miR-24-3p and miR-484 are potential biomarkers for neurodegeneration in multiple sclerosis.

Multiple sclerosis (MS) is a complex, neurodegenerative chronic disorder. Circulating diagnostic biomarkers for MS have remained elusive, and those proposed so far have limited sensitivity and specificity to MS. Plasma-circulating microRNAs (miRNAs) have advantageous biochemical and physiological attributes that can be utilized in clinical testing and disease monitoring. MS miRNA expression microarray datasets analysis resulted in four candidate miRNAs that were assessed for their expression in a separate MS case-control study. Only miR-24-3p was downregulated in all MS patients compared to healthy controls. MiR-484 was significantly upregulated in relapsing-remitting MS (RRMS) patients compared to healthy controls. Mir-146-5p and miR-484 were significantly downregulated in secondary-progressive MS (SPMS) compared to RRMS. MiR-484 downregulation was associated with worsening disability and increased lipocalin-2 levels. Mir-342-3p and miR-24-3p downregulation were associated with increased semaphorin-3A levels in MS and RRMS patients. In conclusion, mir-24-3p downregulation is diagnostic of MS, and mir-484 upregulation and downregulation are potential biomarkers for RRMS and SPMS conversion, respectively. The differential expression of miR-146a-3p in MS subtypes suggests its potential as an SPMS transition biomarker. The association of downregulated mir-24-3p and mir-484 with increased neurodegeneration biomarkers suggests they play a role in MS pathogenesis and neurodegeneration.

Clinical characteristics and dynamics of disability progression in a cohort of patients with multiple sclerosis in Latvians.

There is wide variation in the time from the onset to secondary progressive multiple sclerosis (MS) and some controversy regarding the clinical characteristics of the courses (phenotypes) of MS. The present study aimed to characterize demographic and clinical factors that potentially influence long-term disability progression in the cohort of Latvian MS patients. A descriptive longitudinal incidence study was conducted using a cohort of 288 MS patients beginning in 2011 (disease duration from 1 to 51 years). Socio-demographic and clinical information from the first visit to 15/20 years was analysed in groups stratified by gender and visits at five-time points (the first visit; after a year or 2; after 5 ± 1 year; after 10 ± 2 years; after 15-20 years). Our study was dominated by patients from urban areas and non-smokers. The female/male ratio was 2.4:1; the distribution of clinical courses at the first visit was consistent with most European studies. The most common symptom at presentation in our study was optic manifestations, followed by sensory disturbances and motor deficits. In the Latvian study, gender was not a significant influencing factor on the rate of disease progression; however, patient age was statistically significantly associated with EDSS (Expanded Disability Status Scale) value at the first visit. Early clinical features of MS are important in predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Latvian patients are similar to other regions of the world.

Multiplex Analysis of Cerebrospinal Fluid and Serum Exosomes MicroRNAs of Untreated Relapsing Remitting Multiple Sclerosis (RRMS) and Proposing Noninvasive Diagnostic Biomarkers.

Exosomal microRNAs (miRNAs) are emerging diagnostic biomarkers for neurodegenerative diseases. In this study, we aimed to detect relapsing-remitting multiple sclerosis (RRMS)-specific miRNAs in cerebrospinal fluid (CSF) and serum exosomes with diagnostic potential. One ml of CSF and serum sample were collected from each of the 30 untreated RRMS patients and healthy controls (HCs). A panel of 18 miRNAs affecting inflammatory responses was applied, and qRT-PCR was conducted to detect differentially expressed exosomal miRNAs in CSF and serum of RRMS patients. We identified that 17 out of 18 miRNAs displayed different patterns in RRMS patients compared to HCs. Let-7 g-5p, miR-18a-5p, miR-145-5p, and miR-374a-5p with dual pro-inflammatory and anti-inflammatory actions and miR-150-5p and miR-342-3p with anti-inflammatory action were significantly upregulated in both CSF and serum-derived exosomes of RRMS patients compared to corresponding HCs. Additionally, anti-inflammatory miR-132-5p and pro-inflammatory miR-320a-5p were significantly downregulated in both CSF and serum-derived exosomes of RRMS patients compared to HCs. Ten of 18 miRNAs were differentially expressed in CSF and serum exosomes of the patients. Furthermore, miR-15a-5p, miR-19b-3p, and miR-432-5p were upregulated, and miR-17-5p was downregulated only in CSF exosomes. Interestingly, U6 housekeeping gene was differentially expressed in CSF and serum exosomes, in both RRMS and HCs. As the first report describing CSF exosomal miRNAs expression profile compared to that of serum exosomes in untreated RRMS patients, we showed that CSF and serum exosomes are not identical in terms of biological compounds and display different patterns in miRNAs and U6 expression.

Efficacy and safety of repeated low-dose rituximab therapy in relapsing-remitting multiple sclerosis: A retrospective case series study.

BACKGROUND: Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS), whereas the induction and maintenance regimens vary widely among studies. Few data are available on efficacy and safety of repeated low-dose RTX therapy in MS patients. OBJECTIVE: This study aimed to evaluate the efficacy and safety of repeated low-dose RTX therapy for relapsing-remitting MS (RRMS), the most common form of MS affecting approximately 85% of patients. METHODS: Nine RRMS patients were enrolled and the medical records were retrospectively reviewed. RTX at 100 mg per week for three consecutive weeks was used as induction therapy. Maintenance therapy was reinfusions of RTX at 100 mg every 6 months during the first year, followed by 100 mg every 6 to 12 months. Main outcome measures included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, and T2 lesion burden on MRI for evaluating the efficacy of low-dose RTX regimen. Meanwhile, adverse events (AEs) were recorded to assess the safety of repeated RTX infusions. RESULTS: All patients were females with an average onset age of 25.4 ± 6.7 years. The median disease duration before the first RTX infusion was 56 (range, 3-108) months and the median follow-up period was 30 (range, 15-40) months. No relapses were recorded in all patients after RTX therapy. Repeated low-dose RTX therapy resulted in a dramatic reduction of median ARR (pre-RTX vs post-RTX, 1.1 vs 0, p = 0.012), median EDSS score (2.0 vs 0, p = 0.007), and the number of T2 lesions on MRI (35.6 ± 18.0 vs 29.4 ± 18.1, p = 0.001). A total of 35 episodes of AEs occurred during repeated low-dose RTX therapy, and all of them were mild and transient. CONCLUSION: Repeated low-dose RTX therapy is cost-effective for RRMS patients and shows a good safety profile. It may be a promising option for those having no access or poor response to first-line disease-modified drugs (DMDs), particularly in low- or middle-income countries.

Changes in diffusion tensor imaging indices in basal ganglia and thalamus of patients with Relapsing-Remitting Multiple Sclerosis and relation with clinical conditions: A case-control study.

Background: Multiple sclerosis (MS) is recognized as the most prevalent autoimmune abnormality of the CNS. T1WI, T2WI, and FLAIR are limited in the quantification of tissue damage and detection of tissue alterations in white and grey matter in MS. This study aimed to the evaluation of changes in DTI indices in these patients at the thalamus and basal ganglia. Methods: 30 relapsing-remitting MS (RRMS) cases and 30 normal individuals were included. Conventional MRI (T2, FLAIR) was acquired to confirm NAGM in MS patients. A T1 MPRAGE protocol was used to normalize DTI images. FSL, SPM, and Explore DTI software were employed to reach Mean Diffusivities (MD), Axial Diffusivities (AD), Fractional anisotropy (FA), and Radial Diffusivity (RD) at the thalamus and the basal ganglia. Results: The FA and RD of the thalamus were decreased in healthy controls compared to MS cases (0.319 vs. 0.296 and 0.0009 vs. 0.0006, respectively) (P < 0.05). The AD value in the thalamus and the FA value in the caudate nucleus were significantly lower in MS cases than in controls (0.0009 vs. 0.0011 and 0.16 vs. 0.18, respectively) (P < 0.05). MD values in the thalamus or basal ganglia were not significantly different between groups. Conclusions: DTI measures including FA, RD, and AD have a good diagnostic performance in detecting microstructural changes in the normal-appearing thalamus in cases with RRMS while they had no significant relationship with clinical signs in terms of EDSS. Availability of data and material: Not applicable.

MicroRNAs expression in peripheral blood mononuclear cells of patients with multiple sclerosis propose.

BACKGROUND: MicroRNAs (miRs) are involved in the autoimmune and neurological diseases, including multiple sclerosis (MS), through modulating post-transcriptional gene regulation. Accumulating evidence indicates that miR-10, miR-24a, miR-124, and miR-21 play an imperative role in MS pathogenesis. Therefore, the current research aimed to analyze the expression of the selected miRNAs for MS in Iranian population. METHODS AND RESULTS: Blood sample of 75 relapsing-remitting MS (RRMS) patients and 75 healthy individuals suffering no neurodegenerative illness was collected. Subsequently, the isolation of peripheral blood mononuclear cells (PBMCs) was performed by employing Ficoll-Hypaque density gradient method. Afterward, total RNA was extracted and subjected to qRT-PCR analysis. The obtained results evidenced that the relative expression of miR-10 (P = 0.0002), miR-21 (P = 0.0014), and miR-124 (P = 0.0091) significantly decreased in RRMS patients compared to healthy participants. On the contrary, no notable change was observed between the studies groups regarding miR-24a expression levels (P = 0.107). ROC curve analysis estimated an area under the curve (AUC) value equal to 0.75 with P = 0.0006 for miR-10, while it was decreased for miR-21 (AUC = 0.67 and P = 0.0054) and miR-124 (AUC = 0.66 and P = 0.012). CONCLUSION: The change in miR-10, miR-124, and miR-21 expression patterns was implied to participate in MS development. Further large scale observational studies are recommended.

Association between miRNA-145 and miRNA-155 expression in peripheral blood mononuclear cells of patients with multiple sclerosis: a case-control study.

INTRODUCTION: MicroRNAs (miR or miRNA) are short regulatory RNAs, which modulate post-transcriptional gene expression. Dysregulation of these molecules contributes to pathogenicity of autoimmune disorders, such as multiple sclerosis (MS). AIMS: This study was conducted to investigate changed expression pattern of miRNA-145 and miRNA-155 in MS. METHODS: We collected blood samples of 75 patients with relapsing-remitting MS patients and 75 healthy controls. Ficoll-Hypaque density gradient method was used to isolate peripheral blood mononuclear cells. Also, total RNA was extracted and subjected to RT-PCR analysis. We used the Mann-Whitney U test to evaluate the differences in expression levels of target miRNAs between the groups. RESULTS: We found that expression of miRNA-145 (P = 0.012) and miRNA-155 (P = 0.005) were partly reduced in patients with relapse-remitting MS in comparison with healthy controls. The miRNA-145 had an area under curve (AUC) of 0.621 (P = 0.01) and miRNA-155 levels had an AUC of 0.625 (P = 0.008). CONCLUSION: Decreased expression of miRNA-145 and miRNA-155 contributes to development of relapse-remitting MS, while further large scale observational studies and meta-analyses are required.

Immunomodulatory Potential of Human Mesenchymal Stem Cells and their Exosomes on Multiple Sclerosis.

Purpose: Promising advances have been made in mesenchymal stem cell transplantation to reinducethe immune tolerance in neuroinflammatory animal models and multiple sclerosis (MS)patients. The available evidence demonstrated that immunomodulatory effects of mesenchymalstem cell are particularly exerted through releasing exosomes to their environment. Wetherefore, aimed to comparatively assess the potential effect of mesenchymal stem cells andmesenchymal stem cells-derived exosomes on proliferation and function of the CD4+CD25- conventional T cells, isolated from relapsing-remitting MS patients. Methods: Mesenchymal stem cells were isolated from human umbilical cord tissues and usedfor exosome isolation via ultracentrifugation. Both mesenchymal stem cells and mesenchymalstem cells-derived exosomes were evaluated for their anti-inflammatory effects againstthe proliferation of T cells isolated from two groups of individuals in vitro, MS patients andhealthy subjects. Cytokine production of conventional T cells (interferon-γ, interleukin-10, andinterleukin-17) was also assessed, using flow cytometry for the patients and healthy individuals. Results: Here, evidence shows that MSCs and MSC-derived exosomes dampen proliferationand percentage of conventional T cells that produce IFN-γ (healthy control: P < 0.001) andinterleukin-17 (healthy control: P <0.001, MS patients: P < 0.001), with a significant increaseof IL-10 producing cells in the patients and healthy individuals. Surprisingly, MSC-derivedexosomes demonstrated higher immune-modulating properties on conventional T cellsresponses, compared to mesenchymal stem cells (MSCs). Conclusion: The current study, provides a novel approach of exocytosis on autoimmune therapy.In particular, Mesenchymal stem cell -derived exosomes, which are cell-derived biologics,could be considered as an alternative for Mesenchymal stem cells in treating MS.

Early first-line treatment response and subsequent disability worsening in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Treatment success in relapsing-remitting multiple sclerosis (RRMS) is generally determined using relapse frequency and magnetic resonance imaging (MRI) activity in the first 6 or 12 months on treatment. The association of these definitions of short-term treatment success with disability worsening and disease activity in the longer term is unclear. In this study, we investigated risk factors associated with early first-line treatment failure in RRMS, and the association of early treatment failure with subsequent disability worsening or "no evidence of disease activity" (NEDA-3) status. METHODS: We used data from CombiRx (clinicaltrials.gov identifier NCT00211887) to investigate risk factors associated with early treatment failure, and the association of early treatment failure at 6 and 12 months with subsequent disability worsening or NEDA-3 at 36 months. RESULTS: CombiRx included 1008 treatment-naïve participants with RRMS, who were randomly assigned to treatment with glatiramer acetate, interferon beta, or the combination of both. Early treatment failure at 6 or 12 months by several definitions was associated with NEDA-3 failure at 36 months, but not with subsequent disability worsening at 36 months. Expanded Disability Status Scale (EDSS) was the only baseline characteristic associated with the risk of disability worsening at 36 months. Approximately 70% of NEDA-3 failures occurred due to MRI activity, and <10% occurred due to EDSS worsening. CONCLUSIONS: Our investigation shows that current definitions of early treatment failure in RRMS are unrelated to patient-relevant disability worsening at 36 months of follow-up. Further research into useful definitions of treatment success and failure in RRMS is needed.

Elevated sCD40L in Secondary Progressive Multiple Sclerosis in Comparison to Non-progressive Benign and Relapsing Remitting Multiple Sclerosis.

BACKGROUND: The 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. PURPOSE: Our study aims to identify soluble plasma factors predicting disease progression in multiple sclerosis (MS). RESEARCH DESIGN AND STUDY SAMPLE: We 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. RESULTS: Plasma levels of EGF, sCD40L, MCP1/CCL2, fractalkine/CX3CL1, IL-13, Eotaxin, TNFß/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. CONCLUSIONS: These differences may facilitate personalized precision medicine and aid in the discovery of new therapeutic targets for disease progression through the improvement of patient stratification.

Characteristics of improvements in balance control using vibro-tactile biofeedback of trunk sway for multiple sclerosis patients.

BACKGROUND AND AIMS: Previously, we determined that training with vibrotactile feedback (VTfb) of trunk sway improves MS patients' balance impairment. Here, we posed 5 questions: 1) How many weeks of VTfb training are required to obtain the best short-term carry over effect (CoE) with VTfb? 2) How long does the CoE last once VTfb training terminates? 3) Is the benefit similar for stance and gait? 4) Is position or velocity based VTfb more effective in reducing trunk sway? 5) Do patients' subjective assessments of balance control improve? METHODS: Balance control of 16 MS patients was measured with gyroscopes at the lower trunk. The gyroscopes drove directionally active VTfb in a head-band. Patients trained twice per week with VTfb for 4 weeks to determine when balance control with and without VTfb stopped improving. Thereafter, weekly assessments without VTfb over 4 weeks and at 6 months determined when CoEs ended. RESULTS: A 20% improvement in balance to normal levels occurred with VTfb. Short term CoEs improved from 15 to 20% (p ≤ 0.001). Medium term (1-4 weeks) CoEs were constant at 19% (p ≤ 0.001). At 6 months improvement was not significant, 9%. Most improvement was for lateral sway. Equal improvement occurred when angle position or velocity drove VTfb. Subjectively, balance improvements peaked after 3 weeks of training (32%, p ≤ 0.05). CONCLUSIONS: 3-4 weeks VTfb training yields clinically relevant sway reductions and subjective improvements for MS patients during stance and gait. The CoEs lasted at least 1 month. Velocity-based VTfb was equally effective as position-based VTfb.

Dynamic Functional Connectivity in the Main Clinical Phenotypes of Multiple Sclerosis.

Introduction: Dynamic functional connectivity (dFC) allows capturing recurring patterns (states) of interaction among functional networks. In this study, we investigated resting state (RS) dFC abnormalities across the different clinical phenotypes of multiple sclerosis (MS) and assessed their correlation with motor and cognitive performances. Methods: RS functional magnetic resonance imaging (fMRI) and 3D T1-weighted MRI data were acquired from 128 MS patients (69 relapsing-remitting [RR] MS, 34 secondary progressive [SP] MS, and 25 primary progressive [PP] MS) and 40 healthy controls (HC). RS fMRI data underwent independent component analysis and sliding-window correlations, to identify recurring dFC states and between-group dFC differences in the main networks. Results: dFC identified three recurring connectivity states: State 1 (frequency of appearance during fMRI acquisition = 57%, low dFC strength), State 2 (frequency = 19%, middle-high dFC strength), and State 3 (frequency = 24%, high sensorimotor and visual dFC strength). Compared to HC, MS (as a whole), RRMS, and PPMS patients exhibited lower State1/State 3 dFC (p = 0.0001, corrected) between sensorimotor, cerebellar, and cognitive networks, and some dFC increments (p = 0.001-0.05, uncorrected) in sensorimotor, visual, default-mode, and frontal/attention networks in States 2 and 3. Similar results were observed in SPMS versus RRMS patients. In MS, dFC decrease in sensorimotor, default-mode, and frontal/attention networks was correlated with worse motor and cognitive performances. Conclusions: MS patients exhibited overall lower dFC, and marginally higher dFC in sensorimotor/cognitive networks in the less-frequent middle/high-connected States. dFC abnormalities became more severe in progressive MS and correlated with motor and cognitive impairment, suggesting the presence of maladaptive mechanisms concomitant with accumulation of damage. Impact statement This is the first study exploring reorganization of dynamic functional connectivity in patients with multiple sclerosis (MS) across the main clinical phenotypes of the disease. Here, we demonstrated abnormalities of connectivity dynamism, which were present at all disease stages, but became more severe in progressive MS and correlated with worse motor and cognitive performances. These findings suggested that progressive MS patients might experience a maladaptive neuronal response to transient loss of dynamic coordination and flexibility among sensory and cognitive brain regions, leading to the progression of clinical impairment.

Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.

Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.

Umbilical cord mesenchymal stem cells as well as their released exosomes suppress proliferation of activated PBMCs in multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system (CNS) degenerative disorder which is caused by a targeted autoimmune-mediated attack on myelin proteins. Previously, mesenchymal stem cells were considered as a novel and successful treatment of MS. One of the underlying mechanisms behind their immunomodulatory function is the release of extracellular vesicles, particularly exosomes. In this study, we aimed to evaluate the suppressive efficacy of MSCs and their exosomes on the proliferation of peripheral mononuclear blood cells (PBMC) in relapsing-remitting MS (RRMS) patients and healthy subjects. To do, mesenchymal stem cells were derived from human umbilical cord tissues and used for exosome isolation through ultracentrifugation. Suppressive function of MSCs and MSC-derived exosomes was examined in a coculture with CFSE-labelled PBMCs in vitro. PBMC proliferation of the patients and healthy individuals was measured using flow cytometry. We first demonstrated that proliferation of PBMCs decreased in the presence of MSCs and suppression was more efficient by MSC-derived exosomes, with a minimum alloreaction rate. However, suppression capacity of MSCs and their exosomes significantly decreased during extensive sub-culturing. The present study showed that MSC-derived exosomes as an effective cell-free therapy could prevent proliferation of PBMCs. However, further evaluations are need to move towards a functional approach that can be translated to the clinic.

Effect of Multiple Sclerosis on Daily Activities, Emotional Well-being, and Relationships: The Global vsMS Survey.

BACKGROUND: The vsMS survey was conducted to better understand the negative effects of fatigue, cognitive impairment, emotional burden, and decreased physical functioning on the personal, professional, and social lives of individuals with multiple sclerosis (MS). METHODS: The vsMS survey was an online survey conducted in Australia, Canada, France, Italy, Spain, the United Kingdom, and the United States that assessed the impact of MS on individuals' daily activities, emotional well-being, relationships, and employment. RESULTS: The survey included 1075 participants with relapsing-remitting MS. Almost 42% of participants reported that their ability to perform and manage daily activities had worsened during the previous 2 years. More than 50% reported limitations in daily activities due to fatigue, physical weakness, problems with balance/coordination, heat/cold sensitivity, memory problems, numbness/tingling, trouble concentrating, impaired movement/muscle stiffness, and impaired sleeping. Participants also reported a negative effect on emotional and social factors, including self-esteem, general outlook, well-being, maintaining/starting relationships, ability to progress in their career/keep their job, and ability to cope with life roles. CONCLUSIONS: These data highlight the importance of addressing the impact of MS and the social and emotional disease burdens on daily activities when planning the care of patients with MS.

Acquisition of human immunodeficiency virus infection in a patient with multiple sclerosis: could these conditions positively influence each other's course?

Patients with human immunodeficiency virus (HIV) infection have a decreased risk of developing multiple sclerosis (MS) and MS patients very rarely contract HIV infection. We report on a 35-year-old woman with relapsing-remitting MS, who acquired HIV infection 8 years after MS onset. During 7 years of follow-up without combined antiretroviral therapy (cART), CD4+ counts decreased and HIV viremia increased progressively, but slightly. These trends reverted after starting cART, with optimal viro-immunological control. While the patient had many MS relapses before acquiring HIV infection, she had then only one relapse, shortly after HIV infection, despite irregular or no MS therapy. This case contributes to the discussion about MS and HIV potential interactions and describes for the first time the effects of the MS-targeting drug natalizumab in an HIV-positive patient.

Outcomes in a Modern Cohort of Treated Patients with Multiple Sclerosis from Diagnosis Up to 15 Years.

BACKGROUND: Before disease-modifying therapies (DMTs) were available, the natural history of multiple sclerosis (MS) regarding attainment of accepted disability milestones was reported with fairly wide variance comparing outcomes across studies. The influence of DMTs on these outcomes is unknown. This study aimed to calculate attainment of disability milestones during the first 15 years after onset of DMT-treated relapsing forms of MS (RMS). METHODS: As a retrospective study, all available disability data (collected routinely) on all newly diagnosed patients with RMS seen and initially diagnosed in a single clinic between 1989 and 2006 were reviewed. Times from first symptoms and diagnosis until first treatment with DMTs were also reviewed. Time-to-event statistics were applied using disability milestones. RESULTS: Mean follow-up of 184 adult patients from symptom onset was 13.7 years. Of patients followed up for 15 years after onset, 16 of 86 (19%) reached an Expanded Disability Status Scale (EDSS) score of 6.0. Estimated median time to reach an EDSS score of 3.0 was 10.7 years and to reach an EDSS score of 4.0 was 18.1 years. CONCLUSIONS: There were striking differences between the present results and older data sets and similar results to the few available modern data sets. This analysis of a modern treated RMS cohort provides outcomes data that may be compared favorably with the natural history of RMS.

Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).

BACKGROUND: The CLARINET-MS study assessed the long-term effectiveness of cladribine tablets by following patients with multiple sclerosis (MS) in Italy, using data from the Italian MS Registry. METHODS: Real-world data (RWD) from Italian MS patients who participated in cladribine tablets randomised clinical trials (RCTs; CLARITY, CLARITY Extension, ONWARD or ORACLE-MS) across 17 MS centres were obtained from the Italian MS Registry. RWD were collected during a set observation period, spanning from the last dose of cladribine tablets during the RCT (defined as baseline) to the last visit date in the registry, treatment switch to other disease-modifying drugs, date of last Expanded Disability Status Scale recording or date of the last relapse (whichever occurred last). Time-to-event analysis was completed using the Kaplan-Meier (KM) method. Median duration and associated 95% confidence intervals (CI) were estimated from the model. RESULTS: Time span under observation in the Italian MS Registry was 1-137 (median 80.3) months. In the total Italian patient population (n = 80), the KM estimates for the probability of being relapse-free at 12, 36 and 60 months after the last dose of cladribine tablets were 84.8%, 66.2% and 57.2%, respectively. The corresponding probability of being progression-free at 60 months after the last dose was 63.7%. The KM estimate for the probability of not initiating another disease-modifying treatment at 60 months after the last dose of cladribine tablets was 28.1%, and the median time-to-treatment change was 32.1 (95% CI 15.5-39.5) months. CONCLUSION: CLARINET-MS provides an indirect measure of the long-term effectiveness of cladribine tablets. Over half of MS patients analysed did not relapse or experience disability progression during 60 months of follow-up from the last dose, suggesting that cladribine tablets remain effective in years 3 and 4 after short courses at the beginning of years 1 and 2.

Clinical Characteristics and Disability Progression of Early- and Late-Onset Multiple Sclerosis Compared to Adult-Onset Multiple Sclerosis.

BACKGROUND: Compared to the adult onset of multiple sclerosis (AOMS), both early-onset (EOMS) and late-onset (LOMS) are much less frequent, but are often under- or misdiagnosed. The aims of the present study were: 1. To compare demographic and clinical features of individuals with EOMS, AOMS and LOMS, and 2. To identify predictors for disability progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS). METHOD: Data were taken from the Isfahan Hakim MS database. Cases were classified as EOMS (MS onset 18 years), LOMS (MS onset >50 years) and AOMS (MS >18 and 50 years). Patients' demographic and clinical (initial symptoms; course of disease; disease patterns from MRI; disease progress) information were gathered and assessed. Kaplan-Meier and Cox proportional hazard regressions were conducted to determine differences between the three groups in the time lapse in conversion from relapsing remitting MS to secondary progressive MS. RESULTS: A total of 2627 MS cases were assessed; of these 127 were EOMS, 84 LOMS and 2416 AOMS. The mean age of those with EOMS was 14.5 years; key symptoms were visual impairments, brain stem dysfunction, sensory disturbances and motor dysfunctions. On average, 24.6 years after disease onset, 14.2% with relapsing remitting MS (RRMS) were diagnosed with secondary progressive MS (SPMS). The key predictor variable was a higher Expanded Disability Status Scale (EDSS) score at disease onset. Compared to individuals with AOMS and LOMS, those with EOMS more often had one or two relapses in the first two years, and more often gadolinium-enhancing brain lesions. For individuals with AOMS, mean age was 29.4 years; key symptoms were sensory disturbances, motor dysfunctions and visual impairments. On average, 20.5 years after disease onset, 15.6% with RRMS progressed to SPMS. The key predictors at disease onset were: a higher EDSS score, younger age, a shorter inter-attack interval and spinal lesions. Compared to individuals with EOMS and LOMS, individuals with AOMS more often had either no or three and more relapses in the first two years. For individuals with LOMS, mean age was 53.8 years; key symptoms were motor dysfunctions, sensory disturbances and visual impairments. On average, 14 years after disease onset, 25.3% with RRMS switched to an SPMS. The key predictors at disease onset were: occurrence of spinal lesions and spinal gadolinium-enhancement. Compared to individuals with EOMS and AOMS, individuals with LOMS more often had no relapses in the first two years, and higher EDSS scores at disease onset and at follow-up. CONCLUSION: Among a large sample of MS sufferers, cases with early onset and late onset are observable. Individuals with early, adult and late onset MS each display distinct features which should be taken in consideration in their treatment.

Clinical and MRI efficacy of sc IFN ß-1a tiw in patients with relapsing MS appearing to transition to secondary progressive MS: post hoc analyses of PRISMS and SPECTRIMS.

This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN ß-1a) 44 µg 3 × weekly (tiw) in patients appearing to transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0-5.0; ≥ 2 relapses in previous 2 years), and the SPECTRIMS study included 618 patients with SPMS (EDSS 3.0-6.5 and ≥ 1-point increase in previous 2 years [≥ 0.5 point if 6.0-6.5]) randomly assigned to sc IFN ß-1a 44 or 22 µg or placebo for 2-3 years, respectively. These post hoc analyses examined five subgroups of MS patients with EDSS 4.0-6.0: PRISMS (n = 59), PRISMS/SPECTRIMS (n = 335), PRISMS/SPECTRIMS with baseline disease activity (n = 195; patients with either ≥ 1 relapse within 2 years before baseline or ≥ 1 gadolinium-enhancing lesion at baseline), PRISMS/SPECTRIMS without baseline disease activity (n = 140), and PRISMS/SPECTRIMS with disease activity during the study (n = 202). In the PRISMS and PRISMS/SPECTRIMS subgroups, sc IFN ß-1a delayed disability progression, although no significant effect was observed in PRISMS/SPECTRIMS subgroups with activity at baseline or activity during the study (regardless of baseline activity). In the PRISMS/SPECTRIMS subgroup, over year 1 (0-1) and 2 (0-2), sc IFN ß-1a 44 µg tiw significantly reduced annualized relapse rate (p ≤ 0.001), and relapse risk (p < 0.05) versus placebo. Similar results were seen for the PRISMS/SPECTRIMS with baseline disease activity subgroup. Subcutaneous IFN ß-1a reduced T2 burden of disease and active T2 lesions in the PRISMS/SPECTRIMS subgroups overall, with and without baseline activity. In conclusion, these post hoc analyses indicate that effects of sc IFN ß-1a 44 µg tiw on clinical/MRI endpoints are preserved in a patient subgroup appearing to transition between RRMS and SPMS.