Relapsing Multiple Sclerosis Patients Research Articles

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35–55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Ocrelizumab and ofatumumab comparison: an Italian real-world propensity score matched study

BackgroundThe management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA).Materials and methodsThis is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded.ResultsA total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934–1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability.ConclusionsThe treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up.

The ratio of circulating CD56dim NK cells to follicular T helper cells as a promising predictor for disease activity of relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system primarily mediated by CD4+ T helper cells. This study investigated the dynamic changes of natural killer (NK) cells and follicular T helper (Tfh) cells and their associations in relapsing-remitting MS patients. The findings revealed inverse relationships between NK cells and CD4+ T cells or Tfh cells. Specifically, CD56dim NK cells, not CD56bright NK cells, were negatively correlated with CD4+ T cells and Tfh cells. However, no significant correlations were found between NK cells and sNfL levels or EDSS scores. The ratio of CD56dim NK cells to circulating Tfh (cTfh) cells demonstrated superior discriminatory ability in distinguishing relapsing MS patients from healthy controls (HCs) and remitting patients, as determined by receiver operating characteristic (ROC) analysis. Following treatment with immunosuppressants or disease-modifying therapies (DMTs), a significant increase in the CD56dim NK/cTfh ratio was observed. These findings suggest that the CD56dim NK/cTfh ratio holds promise as a prognostic indicator for clinical relapse and treatment response in MS.

Efficacy and safety of ocrelizumab in patients with relapsing multiple sclerosis: Real-world experience of two Swiss multiple sclerosis centers

BackgroundOcrelizumab (OCR) is a humanized monoclonal antibody directed against CD-20 positive lymphocytes, mainly B-lymphocytes. OCR is approved for treatment of primary progressive (PPMS) and relapsing multiple sclerosis (RMS). This study aims to provide real-world safety and efficacy data of people with RMS treated with OCR in two Swiss Multiple Sclerosis (MS) centers. MethodsWe have conducted a retrospective data analysis using the patient cohorts from the Cantonal Hospital Aarau and Bern University Hospital (RMS: n = 235). Statistical analyses were performed with Mann–Whitney U-Test, Chi-squared test and Spearman-Rho-Correlation. Adjustment for multiple testing was performed by Bonferroni procedure. ResultsAfter initiation of OCR, there was a decrease in disease activity in RMS patients. In our study, 152/190 (80.0 %) RMS patients fulfilled the criteria for NEDA-3 12 months and 88/104 (84.6 %) showed NEDA-3 24 months after OCR initiation. The most frequent adverse events (AEs) in our study were infections, taking place in 78/235 (33.2 %) RMS patients. COVID-19 was the most common infection, followed by urinary infections and other respiratory infections and infectious adverse events occurred significantly more frequent in patients with reduced IgG serum concentration. ConclusionsOur real-world study showed OCR being associated with low rates of any type of MS disease activity as indicated by NEDA-3. The adverse event profile is comparable to the known events especially infections and an association between infections and reduced IgG serum concentration was found.

Diffusion basis spectrum imaging and diffusion tensor imaging predict persistent black hole formation in multiple sclerosis

Background and objectivesDiffusion basis spectrum imaging (DBSI) extracts multiple anisotropic and isotropic diffusion tensors, providing greater histopathologic specificity than diffusion tensor imaging (DTI). Persistent black holes (PBH) represent areas of severe tissue damage in multiple sclerosis (MS), and a high PBH burden is associated with worse MS disability. This study evaluated the ability of DBSI and DTI to predict which acute contrast-enhancing lesions (CELs) would persist as T1 hypointensities (i.e. PBHs) 12 months later. We expected that a higher radial diffusivity (RD), representing demyelination, and higher DBSI-derived isotropic non-restricted fraction, representing edema and increased extracellular space, of the acute CEL would increase the likelihood of future PBH development. MethodsIn this prospective cohort study, relapsing MS patients with ≥1 CEL(s) underwent monthly MRI scans for 4 to 6 months until gadolinium resolution. DBSI and DTI metrics were quantified when the CEL was most conspicuous during the monthly scans. To determine whether the CEL became a PBH, a follow-up MRI was performed at least 12 months after the final monthly scan. ResultsThe cohort included 20 MS participants (median age 33 years; 13 women) with 164 CELs. Of these, 59 (36 %) CELs evolved into PBHs. At Gd-max, DTI RD and AD of all CELs increased, and both metrics were significantly elevated for CELs which became PBHs, as compared to non-black holes (NBHs). DTI RD above 0.74 conferred an odds ratio (OR) of 7.76 (CI 3.77–15.98) for a CEL becoming a PBH (AUC 0.80, CI 0.73–0.87); DTI axial diffusivity (AD) above 1.22 conferred an OR of 7.32 (CI 3.38–15.86) for becoming a PBH (AUC 0.75, CI 0.66–0.83). DBSI RD and AD did not predict PBH development in a multivariable model. At Gd-max, DBSI restricted fraction decreased and DBSI non-restricted fraction increased in all CELs, and both metrics were significantly different for CELs which became PBHs, as compared to NBHs. A CEL with a DBSI non-restricted fraction above 0.45 had an OR of 4.77 (CI 2.35–9.66) for becoming a PBH (AUC 0.74, CI 0.66–0.81); a CEL with a DBSI restricted fraction below 0.07 had an OR of 9.58 (CI 4.59–20.02) for becoming a PBH (AUC 0.80, 0.72–0.87). ConclusionOur findings suggest that greater degree of edema/extracellular space in a CEL is a predictor of tissue destruction, as evidenced by PBH evolution.

Safety of teriflunomide in Chinese adult patients with relapsing multiple sclerosis: A phase IV, 24-week multicenter study.

Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. Eighty-two patients were assigned to variant (n = 42) and wild type groups (n = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUCtau) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. NCT04410965, https://clinicaltrials.gov.

Expression levels of GSDMB and ORMDL3 are associated with relapsing-remitting multiple sclerosis and IKZF3 rs12946510 variant

Multiple sclerosis (MS), a noncurable autoimmune neurodegenerative disease, requires constant research that could improve understanding of both environmental and genetic factors that lead to its occurrence and/or progression. Recognition of the genetic basis of MS further leads to an investigation of the regulatory role of genetic variants on gene expression. Among risk variants for MS, Ikaros zinc finger 3 (IKZF3) gene variant rs12946510 was identified as one of the top-ranked and the expression quantitative trait loci (eQTL) for genes residing in chromosomal locus 17q12-21. The study aimed to investigate the association of gene expression of the immunologically relevant genes, which map to indicated locus, ORMDL3, GSDMB, and IKZF3, with MS and rs12946510 genotype, taking into account disease phase, clinical parameters of disease progression, and severity and immunomodulatory therapy. We used TaqMan® technology for both allelic discrimination and gene expression determination in 67 relapsing MS patients and 50 healthy controls. Decreased ORMDL3 and GSDMB mRNA levels had significant associations with MS and rs12946510 TT rare homozygote among patients. Significant positive correlations between ORMDL3 and GSDMB mRNA expression were observed in both patients and controls. We detected the significant between-effect of sex and rs12946510 on the expression of ORMDL3 in the patient group and interferon β therapy and rs12946510 on GSDMB expression.Our results show the association of ORMDL3 and GSDMB mRNA expression with the clinical manifestation of MS and confirm that IKZF3 rs12946510 exerts the eQTL effect on both genes in multiple sclerosis. Besides providing novel insight related to MS phases and interferon β therapy, the study results confirm previous studies on regulatory genetic variants, autoimmunity, and MS.

Personalized Use of Disease-Modifying Therapies in Multiple Sclerosis.

Multiple sclerosis is an important neurological disease affecting millions of young patients globally. It is encouraging that more than ten disease-modifying drugs became available for use in the past two decades. These disease-modifying therapies (DMTs) have different levels of efficacy, routes of administration, adverse effect profiles and concerns for pregnancy. Much knowledge and caution are needed for their appropriate use in MS patients who are heterogeneous in clinical features and severity, lesion load on magnetic resonance imaging and response to DMT. We aim for an updated review of the concept of personalization in the use of DMT for relapsing MS patients. Shared decision making with consideration for the preference and expectation of patients who understand the potential efficacy/benefits and risks of DMT is advocated.

Development of an LC-MS/MS Method to Measure Sphingolipids in CSF from Patients with Multiple Sclerosis.

Multiple sclerosis is an inflammatory and degenerative disease characterized by different clinical courses including relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). A hallmark of patients with multiple sclerosis (pwMS) includes a putative autoimmune response, which results in demyelination and neuroaxonal damage in the central nervous system. Sphingolipids in cerebrospinal fluid (CSF) have been proposed as potential biomarkers reflective of disease activity in pwMS. Hence, sensitive methods to accurately quantify sphingolipids in CSF are needed. In this study, we report the development of a sensitive high-throughput multiplexed liquid chromatography coupled to a tandem mass spectrometry method to perform quantitation on 14 species of sphingolipids in human CSF. We applied this method to measure CSF sphingolipids in healthy controls (n = 10), PPMS (n = 27), and RMS (n = 17) patients before and after ocrelizumab treatment. The median CSF levels of the 14 sphingolipids measured herein was higher in PPMS (17.2 ng/mL) and RMS (17.6 ng/mL) when compared with the healthy controls (13.8 ng/mL). Levels of sphingolipids were decreased by 8.6% at week 52 after treatment with ocrelizumab in RMS patients but not in PPMS patients. Specifically, C16 glucosylceramide (-26%; P = 0.004) and C18 ceramides (-13%; P = 0.042) decreased from baseline in RMS patients. Additionally, in PPMS patients C16 glucosylceramide levels correlated with CSF neurofilament heavy levels at baseline (Rho =0.532; P = 0.004) and after treatment (Rho =0.424; P = 0.028). Collectively, these results indicate that CSF sphingolipid levels are altered in pwMS and treatment with ocrelizumab results in significant shifts in the sphingolipid profile that may reflect a reduction in disease activity supporting further investigation into sphingolipids as tools to monitor disease state. SIGNIFICANCE STATEMENT: This study describes the development of a new method to measure 14 sphingolipid species in CSF. These results demonstrate that sphingolipids levels are elevated in CSF from pwMS compared to healthy controls. Distinct sphingolipid signatures were observed between patients with different clinical disease courses, and these lipid signatures changed after treatment with ocrelizumab, especially in RMS patients. This method enables further investigation into the role of sphingolipids as candidate biomarkers in pwMS and other central nervous system disorders.

Evaluation of willingness to obtain of Covid 19 vaccine in patients with multiple sclerosis.

Assessing vaccine willingness and understanding sources of vaccine hesitancy in individuals with multiple sclerosis (MS) helps healthcare providers approach patients more effectively while respecting their autonomy to encourage coronavirus disease 2019 (COVID-19) vaccination. A descriptive-analytical cross-sectional study using a researcher-made checklist was conducted on MS patients referred to Neshat Clinic of Hamadan during the years 2020-2021. The checklist contained questions about demographic information, MS phenotype, duration of illness, expanded disability status scale (EDSS) score, and COVID-19 vaccination status. The expanded disability status scale (EDSS) is the most commonly used instrument for measuring disability in patients with multiple sclerosis (MS). The EDSS scale ranges from 0 to 10 in increments of 0.5 units, denoting advanced points of disability. Based on the results, 20 individuals (10%) were in the vaccine non-acceptance group, while 181 individuals (90%) were in the vaccine acceptance group. A significant number of relapsing and remitting (RR) type MS patients (90.7%) and all primary progressive (PP) type MS patients (100%) accepted the vaccine. In comparison, vaccine non-acceptance in the secondary progressive (SP) group was relatively higher (20.7%) compared to other types of MS, and this difference was significant (P < 0.05). Additionally, there was a statistically significant relationship between the history of COVID-19 and vaccine acceptance (P < 0.05). The study results demonstrated a high rate of COVID-19 vaccine acceptance among MS patients. MS phenotype, previous infection experiences, and other influences allow for COVID-19 vaccine acceptance among MS patients. This information can improve health programs and communication strategies for COVID-19 and future possible infectious disease vaccination in individuals with MS.

Ofatumumab and Early Immunological Cells Subset Characterization in Naïve Relapsing Multiple Sclerosis Patients: A Real-World Study.

Ofatumumab (OFA) is a fully human anti-CD20 monoclonal antibody administered with a 20 mg subcutaneous monthly dosing regimen. Inclusion criteria were patients: 1) aged 18-55; 2) with a confirmed diagnosis of relapsing Multiple Sclerosis (RMS), per the revised 2010 McDonald criteria; 2) who started OFA according to Italian Medicines Agency prescription rules and within 12 months from the RMS diagnosis; 3) naïve to any disease-modifying therapy. The primary outcome was to offer an overview of cellular subsets of RMS naïve patients (time 0) and then after 4 weeks (time 1) and 12 weeks (time 2) on therapy with OFA in a real-world setting. Fifteen patients were enrolled. CD3+ T cell frequencies were higher at time 1 (%80.4, SD 7.7) and time 2 (%82.6, SD 5.8) when compared to time 0 (%72.4, SD 9.8), p = .013. B naïve cells were barely detectable in the OFA group at time 1 (%0.4, SD 0.5) and 2 (%1.4, SD 2.9) when compared to time 0 (%11.5, SD 3.8), p < .001. The progressive and increasing use of anti-CD20 drugs imposes the need for larger, prospective, real-world, long-term studies to characterize further immunophenotypes of patients with RMS treated with OFA.

Safety evaluations of offspring breastfed by mothers receiving glatiramer acetate for relapsing multiple sclerosis.

Although the relapse risk is increased after birth in women with relapsing multiple sclerosis (RMS), only a very few disease-modifying therapies (DMTs) are approved during breastfeeding. Glatiramer acetate (GA, Copaxone®) is one of three DMTs that can be used in breastfeeding. The real-world safety of Copaxone® in Offsprings of Breastfeeding and treated RMS pAtients (COBRA) study demonstrated that offspring parameters (hospitalisations, antibiotic use, developmental delays, growth parameters) were similar between offspring breastfed by mothers taking GA or no DMT (control) during breastfeeding. COBRA data analyses were extended to provide further safety data on the impact of maternal GA treatment during breastfeeding on offspring. COBRA was a non-interventional, retrospective study using German Multiple Sclerosis and Pregnancy Registry data. Participants had RMS, gave birth and had GA or no DMT during breastfeeding. Offspring total adverse events (AEs), non-serious AEs (NAEs) and serious AEs (SAEs) up to 18 months postpartum were assessed. Reasons for offspring hospitalisations and antibiotic treatments were explored. Baseline maternal demographics and disease characteristics were similar between cohorts. Each cohort had 60 offspring. Numbers of offspring AEs were comparable between cohorts; total AEs: 82 (GA) vs 83 (control); NAEs: 59vs 61; SAEs: 23vs 22. AEs in both cohorts were diverse with no specific patterns. Duration of GA-exposed breastfeeding was 6 to >574 days for offspring with any AE. For all-cause hospitalisations, 11 offspring had 12 hospitalisations (GA cohort) and 12 control offspring had 16 hospitalisations. Most common reason for hospitalisation was infection: 5/12 (41.7%; GA) vs 4/16 (25.0%, control). Two out of 12 (16.7%) hospitalisations due to infection occurred during GA-exposed breastfeeding; the others occurred 70, 192 and 257 days after discontinuation of GA-exposed breastfeeding. Median (range) duration of GA-exposed breastfeeding was 110 (56 to ≥285) days for offspring hospitalised for infections and 137 (88-396) days for those hospitalised for other reasons. Nine offspring had 13 antibiotic treatments (GA cohort) and nine control offspring had 10 treatments. Ten out of 13 (76.9%) antibiotic treatments occurred during GA-exposed breastfeeding, of which four were primarily due to double kidney with reflux. Other antibiotic treatments occurred 193, 229 and 257 days after discontinuation of GA-exposed breastfeeding. GA treatment of mothers with RMS during breastfeeding did not increase AEs, hospitalisations or antibiotic use in their offspring versus control offspring. These data support previous COBRA data that the benefit of maternal RMS treatment with GA during breastfeeding outweighs the potential, apparently low risk of untoward events, in their breastfed offspring.

Whole blood miRNAs in relapsing MS patients treated with dimethyl fumarate in the phase 4 TREMEND trial

We investigated the impact of dimethyl fumarate (DMF), an oral therapy for relapsing multiple sclerosis (MS), on blood microRNA (miRNA) signatures and neurofilament light (NFL) levels. DMF normalized miR-660-5p and modulated various miRNAs associated with the NF-kB pathway. These alterations reached a peak 4–7 months after treatment. Notably, particular miRNAs correlated with high or low NFL levels, implying their potential role as markers of treatment efficacy. Our findings broaden the understanding of DMF's immunomodulatory effects and may aid in predicting treatment responses.

Evaluating the efficacy and safety of transitioning patients with multiple sclerosis from natalizumab to ocrelizumab (OCTAVE)

Introduction: Natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients infected with John Cunningham virus (JCV). Ocrelizumab has demonstrated efficacy to treat MS; however, its safety in patients previously treated with natalizumab is unclear. Objective: To evaluate the safety and efficacy of ocrelizumab in patients with relapsing MS (RMS) previously treated with natalizumab. Methods: Clinically and radiographically stable RMS patients, ages 18–65 treated with natalizumab for ⩾ 12 months, were enrolled in the study and initiated ocrelizumab 4–6 weeks after their final dose of natalizumab. Relapse assessment, expanded disability status scale, and brain magnetic resonance imaging (MRI) were performed prior to starting ocrelizumab and at months 3, 6, 9, and 12. Results: Forty-three patients were enrolled, and 41 (95%) completed the study. Two patients had a relapse while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. Thirteen serious adverse events (SAEs) were recorded, four of which were considered possibly related to ocrelizumab. Conclusion: Overall, our study indicates clinical and MRI stability for most patients transitioning from natalizumab to ocrelizumab. ClinicalTrials.gov Identifier: NCT03157830

Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

The consequences of switching from Gilenya® to generics for fingolimod.

On May 2017, two generic drugs for fingolimod were introduced into the market in Israel, and most MS patients treated with Gilenya® (Novartis) were switched to fingolimod (Teva), or to Finolim (Rafa). In this study we analyzed the consequences of switching to generic fingolimod in a single MS center. Study population included relapsing MS patients who were treated with Gilenya® for at least two year before May 2017, switched to generic fingolimod and remained on treatment for at least 2 years thereafter. Data before and after the switch were compared. Twenty-seven patients fulfilled the inclusion criteria (F=20, RRMS=20, SPMS=7, average age 49±11.4 years, average disease duration=16.6±7.6 years). Seventeen patients had to be switched back to the original Gilenya® due to intolerable new or worsening clinical adverse events (n=9), clinical relapse (n=1), clinical relapse with adverse events (n=3), elevation of liver enzymes > X3 ULN (n=3) and elevation of amylase (n=1). Expanded Disability Status Scale (EDSS) score increased in 4 patients during the year before the switch, and in 12 patients during the year of treatment with generic fingolimod (p=0.036). The tolerability, retention rate and probably efficacy of generic fingolimod seems to be lower than the original Gilenya®.

Results on SARS-CoV-2 mRNA Vaccine Booster from an Open-Label Multicenter Study in Ofatumumab-Treated Participants with Relapsing Multiple Sclerosis.

Few data exist on how ofatumumab treatment impacts SARS-CoV-2 booster vaccination response. KYRIOS is an ongoing prospective open-label multicenter study on the response to initial and booster SARS-CoV-2 mRNA vaccination before or during ofatumumab treatment in relapsing MS patients. The results on the initial vaccination cohort have been published previously. Here, we describe 23 patients who received their initial vaccination outside of the study but booster vaccination during the study. Additionally, we report the booster results of two patients in the initial vaccination cohort. The primary endpoint was SARS-CoV-2-specific T-cell response at month 1. Furthermore, serum total and neutralizing antibodies were measured. The primary endpoint was reached by 87.5% of patients with booster before (booster cohort 1, N = 8) and 46.7% of patients with booster during ofatumumab treatment (booster cohort 2, N = 15). Seroconversion rates for neutralizing antibodies increased from 87.5% at baseline to 100.0% at month 1 in booster cohort 1 and from 71.4% to 93.3% in booster cohort 2. Of note, 3 of 4 initially seronegative patients in booster cohort 2 and one seronegative patient in the initial vaccination cohort seroconverted after the booster during ofatumumab treatment. Booster vaccinations increase neutralizing antibody titers in ofatumumab-treated patients. A booster is recommended in ofatumumab-treated patients.

Serum neurofilament light chain in relapsing multiple sclerosis patients on a ketogenic diet.

Ketogenic diets have anti-inflammatory and neuroprotective properties which make these diets an attractive complimentary treatment approach for patients living with multiple sclerosis (MS). The objective of this study was to assess the impact of ketogenic diets on neurofilament light chain (NfL), a biomarker of neuroaxonal injury. Thirty-nine subjects with relapsing MS completed a 6-month ketogenic diet intervention. NfL levels were assayed at both baseline (pre-diet) and 6-months on-diet. In addition, ketogenic diet study participants were compared to a cohort (n=31) of historical, untreated MS controls. Baseline (pre-diet) mean NfL was 5.45 pg/ml (95% CI 4.59 - 6.31). After 6 months on ketogenic diet, mean NfL was not significantly changed (5.49 pg/ml; 95% CI 4.82 - 6.19). Compared to untreated MS controls (mean 15.17 pg/ml), NfL levels for the ketogenic diet cohort were relatively low. MS subjects with higher levels of ketosis (as measured by serum beta-hydroxybutyrate) exhibited greater reductions in NfL between baseline and 6-months on ketogenic diet. Ketogenic diets do not worsen biomarkers of neurodegeneration in relapsing MS patients, with stable, low levels of NfL observed throughout the diet intervention. Subjects with greater biomarkers of ketosis experienced a higher degree of improvement in serum NfL. NCT03718247 - "Utilization of the Ketogenic Diet in Patients with Relapsing-Remitting MS" https://clinicaltrials.gov/ct2/show/NCT03718247.

Long-term Safety of Ozanimod in Relapsing Multiple Sclerosis and Moderately to Severely Active Ulcerative Colitis (P7-3.007)

Long-term Safety of Ozanimod in Relapsing Multiple Sclerosis and Moderately to Severely Active Ulcerative Colitis (P7-3.007)

Effects of ocrelizumab on NK cell activation in Relapsing Multiple Sclerosis (P2-3.004)

<h3>Objective:</h3> To evaluate the effects of ocrelizumab on circulating immune asset in Relapsing Multiple Sclerosis (RMS) subjects, with a specific focus on NK cell activation profile. <h3>Background:</h3> Ocrelizumab, a humanized monoclonal anti-CD20 antibody, has shown pronounced effects in reduction of disease activity in RMS. Although the clinical response to ocrelizumab is related to a specific B cell depletion, other circulating lymphocytes may be affected by this treatment. Concerning NK lymphocytes, several studies have shown potential regulatory properties of these cells in MS. Some activator cytotoxicity receptors (CD94/NKG2C, NKG2D, NKp46, and DNAM) were suggested to mediate NK cytotoxic regulatory function. Anti-CD20 agents showed to drive the selective in vitro expansion of CD94/NKG2C+ memory NK cells and to enhance their cytotoxic function. However, the phenotypic changes induced by ocrelizumab on NK cell subsets in vivo and their pathogenetic implication are still unexplored. <h3>Design/Methods:</h3> In this prospective longitudinal study, we enrolled 30 RMS patients. RMS patients were treated with ocrelizumab and followed up for twelve months. Frequency and phenotype of several circulating T cell subsets as well as NK cell phenotypic profile were evaluated by flow cytometry, before and after the treatment. <h3>Results:</h3> Six and twelve months after the treatment, a reduction of absolute lymphocyte count was observed. We also noticed increased percentage of T cell subsets with naïve phenotype (CD4+CD45RA+ and CD8+CD45RA+ cells). In parallel, a reduction of activated/memory T cell percentage was observed (CD4+CD45RO+ and CD8+CD45RO+ cells). Further, flow cytometry phenotypic analysis revealed an increased proportion of NK cells expressing the activating receptors, CD94/NKG2C, NKG2D, NKp46 and DNAM upon ocrelizumab treatment. <h3>Conclusions:</h3> Ocrelizumab affects T cell compartment, favoring reduction of activated/memory T cells in RMS patients. Further, ocrelizumab induces phenotypical changes in NK cells toward a higher cytotoxic/regulatory profile in RMS patients. <b>Disclosure:</b> Dr. Abbadessa has nothing to disclose. Dr. Bruzzaniti has nothing to disclose. Dr. Miele has nothing to disclose. Dr. Piemonte has nothing to disclose. Dr. Lepore has nothing to disclose. Elisabetta Signoriello has nothing to disclose. Giacomo Lus has nothing to disclose. Giuseppe Matarese has nothing to disclose. Mario Galgani has nothing to disclose. Prof. Bonavita has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis, Biogen, Mylan, Sanofi. Prof. Bonavita has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Mylan, Novartis.