Secondary Progressive Multiple Sclerosis Research Articles

Long-term clinical outcomes in patients with CIS treated with interferon beta-1b: results from the 15-year follow up of the BENEFIT trial.

Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15years from initial randomization support long-term benefits of early treatment with IFNB-1b.

Assessment of serum inflammatory parameters in RRMS and SPMS patients

ABSTRACT Objectives Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. Methods The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. Results The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. Discussion Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients.

Contribution of new and chronic cortical lesions to disability accrual in multiple sclerosis

Abstract Cortical lesions are common in multiple sclerosis and are associated with with disability and progressive disease. We asked whether cortical lesions continue to form in people with stable white matter lesions and whether the association of cortical lesions with worsening disability relates to pre-existing or new cortical lesions. 50 adults with multiple sclerosis and no new white matter lesions in the year prior to enrollment (33 relapsing-remitting, 17 progressive) and a comparison group of 9 adults who had formed at least one new white matter lesion in the year prior to enrollment (active relapsing-remitting) were evaluated annually with 7 tesla brain MRI and 3 tesla brain and spine MRI for 2 years, with clinical assessments for 3 years. Cortical lesions and paramagnetic rim lesions were identified on 7 tesla images. Seven total cortical lesions formed in 3/30 individuals in the stable relapsing-remitting group (median 0, range 0-5), four total cortical lesions formed in 4/17 individuals in the progressive group (median 0, range 0-1), and 16 cortical lesions formed in 5/9 individuals in the active relapsing-remitting group (median 1, range 0-10, stable relapsing-remitting vs progressive vs active relapsing-remitting P=0.006). New cortical lesions were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Individuals with at least 3 paramagnetic rim lesions had a greater increase in cortical lesion volume over time (median 16µl, range -61-215 vs median 1µl, range -24-184, P=0.007), but change in lesion volume was not associated with disability change. Baseline cortical lesion volume was higher in people with worsening disability (median 1010µl, range 13-9888 vs median 267µl, range 0-3539, P=0.001, adjusted for age and sex) and in individuals with relapsing-remitting multiple sclerosis who subsequently transitioned to secondary progressive multiple sclerosis (median 2183µl, range 270-9888 vs median 321µl, range 0-6392 in those who remained relapsing-remitting, P=0.01, adjusted for age and sex). Baseline white matter lesion volume was not associated with worsening disability or transition from relapsing-remitting to secondary progressive multiple sclerosis. Cortical lesion formation is rare in people with stable white matter lesions, even in those with worsening disability. Cortical but not white matter lesion burden predicts disability worsening, suggesting that disability progression is related to long-term effects of cortical lesions that form early in disease, rather than to ongoing cortical lesion formation.

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 ​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 ​± ​25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 ​± ​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 ​= ​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 ​= ​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 ​= ​0.006 and HR 2.04, 25%CI 1.22–3.35; p ​= ​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 ​= ​0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.

Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.

People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue. MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA). Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis. MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.

Can autologous stem cell transplantation be a treatment option in a patient diagnosed with secondary progressive multiple sclerosis?:Case report

Can autologous stem cell transplantation be a treatment option in a patient diagnosed with secondary progressive multiple sclerosis?:Case report

Application of Glucocorticoids in Therapy of Multiple Sclerosis

Multiple sclerosis is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. Pulse-dosaged glucocorticoids therapy remains the mainstay of treatment of exacerbations of multiple sclerosis. A total of 98 patients were examined, including 28 patients with relapsing-remitting multiple sclerosis (24 women and 4 men) and 70 patients with secondary progressive multiple sclerosis (57 women and 13 men). The number of glucocorticoids therapy courses in 98 patients at all disease stages totalled 536: 98 in relapsing-remitting multiple sclerosis (9 at debuts and 89 at relapsing-remitting stage) and 438 in secondary progredient multiple sclerosis (11 at debuts, 178 at relapsing-remitting stage, and 249 at secondary progression stage). The efficacy of repeated courses of glucocorticoids therapy in patients with RR and secondary progredient multiple sclerosis was evaluated at different stages of the disease progression: debut in relapsing-remitting and secondary progredient multiple sclerosis, relapsing-remitting stage in relapsing-remitting and secondary progredient multiple sclerosis, and secondary progression stage in secondary progredient multiple sclerosis, including retrospective analysis. Important conclusions have been made about complex systemic reorganisation at different stages of relapsing-remitting and secondary-progredient types of multiple sclerosis, efficiency of glucocorticoids therapy in different types of multiple sclerosis and stages of pathological process and about influence of glucocorticoids therapy on the prognosis of the disease.

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

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. We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6months 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. 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. 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.

A rapid review of differences in cerebrospinal neurofilament light levels in clinical subtypes of progressive multiple sclerosis.

Multiple sclerosis (MS) is divided into three clinical phenotypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). It is unknown to what extent SPMS and PPMS pathophysiology share inflammatory or neurodegenerative pathological processes. Cerebrospinal (CSF) neurofilament light (NfL) has been broadly studied in different MS phenotypes and is a candidate biomarker for comparing MS subtypes. Are CSF NfL levels different among clinical subtypes of progressive MS? A search strategy identifying original research investigating fluid neurodegenerative biomarkers in progressive forms of MS between 2010 and 2022 was applied to Medline. Identified articles underwent title and abstract screen and full text review against pre-specified criteria. Data abstraction was limited to studies that measured NfL levels in the CSF. Reported statistical comparisons of NfL levels between clinical phenotypes were abstracted qualitatively. 18 studies that focused on investigating direct comparisons of CSF NfL from people with MS were included in the final report. We found NfL levels were typically reported to be higher in relapsing and progressive MS compared to healthy controls. Notably, higher NfL levels were not clearly associated with progressive MS subtypes when compared to relapsing MS, and there was no observed difference in NfL levels between PPMS and SPMS in articles that separately assessed these phenotypes. CSF NfL levels distinguish individuals with MS from healthy controls but do not differentiate MS subtypes. Broad biological phenotyping is needed to overcome limitations of current clinical phenotyping and improve biomarker translatability to decision-making in the clinic.

Single-cell Transcriptomic Analysis Identifies a Unique Monocyte Profile that Distinguishes Progressors vs Non-progressors with Secondary Progressive Multiple Sclerosis (P7-6.006)

Single-cell Transcriptomic Analysis Identifies a Unique Monocyte Profile that Distinguishes Progressors vs Non-progressors with Secondary Progressive Multiple Sclerosis (P7-6.006)

A Comprehensive Assessment of Progression Independent of Relapse Activity in a Cohort of Patients with Secondary Progressive Multiple Sclerosis (P8-6.010)

A Comprehensive Assessment of Progression Independent of Relapse Activity in a Cohort of Patients with Secondary Progressive Multiple Sclerosis (P8-6.010)

Understanding the Burden of Illness in People with Nonrelapsing Secondary Progressive Multiple Sclerosis in the United States: A Matched-cohort Study (P8-6.013)

Understanding the Burden of Illness in People with Nonrelapsing Secondary Progressive Multiple Sclerosis in the United States: A Matched-cohort Study (P8-6.013)

Predicting Secondary Progressive Multiple Sclerosis Using Blood IgG Aggregates (S42.005)

Predicting Secondary Progressive Multiple Sclerosis Using Blood IgG Aggregates (S42.005)

Treatment of PIRA with Nasal Foralumab Dampens Microglial Activation and Stabilizes Clinical Progression in Non-active Secondary Progressive MS (S31.002)

Treatment of PIRA with Nasal Foralumab Dampens Microglial Activation and Stabilizes Clinical Progression in Non-active Secondary Progressive MS (S31.002)

Secondary progressive MS cerebrospinal fluid induces axonal degeneration in human primary neurons (P7-6.018)

Secondary progressive MS cerebrospinal fluid induces axonal degeneration in human primary neurons (P7-6.018)

Prospective observational study to evaluate treatment satisfaction and effectiveness in patients with relapsing multiple sclerosis starting cladribine tablets (CLADREAL) in Italy.

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one first-line disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient's experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022.

Retrospective Evaluation of Attacks, EDSS Scores, and MRI Changes Before the Start of Treatment and One Year After the Start of Treatment in Patients Followed by a Diagnosis of Multiple Sclerosis and Using Ocrelizumab in Our Clinic

Objective: Depletion of B cells by anti-CD20 monoclonal antibodies has been proven to reduce relapsing remitting multiple sclerosis (RRMS) activity and progression of primary progressive MS (PPMS). In our study, we aimed to retrospectively present our clinical experience and contribute to real-life data after the use of Ocrelizumab. Material and Methods: Patients aged 18-55 years using Ocrelizumab and diagnosed with MS by McDonald's 2017 criteria were included. Neurological examination findings and EDSS findings available in our file records were used to evaluate the level of disability. Patients with MRI lesions consistent with their clinical complaint lasting more than 24 hours were evaluated as an attack. Patients' ages, MS diagnosis times, and previous immune modulatory treatments were recorded. The number of T2, FLAIR sequence MRI lesions, EDSS before ocrelizumab, and the number of T2, FLAIR sequence MRI lesions 1 year after receiving ocrelizumab were recorded. After 1 year of follow-up, the absence of attacks, no increase in the number of lesions in MRI, and no progress in EDSS were accepted as NEDA 3. Results: Our cases in this study include 30 MS patients. Patients were 26.7% relapsing remitting MS (RRMS), 26.7% primary progressive MS (PPMS), and 46.7% secondary progressive MS (SPMS). There was no attack in 87.5% of the RRMS patient group. In the SPMS patient group, no attacks were observed after ocrelizumab in the cases with attacks. In our study, the rate of patients who did not develop new T2 lesions and whose lesions disappeared was 62.5% in the RRMS patient group, 78.5% in the SPMS patient group, and 75% in the PPMS patient group. In the total patient group, the rate of patients without EDSS increase was 93% (28 patients). Conclusion: In our study, it was determined that ocrelizumab was effective by reducing the attack rates, preserving the EDSS scores and preventing the increase in the lesion burden. Our findings are consistent with real-life data.

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

BackgroundNatalizumab 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...

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries

High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases.

Eomesodermin-expressing (Eomes+) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes+ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes+ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes+ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes+ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024.