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Background/Objectives: Retinal hyperreflective foci, 25–50 µm in diameter, that can be imaged by noninvasive optical coherence tomography (OCT) may represent microglial activity related to inflammation. This study aimed to detect hyperreflective foci in the OCT-hyporeflective avascular outer nuclear layer of the retina in relapsing–remitting MS (RRMS) patients without ongoing eye or optic nerve disease. Methods: A cohort of 13 RRMS patients (8 eyes with and 18 eyes without prior optic neuritis) underwent retinal OCT at baseline, after 1 month, after 6 months, and then every 6 months for 3 years. The data were compared with single-examination data from 106 eyes in 53 age-matched healthy subjects. Results: The prevalence of hyperreflective foci at baseline was higher in RRMS patients than in healthy subjects (46.2% vs. 1.8%, p < 0.005). Patients with optic neuritis had much more foci than those without (p < 0.001). Hyperreflective foci recurred in 23.1% of RRMS patients, bilaterally in one with prior optic neuritis and unilaterally in two without. Conclusions: Patients with RRMS, notably those with prior optic neuritis, had elevated rates of retinal infiltration in the absence of retinal disease, suggesting that the phenomenon may represent elevated activity of an immune surveillance or housekeeping mechanism rather than retinal disease. [ABSTRACT FROM AUTHOR]

Objectives: Fingolimod is approved in Turkey or the treatment of cases of multiple sclerosis (MS) which cannot be controlled with first-line treatments. There is limited information about its efficacy and safety in clinical practice in Turkey. The aim of this study was to evaluate the efficacy and safety of fingolimod treatment in patients with relapsing-remitting multiple sclerosis who were prescribed fingolimod by the Multiple Sclerosis specialists of Bursa Uludağ University Department of Neurology. Methods: This is a single-center observational study evaluating 142 patients using fingolimod who were followed up for at least 12 months in our center between April 2015 and October 2022. Efficacy results were evaluated in terms of mean number of attacks, annualized relapse rate, relapse-free patient rate, disease progression, clinical and radiological disease activity, and no evidence of disease activity (NEDA-3). The safety outcomes are the rates of treatment-related severe adverse events and patients' continuation rates. Results: Over 12 months of treatment with fingolimod, the average number of attacks decreased by 94.6%, the annual relapse rate decreased by 87%, and most patients did not relapse (83.1%). Alongside this, in 76.4% of cases, there was no disability progression and in 83.3% of cases, magnetic resonance imaging (MRI) activation was not observed. Excluding replacement due to ineffectiveness, 89.4% of patients continued fingolimod therapy. Cardiac events, treatment-related infections and a decreased lymphocyte count were observed as side effects. Conclusion: In our center, switching from first-line treatments to fingolimod was effective in reducing disease activity in patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients’ lives; they play an important role in multiple sclerosis (MS) research and practice. We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52  weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient’s experience and self-assessed impact of treatment on daily life. [ABSTRACT FROM AUTHOR]

Introduction: Switching disease-modifying therapy (DMT) may be considered for relapsing–remitting multiple sclerosis (RRMS) if a patient's current therapy is no longer optimal. This was particularly important during the recent COVID-19 pandemic because of considerations around immune deficiency and impaired vaccine response associated with B cell-depleting DMTs. This real-world, single-center study aimed to evaluate change or decline in functional ability and overall disease stability in people with RRMS who were switched from B cell-depleting ocrelizumab (OCRE) to diroximel fumarate (DRF) because of safety concern related to the COVID-19 pandemic. Methods: Adults with RRMS were included if they had been clinically stable for ≥ 1 year on OCRE. Data collected at baseline and 1 year post switch included relapse rate, magnetic resonance imaging (MRI), blood work for assessment of peripheral immune parameters, the Cognitive Assessment Battery (CAB), optical coherence tomography (OCT), and patient-reported outcomes (PROs). Results: Participants (N = 25) had a mean (SD) age of 52 (9) years, and a mean (SD) duration of 26 (8) months' treatment with OCRE before the switch to DRF. Median washout duration since the last OCRE infusion was 7 months (range 4–18 months). No participants relapsed on DRF during follow-up, and all remained persistent on DRF after 1 year. There were no significant changes in peripheral immune parameters, other than an increase in the percentage of CD19+ cells 1 year after switching (p < 0.05). Similarly, there were no significant changes in CAB, OCT, and PROs. Conclusion: These preliminary findings suggest that transition to DRF from OCRE may be an effective treatment option for people with RRMS who are clinically stable but may need to switch for reasons unrelated to effectiveness. Longer follow-up times on larger samples are needed to confirm these observations. [ABSTRACT FROM AUTHOR]

Introduction: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. Methods: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing–remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. Results: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [− 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. Conclusion: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. Clinical Trials Registration: Substudy of ENSEMBLE (NCT03085810). Registration: March 21, 2017. [ABSTRACT FROM AUTHOR]

Introduction: Examining the safety of theBNT162b2 mRNA vaccine in multiple sclerosis (MS) patients remains inconclusive, particularly regarding the potential for disease exacerbations. This study aims to assess the effects of BNT162b2 COVID‐19 vaccination on disease activity in MS patients through sequential MRI imaging. Methods: A retrospective study of 84 MS patients from five Israeli hospitals was conducted. MS lesion load was determined from three brain MRI scans, one postvaccination and two prevaccination scans. A post hoc analysis compared subgroups featuring vaccinated and unvaccinated patients respectively, with early onset MS. Results: The cohort included 70 women with early onset (mean age 16.4 ± 0.8 years) and adult onset (mean age 34.9 ± 1.1 years) MS. Among the early onset group, vaccinated patients showed an increased risk of new lesions (p =.00026), while there was no increased risk among adult‐onset patients. Additionally, a comparison between early onset vaccinated and nonvaccinated groups revealed a higher risk of increased lesions in the vaccinated group (p =.024). Discussion: Overall, the study suggests that the BNT162b2 vaccine is generally safe in MS patients, with no association found between vaccination and new lesions in most patients. However, close MRI follow‐up is recommended for early‐onset MS cases to monitor lesion development. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ofatumumab has demonstrated superior efficacy and favorable safety for up to 2.5 years versus teriflunomide in relapsing multiple sclerosis (RMS). OBJECTIVE: Further characterize efficacy and safety of ofatumumab in RMS. METHODS: Efficacy set: patients randomized to ofatumumab/teriflunomide in ASCLEPIOS I/II (core). Safety set: patients who received ⩾ 1 dose of ofatumumab in ASCLEPIOS I/II, APLIOS, APOLITOS (all core), or ALITHIOS (umbrella open-label extension). Patients received continuous ofatumumab or were newly switched from teriflunomide. Data cut-off: 25 September 2021. RESULTS: In the efficacy set (n = 1882), the continuous ofatumumab group had a low annualized relapse rate (ARR 0.05 (95% confidence interval: 0.04-0.07)), low numbers of gadolinium-enhancing (Gd+) T1 lesions (0.01 lesions/scan) and fewer new/enlarging T2 lesions (annualized rate 0.08). Overall, 78.8% met three-parameter no evidence of disease activity criteria through 4 years. Switching from teriflunomide led to reduced ARR, risk of confirmed disability worsening (CDW), new/enlarging T2 lesions, Gd+ T1 lesions, and serum neurofilament light chain. In the continuous and newly switched ofatumumab groups, cumulative 3- and 6-month CDW rates remained low. In the safety set (n = 1969), the most frequently reported adverse events were infections and infestations (58.35%). No new safety signals were identified. CONCLUSION: Ofatumumab has a favorable longer-term benefit-risk profile in RMS. TRIAL REGISTRY: ALITHIOS (NCT03650114): https://clinicaltrials.gov/ct2/show/NCT03650114.

Multiple sclerosis (MS) is a debilitating neurological disease characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Despite extensive research, the pathology of MS remains incompletely understood. Ocrelizumab (OCRE), a monoclonal antibody targeting CD20-positive B cells, has shown efficacy in relapsing (RR) and primary progressive (PP) MS. Neurofilaments (Nf) are emerging biomarkers of neuroaxonal injury, reflecting disease activity and treatment response in MS. This study aimed to assess the impact of OCRE on serum Nf levels (NfLs) in RRMS and PPMS patients and explore factors influencing treatment response.

Background: Several oral disease-modifying therapies (DMTs) have been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). In the absence of head-to-head randomized data, matching-adjusted indirect comparisons (MAICs) can evaluate the comparative effectiveness and safety of ozanimod versus other oral DMTs in RRMS. Objectives: To synthesize results from the published MAICs of ozanimod and other oral DMTs for 2-year outcomes in RRMS. Methods: Published MAICs involving ozanimod for the treatment of RRMS were identified. Extracted data elements included efficacy [annualized relapse rate (ARR), confirmed disability progression (CDP), and brain volume loss] and safety [adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and infection] outcomes. Results: The four MAIC studies identified compared ozanimod with fingolimod, teriflunomide, dimethyl fumarate (DMF), and ponesimod. All comparisons were adjusted for differences in age, sex, relapses within the previous year, Expanded Disability Status Scale score, and percentage of patients with prior DMTs. Outcomes at 2 years were analyzed based on comparisons that lacked a common comparator arm. Ozanimod was associated with significantly lower ARR versus teriflunomide [ARR ratio (95% CI) 0.73 (0.62, 0.84) and DMF 0.80 (0.67, 0.97)], with no significant difference versus fingolimod or ponesimod. The proportions of patients treated with ozanimod or fingolimod had similar 3- and 6-month CDP. Compared with teriflunomide and DMF, ozanimod was associated with a significantly lower risk of 3-month CDP; 6-month CDP was comparable. Ozanimod was associated with significantly lower rates of any AE and AEs leading to discontinuation compared with the other oral DMTs evaluated. Ozanimod also had significantly lower rates of SAEs versus teriflunomide and DMF and lower rates of reported infection outcomes versus fingolimod and ponesimod. Conclusion: Compared with the other oral DMTs evaluated in MAICs, ozanimod was associated with a favorable safety profile and improved or comparable efficacy outcomes. Plain language summary: An indirect comparison of ozanimod vs other oral treatments in relapsing-remitting multiple sclerosis The many treatment options available for relapsing-remitting multiple sclerosis (RRMS) make treatment decisions difficult. While direct head-to-head treatment comparisons provide useful information, these studies are not available for every pair of treatments. Indirect comparisons of published study results can help fill that evidence gap. A technique called matching-adjusted indirect comparison (MAIC) offers a statistically robust way to compare safety/efficacy outcomes from different studies by accounting for important differences across the studies. We collected data from four MAIC studies that compared 2-year treatment outcomes in patients treated with ozanimod versus those treated with fingolimod, teriflunomide, dimethyl fumarate (DMF), or ponesimod. Each study accounted for differences in age, sex, relapses within the previous year, disability status, and previous therapy use. We found ozanimod was either better than or similar to other treatments based on the outcomes measured. The annual rate of RRMS relapse was lower for patients treated with ozanimod than for patients treated with teriflunomide or DMF and similar for patients treated with ponesimod or fingolimod. Ozanimod-treated patients saw their RRMS progress at rates similar to those treated with fingolimod at 3 and 6 months and teriflunomide and DMF at 6 months; RRMS was more likely to progress at 3 months in patients treated with teriflunomide and DMF versus those treated with ozanimod. Our analyses also found that patients treated with ozanimod had lower rates of side effects, including those serious enough to cause treatment discontinuation, compared with patients receiving other treatments. By comparing findings from existing MAIC studies, we found that patients with RRMS treated with ozanimod had fewer side effects and better or similar efficacy outcomes compared with patients who received other treatments for RRMS. These findings can potentially inform treatment decisions for patients with RRMS. [ABSTRACT FROM AUTHOR]

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one firstline disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient's experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022. [ABSTRACT FROM AUTHOR]

Background: 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. Study Design and Setting: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) causes a variety of symptoms in speech production, such as more frequent pauses and an increase in the duration of pauses in the speech. However, there is almost no data on whether the disease affects speech fluency in other ways, such as changes in the frequency of disfluencies in speech. The main question of this study is the following: if we examine speech fluency in speech tasks requiring different cognitive load, will there be a difference between patients and controls? Twenty people with relapsing-remitting MS (3 men and 17 women) and 20 age- and education-matched control speakers (4 men and 16 women) participated in the study. Speech samples were recorded with each participant in three speech tasks: 1) spontaneous narratives about their own lives, 2) narratives about their previous day, and 3) narrative recalls based on a heard text. In the speech samples, pauses and disfluencies were annotated and the duration of pauses was measured. Then, the frequency of pauses and disfluencies were calculated and the types of disfluencies were examined. The results show that there are differences in the frequency and duration of pauses between people with MS and controls. However, there were no significant differences in the frequency of disfluencies between the groups. The same types of disfluencies occurred in the same frequency in both groups. The results help to better understand the speech production processes in MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic, progressive, inflammatory disorder of the central nervous system. Relapsing–remitting MS (RRMS), the most common form of the disease, is characterized by transient neurological dysfunction with concurrent accumulation of disability. Over the past three decades, disease-modifying therapies (DMTs) capable of reducing the frequency of relapses and slowing disability worsening have been studied and approved for use in patients with RRMS. The first DMTs were interferon-betas (IFN-βs), which were approved in the 1990s. Among them was IFN-β-1a for subcutaneous (sc) injection (Rebif®), which was approved for the treatment of MS in Europe and Canada in 1998 and in the USA in 2002. Twenty years of clinical data and experience have supported the efficacy and safety of IFN-β-1a sc in the treatment of RRMS, including pivotal trials, real-world data, and extension studies lasting up to 15 years past initial treatment. Today, IFN-β-1a sc remains an important therapeutic option in clinical use, especially around pregnancy planning and lactation, and may also be considered for aging patients, in which MS activity declines and long-term immunosuppression associated with some alternative therapies is a concern. In addition, IFN-β-1a sc is used as a comparator in many clinical studies and provides a framework for research into the mechanisms by which MS begins and progresses. [ABSTRACT FROM AUTHOR]

Abstract Introduction Examining the safety of theBNT162b2 mRNA vaccine in multiple sclerosis (MS) patients remains inconclusive, particularly regarding the potential for disease exacerbations. This study aims to assess the effects of BNT162b2 COVID‐19 vaccination on disease activity in MS patients through sequential MRI imaging. Methods A retrospective study of 84 MS patients from five Israeli hospitals was conducted. MS lesion load was determined from three brain MRI scans, one postvaccination and two prevaccination scans. A post hoc analysis compared subgroups featuring vaccinated and unvaccinated patients respectively, with early onset MS. Results The cohort included 70 women with early onset (mean age 16.4 ± 0.8 years) and adult onset (mean age 34.9 ± 1.1 years) MS. Among the early onset group, vaccinated patients showed an increased risk of new lesions (p = .00026), while there was no increased risk among adult‐onset patients. Additionally, a comparison between early onset vaccinated and nonvaccinated groups revealed a higher risk of increased lesions in the vaccinated group (p = .024). Discussion Overall, the study suggests that the BNT162b2 vaccine is generally safe in MS patients, with no association found between vaccination and new lesions in most patients. However, close MRI follow‐up is recommended for early‐onset MS cases to monitor lesion development.

Patient-reported outcomes (PROs) are essential for understanding the effects of MS and its treatments on patients’ lives; they play an important role in multiple sclerosis (MS) research and practice. We present the protocol for an observational study to prospectively assess the effect of cladribine tablets on PROs and their correlation to disability and physical activity in adults with highly active relapsing MS switching from a first disease modifying drug (DMD) to cladribine tablets in routine clinical practice at study sites in Italy. The primary objective will be to evaluate changes from baseline in the impact of highly active MS on self-assessed physical functioning 52 weeks after the switch to cladribine tablets using the Multiple Sclerosis Impact Scale-29 (MSIS-29). Secondary objectives will include self-assessed psychological impact of highly active MS in daily life and general health after the switch to cladribine tablets as well as changes in cognitive function, anxiety, and depression symptoms. Additional PRO measures will include the Hospital Anxiety and Depression Scale (HADS), the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis (WPAI:MS), and the Patient-Reported Outcomes Measurement Information System (PROMIS). Wearable devices will acquire activity data (step counts, walking speed, time asleep, and energy expenditure). Additional clinical, radiological, and laboratory data will be collected when available during routine management. The findings will complement data from controlled trials by providing insight from daily clinical practice into the effect of cladribine tablets on the patient’s experience and self-assessed impact of treatment on daily life.

Abstract Background Multiple sclerosis (MS) is a chronic, autoimmune, and inflammatory disease. The economic burden of MS is substantial, and the high cost of Disease-modifying drugs (DMDs) prices are the main drivers of healthcare expenditures. We conducted a systematic review of studies evaluating the cost-utility and cost-effectiveness of DMDs for relapsing–remitting multiple sclerosis (RRMS). Materials and method Searches were conducted in PubMed, Web of Science, Scopus, and Embase. The search covered articles published between May 2001 and May 2023. Studies that were written in English and Persian and examined the cost-utility and cost-effectiveness of DMDs in patients with MS were included in our review. Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist, and the quality of economic evaluations was assessed using the Quality of Health Economics Studies Instrument (QHES). All costs were converted to 2020 U.S. dollars using Purchasing Power Parity (PPP). Results The search yielded 1589 studies, and 49 studies were eligible for inclusion. The studies were mainly based on a European setting. Most studies employed Markov model to assess the cost–effectiveness. The lowest and highest numerical value of outcome measures were -1,623,918 and 2,297,141.53, respectively. Furthermore, the lowest and highest numerical value of the cost of DMDs of RRMS were $180.67, and $1474840.19, respectively. Conclusions Based on the results of all studies, it can be concluded that for the treatment of patients with MS, care-oriented strategies should be preferred to drug strategies. Also, among the drug strategies with different prescribing methods, oral disease-modifying drugs of RRMS should be preferred to injectable drugs and intravenous infusions.

Abstract Multiple sclerosis (MS) is a chronic, progressive, inflammatory disorder of the central nervous system. Relapsing–remitting MS (RRMS), the most common form of the disease, is characterized by transient neurological dysfunction with concurrent accumulation of disability. Over the past three decades, disease-modifying therapies (DMTs) capable of reducing the frequency of relapses and slowing disability worsening have been studied and approved for use in patients with RRMS. The first DMTs were interferon-betas (IFN-βs), which were approved in the 1990s. Among them was IFN-β-1a for subcutaneous (sc) injection (Rebif®), which was approved for the treatment of MS in Europe and Canada in 1998 and in the USA in 2002. Twenty years of clinical data and experience have supported the efficacy and safety of IFN-β-1a sc in the treatment of RRMS, including pivotal trials, real-world data, and extension studies lasting up to 15 years past initial treatment. Today, IFN-β-1a sc remains an important therapeutic option in clinical use, especially around pregnancy planning and lactation, and may also be considered for aging patients, in which MS activity declines and long-term immunosuppression associated with some alternative therapies is a concern. In addition, IFN-β-1a sc is used as a comparator in many clinical studies and provides a framework for research into the mechanisms by which MS begins and progresses.

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease which can rarely co-exist with neurofibromatosis 1 (NF1), a neurocutaneous inherited disorder that predisposes to oncogenesis. Patients who suffer from both conditions can be challenging cases for clinicians, as clinical symptoms and radiological findings may overlap, while MS immune-modifying treatments could further increase the risk of oncogenesis. Case Presentation: In this study, we describe the case of a 27-year-old woman who presented with signs and symptoms of optic neuritis and was then diagnosed with both MS and NF1. As the patient continued to experience MS relapses despite initial interferon-beta treatment, she was subsequently switched to natalizumab and responded well. Conclusion: This case illustrates how MRI lesion differentiation with the co-existence of MS and NF1 can be difficult due to overlaps in lesion characteristics, while treatment decisions can be challenging mainly due to scarce data on the oncogenic risk of MS immunomodulary therapies. Therefore, clinicians need to balance out the risk of malignancy development with the risk of progressive neurological disability when treating such patients.

Spatial navigation ability is essential for independent living, and it relies on complex cognitive and motor processes that are vulnerable to decline in persons with multiple sclerosis (pwMS). The role of mobility in the physical act of navigation has been well documented; however, its association with cognitive processing that supports efficient navigation and recall of the environment is unknown. This study examined the relation between clinical mobility function and spatial navigation ability in pwMS. In a clinical sample of 43 individuals with relapsing-remitting MS (MPDDS = 2; age 25–67 years), we assessed spatial navigation ability in a virtual Morris water maze that allowed for active search by controlling a joystick while seated at a computer, and subsequent free recall of environment details. Individuals with worse mobility (measured by slower forward and backward walking) traveled less efficient virtual navigation routes to the goal location and recalled fewer accurate details of the environment. A stratified analysis by disability revealed moderate–strong correlations for those with a low level of disability, and effects were attenuated in individuals with a high level of disability. Given that the virtual navigation task was performed while seated, evidence of any correlation with mobility suggests differences in navigation ability that cannot be ascribed to general walking impairment, and instead suggests a role for mobility impairment to modify cognitive processing supporting navigation in pwMS. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic, autoimmune, and inflammatory disease. The economic burden of MS is substantial, and the high cost of Disease-modifying drugs (DMDs) prices are the main drivers of healthcare expenditures. We conducted a systematic review of studies evaluating the cost-utility and cost-effectiveness of DMDs for relapsing–remitting multiple sclerosis (RRMS). Materials and method: Searches were conducted in PubMed, Web of Science, Scopus, and Embase. The search covered articles published between May 2001 and May 2023. Studies that were written in English and Persian and examined the cost-utility and cost-effectiveness of DMDs in patients with MS were included in our review. Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist, and the quality of economic evaluations was assessed using the Quality of Health Economics Studies Instrument (QHES). All costs were converted to 2020 U.S. dollars using Purchasing Power Parity (PPP). Results: The search yielded 1589 studies, and 49 studies were eligible for inclusion. The studies were mainly based on a European setting. Most studies employed Markov model to assess the cost–effectiveness. The lowest and highest numerical value of outcome measures were -1,623,918 and 2,297,141.53, respectively. Furthermore, the lowest and highest numerical value of the cost of DMDs of RRMS were $180.67, and $1474840.19, respectively. Conclusions: Based on the results of all studies, it can be concluded that for the treatment of patients with MS, care-oriented strategies should be preferred to drug strategies. Also, among the drug strategies with different prescribing methods, oral disease-modifying drugs of RRMS should be preferred to injectable drugs and intravenous infusions. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease which can rarely co-exist with neurofibromatosis 1 (NF1), a neurocutaneous inherited disorder that predisposes to oncogenesis. Patients who suffer from both conditions can be challenging cases for clinicians, as clinical symptoms and radiological findings may overlap, while MS immune-modifying treatments could further increase the risk of oncogenesis. Case Presentation: In this study, we describe the case of a 27-year-old woman who presented with signs and symptoms of optic neuritis and was then diagnosed with both MS and NF1. As the patient continued to experience MS relapses despite initial interferon-beta treatment, she was subsequently switched to natalizumab and responded well. Conclusion: This case illustrates how MRI lesion differentiation with the co-existence of MS and NF1 can be difficult due to overlaps in lesion characteristics, while treatment decisions can be challenging mainly due to scarce data on the oncogenic risk of MS immunomodulary therapies. Therefore, clinicians need to balance out the risk of malignancy development with the risk of progressive neurological disability when treating such patients. [ABSTRACT FROM AUTHOR]

The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P -values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors. [ABSTRACT FROM AUTHOR]

Context: Treatment with Alemtuzumab (ALZ) in patients with Relapsing–Remitting Multiple Sclerosis (RRMS) is associated with the development of ALZ-induced Graves' disease (GD-ALZ). Some cases may develop associated Graves´ Orbitopathy (GO-ALZ), with possible visual compromise. Aim: The aim of this study was to describe the main clinical and biochemical characteristics of GD-ALZ, as well as the clinical course of a case series of GO-ALZ Methods: This study is a retrospective observational study, carried out in a reference hospital for the care of patients with RRMS in Spain. Cases treated with ALZ in the period 2014–2022 were included. GO-ALZ cases were identified among those with clinical symptoms compatible with thyroid eye disease after initiating ALZ treatment. Results: A total of 135 cases, with a mean follow-up of 69.6 months after the first ALZ cycle, were included. The incidence of GD-ALZ was 32.6% (44/135), with a predominance of women (77.3%) and mean age of 41.9 years. The presence of first-degree relatives with hypothyroidism was identified as risk factor for the development of GD-ALZ (adjusted P-value: 0.02). GO-ALZ was diagnosed in 6 cases (incidence: 13.6%), of which 3 had severe clinical forms of GO, requiring anti-IL-6 treatment. A favorable response was reported in all of them, with a significant decrease in disease activity and improvement in proptosis. Conclusions: We report one of the largest cohorts of GD-ALZ and GO-ALZ cases. The diagnosis of these entities should be taken into account in patients treated with Alemtuzumab, given the risk of developing severe clinical forms. In moderate-severe forms of GO-ALZ, drugs with anti-IL-6 activity are a safe and effective option. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Peginterferon β-1a (PEG-IFN-β-1a) is the most recent interferon beta formulation approved for treating relapsing-remitting multiple sclerosis (RRMS). We aim to describe the real-world utilization of PEG-IFN-β-1a in RRMS and compare it with other injectable disease-modifying therapies (DMTs). PATIENTS AND METHODS: In this population-based study, we used 2015-2019 routinely collected healthcare data of the Campania region of Italy from National Healthcare System DMT prescriptions, inpatient and outpatient clinical records of hospitals in Campania, and the Federico II University MS clinical registry for a subset of patients. We included individuals with RRMS receiving new prescriptions of PEG-IFN-β-1a [n=281; age = 38.8±12.3 years; females=70.5%; disease duration = 8 .4±8.3 years; Expanded Disability S tatus Scale (EDSS) at baseline=2.0 (1.0-6.5)], glatiramer acetate [n=751; age = 46.0±11.4 years; females= 67.1%; disease duration = 9.8±8.2 years; EDSS=4.0 (1.5-8.5)], and subcutaneous (SC) IFN-β-1a [n=1,226; a ge = 3 9.7±11.7 y ears; f emales= 66.5%; disease duration = 8.2±6.5 years; EDSS 2.5 (1.5-6.5)]. Adherence [medication possession ratio (MPR)], escalation to more effective DMTs, hospitalization rates and costs were measured. We used mixed-effect linear regression models (for adherence, hospitalization rates and costs) and Cox regression models (for escalation) to assess differences between PEGIFN-β-1a (statistical reference), glatiramer acetate, and SC IFN-β-1a. All models included age, sex, previous treatment/untreated, year of treatment initiation, treatment duration, and adherence as covariates. RESULTS: Adherence was lower in glatiramer acetate (MPR = 0.91±0.1; Coeff=-0.11; p<0.01), and IFN-β-1a (MPR = 0.92±0.1; Coeff=-0.08; p<0.01), compared with PEG-IFN-β-1a (MPR = 1.01±0.1). The probability of escalating to more effective DMTs was higher for glatiramer acetate (14.9%; HR=4.09; p<0.01) and IFN-β-1a (9.1%; HR=3.35; p=0.01), compared with PEG-IFN-β-1a (4.9%). No differences in annualized hospitalization rates were identified between glatiramer acetate [annualized hospitalization rates (AHR) = 0.05±0.30; Coeff=0.02; p=0.31), IFN-β-1a (AHR = 0.02±0.21; Coeff=0.01; p=0.97], and P EG-IFN-β-1a (AHR = 0 .02±0.24); h owever, monthly costs for MS admissions were higher for glatiramer acetate (€49.45±€195.27; Coeff=-29.89; p=0.03), compared with IFN-β-1a (€29.42±€47.83; Coeff=6.79; p=0.61), and PEGIFN-β-1a (€23.91±€43.90). CONCLUSIONS: SC PEG-IFN-β-1a and IFN-β-1a were used in relatively similar populations, while glatiramer acetate was preferred in older and more disabled patients. PEG-IFN-β-1a was associated with higher adherence and lower escalation rates toward more effective (and costly) DMTs. [ABSTRACT FROM AUTHOR]

Background: The availability of high-efficacy disease-modifying therapy (DMT), including natalizumab, improved treatment efficacy in adults with highly-active relapsing-remitting multiple sclerosis (RRMS). Natalizumab patent protection has expired, and the natalizumab biosimilar (Tyruko®) has been recently reimbursed by AIFA. As the price of natalizumab biosimilar is expected to be lower as compared with natalizumab originator’s price, a budget impact analysis was conducted to assess the economic impact associated to the introduction of natalizumab biosimilar for patients with highly-active RRMS. Methods: A budget impact model was developed, considering the INHS perspective and a 5-years time horizon. The number of patients treated with natalizumab was estimated based on historical natalizumab consumption data, disease prevalence rates and natalizumab market share. The budget impact population was divided into prevalent and incident patients. The model assumes that some patients in treatment with natalizumab originator will switch to natalizumab biosimilar and that some naïve patients will directly start treatment with natalizumab biosimilar. The ex-factory price of natalizumab originator (intravenous and subcutaneous) and biosimilar (intravenous) and the corresponding administration costs were included. All assumptions were validated by expert opinion. Results: Eligible population was estimated at 7,552, 7,779, 8,090, 8,494 and 8,834 in years 1, 2, 3, 4 and 5 respectively. The introduction of natalizumab biosimilar, considering a progressive increase in market share from 9.6% (year 1) to 40.5% (year 5), would provide an overall savings (5-years time horizon) over € 47 million to the INHS. The scenario analysis highlights that the lower treatment cost of biosimilar natalizumab compared to originator natalizumab would offset the higher cost associated with intravenous versus subcutaneous administration. Conclusion: Considering the results of this budget impact analysis, it is realistic to expect that the presence of biosimilar natalizumab will contribute to the sustainability of public pharmaceutical expenditure.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing–remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient’s experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

BackgroundThe effects of pregnancy on multiple sclerosis (MS) inflammatory activity are not well described in women with moderate to severe disabilities.ObjectiveTo quantify the peripartum annualized relapse rate (ARR) in women with MS with an Expanded Disability Status Scale (EDSS) ≥ 3.MethodsWe performed a retrospective cohort study of 85 pregnancies in 74 subjects with preconception EDSS ≥ 3. We quantified peripartum ARR and tested for risk factors predictive of peripartum relapses, postpartum brain magnetic resonance imaging activity (new T2 or gadolinium-enhancing lesions), and disability worsening.ResultsThere were 74 live births, with a 56% operative delivery rate. In subjects with relapsing-remitting MS, ARR decreased to 0.11 during the third trimester of pregnancy compared to 0.59 in the year preconception and increased to 1.22 in the 3 months postpartum. Women with a higher preconception EDSS had higher odds of postpartum relapses and clinically significant worsening of disability as compared to subjects with a lower EDSS.ConclusionsModerately to severely disabled women with MS have a lower risk of relapse during pregnancy as compared to preconception, followed by a marked increase postpartum. Further studies are needed to identify ways to reduce peripartum inflammatory activity and disability progression in women with MS with moderate to severe disability.

Background: Diroximel fumarate (DRF) is approved for adults with relapsing–remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. Objective: To report final outcomes from EVOLVE-MS-1. Methods: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. Results: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0–2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11–0.15). Conclusion: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS. [ABSTRACT FROM AUTHOR]

Background and purpose: In relapsing–remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real‐world setting, where both drugs are licensed as first‐line therapies for RRMS. Methods: We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12‐month confirmed EDSS worsening were compared using Cox proportional hazard models. Results: In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively). Conclusion: Analysis of real‐world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment. [ABSTRACT FROM AUTHOR]

Objective: Cortical gray matter (GM) atrophy plays a central role in multiple sclerosis (MS) pathology. However, it is not commonly assessed in clinical routine partly because a number of methodological problems hamper the development of a robust biomarker to quantify GM atrophy. In previous work, we have demonstrated the clinical utility of the "mosaic approach" (MAP) to assess individual GM atrophy in the motor neuron disease spectrum and frontotemporal dementia. In this study, we investigated the clinical utility of MAP in MS, comparing this novel biomarker to existing methods for computing GM atrophy in single patients. We contrasted the strategies based on correlations with established biomarkers reflecting MS disease burden. Methods: We analyzed T1‐weighted MPRAGE magnetic resonance imaging data from 465 relapsing‐remitting MS patients and 89 healthy controls. We inspected how variations of existing strategies to estimate individual GM atrophy ("standard approaches") as well as variations of MAP (i.e., different parcellation schemes) impact downstream analysis results, both on a group and an individual level. We interpreted individual cortical disease burden as single metric reflecting the fraction of significantly atrophic data points with respect to the control group. In addition, we evaluated the correlations to lesion volume (LV) and Expanded Disability Status Scale (EDSS). Results: We found that the MAP method yielded highest correlations with both LV and EDSS as compared to all other strategies. Although the parcellation resolution played a minor role in terms of absolute correlations with clinical variables, higher resolutions provided more clearly defined statistical brain maps which may facilitate clinical interpretability. Conclusion: This study provides evidence that MAP yields high potential for a clinically relevant biomarker in MS, outperforming existing methods to compute cortical disease burden in single patients. Of note, MAP outputs brain maps illustrating individual cortical disease burden which can be directly interpreted in daily clinical routine. [ABSTRACT FROM AUTHOR]

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Objectives: Multiple sclerosis (MS) is a chronic, multifaceted, heterogeneous autoimmune disease, with optic neuritis (ON) being a common early manifestation among those with MS. This study aimed to estimate the incidence of ON among Omani patients with MS. Methods: This retrospective cross-sectional study included all Omani patients diagnosed with MS at the Sultan Qaboos University Hospital, Muscat, Oman, between January 1991 and December 2019. The data were collected from the neurology registry and electronic medical records and analysed descriptively using univariant and multivariant statistical techniques. Results: Out of the 185 patients diagnosed with MS during the study period, 170 were included in the analysis. The male-to-female ratio was 1:2 and the mean age was 28 years. The incidence of ON in the population was 28.8%, with 83.7% of ON patients presenting with relapse-remitting MS (RRMS). Overall, 28.6% of patients presented with O N as an initial manifestation of MS, whereas 42.8% developed ON at a later stage. Most patients (49.4%) were from higher-latitude regions of Oman such as Muscat and Al Batinah. Conclusions: The incidence of both MS and ON increased over the study period. While the overall incidence was low in comparison with Western data, it was similar to the rates reported elsewhere in the Arabian Peninsula. Overall, ON was the most common manifestation of MS in the cohort, with younger female patients more frequently presenting with both MS and ON. A significant association was found between the RRMS subtype and ON presentation. [ABSTRACT FROM AUTHOR]

Data on how retinal structural and vascular parameters jointly influence the diagnostic performance of detection of multiple sclerosis (MS) patients without optic neuritis (MSNON) are lacking. To investigate the diagnostic performance of structural and vascular changes to detect MSNON from controls, we performed a cross‐sectional study of 76 eyes from 51 MS participants and 117 eyes from 71 healthy controls. Retinal macular ganglion cell complex (GCC), retinal nerve fiber layer (RNFL) thicknesses, and capillary densities from the superficial (SCP) and deep capillary plexuses (DCP) were obtained from the Cirrus AngioPlex. The best structural parameter for detecting MS was compensated RNFL from the optic nerve head (AUC = 0.85), followed by GCC from the macula (AUC = 0.79), while the best vascular parameter was the SCP (AUC = 0.66). Combining structural and vascular parameters improved the diagnostic performance for MS detection (AUC = 0.90; p<0.001). Including both structure and vasculature in the joint model considerably improved the discrimination between MSNON and normal controls compared to each parameter separately (p = 0.027). Combining optical coherence tomography (OCT)‐derived structural metrics and vascular measurements from optical coherence tomography angiography (OCTA) improved the detection of MSNON. Further studies may be warranted to evaluate the clinical utility of OCT and OCTA parameters in the prediction of disease progression. [ABSTRACT FROM AUTHOR]

Background: Sex-related effects have been observed in relapsing-remitting multiple sclerosis (RRMS), but their impact on functional networks remains unclear. Objective: To investigate the sex-related differences in connectivity strength and time variability within large-scale networks in RRMS. Methods: This is a multi-center retrospective study. A total of 208 RRMS patients (135 females; 37.55 ± 11.47 years old) and 228 healthy controls (123 females; 36.94 ± 12.17 years old) were included. All participants underwent clinical and MRI assessments. Independent component analysis was used to extract restingstate networks (RSNs). We assessed the connectivity strength using spatial maps (SMs) and static functional network connectivity (sFNC), evaluated temporal properties and dynamic functional network connectivity (dFNC) patterns of RSNs using dFNC, and investigated their associations with structural damage or clinical variables. Results: For static connectivity, only male RRMS patients displayed decreased SMs in the attention network and reduced sFNC between the sensorimotor network and visual or frontoparietal networks compared with healthy controls [P<0.05, false discovery rate (FDR) corrected]. For dynamic connectivity, three recurring states were identified for all participants: State 1 (sparse connected state; 42%), State 2 (middle-high connected state; 36%), and State 3 (high connected state; 16%). dFNC analyses suggested that altered temporal properties and dFNC patterns only occurred in females: female patients showed a higher fractional time (P<0.001) and more dwell time in State 1 (P<0.001) with higher transitions (P=0.004) compared with healthy females. Receiver operating characteristic curves revealed that the fraction time and mean dwell time of State 1 could significantly distinguish female patients from controls (area under the curve: 0.838-0.896). In addition, female patients with RRMS also mainly showed decreased dFNC in all states, particularly within cognitive networks such as the default mode, frontoparietal, and visual networks compared with healthy females (P < 0.05, FDR corrected). Conclusion: Our results observed alterations in connectivity strength only in male patients and time variability in female patients, suggesting that sex-related effects may play an important role in the functional impairment and reorganization of RRMS. [ABSTRACT FROM AUTHOR]