Specific Disease-modifying Therapies Research Articles

Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Current and innovative Approaches to Multiple Sclerosis Therapy

The landscape of immunotherapies in the management of Multiple Sclerosis (MS) is currently particularly dynamic. Over 21 immunotherapeutic options are approved by the European Meidcines Agency (EMA), Food and Drug Administration (FDA) and newer approaches are ongoing in clinical trials. With advancements in the understanding of MS pathophysiology and further development of diagnosis criteria, newer and more specific disease-modifying therapies (DMTs) have emerged in recent years. The selection and timing of proper therapeutic approaches is increasingly complex. We provide an overview of the available immunotherapies for a personalized MS treatment and discuss practical insights into their application. The importance of early intervention, distinction between escalation and induction approaches, and consideration of high-efficacy treatments for specific patient groups are in discussed. We emphasize the significance of a patient-centered approach, taking into account various factors such as comorbidities, family planning, administration preferences and potential side effects in treatment decision-making.

Bridging Retinal and Cerebral Neurodegeneration: A Focus on Crosslinks between Alzheimer-Perusini's Disease and Retinal Dystrophies.

In the early stages of Alzheimer-Perusini's disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast sensitivity, and visual acuity problems. As the disease progresses, there is a connection with glaucoma and age-related macular degeneration (AMD) leading to retinal cell death. The retina's involvement suggests a link with the hippocampus, where most AD forms start. A thinning of the retinal nerve fiber layer (RNFL) due to the loss of retinal ganglion cells (RGCs) is seen as a potential AD diagnostic marker using electroretinography (ERG) and optical coherence tomography (OCT). Amyloid beta fragments (Aβ), found in the eye's vitreous and aqueous humor, are also present in the cerebrospinal fluid (CSF) and accumulate in the retina. Aβ is known to cause tau hyperphosphorylation, leading to its buildup in various retinal layers. However, diseases like AD are now seen as mixed proteinopathies, with deposits of the prion protein (PrP) and α-synuclein found in affected brains and retinas. Glial cells, especially microglial cells, play a crucial role in these diseases, maintaining immunoproteostasis. Studies have shown similarities between retinal and brain microglia in terms of transcription factor expression and morphotypes. All these findings constitute a good start to achieving better comprehension of neurodegeneration in both the eye and the brain. New insights will be able to bring the scientific community closer to specific disease-modifying therapies.

Indirect impact of the COVID-19 pandemic on the care and outcomes of people with MS: A combined survey and insurance claims study

BackgroundIn the context of the COVID-19 pandemic, people with multiple sclerosis (pwMS) have been particularly vulnerable to adverse outcomes due to increased risk of severe infection and/or widespread disruptions in care. The CopeMS study led by The University of Texas at Austin and the MS Association of America investigates the long-term impact of the COVID-19 pandemic on healthcare access, disease modifying therapy (DMT) utilization and outcomes of pwMS. MethodsThis retrospective cohort analysis used Optum's de-identified Clinformatics® Data Mart Database (CDM), a large de-identified administrative healthcare claims database to identify pwMS who were continuously enrolled from 01/01/2019 to 12/31/2020 and assessed changes in the utilization of DMTs and healthcare services during the COVID-19 pandemic compared to the year prior. Additionally, a national survey of pwMS and healthcare providers (HCPs) was conducted to further understand the indirect impact of the pandemic on healthcare resource utilization (HCRU), outcomes and prescription patterns. ResultsOut of 529 pwMS in our national survey, over 47 % reported that their overall health and neurologic symptoms had deteriorated during the COVID-19 pandemic, with increased anxiety, and inability to maintain exercise habits as leading perceived causes for worsening. Survey respondents reported widespread disruption of MS-related services during the pandemic. In the Optum database, we identified 39,209 pwMS validating inclusion criteria. We observed a decrease in the utilization of MS-related services in 2020 compared to 2019. Significantly fewer pwMS had visits with their neurologist, primary care provider, physical or occupational therapist despite an increased utilization of telemedicine services. Fewer pwMS had magnetic resonance imaging (MRI) studies of the brain or spinal cord during the pandemic. Only 22.2 % of HCPs surveyed agreed that the perceived risk of more severe COVID-19 infection on a specific DMT influenced their therapeutic decisions. In the Optum database, individuals with an established diagnosis of MS prior to 2019 saw decreases in utilization of platform and moderate efficacy DMTs. In this group, those over the age of 55 saw a decrease in utilization of B-cell therapies (rate ratio 0.79, CI 0.75–0.83), whereas individuals under the age of 55 saw an increase in utilization of B-cell therapies (rate ratio 1.10, CI 1.03–1.17). We did not see any difference in rates of starting DMTs in persons diagnosed in 2019 prior to the pandemic and those diagnosed in 2020. Compared to 2019, B-cell therapies were prescribed more frequently in pwMS diagnosed in 2020 who were younger than 55 or commercially insured (rate ratio 1.35, CI 1.11–1.63). ConclusionThe COVID-19 pandemic was associated with perceived worsening of neurological symptoms in pwMS. Despite the expansion of telemedicine, we observed decreased access to healthcare services important to the comprehensive care of pwMS. Additionally, we observed changes in DMT utilization in pwMS during the pandemic, particularly in older adults with an established diagnosis of MS.

Impact of aging on treatment considerations for multiple sclerosis patients.

With a rapidly aging global population and improvement of outcomes with newer multiple sclerosis (MS)-specific disease-modifying therapies (DMTs), the epidemiology of MS has shifted to an older than previously described population, with a peak prevalence of the disease seen in the 55-65 years age group. Changes in the pathophysiology of MS appear to be age-dependent. Several studies have identified a consistent phase of disability worsening around the fifth decade of life. The latter appears to be independent of prior disease duration and inflammatory activity and concomitant to pathological changes from acute focal active demyelination to chronic smoldering plaques, slow-expanding lesions, and compartmentalized inflammation within the central nervous system (CNS). On the other hand, decreased CNS tissue reserve and poorer remyelinating capacity with aging lead to loss of relapse recovery potential. Aging with MS may imply longer exposure to DMTs, although treatment efficacy in patients >55 years has not been evaluated in pivotal randomized controlled trials and appears to decrease with age. Older individuals are more prone to adverse effects of DMTs, an important aspect of treatment individualization. Aging with MS also implies a higher global burden of comorbid illnesses that contribute to overall impairments and represent a crucial confounder in interpreting clinical worsening. Discontinuation of DMTs after age 55, when no evidence of clinical or radiological activity is detected, is currently under the spotlight. In this review, we will discuss the impact of aging on MS pathobiology, the effect of comorbidities and other confounders on clinical worsening, and focus on current therapeutic considerations in this age group.

Implementing education: Personal communication with a healthcare professional is a critical step to address vaccine hesitancy for people with multiple sclerosis

BackgroundPeople with Multiple Sclerosis (PwMS) were first able to access COVID-19 vaccines in Australia from March 2021, when vaccine hesitancy in the general population was high (14–43%). High uptake of vaccination is important globally and critical to protect this vulnerable population. We conducted an on-line survey to examine factors influencing COVID-19 vaccination willingness among PwMS in Australia. Methods149 PwMS living in Australia completed the on-line survey (April-September 2021) examining demographic, environmental and clinical factors with respect to vaccine willingness, including attitudes towards COVID-19 illness and vaccines. Additional items explored the influence of different information sources on vaccination decisions. Continuous and ordinal data were compared using the Mann-Whitney U test. All tests were two-tailed, with alpha set at 0.5. ResultsA majority of the respondents were female (87.2%) with relapsing-remitting MS (77.5%) treated by a neurologist (94.0%). A majority were on high efficacy disease-modifying therapies (DMTs) (64.9%), while 19.9% were on no DMTs. About one third of respondents (32.9%) had had two doses, 20.8% had received their first dose, and 22.1% were unvaccinated, while 24.2% of responses were missing. When asked about vaccine intentions, 60.6% of the unvaccinated indicated they were likely to extremely likely to get vaccinated, while 15.2% were very unlikely or extremely unlikely to do so and 24.2% were undecided. Unvaccinated people were significantly more concerned about vaccine side effects (mean 5.3 versus 3.1/10; p < .001). Only 53.3% of people on DMTs were vaccinated, compared to 75% of those who were not. People on ocrelizumab therapy (n = 35) had a lower vaccination rate (39%) than those on other medications (n = 86, 59%). Vaccine willingness in the unvaccinated was most highly correlated with knowledge regarding the vaccine (rs2=.709), agreement with the statement that COVID-19 vaccination is “too new for me to be confident about getting vaccinated” (rs2= -.709), anticipation of regret due to side effects of vaccination (rs2= -.642), and lack of knowledge regarding interactions between COVID-19 vaccines and DMTs (rs2= -.570).Almost two thirds had read MS-specific information about COVID-19 vaccinations and found it easy to understand (67.6%) and applicable to their situation (53.6%). However, less than half (47.8%) reported the information helped them make a personal vaccination decision. Over two-thirds (64.9%) had discussed vaccinations with their healthcare professional and 31.1% had not. Those who had not, were significantly more uninformed about the interactions of the vaccine with MS medications (mean 3.9 versus 2.9/10; p = .044) and significantly lower intention of vaccine uptake than those who had (mean 5.8 versus 7.9/10; p = .009). ConclusionOur study highlights that vaccination efforts should be delivered by healthcare professionals, focus on educating those who are managed with DMTs, and include individual recommendations related to specific DMTs, how the vaccines work, expectations regarding potential side-effects, potential exacerbation of MS symptoms, likelihood of recovery from any exacerbation, and the relative risks of side effects versus COVID-19 infection. Specific recommendations are provided.

Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type.

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-β 42 (Aβ42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aβ42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aβ42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aβ42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.

Background and ObjectivesTo determine the effects of dimethyl fumarate (DMF) and glatiramer acetate on iron content in chronic active lesions in patients with multiple sclerosis (MS) and in human microglia in vitro.MethodsThis was a retrospective observational study of 34 patients with relapsing-remitting MS and clinically isolated syndrome treated with DMF or glatiramer acetate. Patients had lesions with hyperintense rims on quantitative susceptibility mapping, were treated with DMF or glatiramer acetate (GA), and had a minimum of 2 on-treatment scans. Changes in susceptibility in rim lesions were compared among treatment groups in a linear mixed effects model. In a separate in vitro study, induced pluripotent stem cell–derived human microglia were treated with DMF or GA, and treatment-induced changes in iron content and activation state of microglia were compared.ResultsRim lesions in patients treated with DMF had on average a 2.77-unit reduction in susceptibility per year over rim lesions in patients treated with GA (bootstrapped 95% CI −5.87 to −0.01), holding all other variables constant. Moreover, DMF but not GA reduced inflammatory activation and concomitantly iron content in human microglia in vitro.DiscussionTogether, our data indicate that DMF-induced reduction of susceptibility in MS lesions is associated with a decreased activation state in microglial cells. We have demonstrated that a specific disease modifying therapy, DMF, decreases glial activity in chronic active lesions. Susceptibility changes in rim lesions provide an in vivo biomarker for the effect of DMF on microglial activity.Classification of EvidenceThis study provided Class III evidence that DMF is superior to GA in the presence of iron as a marker of inflammation as measured by MRI quantitative susceptibility mapping.

The need for a strategic therapeutic approach: multiple sclerosis in check.

Multiple sclerosis (MS) is the most common chronic autoimmune neurological disease. Its therapeutic management has drastically evolved in the recent years with the development of specific disease-modifying therapies (DMTs). Together with the established injectables, oral and intravenous alternatives are now available for MS patients with significant benefits to modulate the disease course. Certain drugs present with a higher efficacy than the others, profiles and frequencies of adverse events differentiate as well. Thus due to the several and different treatment alternatives, the therapeutic approach adopted by neurologists requires a tactical focus for a targeted, timed, and meaningful treatment decision. An integration of rational and emotional control with proper communication skills is necessary for shared decision-making with patients. In this perspective paper, we reinforce the necessary concept of strategic MS treatment approach using all available therapies based on scientific evidence and current experience. We apply a didactic analogy to the strategic game chess. The opening with oriented attack (i.e. already in early disease stages as clinical isolated syndrome), a correct choice of chess pieces to move (i.e. among the several DMTs), a re-assessment reaction to different scenarios (e.g. sustained disease activity, adverse events, and family planning) and the advantage of real-world data are discussed to try the best approach to ultimately successfully approach the best personalized MS treatment.

Effect of Different Disease-Modifying Therapies on Humoral Response to BNT162b2 Vaccine in Sardinian Multiple Sclerosis Patients.

ObjectivesVaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients.MethodsWe obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially influencing humoral immunity from COVID-19 vaccine.ResultsMS patients treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared to untreated patients. We did not observe a statistically significant difference in response between patients treated with the other drugs (dimethyl fumarate, interferon, alemtuzumab and glatiramer acetate) and untreated patients. In addition, older age, male sex and active smoking were significantly associated with lower antibody titers against SARS-CoV-2. MS patients previously infected with SARS-CoV-2 had significantly higher humoral responses to vaccine than uninfected patients.ConclusionHumoral response to BNT162b2 is significantly influenced by the specific DMTs followed by patients, as well as by other factors such as previous SARS-CoV-2 infection, age, sex, and smoking status. These results are important to inform targeted strategies to prevent clinically relevant COVID-19 in MS patients.

COVID-19 Vaccination Reactogenicity in Persons With Multiple Sclerosis.

Background and ObjectivesThere are limited data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine reactogenicity in persons with multiple sclerosis (PwMS) and how reactogenicity is affected by disease-modifying therapies (DMTs). The objective of this retrospective cross-sectional study was to generate real-world multiple sclerosis–specific vaccine safety information, particularly in the context of specific DMTs, and provide information to mitigate specific concerns in vaccine hesitant PwMS.MethodsBetween 3/2021 and 6/2021, participants in iConquerMS, an online people-powered research network, reported SARS-CoV-2 vaccines, experiences of local (itch, pain, redness, swelling, or warmth at injection site) and systemic (fever, chills, fatigue, headache, joint pain, malaise, muscle ache, nausea, allergic, and other) reactions within 24 hours (none, mild, moderate, and severe), DMT use, and other attributes. Multivariable models characterized associations between clinical factors and reactogenicity.ResultsIn 719 PwMS, 64% reported experiencing a reaction after their first vaccination shot, and 17% reported a severe reaction. The most common reactions were pain at injection site (54%), fatigue (34%), headache (28%), and malaise (21%). Younger age, being female, prior SARS-CoV-2 infection, and receiving the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vs BNT162b2 (Pfizer-BioNTech) vaccine were associated with experiencing a reaction after the first vaccine dose. Similar relationships were observed for a severe reaction, including higher odds of reactions among PwMS with more physical impairment and lower odds of reactions for PwMS on an alpha4-integrin blocker or sphingosine-1-phosphate receptor modulator. In 442 PwMS who received their second vaccination shot, 74% reported experiencing a reaction, whereas 22% reported a severe reaction. Reaction profiles after the second shot were similar to those reported after the first shot. Younger PwMS and those who received the mRNA-1273 (Moderna) vs BNT162b2 vaccine reported higher reactogenicity after the second shot, whereas those on a sphingosine-1-phosphate receptor modulator or fumarate were significantly less likely to report a reaction.DiscussionSARS-CoV-2 vaccine reactogenicity profiles and the associated factors in this convenience sample of PwMS appear similar to those reported in the general population. PwMS on specific DMTs were less likely to report vaccine reactions. Overall, the short-term vaccine reactions experienced in the study population were mostly self-limiting, including pain at the injection site, fatigue, headache, and fever.

SARS-CoV-2 infection and seroprevalence in patients with multiple sclerosis

IntroductionThe effect of SARS-CoV-2 infection in patients with multiple sclerosis (MS) and the influence of disease-modifying therapies (DMT) for MS on COVID-19 are unknown. To date, patients with MS have not been shown to present greater risk of COVID-19 or more severe progression of the disease. MethodsWe performed a descriptive study of patients with MS presenting SARS-CoV-2 infection diagnosed with PCR. We analysed demographic, clinical, laboratory, and treatment variables in our sample. Presence of antibodies against the virus was also determined. ResultsRelapsing-remitting MS (RRMS) was the most frequent form of MS in our sample. Prognosis was unfavourable in 10.2% of patients, and was associated with older age and higher scores on the Expanded Disability Status Scale (EDSS). Seroprevalence of antibodies against SARS-CoV-2 was 83.3% in our sample. Development of antibodies was not associated with DMT, lymphocytopaenia, or any of the other variables analysed. ConclusionsThe incidence of COVID-19 was slightly higher in our sample than in the general population in our province. Unfavourable prognosis was associated with older age and higher EDSS scores. DMT and lymphocytopaenia did not influence the clinical course of COVID-19. Seroprevalence of antibodies against the virus in our sample was similar to that reported for the general population with positive PCR results for the virus; the influence of specific DMTs could not be determined.

Infección por SARS-CoV-2 y seroprevalencia en pacientes con esclerosis múltiple

IntroductionThe effect of SARS-CoV-2 infection in patients with multiple sclerosis (MS) and the influence of disease-modifying therapies (DMT) for MS on COVID-19 are unknown. To date, patients with MS have not been shown to present greater risk of COVID-19 or more severe progression of the disease. MethodsWe performed a descriptive study of patients with MS presenting SARS-CoV-2 infection diagnosed with PCR. We analysed demographic, clinical, laboratory, and treatment variables in our sample. Presence of antibodies against the virus was also determined. ResultsRelapsing-remitting MS (RRMS) was the most frequent form of MS in our sample. Prognosis was unfavourable in 10.2% of patients, and was associated with older age and higher scores on the Expanded Disability Status Scale (EDSS). Seroprevalence of antibodies against SARS-CoV-2 was 83.3% in our sample. Development of antibodies was not associated with DMT, lymphocytopaenia, or any of the other variables analysed. ConclusionsThe incidence of COVID-19 was slightly lower in our sample than in the general population in our province. Unfavourable prognosis was associated with older age and higher EDSS scores. DMT and lymphocytopaenia did not influence the clinical course of COVID-19. Seroprevalence of antibodies against the virus in our sample was similar to that reported for the general population with positive PCR results for the virus; the influence of specific DMTs could not be determined.

Increased Within-Network Functional Connectivity May Predict NEDA Status in Fingolimod-Treated MS Patients.

Only a few studies have evaluated the brain functional changes associated with disease-modifying therapies (DMTs) in multiple sclerosis (MS), though none used a composite measure of clinical and MRI outcomes to evaluate DMT-related brain functional connectivity (FC) measures predictive of short-term outcome. Therefore, we investigated the following: (1) baseline FC differences between patients who showed evidence of disease activity after a specific DMT and those who did not; (2) DMT-related effects on FC, and; (3) possible relationships between DMT-related FC changes and changes in performance. We used a previously analyzed dataset of 30 relapsing MS patients who underwent fingolimod treatment for 6 months and applied the “no evidence of disease activity” (NEDA-3) status as a clinical response indicator of treatment efficacy. Resting-state fMRI data were analyzed to obtain within- and between-network FC measures. After therapy, 14 patients achieved NEDA-3 status (hereinafter NEDA), while 16 did not (EDA). The two groups significantly differed at baseline, with the NEDA group having higher within-network FC in the anterior and posterior default mode, auditory, orbitofrontal, and right frontoparietal networks than the EDA. After therapy, NEDA showed significantly reduced within-network FC in the posterior default mode and left frontoparietal networks and increased between-network FC in the posterior default mode/orbitofrontal networks; they also showed PASAT improvement, which was correlated with greater within-network FC decrease in the posterior default mode network and with greater between-network FC increase. No significant longitudinal FC changes were found in the EDA. Taken together, these findings suggest that NEDA status after fingolimod is related to higher within-network FC at baseline and to a consistent functional reorganization after therapy.

Effect of SARS-CoV-2 mRNA Vaccination in MS Patients Treated With Disease Modifying Therapies

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) are known to affect immune response to antigens and possibly to SARS-CoV2 vaccine. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response.Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech, Inc or mRNA-1273, Moderna Tx, Inc). A blood collection for the measure of SARS-CoV-2 antibody before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche Diagnostics).Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariate analysis, the antibody levels of patients on ocrelizumab (178-fold decrease, pInterpretation: In pwMS, therapy with anti-CD20 and fingolimod led to a reduced humoral response to SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·5-higher antibody titers than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 or fingolimod. Since it is still unknown the role of T-cells vaccine response, further information is required about the role of cellular immunity triggered by vaccination to better define the most appropriate strategy to vaccinate pwMS under specific DMTs.Funding Information: FISM [2021/Special-Multi/001]; the Italian Ministry of Health grant ‘Progetto Z844A 5x1000’.Declaration of Interests: MPS reports grants from Roche, during the conduct of the study; personal fees from Biogen, Merck, Roche, Sanofi, personal fees from Novartis, Medday, Geneuro, Celgene, Mylan, outside the submitted work; MI reports consulting fees from Roche, Merck-Serono, Novartis, Sanofi-Genzyme, Biogen; AL has received personal compensation from Novartis, Sanofi Genzyme, Biogen, Merck, and Roche for public speaking and advisory boards. AL received funding for research by Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, and the Italian Ministry of University; CC reports personal fees from Novartis, personal fees from Biogen Idec, personal fees from Almirall, personal fees from Merck Serono, outside the submitted work; DL reports consulting fees Roche, Biogen, Teva, Mylan, Sanofi-Genzyme, fess for advisory boards from Bristol-Celgene, Merck, Novartis, JF reports consulting fees fromSanofi, Biogen, Admirall; ADS reports personal consulting fees from Biogen, Novartis, Genzyme; MS reports research support and personal consulting fees from Merk, Sanofi, Novartis, Biogen, Roche; AU has received personal compensation from Novartis, Biogen, Merck, Roche and Sanofi Genzyme for public speaking and advisory boards. AU received funding for research by Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health and the European Community. IS, LC, CL, GDR, CS, IG, TT, GP, PG, GPB, AM, MLS, MC, ES, MTF, LP, MU, FM, GC, RI, GL, AMR, FC, SC, MAB, DF, have nothing to dislcose.Ethics Approval Statement: The study is done in compliance with the principles of the Declaration of Helsinki. The protocol is approved by the regional (CER Liguria: 5/2021 - DB id 11169- 21/01/2021) and the centralized national ethical committee AIFA/Spallanzani (Parere n 351, 2020/21). Written informed consent was obtained from all participants before starting any study procedures.

Potential Risks and Benefits of Multiple Sclerosis Immune Therapies in the COVID-19 Era: Clinical and Immunological Perspectives.

Coronavirus SARS-CoV2 has emerged as one of the greatest infectious disease health challenges in a century. Patients with multiple sclerosis (MS) have a particular vulnerability to infections through their use of immunosuppressive disease-modifying therapies (DMTs). Specific DMTs pose particular risk based on their mechanisms of action (MOA). As a result, patients require individualized approaches to starting new treatments and continuation of therapy. Additionally, vaccinations must be considered carefully, and individuals on long-term B cell–depleting therapies may have diminished immune responses to vaccination, based on preserved T cells and diminished but present antibody titers to influenza vaccines. We review the immunology behind these treatments and their impact on COVID-19, as well as the current recommendations for best practices for use of DMTs in patients with MS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01008-7.

Therapeutical Management and Drug Safety in Mitochondrial Diseases-Update 2020.

Mitochondrial diseases (MDs) are a group of genetic disorders that may manifest with vast clinical heterogeneity in childhood or adulthood. These diseases are characterized by dysfunctional mitochondria and oxidative phosphorylation deficiency. Patients are usually treated with supportive and symptomatic therapies due to the absence of a specific disease-modifying therapy. Management of patients with MDs is based on different therapeutical strategies, particularly the early treatment of organ-specific complications and the avoidance of catabolic stressors or toxic medication. In this review, we discuss the therapeutic management of MDs, supported by a revision of the literature, and provide an overview of the drugs that should be either avoided or carefully used both for the specific treatment of MDs and for the management of comorbidities these subjects may manifest. We finally discuss the latest therapies approved for the management of MDs and some ongoing clinical trials.

STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies.

Mutations in Munc18-1/STXBP1 (syntaxin-binding protein 1) are linked to various severe early epileptic encephalopathies and neurodevelopmental disorders. Heterozygous mutations in the STXBP1 gene include missense, nonsense, frameshift, and splice site mutations, as well as intragenic deletions and duplications and whole-gene deletions. No genotype-phenotype correlation has been identified so far, and patients are treated by anti-epileptic drugs because of the lack of a specific disease-modifying therapy. The molecular disease mechanisms underlying STXBP1-linked disorders are yet to be fully understood, but both haploinsufficiency and dominant-negative mechanisms have been proposed. This review focuses on the current understanding of the phenotypic spectrum of STXBP1-linked disorders, as well as discusses disease mechanisms in the context of the numerous pathways in which STXBP1 functions in the brain. We additionally evaluate the available animal models to study these disorders and highlight potential therapeutic approaches for treating these devastating diseases.

Use and safety of disease-modifying therapy in pregnant women with multiple sclerosis.

The purpose of this study is to describe dispensing patterns and comparative safety of disease-modifying therapies (DMTs) during pregnancy in women with multiple sclerosis (MS). We identified pregnancies from the Truven Health Marketscan® Commercial Claims and Encounters Database (2011-2015) and ascertained MS before delivery from inpatient and outpatient claims. We computed the proportion of women with DMT dispensing claims around pregnancy and estimated risk ratios of spontaneous abortion, infections, cesarean section, preterm delivery, poor fetal growth, preeclampsia, and major structural malformations by DMT exposure. Of 984058 pregnancies, 1649 were to women with MS. Thirty-five percent of women with MS filled a prescription for a DMT in the 90days before pregnancy. DMT use declined during pregnancy but increased again after delivery. Glatiramer acetate and interferon beta were most commonly dispensed. Pregnancies with and without early DMT exposure had similar risks of outcomes to one another and to pregnancies in women without MS. Small numbers did not allow evaluation of specific DMTs. Approximately one third of commercially insured women with MS in the United States uses DMTs before conception. Neither MS itself nor early pregnancy use of DMTs overall seems to be associated with a substantial risk of adverse pregnancy outcomes.

The genetic etiology in cerebral palsy mimics: The results from a Greek tertiary care center.

Non-progressive genetic disorders may present with motor dysfunction resembling cerebral palsy (CP). Such patients are often characterized as CP mimics. The purpose of this work was to delineate the clinical manifestations and molecular findings of CP mimic patients, with the ultimate goal to offer specific disease-modifying therapy and genetic counseling. Retrospective study of 47 patients diagnosed with CP and no acquired etiology. Chart review of clinical, neuroradiological, biochemical and molecular data was performed. 31,91% of patients manifested with features resembling dyskinetic CP, 19,14% spastic CP, 10,63% ataxic CP and 38,30% mixed CP. In 23 patients molecular diagnosis was reached and included 5 hereditary spastic paraplegia genes (SPG) in spastic CP mimics; HPRT1, TH, QDPR, DDC in dystonic CP mimics; ADCY5 and NIKX2-1 in choreic CP mimics; CANA1A in ataxic CP mimics; and SPG, PDHA1, NIKX2-1, AT, SLC2A1 and SPR in mixed CP mimics. In 14 patients, the etiological diagnosis led to specific treatment. CP mimics show a number of features that differ from classic CP and can be used as diagnostic clues, including presence of mixed motor features, minor dysmorphic features, oculogyric movements, multiple features of autonomic dysfunction, and acquired microcephaly. A more stringent use of the concept of CP focused on acquired lesions during the perinatal and infancy periods, and excluding disorders that could be of genetic origin, could contribute to a purer use of the term. Identification of a specific genetic cause for CP mimics may in certain cases lead to etiologic treatment.