaptan). In accordance, lixivaptan displayed insurmountable antagonism and wash-resistant inhibitory effect on the cellular cAMP level, while not so for mozavaptan. Together, our data provide evidence that binding kinetics, next to their affinity, offers additional information for the dynamic process of ligand-receptor interaction. Hopefully, this study may lead to more kinetics-directed medicinal chemistry efforts and aid the design and discovery of different-in-class of vasopressin V2 receptor ligands for clinical applications.