Guanidinoacetate-creatine in secondary progressive multiple sclerosis: a case report.
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ABSTRACT:
SUBMITTER: Ostojic SM
PROVIDER: S-EPMC8753084 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Secondary progressive multiple sclerosis (SPMS) is characterized by progressive accumulation of disability without intermittent recovery. Treatment of these patients is challenging due to limited understanding of pathogenesis and fewer therapeutic options. This article summarizes difficulties in defining and conducting trials in SPMS, review major clinical trials on therapies approved and unapproved in SPMS and lastly, therapies in pipeline for use in SPMS.
| S-EPMC6472227 | biostudies-literature
Project description:BackgroundThe long-term prognosis of relapsing-remitting multiple sclerosis (RRMS) is usually unfavorable as most patients transition to secondary progressive multiple sclerosis (SPMS) with accumulative disability. A rare form of non-progressive multiple sclerosis (MS) also exists, known as benign MS (BMS or NPMS), which lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after 15 years of disease onset without treatment.PurposeOur study aims to identify soluble plasma factors predicting disease progression in multiple sclerosis (MS).Research design and study sampleWe utilized Luminex multiplex to analyze plasma levels of 33 soluble factors, comparing 32 SPMS patients to age-, sex-, and disease duration-matched non-progressive BMS patients, as well as to RRMS patients and healthy controls.ResultsPlasma levels of EGF, sCD40L, MCP1/CCL2, fractalkine/CX3CL1, IL-13, Eotaxin, TNFβ/LTα, and IL-12p40 were significantly different between the various types of MS. Plasma sCD40L was significantly elevated in SPMS compared to BMS and RRMS. The combination of MCP1/CCL2 and sCD40L discriminated between RRMS and SPMS. MCP1/CCL2 was found to be the most effective classifier between BMS and RRMS, while BMS was most effectively distinguished from SPMS by the combination of sCD40L and IFNγ levels.ConclusionsThese differences may facilitate personalized precision medicine and aid in the discovery of new therapeutic targets for disease progression through the improvement of patient stratification.
| S-EPMC8552403 | biostudies-literature
Project description:Disease-modifying therapies are thought to reduce the conversion rate to secondary progressive multiple sclerosis.To explore the rate, chronology, and contributing factors of conversion to the progressive phase in treated relapsing-remitting multiple sclerosis patients.Our study included 204 patients treated for relapsing-remitting multiple sclerosis between 1995 and 2002, prospectively followed to date. Kaplan-Meier analysis was applied to estimate the time until secondary progressive multiple sclerosis conversion, and multivariate survival analysis with a Cox regression model was used to analyse prognostic factors.Relapsing-remitting multiple sclerosis patients were continuously treated for 13 years (SD 4.5); 36.3% converted to secondary progressive multiple sclerosis at a mean age of 42.6 years (SD 10.6), a mean time of 8.2 years (SD 5.2) and an estimated mean time of 17.2 years (range 17.1-18.1). A multifocal relapse, age older than 34 years at disease onset and treatment failure independently predicted conversion to secondary progressive multiple sclerosis but did not influence the time to reach an Expanded Disability Status Scale of 6.0.The favourable influence of disease-modifying therapies on long-term disability in relapsing-remitting multiple sclerosis is well established. However, the time to progression onset and the subsequent clinical course in treated patients seem similar to those previously reported in natural history studies. More studies are needed to clarify the effect of disease-modifying therapies once the progressive phase has been reached.
| S-EPMC6077906 | biostudies-other
Project description:Transcriptome analysis of RNA samples from human PBMCs of IFN-beta-1a (Rebif) therapy in secondary progressive multiple sclerosis (SPMS) patients. Objective: Untreated multiple sclerosis is inflammatory, with decreased immune control and subnormal type I interferon (IFN) signaling. IFN-ß therapy corrects abnormal IFN-ß signaling, reduces inflammation on MRI, exacerbations, and disease worsening in relapsing-remitting MS (RRMS). For unclear reasons, secondary progressive MS (SPMS) exhibits waning attacks, relentless neurodegeneration, and diminished benefits of therapy. Methods: Peripheral blood mononuclear cells and serum were from 10 healthy controls (HC), 9 therapy-naive RRMS, 20 therapy-naïve SPMS, and 10 IFN-ß-treated SPMS patients after therapy washout and four hours after IFN-ß-1a injection. Global gene expression was assayed with sensitive RNA microarrays and multiplexed serum immune and neuroprotective protein assays. Results: Therapy-naive RRMS cells displayed 8,723 differentially expressed genes (DEG), compared to HC, vs. d only 3,936 DEG in therapy-naive SPMS. In SPMS, gene expression was subnormal in the WNT/ß-catenin pathway that suppresses inflammation and enhances blood-brain barrier integrity. Olfactory receptor (OR) genes, linked to lymphocyte migration, were overexpressed in RRMS (111 DEG), intermediate in SPMS (34 DEG) vs. HC, differentiating RRMS from SPMS (p < 0.007). IFN-ß injections in SPMS decreased expression of pro-inflammatory genes and increased anti-inflammatory, anti-oxidant metallothionein genes. Pro-inflammatory and anti-inflammatory protein levels were balanced in HC, disrupted in RRMS, and intermediate in SPMS. Interpretation: Aberrant gene expression seen in RRMS wanes in SPMS, paralleling fewer clinical exacerbations and diminished therapeutic responses. Novel biomarkers for SPMS suggest new targets to correct subnormal immune regulation and brain repair in this neurodegenerative disease.
2024-03-07 | GSE247181 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-06-20 | GSE231587 | GEO
Project description:Background and purposeBeta-interferons (IFN?) are the most widely prescribed drugs for patients with multiple sclerosis (MS). However, whether or not treatment with IFN? can delay secondary progressive MS (SPMS) onset remains unknown. Our aim was to examine the association between IFN? exposure and SPMS onset in patients with relapsing-remitting MS (RRMS).MethodsA retrospective cohort study using British Columbia (Canada) population-based clinical and health administrative data (1985-2008) was conducted. RRMS patients treated with IFN? (n = 794) were compared with untreated contemporary (n = 933) and historical (n = 837) controls. Cohort entry was the first clinic visit during which patients became eligible for IFN? treatment (baseline). The outcome was time from baseline to SPMS onset. Cox regression models with IFN? as a time-dependent exposure were adjusted for sex, and baseline age, disease duration, disability, *socioeconomic status and *comorbidities (*available for the contemporary cohorts only). Additional analyses included propensity score adjustment.ResultsThe median follow-up for the IFN?-treated, untreated contemporary and historical controls were 5.7, 3.7 and 7.3 years, and the proportions of patients reaching SPMS were 9.2%, 11.8% and 32.9%, respectively. After adjustment for confounders, IFN? exposure was not associated with the risk of reaching SPMS when either the contemporary or the historical untreated cohorts were considered (hazard ratio 1.07; 95% confidence interval 0.93-1.48, and hazard ratio 1.04; 95% confidence interval 0.74-1.46, respectively). Further adjustments and the propensity score yielded results consistent with the main analysis.ConclusionsAmongst patients with RRMS, use of IFN? was not associated with a delayed onset of SPMS.
| S-EPMC5008210 | biostudies-literature
Project description:BackgroundIn multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.ObjectiveTo distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.MethodsThree estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.ResultsPrincipal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.ConclusionBy controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
| S-EPMC8414818 | biostudies-literature
Project description:The purpose of this study is to highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS) and also the results of clinical trial experience to date and review ongoing clinical trials and prospective new treatment options. This study will explain the challenges of clinical trial design in PMS.Multiple sclerosis (MS) has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms. The classification of the course of PMS has been reorganized into categories of active vs. inactive inflammatory disease and the presence vs. absence of gradual disease progression. This differentiation allows clearer conceptualization of PMS and possibly even more efficient recruitment of PMS patients into clinical trials. Clinical trial experience to date in PMS has been negative with anti-inflammatory medications used in relapsing MS. Simvastatin was recently tested in a phase II trial and showed a 43% reduction of annualized atrophy progression in secondary progressive MS. Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod and anti-B-cell therapy ocrelizumab. Several efforts for development of outcome measures in PMS are ongoing.PMS represents a significant challenge, as the pathogenesis of the disease is not well understood, no validated outcome metrics have been established and clinical trial experience to date has been disappointing. Advances in the understanding of the disease and lessons learned in previous clinical trials are paving the way for successful development of disease-modifying agents for this disease.
| S-EPMC4425257 | biostudies-other
Project description:IntroductionCritical gaps exist in the understanding of the continuum of multiple sclerosis (MS) progression, particularly with regard to the patient experience prior to and during the transition from relapsing-remitting MS (RRMS) to secondary-progressive MS (SPMS) stages. To date, there are no clear diagnostic criteria in the determination of the clinical transition. We report here the use of patient experience data to support the development of a qualitative conceptual model of MS that describes the patient journey of transition from active-relapsing disease to progressive MS.MethodsThe study used a single-encounter, multicenter, qualitative observational study design that included a targeted literature review and individual, in-depth interviews with adult patients with a clinically confirmed diagnosis of SPMS and their adult care partners. Descriptions of symptoms and impacts of RRMS and SPMS were extracted from the literature review and used to support development of the interview guide and conceptual model.ResultsParticipants described a slow progression in terms of change in symptoms over time, including both the development of new symptoms and the worsening of existing symptoms.ConclusionsThe conceptual model of the transitionary period from RRMS to SPMS expands the current understanding of the progression of MS from the patient and care partner perspectives.
| S-EPMC8571456 | biostudies-literature
Project description:ObjectivesTransitioning to secondary progressive multiple sclerosis (SPMS) is demanding for both patients and healthcare professionals. The particular challenges and the ways patients cope are poorly understood. The present study examines what challenges people face when diagnosed with SPMS by exploring experiences of people who have transitioned recently (up to 5 years).DesignSemistructured qualitative interviews at two time points a year apart. Interviews were analysed using inductive thematic analysis.SettingUK.ParticipantsWe interviewed 21 people at baseline and 17 participated in the follow-up interviews.ResultsThe majority of participants reported expecting to transition to SPMS, and the diagnosis did not make much difference to them. Participants described increasing emotional and physical challenges after transitioning to SPMS and between the first and second interviews. Planning, using distractions and maintaining social roles helped participants cope with the increased challenges. The same coping strategies were used between the two interviews. Participants felt there was not much left to do regarding the management of their symptoms. A key theme was the sense of abandonment from healthcare services after transitioning to SPMS.ConclusionsAfter transitioning to SPMS, people are faced with multiple challenges. Participants described a lack of directions for symptoms management and lack of support from the healthcare system. An integrated multidisciplinary healthcare approach is crucial at the progressive stage of the disease to alleviate feelings of helplessness and promote symptom management.
| S-EPMC6429969 | biostudies-literature