Moving toward personalized B cell depletion in multiple sclerosis?

B cell depletion is becoming a preferred long-term treatment even in early multiple sclerosis, but concerns about the risks of impaired immune competence persist. In their observational study Schuckmann et al. thoroughly assessed the impact of B cell-adapted extended interval dosing on immunoglobulin levels as a surrogate of adverse immunosuppressive effects.

COVID-19 and the Pandemic-Related Aspects in Pediatric Demyelinating Disorders.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as Coronavirus-19 (COVID-19) infection, has been associated with several neurological symptoms, including acute demyelinating syndromes (ADS). There is a growing body of literature discussing COVID-19 and demyelinating conditions in adults; however, there is less published about COVID-19 demyelinating conditions in the pediatric population. This review aims to discuss the impact of COVID-19 in pediatric patients with central nervous system ADS (cADS) and chronic demyelinating conditions. We reviewed PubMed, Google Scholar, and Medline for articles published between December 1, 2019 and October 25, 2022 related to COVID-19 and pediatric demyelinating conditions. Of 56 articles reviewed, 20 cases of initial presentation of ADS associated with COVID-19 were described. The most commonly described cADS associated with COVID-19 infection in children was Acute Disseminated Encephalomyelitis followed by Transverse Myelitis. Cases of Myelin Oligodendrocyte Glycoprotein Antibody Disease, Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis are also described. The risk of severe COVID-19 in pediatric patients with demyelinating conditions appears low, including in patients on disease modifying therapies, but studies are limited. The pandemic did affect disease modifying therapies in ADS, whether related to changes in prescriber practice or access to medications. COVID-19 is associated with ADS in children and the COVID-19 pandemic has impacted pediatric patients with demyelinating conditions in various ways.

Navigating the landscape of COVID-19 for Multiple Sclerosis patients and clinicians.

The purpose of this literature review was to summarise relevant findings regarding the clinical management of multiple sclerosis (MS) in the COVID-19 pandemic, with the focus on patient risks, and the implications of disease-modifying treatment, both on COVID-19 severity and on the response to the SARS-CoV-2 vaccinations. Although MS per se does not seem to put patients at risk for more severe COVID-19, alongside the risk factors known to apply to the general population, progressive disease course, higher disability status, and B-cell depleting therapies may all negatively affect infection severity. The question of COVID-19 sequelae in patients with MS (pwMS) remains unresolved, challenging researchers to further explore this area. The safety profile of COVID-19 vaccinations in pwMS is similar to that of the general population. The efficacy of the vaccination might be affected by B-cell depletion, as well as by S1PR-modulating medications that attenuate humoral responses to the COVID-19 vaccination. Future research should focus on gathering evidence regarding the clinical course of MS following COVID-19 infection and vaccination in larger studies, as well as on establishing the safest and most efficient schedule of COVID-19 vaccination in pwMS on cell-depleting therapies.

Evaluating the feasibility and preliminary efficacy of a Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS): an update to the protocol for a feasibility cluster-randomised controlled trial.

BACKGROUND: Cognitive difficulties experienced by people with multiple sclerosis (MS) impact on quality of life and daily functioning, from childcare and work to social and self-care activities. The Cognitive Occupation-Based programme for people with MS (COB-MS) was developed as a holistic, individualised cognitive rehabilitation intervention to address the wide-ranging symptoms and functional difficulties that present in MS, including the ability to maintain employment, social activities, home management and self-care. The aim of the research is to evaluate the feasibility and preliminary efficacy of COB-MS for people with MS. METHODS: Due to the impacts of COVID-19, trial activities that were planned for in-person delivery were completed remotely. One hundred and twenty people with MS will be assigned to participate in either the COB-MS programme or a treatment-as-usual, wait-list control group as part of this single-blind, cluster-randomised controlled feasibility and preliminary efficacy trial of the COB-MS programme. The COB-MS group will participate in an eight-session occupational-based cognitive rehabilitation programme over 9 weeks. The COB-MS intervention was planned for in-person delivery but was delivered online by occupational therapists to small groups of people with MS. The primary outcome measure is the Goal Attainment Scaling at 12 weeks. Participants will be assessed pre-intervention, post-intervention, 12 weeks post-intervention and 6 months post-intervention. Qualitative evaluations of participants' perspectives will also be examined as part of the feasibility study. Data, due to be collected in-person, was collected online or by post. The original study design, including the statistical analysis plan, remains unchanged despite the shift to a remote trial conduct. DISCUSSION: Results will provide recommendations for a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy. TRIAL REGISTRATION: ISRCTN ISRCTN11462710 . Registered on 9 September 2019 and updated on 23 September 2020 to account for changes outlined here.

Healthcare complexities during community crises: Recommendation for access to healthcare for Australians with multiple sclerosis.

BACKGROUND: In 2019 and 2020, over 17 million hectares of Australia burned, and half of the Australian population was affected by toxic bushfire smoke. Then in 2020, restrictions designed to curtail the spread of COVID-19 resulted in significant changes to healthcare access. There is no Australian emergency management standard for persons with disabilities, including those with multiple sclerosis (MS). Persons with MS often require multidisciplinary and complex care, with continuity of treatment essential to prevent disease progression. OBJECTIVE: To identify limitations in access to healthcare from the perspective of persons with MS as well as MS care providers during recent crises and make recommendations for policy to improve MS healthcare access during a crisis. METHOD: In mid-2020, we undertook online surveys and interviews with persons with MS, their carers, healthcare professionals and staff of MS service providers (i.e., care providers). We used descriptive analysis for quantitative, and a general inductive approach for qualitative data. RESULTS: One-hundred and thirteen persons with MS and a total of 63 MS care providers, who were close carers, healthcare professionals and service providers provided survey responses. For participants with MS, limited access to general practitioners and medical tests were of the most significant concern during the bushfires and the pandemic. In contrast, during the pandemic accessing physiotherapy was another top concern. Twenty-nine people participated in in-depth interviews, revealing that reduced healthcare access during the bushfire and the pandemic caused concern. The use of telehealth received both positive and negative reviews. All participants indicated a need for preparation and planning for healthcare access before a crisis. Persons with MS recommended centralised information sources, prioritised access to healthcare and increased levels of MS nurses and other allied healthcare. Care providers recommended centralised information sources, more nursing and mental health care access, and increased opportunities for multidisciplinary telehealth delivery. CONCLUSIONS: We recommend the involvement of the MS community in creating and designing disaster preparation plans, which should cater to a range of disaster types, to improve disaster preparedness in a community that is vulnerable to increasingly common community crises.

Changes in physiotherapy services and use of technology for people with multiple sclerosis during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has led to reorganization or reduction of neurorehabilitation services for people with multiple sclerosis (PwMS). The aim of this study was to explore the changes in the organizational framework and technology usage in physiotherapy services for PwMS during the COVID-19 pandemic. METHODS: This international cross-sectional survey study was designed, developed, and disseminated by RIMS European Network for Best Practice and Research in Multiple Sclerosis Rehabilitation. Physiotherapists from nine countries (Australia, Belgium, Czech Republic, Ireland, Israel, Italy, Norway, Spain, Turkey) who provided physiotherapy services to PwMS, were invited to complete an online survey to compare physiotherapy delivery to PwMS prior to and during the pandemic period. RESULTS: The survey was completed by 215 physiotherapists. Accessibility, the average number, length and perceived effectiveness of physiotherapy sessions provided to PwMS were significantly reduced during the COVID-19 pandemic (p=0.001). Physiotherapists increased the advice of mobile apps, recorded videos for rehabilitation and exercise websites during the pandemic (p<0.001) while the use of telerehabilitation and virtual reality technology did not change. CONCLUSION: There was of a reduction in the number, duration and perceived effectiveness of rehabilitation sessions for people with multiple sclerosis during the COVID-19 pandemic while use of remote technologies for physiotherapy did not change. To ensure the continuity of physiotherapy for PwMS with complex healthcare needs also during pandemics, the provision of guidelines and training in telehealth technologies in professional education becomes crucial.

SARS-CoV-2-infection in the setting of autotransplants for multiple sclerosis.

The severe adult respiratory syndrome virus type 2 (SARS-CoV-2) related acute respiratory distress syndrome (ARDS) has a strong immunological and inflammatory component; accordingly investigators are employing monoclonal antibodies to ameliorate the virus-induced cytokine storm such as antibodies against interleukin 6 (IL-6), tumor necrosis factors alpha (TNF-alpha) and CC chemokine receptor 5 (CCR5) (1). Cyclophosphamide (Cy) has proven its role in various settings including autoimmune diseases, and in the post-haploidentical stem cell transplant setting; Cy depletes cytotoxic and effector T cell populations while relatively sparing the regulatory T cells (Tregs) and could tip the balance away from the overtly pro-inflammatory setting (1). We present here the cases of three persons who were infected by the SARS-CoV-2 virus during the Cy-induced pancytopenia of an autologous hematopoietic stem cell transplantation (HSCT), aimed to down-regulate the immune response in multiple sclerosis (MS) (2). The surprisingly benign course of the COVID-19 in the three cases suggest that the Cy could have had a role in abrogating the inflammatory response in these persons.

Multiple sclerosis-disease modifying therapies affect humoral and T-cell response to mRNA COVID-19 vaccine.

Background: The mRNA vaccines help protect from COVID-19 severity, however multiple sclerosis (MS) disease modifying therapies (DMTs) might affect the development of humoral and T-cell specific response to vaccination. Methods: The aim of the study was to evaluate humoral and specific T-cell response, as well as B-cell activation and survival factors, in people with MS (pwMS) under DMTs before (T0) and after two months (T1) from the third dose of vaccine, comparing the obtained findings to healthy donors (HD). All possible combinations of intracellular IFNγ, IL2 and TNFα T-cell production were evaluated, and T-cells were labelled "responding T-cells", those cells that produced at least one of the three cytokines of interest, and "triple positive T-cells", those cells that produced simultaneously all the three cytokines. Results: The cross-sectional evaluation showed no significant differences in anti-S antibody titers between pwMS and HD at both time-points. In pwMS, lower percentages of responding T-cells at T0 (CD4: p=0.0165; CD8: p=0.0022) and triple positive T-cells at both time-points compared to HD were observed (at T0, CD4: p=0.0007 and CD8: p=0.0703; at T1, CD4: p=0.0422 and CD8: p=0.0535). At T0, pwMS showed higher plasma levels of APRIL, BAFF and CD40L compared to HD (p<0.0001, p<0.0001 and p<0.0001, respectively) and at T1, plasma levels of BAFF were still higher in pwMS compared to HD (p=0.0022).According to DMTs, at both T0 and T1, lower anti-S antibody titers in the depleting/sequestering-out compared to the enriching-in pwMS subgroup were found (p=0.0410 and p=0.0047, respectively) as well as lower percentages of responding CD4+ T-cells (CD4: p=0.0394 and p=0.0004, respectively). Moreover, the depleting/sequestering-out subgroup showed higher percentages of IFNγ-IL2-TNFα+ T-cells at both time-points, compared to the enriching-in subgroup in which a more heterogeneous cytokine profile was observed (at T0 CD4: p=0.0187; at T0 and T1 CD8: p =0.0007 and p =0.0077, respectively). Conclusion: In pwMS, humoral and T-cell response to vaccination seems to be influenced by the different DMTs. pwMS under depleting/sequestering-out treatment can mount cellular responses even in the presence of a low positive humoral response, although the cellular response seems qualitatively inferior compared to HD. An understanding of T-cell quality dynamic is needed to determine the best vaccination strategy and in general the capability of immune response in pwMS under different DMT.

Social determinants of health in multiple sclerosis.

Social determinants of health are the conditions in which people are born, grow, live, work and age. These circumstances are the non-medical factors that influence health outcomes. Evidence indicates that health behaviours, comorbidities and disease-modifying therapies all contribute to multiple sclerosis (MS) outcomes; however, our knowledge of the effects of social determinants - that is, the 'risks of risks' - on health has not yet changed our approach to MS. Assessing and addressing social determinants of health could fundamentally improve health and health care in MS; this approach has already been successful in improving outcomes in other chronic diseases. In this narrative Review, we identify and discuss the body of evidence supporting an effect of many social determinants of health, including racial background, employment and social support, on MS outcomes. It must be noted that many of the published studies were subject to bias, and screening tools and/or practical interventions that address these social determinants are, for the most part, lacking. The existing work does not fully explore the potential bidirectional and complex relationships between social determinants of health and MS, and the interpretation of findings is complicated by the interactions and intersections among many of the identified determinants. On the basis of the reviewed literature, we consider that, if effective interventions targeting social determinants of health were available, they could have substantial effects on MS outcomes. Therefore, funding for and focused design of studies to evaluate and address social determinants of health are urgently needed.

B- and T-Cell Responses After SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Receiving Disease Modifying Therapies: Immunological Patterns and Clinical Implications.

Background: Vaccination campaign to contrast the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has raised the issue of vaccine immunogenicity in special populations such as people with multiple sclerosis (PwMS) on highly effective disease modifying treatments (DMTs). While humoral responses to SARS-CoV-2 mRNA vaccines have been well characterized in the general population and in PwMS, very little is known about cell-mediated responses in conferring protection from SARS-CoV-2 infection and severe coronavirus disease-2019 (COVID-19). Methods: PwMS on ocrelizumab, fingolimod or natalizumab, vaccinated with two doses of mRNABNT162b2 (Comirnaty®) vaccine were enrolled. Anti-Spike (S) and anti-Nucleoprotein (N) antibody titers, IFN-gamma production upon S and N peptide libraries stimulation, peripheral blood lymphocyte absolute counts were assessed after at least 1 month and within 4 months from vaccine second dose administration. A group of age and sex matched healthy donors (HD) were included as reference group. Statistical analysis was performed using GraphPad Prism 8.2.1. Results: Thirty PwMS and 9 HDs were enrolled. All the patients were negative for anti-N antibody detection, nor reported previous symptoms of COVID-19. Peripheral blood lymphocyte counts were assessed in PwMS showing: (i) reduction of circulating B-lymphocytes in PwMS on ocrelizumab; (ii) reduction of peripheral blood B- and T-lymphocyte absolute counts in PwMS on fingolimod and (iii) normal B- and T-lymphocyte absolute counts with an increase in circulating CD16+CD56+ NK-cells in PwMS on natalizumab. Three patterns of immunological responses were identified in PwMS. In patients on ocrelizumab, anti-S antibody were lacking or reduced, while T-cell responses were normal. In patients on fingolimod both anti-S titers and T-cell mediated responses were impaired. In patients on natalizumab both anti-S titers and T-cell responses were present and comparable to those observed in HD. Conclusions: The evaluation of T-cell responses, anti-S titers and peripheral blood lymphocyte absolute count in PwMS on DMTs can help to better characterize the immunological response after SARS-CoV-2 vaccination. The evaluation of T-cell responses in longitudinal cohorts of PwMS will help to clarify their protective role in preventing SARS-CoV-2 infection and severe COVID-19. The correlation between DMT treatment and immunological responses to SARS-CoV-2 vaccines could help to better evaluate vaccination strategies in PwMS.

The effects of continuous care model using a smartphone application on adherence to treatment and self-efficacy among patients with multiple sclerosis.

BACKGROUND: Adherence to disease-modifying therapy is important in patients with Multiple Sclerosis (MS) to increase the positive outcomes and improve the quality of life. This study aimed to determine the effects of Continuous Care Model (CCM) using a smartphone application on adherence to treatment and self-efficacy among MS patients. METHODS: This quasi-experimental study with pre/posttest design was conducted on 72 MS patients in Shiraz, Iran from June 2020 to August 2021. The samples were randomly assigned to intervention (n = 36) and control (n = 36) groups. In the intervention group, the CCM using a smartphone application was implemented during two months. However, no intervention was performed for the control group. The data were collected using the self-report Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ) and MS Self-Efficacy Scale (MSSS) at baseline and two and four months after the intervention. RESULTS: The results showed an improvement in adherence to treatment and self-efficacy in the intervention group compared to the control group after implementing the virtual CCM and at the two-month follow-up (p < 0.001). CONCLUSIONS: Implementing the CCM using a smartphone application resulted in improvements in the MS patients' adherence to treatment and self-efficacy. It can be concluded that providing care using an interactive multimedia application can improve the outcomes as well as patients' satisfaction, especially during the COVID-19 pandemic. Therefore, this approach is recommended to be used for nurses, healthcare providers, and clinicians.

SARS-CoV-2 infection in multiple sclerosis patients: interaction with treatments, adjuvant therapies, and vaccines against COVID-19.

The SARS-CoV-2 pandemic has raised particular concern for people with Multiple Sclerosis, as these people are believed to be at increased risk of infection, especially those being treated with disease-modifying therapies. Therefore, the objective of this review was to describe how COVID-19 affects people who suffer from Multiple Sclerosis, evaluating the risk they have of suffering an infection by this virus, according to the therapy to which they are subjected as well as the immune response of these patients both to infection and vaccines and the neurological consequences that the virus can have in the long term. The results regarding the increased risk of infection due to treatment are contradictory. B-cell depletion therapies may cause patients to have a lower probability of generating a detectable neutralizing antibody titer. However, more studies are needed to help understand how this virus works, paying special attention to long COVID and the neurological symptoms that it causes.

"I wanna live and not think about the future" what place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study.

BACKGROUND: Little is known about how people with multiple sclerosis (MS) and their families comprehend advance care planning (ACP) and its relevance in their lives. AIM: To explore under what situations, with whom, how, and why do people with MS and their families engage in ACP. METHODS: We conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach. RESULTS: Participants' narratives focused on three major themes: (i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals' accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate ACP-related discussions. Some shared concerns of their lack of confidence when having these discussions. CONCLUSION: These findings support the need for a whole system strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services.

The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

A group resilience training program for people with multiple sclerosis: Study protocol of a multi-centre cluster-randomized controlled trial (multi-READY for MS).

INTRODUCTION: REsilience and Activities for every DaY (READY) is an Acceptance and Commitment Therapy-based group resilience-training program that has preliminary empirical support in promoting quality of life and other psychosocial outcomes in people with multiple sclerosis (PwMS). Consistent with the Medical Research Council framework for developing and evaluating complex interventions, we conducted a pilot randomized controlled trial (RCT), followed by a phase III RCT. The present paper describes the phase III RCT protocol. METHODS AND ANALYSIS: This is a multi-centre cluster RCT comparing READY with a group relaxation program (1:1 ratio) in 240 PwMS from eight centres in Italy (trial registration: isrctn.org Identifier: ISRCTN67194859). Both interventions are composed of 7 weekly sessions plus a booster session five weeks later. Resilience (primary outcome), mood, health-related quality of life, well-being and psychological flexibility will be assessed at baseline, after the booster session, and at three and six month follow-ups. If face-to-face group meetings are interrupted because of COVID-19 related-issues, participants will be invited to complete their intervention via teleconferencing. Relevant COVID-19 information will be collected and the COVID-19 Peritraumatic Distress scale will be administered (ancillary study) at baseline and 3-month follow-up. Analysis will be by intention-to-treat to show superiority of READY over relaxation. Longitudinal changes will be compared between the two arms using repeated-measures, hierarchical generalized linear mixed models. CONCLUSION: It is expected that his study will contribute to the body of evidence on the efficacy and effectiveness of READY by comparing it with an active group intervention in frontline MS rehabilitation and clinical settings. Results will be disseminated in peer-reviewed journals and at other relevant conferences.

Multiple Sclerosis Management During the COVID-19 Pandemic.

PURPOSE OF REVIEW: COVID-19 has posed a continuously evolving challenge for providers caring for patients with multiple sclerosis (MS). While guidelines from national and international organizations came quickly, these have required constant reassessment and modification as the pandemic has progressed. This review aims to assess the first 2 years of literature on COVID-19 relevant to the clinical management of patients with MS. In particular, we will review how MS impacts the risk of COVID-19 infection, how disease-modifying therapies may alter this risk, and explore considerations regarding disease-modifying therapy (DMT) and vaccination for COVID-19. We will also explore potential ways in which a COVID-19 infection may impact multiple sclerosis. Our goal is to provide an overarching review of the major findings at this stage of the pandemic relevant to those that care for patients with MS. RECENT FINDINGS: Over the course of the COVID-19 pandemic, providers have had to re-evaluate the priorities in the management of MS. A growing number of studies have evaluated the relevant risk factors and considerations regarding MS and particular disease-modifying therapies. The long-term impacts of the pandemic on the health of those with MS will continue to be revealed. In general, most patients with MS do not need major revisions to their treatment plan due to COVID-19 risk. However, individuals who are older, more disabled, and on more potent therapies may need to consider strategies for decreasing their overall risk. Regardless, continued improvement in our understanding of interactions between infections, disease-modifying therapy, and MS are paramount to optimizing the care of those with MS going forward.

Yoga provision for individuals living with Multiple Sclerosis: Is the future online?

BACKGROUND: Yoga has multiple benefits for individuals living with Multiple Sclerosis (MS), including reduced pain, depression, fatigue, strength, and improved quality of life. During the COVID-19 pandemic, home-based delivery of yoga increased. However, no studies to date have explored online home-based yoga for individuals living with MS, more specifically the motivations, experiences, or the sustainability of home-based yoga practice for individuals living with MS. AIM: This study aimed to explore the facilitators and barriers of online yoga provision for individuals living with MS. METHODS: One focus group and three semi-structured interviews were carried out online via Zoom with one yoga instructor and seven yoga participants living with MS. Thematic Analysis was used to analyse this data. FINDINGS: Two themes were generated from the interviews, the environment and future provision, each with their own sub-themes. The themes reflect various facilitators and barriers of home-based yoga provision which differed depending upon the individuals home environment, social connections, physical ability, and confidence practising yoga. Furthermore, preferences of home provision fluctuated over time depending upon symptoms of MS. CONCLUSIONS: Home-based yoga practice is a viable and enjoyable option for individuals living with MS. It is recommended that yoga studios offering home-based yoga provision consider individual differences in preference, as well as fluctuations in symptoms that may create inequitable access to services and may prevent participation for some.