Relapsing-remitting Multiple Sclerosis Research Articles

Investigating the Effect of COVID-19 Vaccination on the Course of Disease and Recurrence of Attacks in Patients with Multiple Sclerosis

Background: The COVID-19 pandemic, with its high mortality rate, has underscored the urgent need for the rapid production of vaccines. This has prompted research into the effects of vaccines on specific populations, including patients with immune diseases such as multiple sclerosis (MS). Objectives: This study aimed to examine the impacts of COVID vaccination on individuals with MS. Methods: A retrospective cohort study was conducted involving 302 patients with relapsing-remitting MS who had received the coronavirus vaccine. These patients were referred to the MS clinic of two referral hospitals affiliated with Tehran University of Medical Sciences. The data collection instrument used was a checklist that included demographic information and disease-related details, such as the duration of the disease, underlying conditions, type and timing of vaccine administration, and the occurrence of attacks before and after the vaccination rounds. Results: During the first and second rounds of vaccination, the majority of patients (90.7% and 87.1%, respectively) received the Sinopharm vaccine. In the third round, approximately one-third (32.8%) did not receive the vaccine, and in the fourth round, the majority of individuals (85.8%) also did not receive it. However, most vaccinated individuals had received the Sinopharm vaccine. Among the sample, 34 individuals (11.3%) were newly diagnosed with MS after receiving the vaccine. Additionally, 41.7% of individuals experienced an attack within three months after receiving one of the vaccine doses. Conclusions: Vaccinations during the COVID era have significantly contributed to saving lives and preventing death. However, they have also had consequences that need careful examination and consideration in future vaccine production and epidemic management. The results obtained from this study can be associated with the vaccine, but given the retrospective nature of the study, further research on the long-term effects of the vaccine is needed to generalize the findings.

Disease Activity in Pregnant and Postpartum Women With Multiple Sclerosis Receiving Ocrelizumab or Other Disease-Modifying Therapies.

Women with multiple sclerosis (MS) are at risk of disease reactivation in the early postpartum period. Ocrelizumab (OCR) is an anti-CD20 therapy highly effective at reducing MS disease activity. Data remain limited regarding use of disease-modifying therapies (DMTs), including OCR, and disease activity during peripregnancy periods. We performed a retrospective cohort study using data from the MSBase Registry including pregnancies conceived after December 31, 2010, from women aged 18 years and older, with relapsing-remitting MS or clinically isolated syndrome. Women were classified by preconception exposure to DMTs, including OCR, rituximab (RTX), natalizumab (NAT), stratified into active (NAT-A; continued ≥28 weeks of gestation, restarted ≤1 month postpartum) or conservative (NAT-C; continued ≤4 weeks of gestation, restarted >1 month postpartum) strategies, dimethyl fumarate (DMF) or low-efficacy DMTs (interferon-beta, glatiramer acetate). Annualized relapse rates (ARRs) were calculated for 12-month prepregnancy, pregnancy, and 6-month postpartum periods. A total of 2,009 live births from 1,744 women were analyzed, including 73 live births from 69 women treated with preconception OCR. For OCR, no within-pregnancy relapse was observed and 3 women (4.1%) experienced 1 relapse in the postpartum period (ARR 0.09 [95% CI 0.02-0.27]). For NAT-A, 3 (3.7%) of 82 women relapsed during pregnancy (0.05 [0.01-0.15]) and 4 (4.9%) relapsed during postpartum (0.10 [0.03-0.26]). However, for NAT-C, 13 (15.9%) of 82 women relapsed within pregnancy (0.32 [0.20-0.51]) and 25 (30.5%) relapsed during postpartum (0.74 [0.50-1.06]). In the low-efficacy DMT group, 101 (7.6%) of 1,329 women experienced within-pregnancy relapse (0.12 [0.10-0.14]), followed by an increase in postpartum relapse activity with 234 women (17.6%) relapsing (0.43 [0.38-0.48]). This was similarly seen in the DMF group with 13 (7.9%) of 164 women experiencing within-pregnancy relapse (0.12 [0.06-0.20]) and 25 (15.2%) of 164 relapsing postpartum (0.39 [0.26-0.57]). Our RTX cohort had 0 of 24 women experiencing within-pregnancy relapse and 3 (12.5%) of 24 experiencing postpartum relapse. Women treated with OCR or NAT-A were observed to have low relapse rates during pregnancy and postpartum. NAT-C was associated with increased risk of relapses. There was no within-pregnancy relapse in our RTX cohort, although we caution overinterpretation due to our sample size. An effective DMT strategy with a favorable safety profile for the mother and infant should be discussed and implemented well in advance of planning a family. This study provides Class III evidence that for women with relapsing-remitting MS or clinically isolated syndrome who become pregnant, ocrelizumab, rituximab, and natalizumab (continued ≥28 weeks of gestation and restarted ≤1 month postpartum) were associated with reduced risk of relapses, compared with other therapeutic strategies.

Advanced Quantitative MRI Unveils Microstructural Thalamic Changes Reflecting Disease Progression in Multiple Sclerosis.

In patients with multiple sclerosis (PwMS), thalamic atrophy occurs during the disease course. However, there is little understanding of the mechanisms leading to volume loss and of the relationship between microstructural thalamic pathology and disease progression. This cross-sectional and longitudinal study aimed to comprehensively characterize in vivo pathologic changes within thalamic microstructure in PwMS using advanced multiparametric quantitative MRI (qMRI). Thalamic microstructural integrity was evaluated using quantitative T1, magnetization transfer saturation, multishell diffusion, and quantitative susceptibility mapping (QSM) in 183 PwMS and 105 healthy controls (HCs). The same qMRI protocol was available for 127 PwMS and 73 HCs after a 2-year follow-up period. Inclusion criteria for PwMS encompassed either an active relapsing-remitting MS (RRMS) or inactive progressive MS (PMS) disease course. Thalamic alterations were compared between PwMS and HCs and among disease phenotypes. In addition, the study investigated the relationship between thalamic damage and clinical and conventional MRI measures of disease severity. Compared with HCs, PwMS exhibited substantial thalamic alterations, indicative of microstructural and macrostructural damage, demyelination, and disruption in iron homeostasis. These alterations extended beyond focal thalamic lesions, affecting normal-appearing thalamic tissue diffusely. Over the follow-up period, PwMS displayed an accelerated decrease in myelin volume fraction [mean difference in annualized percentage change (MD-ApC) = -1.50; p = 0.041] and increase in quantitative T1 (MD-ApC = 0.92; p < 0.0001) values, indicating heightened demyelinating and neurodegenerative processes. The observed differences between PwMS and HCs were substantially driven by the subgroup with PMS, wherein thalamic degeneration was significantly accelerated, even in comparison with patients with RRMS. Thalamic qMRI alterations showed extensive correlations with conventional MRI, clinical, and cognitive disease burden measures. Disability progression over follow-up was associated with accelerated thalamic degeneration, as reflected by enhanced diffusion (β = -0.067; p = 0.039) and QSM (β = -0.077; p = 0.027) changes. Thalamic qMRI metrics emerged as significant predictors of neurologic and cognitive disability even when accounting for other established markers including white matter lesion load and brain and thalamic atrophy. These findings offer deeper insights into thalamic pathology in PwMS, emphasizing the clinical relevance of thalamic damage and its link to disease progression. Advanced qMRI biomarkers show promising potential in guiding interventions aimed at mitigating thalamic neurodegenerative processes.

Microstructural alterations of cerebellar peduncles in multiple sclerosis: a diffusion tensor imaging study.

Ataxia, tremors, dysarthria, and sometimes impaired cognition are the signs of cerebellum involvement in multiple sclerosis (MS). These symptoms affect up to 80% of patients and are usually hard to treat. To find the underlying involvement of the cerebellum in MS, we assessed the microstructural alterations with DTI in the cerebellar peduncles of the affected subjects. We included 58 relapsing-remitting MS patients and 27 healthy controls. Patients were divided into 18 patients of relapsing-remitting MS with cerebellar impairment (RRMSc) and 40 without cerebellar impairment (RRMSnc). Using Diffusion Tensor Imaging (DTI), we calculated fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) metrics in all subjects. We also checked if there were associations between DTI metrics and clinical cerebellar measures (i.e., tremor severity and the scale for the assessment and rating of ataxia). ANOVA and post-hoc results showed significant differences in DTI metrics between RRMSc and HC and between RRMSnc and HC subjects. Inferior peduncle RD remained the only metric with a significant difference across all pairwise comparisons. The general linear model assessing the effects of the three study groups on the association between DTI metrics and clinical cerebellar measures yielded no significant result. Our study showed that DTI can mainly reveal significant differences between different MS groups and HCs. Our results imply the role of cerebellar peduncles in the pathophysiology of MS and that this role does not necessarily reflect the severity of cerebellar signs of the patients.

OA08 Ocrelizumab in pregnancy in a patient with juvenile onset systemic lupus erythematosus

Abstract Introduction Juvenile-onset systemic lupus erythematosus (jSLE) is a multisystem autoimmune disease that results in increased disease activity compared to adult-onset SLE. jSLE in pregnancy results in a greater incidence of disease flares as well as adverse pregnancy outcomes. Management of SLE in pregnancy is particularly difficult due to lack of safety data for immunosuppressant medications and is therefore limited. Ocrelizumab is a humanised monoclonal antibody that selectively targets CD20 B cells and is approved for the treatment of multiple sclerosis. Despite never being trialled in a patient with active SLE in pregnancy, this case demonstrates its use with a successful outcome. Case description An 18-year-old female was diagnosed at age 14 with juvenile onset systemic lupus erythematosus with the presence of a photosensitive malar rash, arthralgia, alopecia, aphthous ulcers and headache. At the time of diagnosis her investigations revealed ANA 1:5120 with homogenous pattern, high dsDNA, low C3 and C4, thrombocytopenia, antibodies to Smith, Ro, RNP, anti-Rib-P, strongly positive lupus anticoagulant antibodies and low titre anti-cardiolipin IgG and IgM. Previous treatment included methotrexate, mycophenolate mofetil and cyclosporin which were discontinued either due to patient choice, inefficacy or adverse reaction. Azathioprine was contraindicated due to low TMPT. Rituximab was trialled and although effective had to be stopped due to adverse reaction. Unfortunately, she experienced a primigravida pregnancy loss at 15-20 weeks secondary to active SLE and pre-eclampsia. Shortly after this, she developed a rare case of anti-fascin antibody neuropathy and was treated with ocrelizumab. Six months later during her second pregnancy, she was treated with hydroxychloroquine 400 mg, aspirin 150 mg, folic acid 5 mg and low molecular weight heparin prophylaxis which were continued throughout the pregnancy. Due to concerns of active lupus at 13 weeks due to facial rash and fatigue, prednisolone was commenced at 10 mg daily and continued. After careful consideration, Ocrelizumab was given in the second trimester at 17 and 19 weeks’ gestation. Following this, symptoms remained under control and disease activity was low with normal C3/C4 and dsDNA levels without significant proteinuria. A newborn baby was delivered at 38 weeks by caesarean section without complication or foetal abnormalities. Both the mother and baby remain under close follow- up but have not demonstrated adverse outcomes at 3 months postpartum. Discussion This case demonstrates the use of Ocrelizumab in the second trimester of a high-risk pregnancy complicated by active jSLE. At present, there is no license for use of Ocrelizumab in SLE and no safety data on its use in pregnancy. However, there was a good outcome for this patient which resulted in no antenatal or postpartum complications and the successful birth of a healthy newborn without foetal abnormalities. Ocrelizumab is used for the treatment of early relapsing-remitting multiple sclerosis (RRMS) and is increasingly used by neurologists in women of childbearing age despite being unlicensed for use in pregnancy. Concerns of its use in pregnancy surround B cell depletion in the neonate which while tends to be transient, causes significant concern regarding long term immunological development and response to vaccination. B cell depleting therapies are widely used in the context of active and refractory SLE and therefore use of Ocrelizumab has been evaluated in cases of SLE in two phase III clinical trials. The first study examined the efficacy of Ocrelizumab in SLE without renal involvement (BEGIN) and the second recruited patients with lupus nephritis (BELONG). The BEGIN study was terminated early due to lack of response and the BELONG study was terminated due to a significant increase in serious infections (in the Ocrelizumab plus mycophenolate treatment group). However, results on disease activity were positive with complete renal response being achieved non-statistically more frequently in the Ocrelizumab treated patients versus placebo. Real world evidence shows the importance of achieving disease control in SLE around pregnancy to prevent adverse outcomes. The decision for the use of Ocrelizumab therefore needs to be balanced carefully against potential harm to the baby either from direct foetal exposure to the drug, or from gestation in an immunocompromised mother. Key learning points • Pre-pregnancy counselling is of paramount importance in severe cases of active SLE and when possible, pregnancy should be postponed in these instances until disease activity is stabilised with contraception counselling offered to those on teratogenic immunosuppressive agents. • A multidisciplinary approach to the management of complex SLE in pregnancy in essential with obstetrician, midwife, maternal medicine physician and rheumatologist input. • The benefit of potentially life-saving immunosuppressive treatment should be carefully balanced against the poor outcomes of active SLE in pregnancy and decisions should be made on a case-by-case basis.

Cancer and mortality risks among people with multiple sclerosis: A population-based study in Isfahan, Iran.

Multiple sclerosis (MS) and cancer present substantial global health challenges. Understanding cancer patterns among people with MS (PwMS) is crucial due to potential variations across demographics and geographic regions. Isfahan province in Iran, known for its high MS incidence ratio, offers a significant population for comprehensive studies on MS. In this study, we aim to investigate the association between risk of cancer and MS. Data on PwMS were collected utilizing the National Multiple Sclerosis Registry System of Iran (NMSRI), with diagnoses confirmed using McDonald criteria by neurologists specialized in MS. Cancer incidence was investigated using the Iranian National Population-Based Cancer Registry (INPCR) data, collected following international protocols. Descriptive statistics and regression analyses were employed to assess factors associated with cancer and mortality risks among PwMS. Survival analysis was conducted using Kaplan-Meier curves. Out of 10,049 PwMS, 123 were diagnosed with cancer, with an mean age at the time of cancer diagnosis being 40.41 years and a mean MS duration of 6.76 years. The majority had relapsing-remitting MS (81.2%), and Interferon-β was the most common disease-modifying therapy (DMT) (42.4%). Cancer incidence was 125.6 per 100,000 person-years, peaking at ages 60-64 (677.9 per 100,000 person-years). Receiving monoclonal antibody medications and older age were significantly associated with higher cancer risk (OR:1.542 (1.009-2.357), OR:1.033 (1.015-1.051), respectively). Female breast cancer had the highest incidence ratio among PwMS (40.17 per 100,000 person-years), followed by thyroid (18.38 per 100,000 person-years) and digestive system cancers (17.36 per 100,000 person-years). Breast cancer was the predominant cancer in women, while digestive system cancers were most common among men. Being male and having longer MS duration were linked to higher cancer mortality risk (HR: 2.683, 1.087, respectively). Cancer incidence among 10,049 people with multiple sclerosis was significant, especially in older individuals, with breast cancer being the most common. Male gender and longer MS duration were linked to higher cancer mortality risk.

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma.

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Spatial structural abnormality maps associated with cognitive and physical performance in relapsing-remitting multiple sclerosis.

We aimed to characterize the brain abnormalities that are associated with the cognitive and physical performance of patients with relapsing-remitting multiple sclerosis (RRMS) using a deep learning algorithm. Three-dimensional (3D) nnU-Net was employed to calculate a novel spatial abnormality map by T1-weighted images and 281 RRMS patients (Dataset-1, male/female = 101/180, median age [range] = 35.0 [17.0, 65.0] years) were categorized into subtypes. Comparison of clinical and MRI features between RRMS subtypes was conducted by Kruskal-Wallis test. Kaplan-Meier analysis was conducted to investigate disability progression in RRMS subtypes. Additional validation using two other RRMS datasets (Dataset-2, n = 33 and Dataset-3, n = 56) was conducted. Five RRMS subtypes were identified: (1) a Frontal-I subtype showing preserved cognitive performance and mild physical disability, and low risk of disability worsening; (2) a Frontal-II subtype showing low cognitive scores and severe physical disability with significant brain volume loss, and a high propensity for disability worsening; (3) a temporal-cerebellar subtype demonstrating lowest cognitive scores and severest physical disability among all subtypes but remaining relatively stable during follow-up; (4) an occipital subtype demonstrating similar clinical and imaging characteristics as the Frontal-II subtype, except a large number of relapses at baseline and preserved cognitive performance; and (5) a subcortical subtype showing preserved cognitive performance and low physical disability but a similar prognosis as the occipital and Frontal-II subtypes. Additional validation confirmed the above findings. Spatial abnormality maps can explain heterogeneity in cognitive and physical performance in RRMS and may contribute to stratified management. Question Can a deep learning algorithm characterize the brain abnormalities associated with the cognitive and physical performance of patients with RRMS? Findings Five RRMS subtypes were identified by the algorithm that demonstrated variable cognitive and physical performance. Clinical relevance The spatial abnormality maps derived RRMS subtypes had distinct cognitive and physical performances, which have a potential for individually tailored management.

Investigation of pregnancy tendency, reproductive characteristics, and disability in women with multiple sclerosis: A secondary data analysis of the national registry in Iran

Abstract Background: Multiple sclerosis (MS) predominantly affects women of childbearing age, significantly impacting their quality of life (QOL).The diagnosis of MS can influence pregnancy intention, and the level of disability associated with MS may change before and after pregnancy. This study aims to analyze the reproductive characteristics of Iranian female patients with MS (PwMS) and their association with the Expanded Disability Status Scale (EDSS) and pregnancy tendency, providing valuable insights into disease progression and the development of tailored treatments. Methods: A cross-sectional study was conducted using data from the nationwide MS registry of Iran (NMSRI) from 2018 to 2021. Patients without a documented history of pregnancy, MS type, or EDSS score were excluded from the study. Various statistical methods, including nonparametric tests, the generalized estimating equation (GEE) model, and multiple logistic regression, were employed to analyze the data. Results: The study included 1120 PwMS with a median diagnostic age of 31 and a disease duration of 6 years. The majority had relapsing-remitting MS (RRMS) and the mean EDSS score at bassline was 1.5 ± 1.4. A history of pregnancy or abortion was associated with higher EDSS scores. Multiparity before MS diagnosis was linked to EDSS score ≥ 5, while this EDSS range was associated with decreased parity after MS diagnosis (all P-values &lt; 0.05). Conclusion: Pregnancy and parity can affect the disability in female PwMS irrespective of clinical symptoms, diagnosis age, and MS type. Moreover, the chance of parity may be affected by a higher disability score, which should be considered in the clinical setting.

Uveitis characteristics and multiple sclerosis phenotype of patients with multiple sclerosis-associated uveitis: A systematic review and meta-analysis.

To summarize and meta-analyze uveitis characteristics and multiple sclerosis (MS) phenotype of patients with multiple sclerosis-associated uveitis (MSAU) within a systematic review and meta-analysis. A comprehensive literature search was performed on January 25, 2023, utilizing PubMed, Embase, and Virtual Health Library (VHL) databases. We included studies involving patients with MSAU, such as case series with over 10 patients, cross-sectional, case-control, and cohort studies. Quality and risk of bias were assessed using CLARITY tools and validated metrics like the Hoy et al. and Hassan Murad et al. tools. The pooled analysis focused on 1) uveitis characteristics, 2) ocular complications, 3) MS phenotype, and 3) administered treatments for uveitis and MS. Gender-based subgroup analysis was conducted across continents; heterogeneity was measured using the I2 statistic. Statistical analysis was performed using R software version 4.3.1. The study was registered in PROSPERO with CRD42023453495 number. Thirty-six studies were analyzed (24 with a low risk of bias, 8 with some concerns, and 4 with a high risk of bias), including 1,257 patients and 2,034 eyes with MSAU. The pooled analysis showed a mean age of 38.2 ± 12.1 years with a notable female predominance (67%, 95% CI [59%-73%]). MS before uveitis was seen in 59% of the cases (95% CI [48%-69%]), while uveitis was present before MS in 38% (95% CI [30%-48%]). The mean age for the first uveitis episode was 35.7 ± 8.3 years, predominantly affecting both eyes (77%, 95% CI [69%-83%], from 23 studies involving 452 patients). Intermediate uveitis was the most frequent anatomical location (68%, 95% CI [49%-82%], from 22 studies involving 530 patients), often following a recurrent course (63%, 95% CI [38%-83%]). Key complications included vision reduction (42%, 95% CI [19%-70%], from five articles involving 90 eyes), macular compromise (45%, 95% CI [20%-73%], from 4 studies involving 95 eyes), and cataracts (46%, 95% CI [32%-61%], from eight articles involving 230 eyes). Concerning MS phenotype, relapsing-remitting MS (RRMS) was the most common subtype (74%, 95% CI [64%-82%], from eight articles involving 134 patients), followed by secondary progressive MS (24%, 95% CI [18%-33%], from eight articles involving 125 patients). The most frequently occurring central nervous lesions were supratentorial (95%, 95% CI [70%-99%], from two articles involving 17 patients) and spinal cord (39%, 95% CI [16%-68%], from two articles involving 29 patients). The mean Expanded Disability Status Scale (EDSS) score and annual recurrence rates were 2.9 ± 0.6 and 1.07 ± 0.56, respectively. Treatment trends showed the prevalent use of Fingolimod (96%, 95% CI [17%-100%], from two articles involving 196 patients), Mycophenolate (48%, 95% CI [11%-87%], from four articles involving 51 patients), and Interferon-beta (43%, 95% CI [24%-65%], from 11 articles involving 325 patients). MSAU primarily affects young adult females, typically presenting as bilateral intermediate uveitis with vision-related complications. The most common MS phenotype is RRMS, often associated with supratentorial and spinal cord lesions on imaging. These findings give ophthalmologists and neurologists a comprehensive clinical picture of MSAU, facilitating prompt diagnosis.

Real-World Persistence with Ocrelizumab in Multiple Sclerosis: a Systematic Review.

In clinical trials, the percentage of patients discontinuing treatment with ocrelizumab due to adverse events was low. However, real-world populations are often more diverse than randomized controlled trials (RCTs), therefore it is important to assess discontinuation rates in real-world studies. This systematic literature review (SLR) was conducted to identify real-world discontinuation and persistence data for ocrelizumab in studies of patients with relapsing remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Searches were conducted in MEDLINE and Embase to identify relevant real-world studies that met pre-determined Population, Intervention, Comparison, Outcomes, and Study (PICOS) criteria. Only articles published in English were included, but the study country was not restricted. A total of 30 studies were included, with the majority reporting real-world persistence data that appear to be similar to or better than in the pivotal clinical trials, with only 1 study reporting higher discontinuation rates due to adverse events compared with the clinical trials. Other studies identified reported that the risk of discontinuation was higher for other disease-modifying therapies (DMTs) compared with ocrelizumab, and adherence was also higher for ocrelizumab versus other DMTs. These findings have clinical relevance, as other studies have reported improved clinical outcomes and lower care costs for patients that are persistent or adherent to other DMTs.

Exploring the Gene Expression and Plasma Protein Levels of HSP90, HSP60, and GDNF in Multiple Sclerosis Patients and Healthy Controls.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by immune-mediated inflammation and neurodegeneration in the central nervous system (CNS). In this study; we aimed to investigate the gene expression and plasma protein levels of three neuroprotective genes-heat shock proteins (HSP90 and HSP60) and glial cell line-derived neurotrophic factor (GDNF)-in MS patients compared to healthy controls. Forty patients with relapsing-remitting MS and 40 healthy volunteers participated in this study. Gene expression was measured using reverse transcription quantitative real-time PCR, and protein levels were assessed via ELISA. The results showed a significant increase in HSP90 (1.7-fold) and HSP60 (2-fold) gene expression in MS patients compared to controls, along with corresponding increases in protein levels (1.5-fold for both HSP90 and HSP60). In contrast, GDNF gene expression and protein levels were significantly reduced in MS patients, with a 7-fold decrease in gene expression and a 1.6-fold reduction in protein levels. Notably, a non-linear relationship between GDNF gene expression and protein concentration was observed in MS patients, suggesting complex regulatory mechanisms influencing GDNF in the disease. The upregulation of HSP90 and HSP60 in MS highlights their roles in immune regulation and stress responses, while the reduction in GDNF indicates impaired neuroprotection. These findings suggest that HSP90, HSP60, and GDNF could serve as biomarkers for disease progression and as potential therapeutic targets in MS, offering promising avenues for future research and treatment development.

Cladribine tablets in relapsing-remitting multiple sclerosis preferentially target B-cells

Recent studies demonstrate the efficacy of B cell-targeting therapies in managing multiple sclerosis (MS) activity, emphasizing the critical role of B cells in MS pathogenesis. CladB study aimed to quantify the temporal changes in peripheral immune cells and their activity over 96 weeks of Cladribine tablets (CladT) treatment in relapsing-remitting MS (RRMS).Ten participants (3 males, 7 females) had blood samples collected at multiple intervals (Day 0, 1, 5, then weekly for 8 weeks, biweekly for up to 24 weeks, and monthly for up to 96 weeks) for immune cell analysis, compared to a historical alemtuzumab-treated cohort. Paired cerebrospinal fluid (CSF) was also taken for various analyses, alongside clinical and brain imaging assessments.CladT depleted memory B cells, while alemtuzumab rapidly depleted T and B cells. The кFLC index decreased from 164.5 ± 227.1 to 71.3 ± 84.7 at 48 weeks (p = 0.002) and to 64.4 ± 67.3 at 96 weeks (p = 0.01). The IgG index dropped from 1.1 ± 0.5 at baseline to 0.8 ± 0.4 at 48 weeks (p = 0.014) and to 0.8 ± 0.3 at 96 weeks (p = 0.02). CSF CXCL-13 decreased from 88.6 ± 68.4 pg/mL to 39.4 ± 35.2 pg/mL at 48 weeks (p = 0.037) and 19.1 ± 11.7 pg/mL at 96 weeks (p = 0.027). CSF NfL levels were reduced at 48 weeks (p = 0.01).CladT primarily depletes memory B cells and antibody-secreting cell precursors in RRMS, leading to sustained effects on intrathecal antibody production and total IgG, and a reduction in CSF CXCL-13.

Routine CSF parameters as predictors of disease course in multiple sclerosis: an MSBase cohort study

BackgroundIt remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course.MethodsThis large-scale cohort study included persons with MS with CSF data documented...

Trajectories of self-reported fatigue following initiation of multiple sclerosis disease-modifying therapy

BackgroundWe analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing–remitting multiple sclerosis (RRMS), to identify trajectories of fatigue and their association with...

Circulatory Indicators of Lipid Peroxidation, the Driver of Ferroptosis, Reflect Differences between Relapsing–Remitting and Progressive Multiple Sclerosis

Ferroptosis, a lipid peroxidation- and iron-mediated type of regulated cell death, relates to both neuroinflammation, which is common in relapsing-remitting multiple sclerosis (RRMS), and neurodegeneration, which is prevalent in progressive (P)MS. Currently, findings related to the molecular markers proposed in this paper in patients are scarce. We analyzed circulatory molecular indicators of the main ferroptosis-related processes, comprising lipid peroxidation (malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and hexanoyl–lysine adduct (HEL)), glutathione-related antioxidant defense (total glutathione (reduced (GSH) and oxidized (GSSG)) and glutathione peroxidase 4 (GPX4)), and iron metabolism (iron, transferrin and ferritin) to estimate their contributions to the clinical manifestation of MS and differences between RRMS and PMS disease course. In 153 patients with RRMS and 69 with PMS, plasma/serum lipid peroxidation indicators and glutathione were quantified using ELISA and colorimetric reactions, respectively. Iron serum concentrations were determined using spectrophotometry, and transferrin and ferritin were determined using immunoturbidimetry. Compared to those with RRMS, patients with PMS had decreased 4-HNE (median, 1368.42 vs. 1580.17 pg/mL; p = 0.03). Interactive effects of MS course (RRMS/PMS) and disease-modifying therapy status on MDA (p = 0.009) and HEL (p = 0.02) levels were detected. In addition, the interaction of disease course and self-reported fatigue revealed significant impacts on 4-HNE levels (p = 0.01) and the GSH/GSSG ratio (p = 0.04). The results also show an association of MS course (p = 0.03) and EDSS (p = 0.04) with GSH levels. No significant changes were observed in the serum concentrations of iron metabolism indicators between the two patient groups (p &gt; 0.05). We suggest circulatory 4-HNE as an important parameter related to differences between RRMS and PMS. Significant interactions of MS course and other clinically relevant parameters with changes in redox processes associated with ferroptosis support the further investigation of MS with a larger sample while taking into account both circulatory and central nervous system estimation.

Recent Advances in Metabolomics and Lipidomics Studies in Human and Animal Models of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative and inflammatory disease of the central nervous system (CNS) that leads to a loss of myelin. There are three main types of MS: relapsing-remitting MS (RRMS) and primary and secondary progressive disease (PPMS, SPMS). The differentiation in the pathogenesis of these two latter courses is still unclear. The underlying mechanisms of MS are yet to be elucidated, and the treatment relies on immune-modifying agents. Recently, lipidomics and metabolomics studies using human biofluids, mainly plasma and cerebrospinal fluid (CSF), have suggested an important role of lipids and metabolites in the pathophysiology of MS. In this review, the results from studies on metabolomics and lipidomics analyses performed on biological samples of MS patients and MS-like animal models are presented and analyzed. Based on the collected findings, the biochemical pathways in human and animal cohorts involved were investigated and biological mechanisms and the potential role they have in MS are discussed. Limitations and challenges of metabolomics and lipidomics approaches are presented while concluding that metabolomics and lipidomics may provide a more holistic approach and provide biomarkers for early diagnosis of MS disease.

Feasibility and assessment of self-reported dietary recalls among newly diagnosed multiple sclerosis: a quasi-experimental pilot study.

Individuals who are newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) may choose not to undergo disease-modifying therapies (DMTs) due to concerns about expenses or potential adverse effects. Thus, many individuals will opt for alternative therapies, such as dietary modifications. Among these dietary approaches, the modified Paleolithic elimination diet has shown promise for improving MS-related symptoms; however, restriction of certain food groups can lead to inadequate intake of nutrients. Three-day self-reported 24-h dietary recalls using the Automated Self-Administered 24-h (ASA24) Dietary Assessment Tool were assessed during a 12-month quasi-experimental (i.e., non-randomized) trial among individuals who either voluntarily declined DMTs and received health behavior (HB) intervention, (n = 29) or included DMTs and opted for the standard of care (SOC; n = 15). Participants in the HB group received a multimodal intervention that included dietary modifications, a walking program, and breathing exercises. Usual intake of each micronutrient was estimated and then evaluated with the estimated average requirement (EAR)-cut point method. At 12 months, >80% of both HB and SOC groups completed 3 days of the self-reported 24-h recalls, indicating the potential feasibility of ASA24. From baseline to 12 months, the HB group had a decreased mean ratio in total grains (0.64; 95% CI 0.43-0.93; p = 0.02) and added sugars (0.52; 95% CI 0.35-0.75; p ≤ 0.001), and an increased mean ratio intake of cured meats (1.74; 95% CI 1.05-2.90; p = 0.04); whereas, the SOC group had a decreased mean ratio intake for beef, veal, pork, lamb, and game meat (0.60; 95% CI 0.40-0.90; p = 0.01). At baseline, both groups had high proportions with inadequate intake of vitamin E and calcium. The SOC group also had a high proportion with inadequate intake of vitamin D. By 12-months, the HB group exhibited severe proportions of nutrient inadequacies (>20% of the group) for vitamin D (43.5%), vitamin E (29.1%), calcium (69.9%), and copper (27.8%). The SOC group, following their own diet, had inadequacies for all the same micronutrients, except for copper, as the HB group. The SOC group also had additional inadequacies: vitamin A (21.3%), thiamin (26.3%), riboflavin (24.2%), folate (24.8%), vitamin B12 (27.8%), and zinc (28.2%). Compared to the usual diet, adhering to the modified Paleolithic elimination diet, as a component of a 12-month multimodal intervention, may lead to reduced consumption of specific food groups, such as added sugars, as well as decreased risk of severe proportions of inadequacy for certain nutrients. The utilization of the ASA24 for acquiring dietary recalls from participants with MS may be feasible for future studies. clinicaltrials.gov identifier NCT04009005.

Impact of Cognitive and Psychological Functions in Relapsing-Remitting Multiple Sclerosis: A Cross-Sectional Study.

To compare the cognitive functions and trait anxiety in patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) to those of matched healthy controls (HCs). In addition, the study aims to investigate the correlations among cognitive functions, anxiety, depression, and quality of life (QOL) in this clinical population. The sample included RRMS patients (n = 21) and an equal number of age-, education-, and sex-matched HCs. Participants were assessed on the Indian version of the Wechsler Adult Intelligence Scale-IV, auditory and visual learning and memory, and visual-spatial construction and memory. RRMS patients were also assessed for levels of anxiety, depression, and their QOL. Comparative analyses between RRMS patients and HCs were carried out for neuropsychological assessments. Correlations among cognitive functions, anxiety, depression, and QOL in RRMS patients were examined. RRMS patients showed significant deficits across various cognitive domains, including processing speed and verbal learning, compared to HCs (P < 0.05). In addition, they reported higher levels of trait anxiety compared to HCs (P < 0.01), along with moderate state anxiety and mild depression. A significant correlation among anxiety, depression, and QOL was observed in RRMS patients. This study highlights significant cognitive impairments and psychological distress experienced by RRMS individuals, underscoring the critical need for comprehensive care addressing both cognitive impairments and psychological distress to enhance QOL.