Background and Aims:
The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, ...the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.
Methods:
We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.
Results:
Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.
Conclusions:
Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.
Background:
Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed.
...Objective:
Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients.
Methods:
We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients.
Results:
Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18–55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs.
Conclusion:
COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.
Pediatric onset multiple sclerosis patients (POMS) are defined as multiple sclerosis with an onset before the age of 18 years. Compared to adult onset multiple sclerosis (AOMS), POMS has more severe ...disease activity at onset, but better recovery. Little is known about the molecular mechanism responsible for the differences in the clinical presentations.
Peripheral Blood Mononuclear Cells samples were taken from 22 POMS patients (mean age 14.1 ± 2.4 years, 15 females, 7 male), and 16 AOMS patients, (mean age 30.8 ± 6.1 years,10 females, 6 males), and gene-expression were analyzed using Affymetrix Inc. HU-133-A2 microarrays. Differentially Expressed Genes (DEGs) that significantly distinguished between POMS and AOMS with pvalue <0.05 after false discovery rate correction were evaluated using Partek software. Twenty-one matched age and gender control was applied to clarify age-related changes. Clinical assessment was performed by analysis of expanded disability status scale (EDSS) and brain MRI lesion loads. Gene functional analysis was performed by Ingenuity Pathway Analysis software.
Compared to AOMS, POMS had higher EDSS (3.0 IQR 2.0–3.0 and 2.0 IQR 2.0–3.0, p = 0.005), volume of T1 (2.72 mm3, IQR 0.44–8.39 mm3 and 0.5 mm3 IQR 0–1.29 mm3 respectively, p = 0.04) and T2 (3.70 mm3, IQR 1.3–9.6 and 0.96 mm3, IQR 0.24–4.63 respectively, p = 0.02) brain MRI lesions. The POMS transcriptional profile was characterized by 551 DEGs, enriched by cell cycling, B lymphocyte signaling and senescent pathways (p < 0.02). Of these, 183 DEGs significantly correlated with T2 lesions volume. The POMS MRI correlated DEGs (n = 183) and their upstream regulators (n = 718) has overlapped with age related DEGs obtained from healthy subjects (n = 497). This evaluated common DEGs (n = 29) defined as POMS age-related regulators, suggesting to promote effect on disease severity.
Our finding of higher transcriptional levels of genes involved in cell cycle, cell migration and B cell proliferation that promoted by transcriptional level of age-associated genes and transcription factors allows better understanding of the more aggressive clinical course that defines the POMS.
•Pediatric onset multiple sclerosis (POMS) has more severe course than adults.•POMS has more active inflammatory blood transcription profile than adult patients.•POMS disease activity is promoted by age-related blood transcriptional mechanism.
Abstract Background Gait impairment is a significant problem in multiple sclerosis (MS), leading to decreased activity and limitations in function. However, specific characterization of abnormal gait ...in MS patients has only been described in small groups of patients, mainly using observational tools. Objective The aim of the current study was to characterize the spatio-temporal gait parameters in MS patients and ascribe them to clinical variables, in order to enable target-oriented management. Methods Eighty-one MS patients with relatively short disease duration (5.3; S.E. = 0.3) able of independent walking and 25 age-matched healthy subjects were evaluated using the GAITRite Functional Ambulation System. Subjects also underwent a thorough neurological examination to assess their disability using the Expanded Disability Status Scale (EDSS). Gait parameters were compared between patients and able-bodied controls to characterize the gait impairments in MS. Within the group of patients the correlation of gait parameters with clinical neurological variables was investigated. Results MS patients demonstrated significant impairments in all spatio-temporal gait parameters compared to able-bodied healthy subjects. MS patients had a mean Functional Ambulation Profile (FAP) score of 83.0 and a mean velocity of 85.5 m/s while the controls had a FAP score of 95.0 ( p < 0.001) and a velocity of 138.6 m/s ( p < 0.001). Cadence was 94.4 steps/min in MS patients and 115.2 in controls ( p < 0.001). Step length was 45.3 cm in MS patients and 72.1 cm in controls ( p < 0.001). FAP score negatively correlated with disease duration ( p < 0.001) and EDSS ( p < 0.001). The most significant correlations of the FAP were found with the pyramidal ( p < 0.002), and the cerebellar ( p < 0.05) functional scores. Specifically, gait velocity, single support time and swing time negatively correlated with the pyramidal functional score, while double support time positively correlated with the pyramidal score. The base support width positively correlated with cerebellar functional score. Conclusions Gait parameters were impaired in MS, even in patients with relatively short disease duration. The impaired gait patterns correlated with the associated neurological disability. Specific and accurate assessment of gait can be a useful tool to monitor MS evolution and can be used to advise target-oriented rehabilitative management of MS patients.
Background
The majority of multiple sclerosis MS patients treated with fingolimod fail to develop a protective level of IgG humoral and adaptive cellular immune responses following full BNT162b2 ...SARS-CoV-2 vaccination.
Objective
To compare the efficacy of the third COVID-19 vaccine dose in vaccine non-responders fingolimod-treated MS patients.
Study design
This is a prospective 3-month, single-center, randomized clinical trial.
Methods
Twenty relapsing MS patients who had been on fingolimod therapy ≥ 12 months and failed to develop humoral IgG immune response to 2-dose Pfizer BNT162b2 COVID-19 vaccination were randomized into two groups: fingolimod-continuation group and fingolimod-discontinuation group. Humoral and memory cellular immune responses were assessed within 1 and 3 months following the third Pfizer BNT162b2 vaccine dose and compared between the groups.
Results
A higher rate of patients in the fingolimod-discontinuation group
n
= 8/10 compared to fingolimod-continuation group
n
= 2/10 developed positive SARS-COV-2 IgG. Median IgG titer 1 month following the third dose was 202.3 BAU/ml vs. 26.4 BAU/ml, respectively,
p
= 0.022. The development of IgG humoral response correlated with absolute lymphocyte count. Specific SARS-COV-2 memory B cell and T cell immune responses were not detected in both groups, either at 1 month or 3 months following the third COVID-19 vaccine dose.
Conclusions
Short period of fingolimod treatment discontinuation was associated with the development of humoral protection but not with adaptive cellular immunity.
Although the causes of multiple sclerosis are largely unknown, genetic and environmental components play an important role. Geographic distribution, varying with latitude, reflects both genetic and ...environmental influences. We conducted a retrospective exploratory observational study to characterize the disability progression of 2396 Jewish patients with relapsing-remitting multiple sclerosis, followed at the Sheba Multiple Sclerosis Center, Tel-Aviv, Israel; 188 patients who originated in Iraq and 2207 patients who originated in northern Europe. Peripheral blood microarray gene expression analysis was performed in a subgroup of patients to identify molecular pathways associated with faster disability progression. During a follow-up period of 18.8 and 19.8 years, respectively, 51.6% of patients with an Iraqi origin progressed to moderate disability defined as expanded disability status scale (EDSS) score of 3.0 to 5.5, compared to 44.2% of patients with a northern European origin (odds ratio 1.347, 95% CI 1.0-1.815, p = 0.049). An Iraqi origin was associated with increased risk of progression to moderate disability adjusted for sex, disease duration, age at onset, and treatment with immunomodulatory drugs (hazard ratio 1.323; 95% CI, 1.049-1.668, p = 0.02), but not to severe disability defined as EDSS score > = 6.0 (i.e., walking aids are required for a distance of 100 meters, (hazard ratio 1.311; 95% CI, 0.918-1.874, p = 0.136). Gene expression analysis disclosed 98 differentially expressed genes (79 over-expressed and 19 under-expressed) between relapsing-remitting multiple sclerosis patients of Iraqi origin (N = 17) and northern European (N = 34) origin. Interestingly, this gene expression was enriched with genes related to neuronal pathways associated with morphology of axons, branching of neurites, proliferation of neocortical neurons, and formation of myelin sheath, suggesting an augmented process of neurodegeneration in relapsing-remitting multiple sclerosis patients with an Iraqi origin. The study results suggest that relapsing-remitting multiple sclerosis patients with an Iraqi origin progress faster to disability possibly due to an enhanced process of neurodegeneration.
Objective An association between uveitis and multiple sclerosis (MS) is well-established, but the actual nature of that association remains poorly understood. We sought to determine the association ...between the presence of a uveitis diagnosis prior to an MS diagnosis compared to no pre-existing uveitis diagnosis in MS patients. Methods Patients in whom the presentation of uveitis preceded the presentation of MS (study group) and patients with MS and no uveitis (control group) were randomly selected at a ratio of 1:3 from the Sheba Multiple Sclerosis Center computerized database. Results Eleven patients presented with uveitis prior to MS diagnosis (study group), and 31 randomly selected patients had MS without uveitis (control group). Only one patient in the study group deteriorated to EDSS 3 during the follow-up period, compared to 15 patients in the control group (9.1% vs 48.4%, P = 0.049). None of the patients in the study group reached EDSS 6 during the 10 years of follow-up compared to 6 (19.4%) patients in the control group (P = 0.194). Conclusions MS patients who presented with uveitis that preceded their neurological symptoms of MS demonstrated a clinically significant better neurological prognosis, than our MS patients with no uveitis.
Abstract
Background
Approximately 60% of people with multiple sclerosis (PwMS) suffer from upper limb dysfunction. Our primary goal is to implement a single-blind, randomized control trial (RCT) ...designed to compare the effectiveness of an 8-week home-based telerehab virtual reality (VR) program with conventional therapy in PwMS with manual dexterity difficulties. Secondary aims include (a) evaluating the impact of the programs on quality of life after the intervention and a follow-up 1 month later and (b) evaluating the impact of the programs on adherence and satisfaction.
Methods
Twenty-four PwMS will be recruited to the study which will be conducted at two established MS centers: (1) The Regional Center for Diagnosis and Treatment of Multiple Sclerosis, Binaghi Hospital, Cagliari, Italy, and (2) The Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. Participants will complete a total of three assessments focusing on upper limb functions. Both groups will receive 16 training sessions focusing on functional upper limb activities. The home-based telerehab VR intervention will comprise a custom-made software program running on a private computer or laptop. PwMS will perform several activities of daily living (ADL) functions associated with self-care, dressing, and meal preparation. Conventional therapy will focus on task-related upper-limb treatments while in a sitting position, indicative of the standard care in MS. Following 8 weeks of training, participants will complete a further outcome assessment. The same tests will be conducted 1 month (as a follow-up) after completion of the intervention.
Discussion
The outcomes of this study have tremendous potential to improve the quality of evidence and informed decisions of functional upper limb activities in PwMS. If comparable results are found between the treatments in improving upper limb outcomes, this would suggest that PwMS can choose the program that best meets their personal needs, e.g., financial concerns, transportation, or accessibility issues. Secondly, this information can be used by healthcare providers and medical professionals in developing upper limb exercise programs that will most likely succeed in PwMS.
Trial registration
ClinicalTrials.gov
NCT04032431
. Registered on 19 July 2019.
Balance impairment is common in people with multiple sclerosis (PwMS) and frequently impacts quality of life by decreasing mobility and increasing the risk of falling. However, there are only scarce ...data examining the contribution of specific neurological functional systems on balance measures in MS. Therefore, the primary aim of our study was to examine the differences in posturography parameters and fall incidence according to the pyramidal, cerebellar and sensory systems functional systems in PwMS. The study included 342 PwMS, 211 women and mean disease duration of 8.2 (S.D = 8.3) years. The study sample was divided into six groups according to the pyramidal, cerebellar and sensory functional system scores, derived from the Expanded Disability Status Scale (EDSS) data. Static postural control parameters were obtained from the Zebris FDM-T Treadmill (zebris® Medical GmbH, Germany). Participants were defined as "fallers" and "non-fallers" based on their fall history. Our findings revealed a trend that PwMS affected solely in the pyramidal system, have reduced stability compared to patients with cerebellar and sensory dysfunctions. Moreover, the addition of sensory impairments to pyramidal dysfunction does not exacerbate postural control. The patients in the pure sensory group demonstrated increased stability compared to each of the three combined groups; pyramidal-cerebellar, pyramidal-sensory and pyramidal-cerebellar-sensory groups. As for fall status, the percentage of fallers in the pure pyramidal, cerebellar and sensory groups were 44.3%, 33.3% and 19.5%, respectively. As for the combined functional system groups, the percentage of fallers in the pyramidal-cerebellar, pyramidal-sensory and pyramidal-cerebellar-sensory groups were 59.7%, 40.7% and 65%, respectively. This study confirms that disorders in neurological functional systems generate different effects on postural control and incidence of falls in the MS population. From a clinical standpoint, the present information can benefit all those engaged in physical rehabilitation of PwMS.
•COVID-19 convalescents displayed an adaptive immune response for up to 7 months.•The T cell response is characterized by IFN-γ-, IL2-, and IFN-γ+IL2-secreting memory T cells.•Waning anti-SARS-CoV-2 ...IgG is associated with robust memory B cell and memory T cell responses.•The SNMO peptide pools elicited the strongest memory T cell response.
Antiviral adaptive immunity involves memory B cells (MBC) and memory T cells (MTC). The dynamics of MBC and MTC in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescents warrant further investigation.
In this cross-sectional and longitudinal study, blood-derived MBC and MTC responses were evaluated in 68 anti-spike IgG-positive mild coronavirus disease 2019 (COVID-19) convalescents at visit 1, between 1 and 7 months (median 4.1 months) after disease onset. SARS-CoV-2 anti-spike IgG was determined by ELISA, MBC by SARS-CoV-2-specific receptor binding domain (RBD) ELISpot, and interferon gamma (IFN-γ)-, interleukin 2 (IL2)-, and IFN-γ+IL2-secreting MTC by IFN-γ and IL2 SARS-CoV-2 FluoroSpot. For 24 patients sampled at the first visit, the IgG, MBC, and MTC analyses were also performed 3 months later at the second visit.
Seventy-two percent of convalescents were both MBC- and MTC-positive, 18% were MBC-positive and MTC-negative, and 10% were MTC-positive and MBC-negative. The peak MBC response level was detected at 3 months after COVID-19 onset and persisted up to 7 months post infection. Significant MTC levels were detected 1 month after onset in response to S1, S2_N, and SNMO peptide pools. The frequency and magnitude of the MTC response to SNMO was higher than those to S1 and S2_N. Longitudinal analysis demonstrated that even when specific humoral immunity declined, the cellular immunity persisted.
The study findings demonstrate the durability of adaptive cellular immunity at least for 7 months after SARS-CoV-2 infection, suggesting long-lasting protection.
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