Myeloid-derived Suppressor Cells and Multiple Sclerosis.

Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that play important roles in maintaining immune homeostasis and regulating immune responses. MDSCs can be divided into two main subsets based on their surface markers and functional properties: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). Recently greatest attention has been paid to innate immunity in Multiple Sclerosis (MS), so the aim of our review is to provide an overview of the main characteristics of MDSCs in MS and its preclinical model by discussing the most recent data available. The immunosuppressive functions of MDSCs can be dysregulated in MS, leading to an exacerbation of the autoimmune response and disease progression. Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach for autoimmune diseases, but the cellular mechanisms behind successful therapy remain poorly understood. Therefore, targeting MDSCs could be a promising therapeutic approach for MS. Various strategies for modulating MDSCs have been investigated, including the use of pharmacological agents, biological agents, and adoptive transfer of exogenous MDSCs. However, it remained unclear whether MDSCs display any therapeutic potential in MS and how this therapy could modulate different aspects of the disease. Collectively, all the described studies revealed a pivotal role for MDSCs in the regulation of MS.

NEDA-3 achievement in early highly active relapsing remitting multiple sclerosis patients treated with Ocrelizumab or Natalizumab.

BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

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

BACKGROUND: The 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 METHODS: This 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. RESULTS: A 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. CONCLUSIONS: The 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.

Ocrelizumab Extended Interval Dosing in Primary Progressive Multiple Sclerosis: An Italian Experience.

BACKGROUND: The intervals between two courses of anti CD20 therapies in the COVID19 pandemic era provided the opportunity to individually delay therapy, known as extended interval dosing (EID). METHODS: We collect real-world data on patients with primary progressive MS (PPMS) treated with Ocrelizumab (OCR) during the COVID'19 pandemic. The observation period in which the standard interval dosing (SID) or EID occurred (always a maintenance cycle, 600 mg) was from January 2020 to June 2021. All patients had two infusions during the observation period. Our first aim was to compare confirmed disability progression (CDP) between SID and EID patients. RESULTS: From a total cohort of 410 patients treated with OCR, 96 patients fulfilled the inclusion criteria. All patients received two infusions during the index window, 71 received only SID infusions whilst 25 received at least one EID infusion throughout the entire follow-up. During the entire available follow-up (median 10 months, IQR 7-11), CDP was recorded in 5 patients (3/71, 4.2% SID and 2/25, 8% EID, V-Cramer = 0.141, p-value = 0.167). EID regimen did not influence the risk of CDP during the investigated follow up. CONCLUSION: In our multicentre real-world cohort, the EID regimen in PPMS patients did not result in increased CDP during the available follow-up.

MiRNA 106a-5p in cerebrospinal fluid as signature of early relapsing remitting multiple sclerosis: a cross sectional study.

Background: Circulating microRNAs (MiRNAs) have been investigated for their role in fine-tuning the adaptive immune response to inflammatory factors and in Multiple Sclerosis (MS). They have been investigated as possible biomarkers for the diagnosis and prognosis of the disease. Methods: A cross sectional study conducted at the MS centre of Foggia, Italy. We enrolled patients with (1) an age between 18 and 55 years, (2) a definitive diagnosis of relapsing remitting MS (RRMS) as per the revised McDonald criteria, and (3) naïve to any disease modifying therapy (DMTs), as well as (4) patients with other neurological disorders (OND). The aim of the study was to compare the levels of expression of miRNA 21-5p, miRNA 106a-5p, miRNA 146a-5p, and miRNA223-3p in cell-free cerebrospinal fluid (CSF) in RRMS patients and OND. Investigated MiRNAs were extracted, retrotranscribed, and then assessed by real-time polymerase chain reaction assay (q-PCR). A receiver-operator characteristic (ROC) curve was used to test MiRNAs as a biomarker for diagnosing MS. A linear regression analysis was done to find any association with disease characteristics at the time of diagnosis. Results: A total cohort of 70 subjects (70% women) was analyzed. Out of them, 35 had a RRMS diagnosis. MiRNA 106a-5p (7.8 ± 3.8 vs 1.3 ± 0.9, p=0.03) had higher levels in RRMS patients when compared to OND. The ROC curve indicated that MiRNA 106a-5p could be considered as a disease biomarker with an area under the curve of 0.812 (p<.001; 95% CI 0.686-0.937). Linear regression analysis showed an association between the number of oligoclonal bands and MiRNA 106a-5p levels (B-coeff 2.6, p<.001; 95% CI 1.3-4.9). Conclusion: We described miRNA 106a-5p as a possible signature in the CSF of RRMS patients in early phases of the disease. Further studies are needed to characterize its role in early MS as a disease biomarker.

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

BACKGROUND: Ofatumumab (OFA) is a fully human anti-CD20 monoclonal antibody administered with a 20 mg subcutaneous monthly dosing regimen. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Quality of care provided by Multiple Sclerosis Centers during Covid-19 pandemic: Results of an Italian multicenter patient-centered survey.

BACKGROUND: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed. METHODS: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance. RESULTS: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic. CONCLUSIONS: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC.

Personality Traits and Fatigue in Multiple Sclerosis: A Narrative Review.

(1) Background: Multiple sclerosis (MS) is a chronic neurodegenerative autoimmune disease. Fatigue is a prevalent and debilitating symptom that significantly impacts the quality of life of these patients. A relationship between personality traits and fatigue in MS has been hypothesized but not clearly defined. (2) Methods: A literature search was carried out from databases up to April 2023 for studies correlating personality traits and fatigue in patients suffering from MS. (3) Results: A total of ten articles was included; most of the studies depict a neuroticism-fatigue correlation; however, they were not consistent in terms of the fatigue, personality, and covariate assessments. (4) Conclusions: The clinical and methodological heterogeneity of the included studies prevented us from drawing any firm conclusion on the link between personality traits and fatigue in MS. Several models of personality and different fatigue assessments have been found. Despite this, a common pathway shows that the neuroticism trait or similar personality patterns has a role in fatigue diagnosis. This may be a useful target to improve the quality of life and enhance the modification of the disease treatment results. Further homogeneous and longitudinal studies are needed.

Relapse-associated worsening in a real-life multiple sclerosis cohort: the role of age and pyramidal phenotype.

BACKGROUND AND PURPOSE: The overall disability in patients with relapsing-remitting multiple sclerosis is likely to be partly rather than entirely attributed to relapse. MATERIALS AND METHODS: The aim was to investigate the determinants of recovery from first relapse and relapse-associated worsening (RAW) in relapsing-remitting multiple sclerosis patients from the Italian MS Registry during a 5-year epoch from the beginning of first-line disease-modifying therapy. To determine recovery, the functional system (FS) score was used to calculate the difference between the score on the date of maximum improvement and the score before the onset of relapse. Incomplete recovery was defined as a combination of partial (1 point in one FS) and poor recovery (2 points in one FS or 1 point in two FSs or any other higher combination). RAW was indicated by a confirmed disability accumulation measured by the Expanded Disability Status Scale score confirmed 6 months after the first relapse. RESULTS: A total of 767 patients had at least one relapse within 5 years of therapy. Of these patients, 57.8% experienced incomplete recovery. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01-1.04; p = 0.007) and pyramidal phenotype were associated with incomplete recovery (OR = 2.1, 95% CI 1.41-3.14; p < 0.001). RAW was recorded in 179 (23.3%) patients. Age (OR = 1.02, 95% CI 1.01-1.04; p = 0.029) and pyramidal phenotype (OR = 1.84, 95% CI 1.18-2.88; p = 0.007) were the strongest predictors in the multivariable model. CONCLUSIONS: Age and pyramidal phenotype were the strongest determinants of RAW in early disease epochs.

Neural precursor cells tune striatal connectivity through the release of IGFBPL1.

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity.

Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

Stopping Interferon Beta 1b Does Not Influence the Risk of Disability Accrual in Non-Active SPMS: Results from an Italian Real-World Study.

BACKGROUND: No consensus exists on the possibility to stop disease modifying therapies (DMTs) in Secondary Progressive Multiple Sclerosis (SPMS). METHODS: The primary outcome was the time to reach 24-weeks confirmed Expanded Disability Status Scale (EDSS) 7.0. We enrolled all patients with a confirmed diagnosis of non-active SPMS (here, absence of clinical or radiological activity for at least 24 months before the conversion) between 1 January 2010 and 31 December 2015, at MS centers of Catania and Foggia, Italy. Patients were divided into two groups, according to the shared decision to stop DMTs (group A) or to maintain/switch to licensed interferon beta 1b for SPMS (group B). A Cox model adjusted with an inverse probability weighted propensity score (IPTW-PS) was employed. RESULTS: A cohort of 311 patients was enrolled, 165 were in group A and 146 were in group B. Patients in the two groups were similar for baseline characteristics. The IPTW-PS adjusted Cox model for the event time to 24-weeks confirmed EDSS 7.0 did not show differences between the two groups (ExpB 0.96, CI 0.739-1.271, p = 0.819). CONCLUSIONS: In a real-world setting, in patients with non-active SPMS, the maintaining or switching to the licensed interferon beta 1b did not reduce the risk of reaching confirmed EDSS 7.0.

Immunological Subsets Characterization in Newly Diagnosed Relapsing-Remitting Multiple Sclerosis.

Objectives: Using flow cytometry, we characterized myeloid, B, and T cells in patients recently diagnosed with relapsing-remitting multiple sclerosis (RRMS) naive to disease-modifying therapies (DMTs). Methods: This prospective case-control study was conducted in the tertiary MS center of Catania, Italy. Demographic/clinical data and peripheral bloods were collected from 52 naive patients recently diagnosed with RRMS and sex/age-matched healthy controls (HCs) in a 2:1 ratio. We performed flow cytometry on isolated peripheral blood mononuclear cells to assess immune cell subsets differences between RMMS patients and HCs. We explored the biomarker potential of cell subsets using receiver operating characteristic (ROC) curves and relative area under the curve (AUC) analyses. Results: Monocytic myeloid-derived suppressor cells (Mo-MDSCs CD14+/HLADR-/low) and inflammatory monocytes (CD14+CD16+) displayed higher frequencies in RRMS patients when compared with HCs (p <.05). A lower percentage of B-unswitched memory cells was observed in RRMS patients when compared with HCs (p = .026). T cells had a higher frequency of T-helper CD4+ cells and their subset, CD4+CD161+, in RRMS patients when compared with HCs (p <.001). ROC analyses revealed an AUC >70% for Mo-MDSCs CD14+/HLADR-/low and inflammatory CD14+CD16+, T-helper CD3+CD4+, and T-helper CD4+CD161+. Conclusions: Patients with a recent RRMS diagnosis and naive to DMTs, showed peculiar myeloid, B-, and T-cell immunophenotypes.

Real world comparison of teriflunomide and dimethyl fumarate in naïve relapsing multiple sclerosis patients: Evidence from the Italian MS register.

BACKGROUND: Teriflunomide (TERI) and dimethyl fumarate (DMF) are licensed as first-line disease-modifying treatments (DMTs) for relapsing remitting Multiple Sclerosis (RRMS) and are largely replacing injectable DMTs. METHODS: All RRMS patients starting TERI or DMF between January 1, 2013, and December 31, 2017, were included in the analysis. Time to first relapse, time to confirmed disability progression (CDP), and time to DMT discontinuation have been investigated. Propensity score with inverse probability treatment weighting (IPTW-PS) was used to adjust comparisons for baseline confounders. The aim of the study was to compare the effectiveness, and rate of discontinuation of TERI and DMF as first therapeutic choice in the Italian MS register. RESULTS: A total of 683 patients were considered for the analyses, 185 on TERI and 498 on DMF. Patients on TERI had higher number of relapses (2.3 ± 1.4 vs 1.9 ± 1.1, p=.033) and higher baseline disability level assessed by Expanded Disability Status Scale (EDSS) (2.0, interquartile range-IQR 1.0-3.0 vs 1.5, IQR 1.0-2.0, p=.013). IPTW adjusted Cox models did not reveal any difference between the investigated DMTs for the investigated outcomes. CONCLUSIONS: TERI and DMF have similar effectiveness and rate of discontinuation when employed as first therapeutic choice in RRMS patients.

First-line therapies in late-onset multiple sclerosis: An Italian registry study.

BACKGROUND AND PURPOSE: The diagnosis of late-onset (age ≥50 years old) relapsing remitting multiple sclerosis (LORRMS) has been increasingly described in clinical practice, whereas data focusing on the specific therapeutic management of LORRMS are scarce. Our objective was to compare the effectiveness of injectable and oral first-line disease-modifying therapies (DMTs) in a cohort of LORRMS patients with time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation. METHODS: This is a multicenter, observational, retrospectively acquired cohort study on LORRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2013 and December 31, 2017. LORRMS patients were divided into two groups, namely the injectable group (IG) and oral group (OG). Cox models adjusted with inverse probability-weighted propensity score were built for the investigated outcomes. RESULTS: Of a cohort of 3989 patients, 302 were enrolled (203 in the IG and 99 in the OG). The two cohorts did not differ in baseline characteristics. Time to first relapse did not show any difference between the two groups (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 0.50-2.46, p = 0.797). Furthermore, no differences were found between the two groups with respect to the risk of CDP (HR: 1.04; 95% CI: 0.35-3.06, p = 0.939), nor for the risk of DMT discontinuation (HR: 0.90; 95% CI: 0.17-2.08, p = 0.425). CONCLUSIONS: Real-world data from the Italian MS Register suggested that both injectables and oral first-line DMTs similarly controlled the investigated outcomes in LORRMS.

Metabolic Abnormalities, Dietary Risk Factors and Nutritional Management in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal muscles and eventual respiratory failure. Although a small percentage of patients may have a longer survival time (up to 10 years), in most cases, the median survival time is from 20 to 48 months. The pathogenesis and risk factors for ALS are still unclear: among the various aspects taken into consideration, metabolic abnormalities and nutritional factors have been the focus of recent interests. Although there are no consistent findings regarding prior type-2 diabetes, hypercholesterolemia and ALS incidence, abnormalities in lipid and glucose metabolism may be linked to disease progression, leading to a relatively longer survival (probably as a result of counteract malnutrition and cachexia in the advanced stages of the disease). Among potential dietary risk factors, a higher risk of ALS has been associated with an increased intake of glutamate, while the consumption of antioxidant and anti-inflammatory compounds, such as vitamin E, n-3 polyunsaturated fatty acids, and carotenoids, has been related to lower incidence. Poor nutritional status and weight loss in ALS resulting from poor oral intake, progressive muscle atrophy, and the potential hypermetabolic state have been associated with rapid disease progression. It seems important to routinely perform a nutritional assessment of ALS patients at the earliest referral: weight maintenance (if adequate) or gain (if underweight) is suggested from the scientific literature; evidence of improved diet quality (in terms of nutrients and limits for pro-inflammatory dietary factors) and glucose and lipid control is yet to be confirmed, but it is advised. Further research is warranted to better understand the role of nutrition and the underlying metabolic abnormalities in ALS, and their contribution to the pathogenic mechanisms leading to ALS initiation and progression.