Exploring the association of disease-modifying therapies for multiple sclerosis and BTK inhibitors with epilepsy.

Background: Multiple lines of evidence suggest a role of inflammation in epilepsy. Seizure incidence in patients with multiple sclerosis (MS) is twofold to threefold higher than the age-matched general population. Objectives: To explore the association of MS disease-modifying therapies (DMTs) and FDA-approved Bruton tyrosine kinase inhibitors (for lymphocytic malignancies) with the occurrence of epilepsy using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Design: Secondary analysis of the FAERS database. Methods: We conducted a disproportionality analysis of FAERS between 2003-Q4 and 2023-Q3. MS DMTs and the Bruton tyrosine kinase inhibitor, ibrutinib, were included in the analysis. An inverse association was defined by a 95% confidence interval (CI) upper limit of reporting odds ratio (ROR) <1. Results: We found an inverse association of ibrutinib, ocrelizumab, ofatumumab, rituximab, and teriflunomide with epilepsy. The strongest inverse association was seen with ibrutinib (ROR: 0.338; 95% CI: 0.218-0.524). Conclusion: Our findings suggest the possibility of considering these medications for repurposing opportunities in epilepsy and support a potential pathogenic role of leukocyte subsets in seizure perpetuation.

How multiple sclerosis treatments and Bruton tyrosine kinase inhibitors may be linked to epilepsy The research presented in this manuscript attempts to elucidate the potential relationship between inflammation and epilepsy. Multiple sclerosis (MS) is the most common inflammatory disorder of the brain and spinal cord in humans. There are over 20 FDA-approved disease-modifying therapies (DMTs) for MS. Other anti-inflammatory agents called Bruton tyrosine kinase (BTK) inhibitors are in clinical development. We show that the use of some DMTs and a BTK inhibitor appear to be associated with a lower chance of epilepsy.

An overview on disease modifying and symptomatic drug treatments for multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an inflammatory and degenerative autoimmune condition, resulting frequently in a disabling condition. Significant improvements of long-term prognosis have been recently achieved with an early and more aggressive use of disease modifying therapies (DMTs). Addressing the complexity of managing its progressive forms remains a significant challenge. AREAS COVERED: This review provides an update on DMTs for relapsing-remitting MS (RRMS) and progressive MS and their efficacy, safety, and mechanism of action, emphasizing the critical role of biomarkers in optimizing treatment decisions. Moreover, some key information on drugs used to manage symptoms such as pain, fatigue, spasticity and urinary problems will be provided. The literature search was conducted using PubMed, Embase, and Cochrane Library databases covering the period from January 2000 to January 2024. EXPERT OPINION: Major advances have been achieved in the treatment of RRMS. Treatment should start immediately as soon as the neurologist is confident with the diagnosis and its choice should be based on the prognostic profile and on the patient's propensity to accept drug-related risks. The therapeutic landscape for progressive MS is quite disappointing and necessitates further innovation. Personalized medicine, leveraging biomarker insights, holds promise for refining treatment efficacy and patient outcomes.

COVID-19 vaccination in patients with multiple sclerosis: what you need to know - a review.

Background: The appearance of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) initiated the COVID-19 pandemic, resulting in millions of confirmed cases and numerous fatalities. In response, rapid vaccine development efforts were launched to mitigate the pandemic's impact. Despite the high efficacy of COVID-19 vaccines, they are also associated with several common side effects/complications, some of them specific to the multiple sclerosis population. Our goal is to review various types of COVID-19 vaccines, assessing their efficacy, adverse events, their association with an MS relapse following vaccination, and the influence of disease modifying therapies (DMTs) on vaccines' efficacy. Methods: The review was based on a database search that included PubMed/Medline, Embase, Scopus, and the Web of Science conducted from January 2020 to July 2024 using the following MeSH terms: MS, COVID-19, COVID-19 vaccination, vaccine side effects, and vaccine hesitancy. Results: Receiving any type of COVID-19 vaccine is a safer and more reliable approach to building immunity compared to becoming infected with the virus. Complications tend to be mild to moderate, occasionally severe. DMTs could affect the humoral response to the COVID-19 vaccine. Among all DMTs, a notable reduction in the humoral response has been observed in patients who received anti-CD20 and sphingosine-1-phosphate (S1P) receptor modulator drugs after their COVID-19 vaccination. Conclusion: Despite certain drawbacks, the benefits of the COVID-19 vaccine significantly outweigh the associated risks, making it a recommended course of action for people with multiple sclerosis (pwMS). However, physicians need to be mindful of potential complications especially in patients undergoing anti CD20 and manage them appropriately.

Insights into the use of biomarkers in clinical trials in Alzheimer's disease.

Biomarkers have been instrumental in population selection and disease monitoring in clinical trials of recently FDA-approved drugs targeting amyloid-ß to slow the progression of Alzheimer's disease (AD). As new therapeutic strategies and biomarker techniques emerge, the importance of biomarkers in drug development is growing exponentially. In this emerging landscape, biomarkers are expected to serve a wide range of contexts of use in clinical trials focusing on AD and related dementias. The joint FDA-NIH BEST (Biomarkers, EndpointS, and other Tools) framework provides standardised terminology to facilitate communication among stakeholders in this increasingly complex field. This review explores various applications of biomarkers relevant to AD clinical trials, using the BEST resource as a reference. For simplicity, we predominantly provide contextual characterizations of biomarkers use from the perspective of drugs targeting amyloid-ß and tau proteins. However, general definitions and concepts can be extrapolated to other targets.

Effects of disease-modifying therapies on remyelination in multiple sclerosis; evaluation via visual evoked potential test.

BACKGROUND: Assessment of the visual pathway, which is frequently affected by MS, provides the opportunity to measure the remyelination of acute and chronic MS lesions in vivo and non-invasively. VEP can be used in this context. Amplitude is a parameter of axonal loss, whereas latency is an in vivo biomarker of myelin repair. This study aimed to evaluate DMT's neuroprotective and pro-remyelinating potential by evaluating VEP latency and amplitude in MS patients. MATERIALS AND METHODS: A total of 74 patients with relapsing MS who had no evidence of optic neuritis were included in the study. Patient data were retrospectively analyzed and recorded. In the VEP test, latency above 118 ms and amplitude below 5.0 µV were considered abnormal. Classified according to DMTs (injectables, teriflunomide, dimethyl fumarate, fingolimod, cladribine, and alemtuzumab). Visual evoked potential tests, clinical features, and cerebrospinal fluid examinations were evaluated by three independent neurologists and one clinical neurophysiologist. RESULTS: The mean age at diagnosis was 29.2 ± 9.01, and the mean age at first VEP was 34.97 ± 10.64. In women, latency was lower, and amplitude was higher. The mean differences in latency and amplitude were, respectively, latency prolonged by 0.7 ms on the right and 0.5 ms on the left, and amplitude increased by 0.6 µV on the right and 0.37 µV on the left. However, these changes were not statistically significant. Latency worsening was more prominent in those with longer disease duration (p = 0.011). Those with amplitude or latency worsening had higher EDSS (p = 0.016 and 0.013, respectively). DMTs did not affect these changes. CONCLUSION: Prolonged latency is associated with a long disease duration. Deterioration in both amplitude and latency is evident in high EDSS. These results may be an indirect consequence of axonal degeneration dominating remyelination. DMTs do not ameliorate impaired remyelination and neurodegeneration but seem to be sufficient for short-term maintenance of the current state.

Evaluation of a Quality Measure for Multiple Sclerosis Care: Disease-Modifying Therapy Initiation at the University of North Carolina's Outpatient Neurology Clinic.

BACKGROUND: Multiple sclerosis (MS) is a neurological condition leading to significant disability and challenges to quality of life. To slow progression and reduce relapses, it is critical to rapidly initiate disease-modifying therapy (DMT) after diagnosis. Patient demographics may play a role in timely DMT initiation. Financial barriers may also result in delays in DMT access. METHODS: This retrospective, single-center, cross-sectional study included patients seen at a neurology clinic at a large academic medical center for an initial evaluation of MS between January 1, 2022, and June 30, 2022. As an indicator of the quality of care, the primary study outcome was whether patients were offered DMT initiation on their first clinic visit. Secondary outcomes evaluated the time to DMT initiation, including differences in care based on demographic factors and financial coverage. RESULTS: Of the 49 eligible individuals studied, 45 (91.8%) were offered DMT at their initial MS visit. Descriptive statistics appeared to demonstrate that demographic factors did not impact whether DMT was offered. However, the majority of patients experienced access barriers relating to prior authorization requirements (80.0%) and/or the need for co-pay assistance (52.0%). CONCLUSIONS: DMT was appropriately offered to a majority of patients at their initial MS visit, regardless of demographic considerations. No offer of DMT and delays in initiation were primarily due to the need for imaging and specialty referrals, as well as financial barriers. Medication assistance teams may play a crucial role in limiting delays and financial hurdles associated with insurance coverage and co-pay assistance.

Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis.

INTRODUCTION: Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing-remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb. METHODS: Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12 mg) and SC (12, 36, and 60 mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60 mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4 years. RESULTS: Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12 months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0-7.5 days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow's disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator. CONCLUSIONS: These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs. TRIAL REGISTRATION: NCT02282826, NCT02977533, NCT02313285.

Disease-Modifying Symptomatic Treatment (DMST) Potential of Cannabinoids in Patients with Multiple Sclerosis.

With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms. Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS. Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control. This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs).

Selecting informative patients for phase 2 progressive trials in MS: Design considerations for phase 2 clinical trials in progressive MS.

While relapsing-remitting multiple sclerosis (MS) has many therapeutic options, progressive forms of MS remain largely untreatable. Phase 2 clinical trials are our main tool to advance new treatments for progressive MS. Given the complexities of progressive MS, it will likely require many phase 2 trials to improve its treatment. To conduct informative and efficient phase 2 trials, it is important that such trials are designed in a way that they can identify a successful treatment as quickly and with as few participants as possible. In this topical review, we discuss cohort selection, outcome selection, cohort enrichment, and dosing selection as strategies to optimize the efficiency of phase 2 clinical trials in progressive MS.

Multiple Sclerosis and COVID-19: An Overview on Risk, Severity, and Association With Disease Modifying Therapies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, emerged in December 2019, sparking a global health crisis. While initially recognized as a respiratory illness, it has become evident that Coronavirus disease 2019 (COVID-19) also affects the central nervous system. This comprehensive review focuses on the neurological manifestations of COVID-19 and its impact on patients with preexisting neurological disorders, particularly those with multiple sclerosis (MS) receiving disease-modifying therapies. Advancements in management, including vaccinations, antiviral therapy, and targeted prophylaxis, have led to a decline in the incidence and severity of COVID-19. Nevertheless, significant complications persist, particularly in patients with advanced MS, who are highly vulnerable to infectious agents like SARS-CoV-2. This review explores the evolving understanding of MS and its association with SARS-CoV-2, encompassing neuroinvasiveness, pathogenesis, disease severity, and outcomes. Research findings reveal substantial neurological implications for some MS patients with COVID-19, with a potential risk of disease relapse and severity. A notable proportion of MS patients experiencing COVID-19 may manifest new symptoms, experience exacerbation of existing symptoms, or encounter both simultaneously, underscoring the diverse neurological effects of the virus. While vaccination and therapeutics have mitigated the overall impact, specific subgroups, especially those on anti-CD20 therapy and with existing disability, remain at higher risk, necessitating ongoing vigilance and tailored care.

Pure spinal multiple sclerosis: A case series of a possible new entity.

BACKGROUND: Recent literature describes a condition similar to multiple sclerosis (MS) but with demyelinating lesions limited to the spinal cord. This condition, referred to as "pure spinal" MS, might benefit from disease-modifying treatment (DMT). METHODS: We screened the medical records of approximately 8000 patients with demyelinating diseases at the Isfahan MS clinic in Iran. Criteria for inclusion in the case series were adults with a demyelinating disease limited to the spinal cord, positive oligoclonal IgG bands in cerebrospinal fluid (CSF), and negative results for other potential diagnoses. RESULTS: Seven people with pure spinal MS were identified (all women, mean age [SD]: 40.14 [6.17] years at the first visit, mean follow-up duration [SD]: 98 [39.41] months). Two had a family history of conventional MS in their siblings. All patients exhibited lower limb weakness and tested negative for anti-MOG and anti-AQP4 antibodies. They experienced relapsing-remitting partial myelitis, with new spinal cord lesions on MRI but no extraspinal CNS lesions. DMT significantly reduced relapse rates in all patients, and two showed no increase in EDSS scores. CONCLUSION: Pure spinal MS might be an atypical form of MS. Those affected may benefit from DMT; therefore, further investigation and consideration in the upcoming revisions of the McDonald criteria are recommended.

Multiple sclerosis treatment underutilization predicts high risk for obstructive sleep apnea in patients with multiple sclerosis.

BACKGROUND: Obstructive sleep apnea (OSA) is more common in patients with multiple sclerosis (MS) than in the general population, which suggests MS may predispose patients to OSA. However, the relationships between MS treatment, disease activity, disease severity, fatigue, and OSA are unknown. OBJECTIVES: To evaluate the connections between OSA risk, MS fatigue, and MS severity, controlling for well-established risk factors for OSA in the general population. METHODS: We administered OSA and fatigue-related questionnaires to patients with MS and collected relevant demographic and clinical data. Then, we utilized multivariate logistic regression to examine relationships between OSA risk and MS disease severity. RESULTS: We identified an inverse correlation between medication possession ratio (MPR) and high OSA risk. Statistical models also demonstrated a positive correlation between fatigue and nonwhite race with high OSA risk, controlling for male sex, younger age, and body mass index (BMI). CONCLUSION: We identified disease-modifying therapy (DMT) underutilization, fatigue, and nonwhite race as predictors of high OSA risk in patients with MS. These findings support aggressive treatment of MS to avoid risk of comorbid OSA and MS-induced fatigue.

Pediatric inflammatory leukoencephalopathies.

Acquired demyelinating syndromes (ADS) represent acute neurologic illnesses characterized by deficits persisting for at least 24hours and involving the optic nerve, brain, or spinal cord, associated with regional areas of increased signal on T2-weighted images. In children, ADS may occur as a monophasic illness or as a relapsing condition, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Almost all young people with MS have a relapsing-remitting course with clinical relapses. Important strides have been made in delineating MS from other ADS subtypes. Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and aquaporin 4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) were once considered variants of MS; however, studies in the last decade have established that these are in fact distinct entities. Although there are clinical phenotypic overlaps between MOGAD, AQP4-NMOSD, and MS, cumulative biologic, clinical, and pathologic evidence allows discrimination between these conditions. There has been a rapid increase in the number of available disease-modifying therapies for MS and novel treatment strategies are starting to appear for both MOGAD and AQP4-NMOSD. Importantly, there are a number of both inflammatory and noninflammatory mimics of ADS in children with implications of management for these patients in terms of treatment.

The cost-of-illness of multiple sclerosis in Jordan.

BACKGROUND: Multiple Sclerosis (MS) imposes a significant financial burden on health-care systems. This study aims to determine the cost-of-illness (COI) for MS in Jordan, a country where data on the economic impact of MS are scarce. METHODS: Data were collected for one year, annual COI was estimated using a cross-sectional snowball sampling design. Eligible patients completed a self-reported questionnaire to provide sociodemographic, physician visit, and diagnostic and laboratory test data. Indirect costs were estimated using an adjusted Human Capital Approach. RESULTS: This study included 383 patients, (73% females, 61% between 26-45). Eighty % took disease-modifying therapies (DMTs), and 40% had relapses in that year. One-third use non-DMTs and equipment for assistance. The average annual cost per patient was $11,719 (direct costs=$11,252, indirect costs=$467). The total annual cost for all participants was $748,299. The estimated cost of non-DMT, medical tools, diagnostic tests, and hospitalization per patient was $53, 51, 99, and 235 respectively. CONCLUSION: High costs of DMTs state the necessity of resource optimization in Jordan public healthcare facilities. Such findings yield policy-informing actionable insights, suggesting strategic investments in more cost-effective DMTs with potential improvement in accessibility and reduction in the overall economic burden faced by both patients and governments.

[Adherence to treatment in the management of patients with multiple sclerosis]. / Priverzhennost' lecheniyu v vedenii patsientov s rasseyannym sklerozom.

Adherence to therapy largely determines the success of treatment interventions: low levels of adherence are associated with reduced treatment effectiveness. For many chronic diseases, the level of adherence to treatment is about 50% or less, which confirms the relevance of this topic and requires its research. The high costs of treatment, the need for long-term continuous use of drugs and the special socio-economic significance of a disease such as multiple sclerosis (MS) determine the importance of maintaining a high level of adherence to its treatment. An analysis of literature data on the concept of treatment adherence, methods of its definition and influencing factors was carried out, the values of the level of adherence in the treatment of MS, as well as measures to maintain it during the COVID-19 pandemic were considered. Increasing awareness of healthcare professionals about the problem of treatment adherence and ways to improve it helps to improve the efficiency of managing patients with MS. The paper considers the primary stage of the strategy to improve treatment adherence among patients with MS, namely the formation of expanded knowledge of the problem by specialists of a multidisciplinary team involved in the diagnosis and treatment of patients with MS.

Prognostic factors for tube feeding in type I SMA patients treated with disease-modifying therapies: a cohort study.

The aim of this study was to assess the need for tube feeding in a cohort of treated infants with type I SMA and to identify predictive factors. All patients were classified at baseline, when treatment started, and at follow-up according to their functional level and the need for tube feeding. Fisher's exact test was used to examine the associations between the outcome at the last follow-up and SMA type, SMN2 copy number, and baseline nutritional status. ANOVA was performed to compare CHOP INTEND scores and age at treatment initiation with outcomes. The cohort includes 75 type I SMA infants treated between 0.1 and 5 years of age. At the last follow-up, 34 had no need for tube feeding, 9 had tube feeding but were also able to be fed by mouth, and 32 had tube feeding and were unable to be fed by mouth. Thirty of the 41 infants with tube feeding at follow-up already had feeding difficulties when treatment was started. The need for tube feeding at follow-up was associated with the level of feeding involvement at baseline and with CHOP INTEND scores [p < 0.001] but not with SMN2 copy number, SMA type 1 subtypes or age at treatment. The results of this study suggest that the need for tube feeding is not frequent in treated infants with type I SMA and, when occurring, can be predicted by the level of feeding involvement and low CHOP INTEND scores at baseline. What is Known: • The advent of disease-modifying therapies is increasingly changing the approach to swallowing and nutritional management in type I SMA. • Clinical trials and real-world data using all three disease-modifying therapies report a rather wide variability of feeding outcome and need for tube feeding that is often related to different cohorts that makes comparison between studies very difficult. What is New: • The real-world findings of this study, including all the children treated since treatments became available, confirmed that the need for tube feeding is not an invariable finding. • The level of feeding involvement at baseline appears to be a reliable prognostic indicator of bulbar outcome. • The results highlight the need for interventional studies with structured Speech and Language Therapist protocols that will help to better understand the extent to which bulbar function can be maintained or regained even in children requiring tube feeding.

Anti-RBD Antibody Levels and IFN-γ-Specific T Cell Response Are Associated with a More Rapid Swab Reversion in Patients with Multiple Sclerosis after the Booster Dose of COVID-19 Vaccination.

This study investigated the incidence and severity of SARS-CoV-2 breakthrough infections (BIs) and the time to swab reversion in patients with multiple sclerosis (PwMS) after the booster dose of COVID-19 mRNA vaccines. We enrolled 64 PwMS who had completed the three-dose mRNA vaccine schedule and had never experienced COVID-19 before. Among the 64 PwMS, 43.8% had BIs with a median time since the third vaccine dose of 155 days. BIs occurred more frequently in ocrelizumab-treated patients (64.7%). Patients with a relapsing-remitting MS course showed a reduced incidence of BIs compared with those with a primary-progressive disease (p = 0.002). Having anti-receptor-binding domain (RBD) antibodies represented a protective factor reducing the incidence of BIs by 60% (p = 0.042). The majority of BIs were mild, and the only severe COVID-19 cases were reported in patients with a high Expanded Disability Status Scale score (EDSS > 6). The median time for a negative swab was 11 days. Notably, fingolimod-treated patients take longer for a swab-negativization (p = 0.002). Conversely, having anti-RBD antibodies ≥ 809 BAU/mL and an IFN-γ-specific T cell response ≥ 16 pg/mL were associated with a shorter time to swab-negativization (p = 0.051 and p = 0.018, respectively). In conclusion, the immunological protection from SARS-CoV-2 infection may differ among PwMS according to DMTs.

Impact of Disease Severity and Disease-Modifying Therapies on Myostatin Levels in SMA Patients.

Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels' correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients' age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials.

Disease-modifying therapies, outcomes, risk factors and severity of COVID-19 in multiple sclerosis: A MENACTRIMS registry based study.

BACKGROUND: There is a lack information regarding risk factors associated with worse COVID-19 outcomes in patients with multiple sclerosis (MS) in the MENA region. METHODS: This is a multicenter, retrospective cohort study that included all MS patients with a suspected or confirmed COVID-19 infection using the MENACTRIMS registry. The association of demographics, disease characteristics, and use of disease-modifying therapies (DMTs) with outcomes and severity of COVID-19 were evaluated by multivariate logistic model. RESULTS: A total of 600 MS patients with confirmed (n = 542) or highly suspected (n = 58) COVID-19 were analyzed. Seventy-three patients (12.2 %) had a COVID-19 severity score of ≥3 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]), and 15 patients (2.5 %) died. Out of 73 patients with a severity score ≥3, 90.4 % were on DMTs; 50.6 % of them were on anti-CD20, including ocrelizumab and rituximab. Multivariate logistic regression showed that older age (odds ratio per 10 years, 1.4 [95 %CI, 1.0-1.8]), disability (OR for EDSS 3.0-5.5, 2.9 [95 %CI. 1.5-5.7], OR for EDSS ≥6.0, 2.3 [95 %CI. 1.0-5.1]), obesity (OR, 3.0 [95 %CI, 1.5-6.0]), and treatment with rituximab (OR, 9.0 [95 %CI, 3.1-25.3]) or off-label immunosuppressive medications (OR, 5.6 [95 %CI. 1.1-27.8]) were risk factors for moderate or severe COVID-19. CONCLUSION: In this registry-based study of MS patients, age, sex, EDSS, obesity, progressive MS were risk factors for severe COVID-19. Moreover, there was an association found between exposure to anti-CD20 DMTs and COVID-19 severity.

MS treatment de-escalation: review and commentary.

Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, such as extended or reduced dosing, switching from high-efficacy DMTs having higher risks to moderately effective DMTs with lesser risks, or treatment discontinuation. Studies have suggested that for natalizumab extended dosing maintained clinical efficacy while reducing the risk of PML. Extended interval dosing of ocrelizumab mitigated the decline of Ig levels. Retrospective and observational discontinuation studies demonstrate that age is an essential modifier of drug efficacy. Discontinuation of MS treatment in older patients has been associated with a stable disease course, while younger patients who discontinued treatment were more likely to experience new clinical activity. A recently completed 2-year randomized-controlled discontinuation study in 260 stable pwMS > 55 years found stable clinical multiple sclerosis with only a small increased risk of new MRI activity upon discontinuation. DMT de-escalation or discontinuation in MS patients older than 55 years may be non-inferior to continued treatment with immunosuppressive agents having higher health risks. However, despite several small studies, a definite conclusion about treatment de-escalation in older pwMS will require larger and longer studies. Ideally, comparison of de-escalation versus continuation versus discontinuation of DMTs should be done by prospective randomized-controlled trials enrolling sufficient numbers of subjects to allow comparisons for MS patients of both sexes within age groups, such as 55-59, 60-65, 66-69, etc. Optimally, such studies should be 3 years or longer and should incorporate testing for specific markers of immunosenescence (such as T-cell receptor excision circles) to account for differential aging of individuals.