Anti-CD20 Therapies in Drug-Naive Patients With Primary Progressive Multiple Sclerosis: A Multicenter Real-Life Study.

BACKGROUND AND OBJECTIVES: Although rituximab failed to demonstrate a significant effect on disability progression in primary progressive multiple sclerosis (PPMS), ocrelizumab succeeded. Our main objective was to analyze confirmed disability progression (CDP) in a cohort of patients with PPMS treated with anti-CD20 therapies compared with a weighted untreated control cohort. METHODS: This was a retrospective study using data from the French MS registry (Observatoire Français de la Sclérose En Plaques). We included patients with PPMS treated or never treated with anti-CD20 therapies from 2016 to 2021, with an Expanded Disability Status Scale score of ≤6.5 at baseline. The primary outcome was time to first CDP. The secondary outcomes were time to first relapse, MRI activity at 2 years, identification of risk factors associated with CDP, and serious infection incidence rates (IIRs). Each outcome was studied using an inverse probability of treatment weighting method. The outcomes were modeled using a weighted proportional Cox model for the time-to-event outcomes and by a logistic regression regarding the MRI activity. RESULTS: A total of 1,184 patients (426 treated and 758 untreated) fulfilled the inclusion criteria. Median age (Q1-Q3) was 56 years (49.3-63.8), and 52.7% were female. Among treated patients, 295 received rituximab, whereas 131 received ocrelizumab. At baseline, anti-CD20-treated patients were younger (median 51.9 vs 58.6 years, Cohen d = 0.683) and had more active disease (54.5 vs 27.8%, Cohen d = 0.562). 91.6% were drug-naive at inclusion. In time to first CDP analysis, no statistical significance was observed (hazard ratio [HR], 1.13; 95% CI 0.93-1.36, p = 0.2113). In time to first relapse analysis, a nonsignificant trend toward fewer patients relapsing in the treated group was observed (HR 0.83; 95% CI 0.48-1.28, p = 0.0809). For MRI activity, no significant difference was found between the 2 groups. Risk factors associated with CDP in the treated group were male sex and MS duration. IIR was 6.67 (95% CI 3.12-14.25) per 100 person-years in the treated group vs 2.67 (95% CI 0.80-8.86) in the untreated group. DISCUSSION: Time to first CDP was not different between anti-CD20 treated and untreated patients with PPMS. Although our study is retrospective and mainly included patients treated by rituximab, our results indicate that there should be a constant evaluation of all available data to ascertain the best risk/benefit ratio for patients with PPMS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti-CD20 therapy of previously untreated patients with PPMS was not superior to no therapy in delaying time to first CDP.

The Faces of "Too Late"-A Surprisingly Progressive Cohort of "Stable" Relapsing Remitting Multiple Sclerosis Patients.

Background and Objectives: Although available therapies have changed the natural evolution of multiple sclerosis (MS), in time some patients assume a progressive course and no longer respond to treatment. There is no definitive clinical or laboratory parameter to certify MS progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS) in early phases of transition. Our study aims to evaluate the value of clinical parameters and serum neurofilament light chain levels (sNfLs) as early warning signs of conversion to SPMS. Materials and Methods: The Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), 25-foot walk test (25FWT) and Symbol Digit Modalities Test (SDMT) were evaluated at 12 months apart in a cohort of 83 RRMS treated patients. sNfLs were evaluated at the second time point. Results: sNfLs correlate with EDSS and SDMT, with EDSS change and disease duration. Clinical parameters correlate among themselves and perform well in supporting the diagnosis of SPMS in logistic regression and ROC curves analysis. Eighty percent of the RRMS patients in our study (of which 65% are treated with high-efficacy disease-modifying drugs) showed some type of progression independent of relapses (PIRA) after 12 months, with one in five patients experiencing isolated cognitive worsening and almost two-thirds some type of motor worsening. We found no differences in terms of progression between patients treated with platform drugs versus high-efficacy drugs. Conclusions: An elevated level of progression independent of relapses (PIRA) was found in our cohort, with high-efficacy drugs providing no supplementary protection. As sNfL levels were correlated with the progression of EDSS (the main clinical progression marker), they may be considered potential prognostic markers, but further studies are necessary to precisely define their role in this direction. The lack of early sensitive markers for risk of progression may contribute to therapeutic delay and failure.

Immunomodulators and immunosuppressants for progressive multiple sclerosis: a network meta-analysis.

BACKGROUND: In recent years a broader range of immunomodulatory and immunosuppressive treatment options have emerged for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, their relative benefit and safety profiles remain unclear due to a lack of direct comparison trials. OBJECTIVES: To compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase up to August 2022, as well as ClinicalTrials.gov and the WHO ICTRP. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We performed data synthesis by pair-wise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE. MAIN RESULTS: We included 23 studies involving a total of 10,167 participants. The most frequent (39% of studies) reason for a rating of high risk of bias was sponsor role in study authorship and data management and analysis. Other concerns were performance, attrition, and selective reporting bias, with 8.7% of studies at high risk of bias for all three of these domains. The common comparator for network analysis was placebo. Relapses over 12 months: assessed in one study (318 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 24 months: assessed in six studies (1622 participants). The number of people with clinical relapses is probably trivially reduced with rituximab (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.19 to 1.95; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 36 months: assessed in four studies (2095 participants). The number of people with clinical relapses is probably trivially reduced with interferon beta-1b (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 24 months: assessed in 11 studies (5284 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 36 months: assessed in five studies (2827 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Serious adverse events: assessed in 15 studies (8019 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Discontinuation due to adverse events: assessed in 21 studies (9981 participants). The number of people who discontinued treatment due to adverse events is trivially increased with interferon beta-1a (odds ratio (OR) 2.93, 95% CI 1.64 to 5.26; high certainty evidence). The number of people who discontinued treatment due to adverse events is probably trivially increased with rituximab (OR 4.00, 95% CI 0.84 to 19.12; moderate certainty evidence); interferon beta-1b (OR 2.98, 95% CI 1.92 to 4.61; moderate certainty evidence); immunoglobulins (OR 1.95, 95% CI 0.99 to 3.84; moderate certainty evidence); glatiramer acetate (OR 3.98, 95% CI 1.48 to 10.72; moderate certainty evidence); natalizumab (OR 1.02, 95% CI 0.55 to 1.90; moderate certainty evidence); siponimod (OR 1.53, 95% CI 0.98 to 2.38; moderate certainty evidence); fingolimod (OR 2.29, 95% CI 1.46 to 3.60; moderate certainty evidence), and ocrelizumab (OR 1.24, 95% CI 0.54 to 2.86; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. AUTHORS' CONCLUSIONS: The number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a. We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision. These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results. Future research on PMS should include head-to-head rather than placebo-controlled trials, with a longer follow-up of at least three years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable and meaningful to people with PMS should be consistently adopted and measured to permit the evaluation of relative effectiveness among treatments.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

Targeting CNS myeloid infiltrates provides neuroprotection in a progressive multiple sclerosis model.

Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+ cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach.

Siponimod following Alemtuzumab in secondary progressive MS: investigating sequential therapy-A case series.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of highly active relapsing multiple sclerosis (MS) but requires vigilant post-treatment monitoring due to associated risks. The prescription of subsequent therapies following Alemtuzumab, as mandated by label guidance for a treatment-free period of at least 5 years, presents a complex challenge, particularly if there is concurrent conversion to secondary progressive disease course. We described a case-series of five patients starting therapy with Siponimod and followed up for 12 months period converted to secondary progressive MS previously exposed to Alemtuzumab. All patients received Siponimod 2 mg. Clinical evaluation measured with Expanded Disability Status Scale and cognitive evaluation measured with Brief International Cognitive Assessment for Multiple Sclerosis were stable after 12 months on therapy. No severe lymphopenia was recorded, nor serious adverse events. In conclusion, the long-term management of patients treated with Alemtuzumab transitioning to secondary progressive MS requires a proactive and multidisciplinary approach. By addressing the challenges associated with treatment limitations and short-term monitoring recommendations while considering alternative therapeutic options like Siponimod, clinicians can optimize outcomes and ensure continuity of care for individuals with MS.

Siponimod from fingolimod direct switch in patients transitioning in secondary progressive multiple sclerosis: A single center case series.

INTRODUCTION: The transition from fingolimod (FIN) to siponimod (SIP) for Multiple Sclerosis (MS) treatment in the occurrence of Secondary Progressive Multiple Sclerosis (SPMS) diagnosis has increasingly attracted considerable interest in the recent literature. METHODS: We evaluated the efficacy and safety of a direct switch from FIN to SIP in nine MS patients who had switched directly from FIN to SIP due to SPMS diagnosis at the Multiple Sclerosis Center of the University Hospital Policlinico of Bari. RESULTS AND CONCLUSION: Real-world results from our cohort demonstrated that the direct switch from FIN to SIP in patients transitioning in SP course is associated with clinical and disability progression stability, with a favorable safety profile.

Prevalence of elevated sNFL in a real-world setting: Results on 908 patients with different multiple sclerosis types and treatment conditions.

BACKGROUND: In the field of research for new validated surrogate biomarkers of treatment efficacy, disease activity and progression in Multiple Sclerosis (MS), serum neurofilament light-chain (sNFL) are actually the best candidate for MS patient monitoring. However, before they can be implemented in clinical practice, their usefulness as additional red flag routine measure must be demonstrated. To tackle the problem, this real-life cross-sectional study at the Regional Referring Center for Multiple Sclerosis (CRESM) aims to characterize sNFL levels and prevalence of elevated sNFL, according to our age-dependent cut-off values, in a large group of patients with different types of MS and treatment conditions. METHODS: 908 serum samples from as many MS patients being admitted at CRESM for diagnostic definition and/or during routinary treatment monitoring were consecutively collected between January 2019 and January 2020. sNFL levels were measured by single molecule array (Simoa™) technology on SR-X instrument using NF-light assays (Quanterix); results were interpreted using previously published cut-off values. RESULTS: Primary and Secondary Progressive MS (PPMS, SPMS) forms demonstrate higher levels and prevalence of elevated sNFL (PPMS= 32 %, SPMS= 21 %) compared to the Relapse and Remitting one (RRMS = 12 %). Besides, naïve samples of RRMS and PPMS subtypes showed higher prevalence of elevated sNFL (RRMS naïve= 31 %, PPMS naïve=67 %) compared to samples from patients treated for more than 12 months (RRMS treat>12m= 9 %, PPMS treat>12m= 19 %); treated SPMS patients demonstrated higher sNFL levels and a prevalence (22 %) of elevated sNFL compared to RRMS treated patients. Focusing on RRMS, no statistical difference was found between groups of patients treated for whatever time (up to or more than 60 months) and with either DMT type (high or low-efficacy DMT). Finally, RRMS patients treated with all DMTs for more than 12 months, with the exception of teriflunomide and alemtuzumab showed a prevalence of elevated sNFL in the range of 5-10 %. CONCLUSION: in a real-world setting comprising about 1000 MS patients, sNFL quantification was elevated in 5-to-67 % of patients, in different MS forms and treatment conditions. Elevated levels of sNFL must be considered a red-flag suggesting the need of a further clinical monitoring in any circumstance, as it can be indicative of new inflammation, ongoing degeneration or co-morbidities. This study supports the introduction of sNFL quantification in everyday patient management.

Ocrelizumab in people with primary progressive multiple sclerosis: A real-world multicentric study.

BACKGROUND: Ocrelizumab is the only disease-modifying therapy (DMT) approved for the treatment of people with primary progressive multiple sclerosis (pwPPMS). OBJECTIVES: To provide real-world evidence of ocrelizumab effectiveness and safety in pwPPMS in Croatian MS centers. METHODS: A retrospective observational multi-center study of pwPPMS who were started on ocrelizumab in 7 MS centers in Croatia. RESULTS: We identified 230 pwPPMS of whom 176 fulfilled the inclusion criteria. The median follow-up of the cohort was 2.73 (0.51-5.77) years. During the follow-up, 50 (28.4%) pwPPMS experienced confirmed disability worsening (CDW) and 19 (10.8%) stopped treatment with ocrelizumab. Baseline EDSS >5 was a statistically significant positive predictor for the development of CDW and/or stop of the treatment due to any cause (OR 2.482, 95% C.I. 1.192-5.166, p = 0.015). However, there was no significant difference in the development of CDW and/or stop of the treatment due to any cause if stratifying the patients based on active PPMS, age at treatment start (≤55 years vs >55 years), disease duration at treatment start (≤10 years vs >10 years), or EDSS at treatment start (≤5.0 vs >5.0). During the follow-up, 26 (14.8%) pwPPMS experienced infusion reactions, 64 (36.4%) had an infection and 4 (2.3%) developed a tumor. The percentage of pwPPMS with low levels of IgG was persistently above 10% and with low levels of IgM was persistently above 20% after cycle 4. CONCLUSION: Our real-world data support the use of ocrelizumab in a much broader pwPPMS population than in the original randomized controlled trial.

Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis.

Background: Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients. Methods: Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery. Results: SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod's protective effects. Conclusion: Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target.

Long-term effectiveness of natalizumab in secondary progressive multiple sclerosis: A propensity-matched study.

Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 â€‹at 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 â€‹± â€‹25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 â€‹± â€‹19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p â€‹= â€‹0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p â€‹= â€‹0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67-5.7; p â€‹= â€‹0.006 and HR 2.04, 25%CI 1.22-3.35; p â€‹= â€‹0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04-4.87; p â€‹= â€‹0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Real-world effectiveness, safety and immunogenicity of ocrelizumab in turkish multiple sclerosis patients: a single-center experience for 4-year follow-up.

OBJECTIVE: The aim of this study was to evaluate postmarketing ocrelizumab safety and effectiveness in a real-world population with multiple sclerosis (MS) and matching these parameters among MS disease types. METHODS: This was a retrospective, single-center study with MS patients treated with ocrelizumab. Demographic, clinical characteristics and immunological data were analyzed, including annualized relapse rate (ARR), relapse-free rate, Expanded Disability Status Scale (EDSS), complete blood count parameters, immunoglobulin (Ig) levels, liver function tests (LFT), hepatitis markers and adverse events in the 4-year follow-up. A total of 96 patients, 22 with relapsing-remitting MS (RRMS), 54 with secondary progressive MS (SPMS), and 20 with primary progressive MS (PPMS) who were treated with at least two doses of ocrelizumab between January 2018 and September 2023 were included in the study. RESULTS: Sixty-five (68%) were women and 31 (32%) were men. The mean age was 48.4 ± 11.1 years (20-70 years). Ninety-three patients were evaluated in the first year, 65 in the second year, 39 in the third year and 24 in the fourth year of treatment. 96% of patients were relapse-free rate in the first year, 91% in the second year, 85% in the third year and 75% in the fourth year. Eighty-six percent of patients were progression free in the 1st year of treatment, 71% in the 2nd year, in 64% in the 3rd year, and in 62% in the 4th year. During the follow-up of the cases, EDSS remained stable in 77% of RRMS patients, improved in 14%, and worsened in 9%; while EDSS remained stable in 65% of SPMS patients with attacks, it improved in 9% and worsened in 26%; while EDSS remained stable in 60% of PPMS patients, worsening was observed in 40%. There is a significant decrease in IgM and IgG values during the follow-up of ocrelizumab therapy (p < 0.001, p = 0.014). There is no significant difference in IgA, lymphocyte and neutrophil values (p = 0.713, p = 0.086, p = 0.999). No significant relationship was found between low serum IgM levels and the risk of developing infection (p > 0.05). Liver function tests was found to be within normal limits in 94% of the patients over a 4-year period. No hepatitis B, C or A infection, hepatitis B reactivation, tuberculosis, HIV infection, malignancy or drug related death occurred during 4-years follow-up. The most common side effect during ocrelizumab treatment is urinary tract infection (29%); others were upper respiratory tract infections (13%), numbness/tingling of the face, trunk, or extremities (8%), insomnia (6%), headache (5%), and soft tissue infections (cellulitis and dental abscess, 2%). CONCLUSIONS: Our results show that ocrelizumab reduces the frequency of attacks and prevent the disease progression in RRMS patients, and reducing the disease progression by primarily stabilizing EDSS scores in SPMS with attacks and PPMS. It is thought that the relatively high rates of urinary tract infection detected in this study may be related with advanced stage of the disease. The absence of hepatitis B reactivation, chronic infection or malignancy in the 4-year follow-up of our cases supports the long-term safety of ocrelizumab treatment. Ocrelizumab may be preferred as an effective and reliable treatment of different types of MS due to non-serious side effects.

A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial.

Introduction: Despite advances in immunomodulatory treatments of multiple sclerosis (MS), patients with non-active progressive multiple sclerosis (PMS) continue to face a significant unmet need. Demyelination, smoldering inflammation and neurodegeneration are important drivers of disability progression that are insufficiently targeted by current treatment approaches. Promising preclinical data support repurposing of metformin for treatment of PMS. The objective of this clinical trial is to evaluate whether metformin, as add-on treatment, is superior to placebo in delaying disease progression in patients with non-active PMS. Methods and analysis: MACSiMiSE-BRAIN is a multi-center two-arm, 1:1 randomized, triple-blind, placebo-controlled clinical trial, conducted at five sites in Belgium. Enrollment of 120 patients with non-active PMS is planned. Each participant will undergo a screening visit with assessment of baseline magnetic resonance imaging (MRI), clinical tests, questionnaires, and a safety laboratory assessment. Following randomization, participants will be assigned to either the treatment (metformin) or placebo group. Subsequently, they will undergo a 96-week follow-up period. The primary outcome is change in walking speed, as measured by the Timed 25-Foot Walk Test, from baseline to 96 weeks. Secondary outcome measures include change in neurological disability (Expanded Disability Status Score), information processing speed (Symbol Digit Modalities Test) and hand function (9-Hole Peg test). Annual brain MRI will be performed to assess evolution in brain volumetry and diffusion metrics. As patients may not progress in all domains, a composite outcome, the Overall Disability Response Score will be additionally evaluated as an exploratory outcome. Other exploratory outcomes will consist of paramagnetic rim lesions, the 2-minute walking test and health economic analyses as well as both patient- and caregiver-reported outcomes like the EQ-5D-5L, the Multiple Sclerosis Impact Scale and the Caregiver Strain Index. Ethics and dissemination: Clinical trial authorization from regulatory agencies [Ethical Committee and Federal Agency for Medicines and Health Products (FAMHP)] was obtained after submission to the centralized European Clinical Trial Information System. The results of this clinical trial will be disseminated at scientific conferences, in peer-reviewed publications, to patient associations and the general public. Trial registration: ClinicalTrials.gov Identifier: NCT05893225, EUCT number: 2023-503190-38-00.

Effect of siponimod on lymphocyte subsets in active secondary progressive multiple sclerosis and clinical implications.

BACKGROUND: Circulating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes. METHODS: We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6 months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs. RESULTS: At baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = -24/-17, 95% CI range = -31.60 to -10.40), B lymphocyte (coeff. range = -3.77/-2.54, 95% CI range = -6.02 to -0.35), memory regulatory B cells (coeff. range = -0.78/-0.57, 95% CI range = -1.24 to -0.17) and CD4/CD8 ratio (coeff. range = -4.44/-0.67, 95% CI range = -1.61 to -0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = -4.23/-2.32, 95% CI range = -7.53 to -0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03) vs. patients experiencing progression. CONCLUSIONS: Patients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes.

Therapeutic lag: Is treatment effect delayed in progressive MS?

BACKGROUND: Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression. OBJECTIVES: To investigate whether the failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics. METHODS: We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t0, and constant hazard ratio (HR) after time = t0. We selected the best-fitting t0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset. RESULTS: The time-dependent Cox model revealed a significant benefit of treatment delayed by t0 = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43-0.98), p = 0.041), and delayed by t0 = 2 years for the PROMISE study (HR = 0.65, (0.42-0.99), p = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p < 0.001. CONCLUSION: The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment.

Spinal Segmental Myoclonus in Primary Progressive Multiple Sclerosis.

Background: A wide variety of associated movement disorders has been described in multiple sclerosis. Phenomenology Shown: A 57-year-old woman with primary progressive multiple sclerosis developed spinal segmental myoclonus associated with focal myelitis. Educational Value: Movement disorders in multiple sclerosis are phenomenologically diverse and have varied pathophysiological mechanisms, making it essential to identify them to initiate appropriate treatment.

Siponimod Attenuates Neuronal Cell Death Triggered by Neuroinflammation via NFκB and Mitochondrial Pathways.

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS), consisting of heterogeneous clinical courses varying from relapsing-remitting MS (RRMS), in which disability is linked to bouts of inflammation, to progressive disease such as primary progressive MS (PPMS) and secondary progressive MS (SPMS), in which neurological disability is thought to be linked to neurodegeneration. As a result, successful therapeutics for progressive MS likely need to have both anti-inflammatory and direct neuroprotective properties. The modulation of sphingosine-1-phosphate (S1P) receptors has been implicated in neuroprotection in preclinical animal models. Siponimod/BAF312, the first oral treatment approved for SPMS, may have direct neuroprotective benefits mediated by its activity as a selective (S1P receptor 1) S1P1 and (S1P receptor 5) S1P5 modulator. We showed that S1P1 was mainly present in cortical neurons in lesioned areas of the MS brain. To gain a better understanding of the neuroprotective effects of siponimod in MS, we used both rat neurons and human-induced pluripotent stem cell (iPSC)-derived neurons treated with the neuroinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Cell survival/apoptotic assays using flow cytometry and IncuCyte live cell analyses showed that siponimod decreased TNF-α induced neuronal cell apoptosis in both rat and human iPSCs. Importantly, a transcriptomic analysis revealed that mitochondrial oxidative phosphorylation, NFκB and cytokine signaling pathways contributed to siponimod's neuroprotective effects. Our data suggest that the neuroprotection of siponimod/BAF312 likely involves the relief of oxidative stress in neuronal cells. Further studies are needed to explore the molecular mechanisms of such interactions to determine the relationship between mitochondrial dysfunction and neuroinflammation/neurodegeneration.

Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis.

BACKGROUND: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS. METHODS: Patients with primary/secondary progressive MS from seven AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab, were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise-censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARRs), using Andersen-Gill proportional hazards models and conditional negative binomial model. RESULTS: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (HR 1.49, 95% CI 0.70 to 3.14) and improvement (HR 1.50, 95% CI 0.22 to 10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±SD 0.08±0.28 vs 0.08±0.25; HR 1.05, 95% CI 0.39 to 2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required intensive care unit admission and 36 patients experienced complications after discharge. No treatment-related deaths were reported. CONCLUSION: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity.

SUNCT syndrome secondary to multiple sclerosis: Not only trigeminal neuralgia.

BACKGROUND: Facial pain in multiple sclerosis is often due to trigeminal neuralgia but atypical pictures can be observed. CASE PRESENTATION: A man with primary progressive multiple sclerosis developed severe unilateral facial pain in the right orbital region. Spontaneous and triggered attacks were associated with ipsilateral conjunctival injection and lacrimation. A diagnosis of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing was made, and symptoms significantly improved with lamotrigine. CONCLUSION: Pain is poorly investigated in multiple sclerosis, with a dramatic impact on patients' life quality. In this light, standardized evaluation of pain is needed to improve patient management.