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Introduction: CD20-depleting therapies are a real milestone in the treatment of multiple sclerosis (MS). This study examined the ocrelizumab (OCR) use in patients with primary progressive (PP) and relapsing remitting (RR) MS, also evaluating the predictors of treatment response. Methods: Patients with MS treated with OCR between 2017 and 2022 were included, and OCR use trends examined. The patients' characteristics were assessed at baseline and after 24 months of OCR to assess the NEDA-3 status. Results: This study included 421 patients: 33 (7.9%) with PP and 388 (92.1%) with RR MS. Among these, 67 (17.3%) were naïve, while switchers from first- and second-line disease-modifying therapies (DMTs) were 199 (51.3%) and 122 (31.4%), respectively. An increasing trend in OCR use was reported. For six patients treated with rituximab, OCR was chosen to improve tolerability; for 390 switcher patients, the choice was due to ineffectiveness; and for 25, as an exit strategy from natalizumab due to JC virus positivity. NEDA-3 status was calculated for subjects exposed to 24 months of OCR and was achieved by 163/192 (84.9%) RR patients and 9/16 (56%) PP patients, with younger age (p = 0.048) and annualized relapse rate in the year previous to OCR (p = 0.005) emerging as determinants. For the 25 patients who switched to OCR after natalizumab, no clinical or MRI activity after 12 months was reported. Conclusion: OCR has been confirmed to be a highly efficacious option for patients with PP and RR MS, even proving to be a valid exit strategy for natalizumab. [ABSTRACT FROM AUTHOR]

Introduction: The real-world data on the medium- to long-term effectiveness and safety of teriflunomide in Chinese patients with relapsing multiple sclerosis (MS) is limited. Therefore, this study aims to assess the treatment outcomes of teriflunomide in Chinese patients with MS over a medium- to long-term period. Methods: This cohort study was carried out in three tertiary hospitals and regional MS centers located in the Greater Bay Area of China. We obtained the historical clinical data of patients who underwent teriflunomide treatment for at least 6 months. The primary objective was to evaluate the proportion of patients achieving no evidence of disease activity (NEDA)-3 status, which is characterized by the absence of relapses, confirmed disability worsening, and new or enlarging MRI lesions, over time. Secondary objectives included assessing the proportion of patients meeting each NEDA-3 criterion, changes in motor and cognitive function, as well as the incidence of adverse events and treatment discontinuations. Results: A total of 160 patients with MS were enrolled, including 125 patients treated with teriflunomide for at least 1 year (≥ 1-year completers) and 71 patients treated for at least 2 years (≥ 2-year completers). A total of 85.63% of the overall population achieved clinical NEDA-3 status at 6 months of teriflunomide treatment, and 71.20% of ≥ 1-year completers achieved NEDA-3 status at 12 months of teriflunomide treatment. The median timed 25-foot walk test (T25FW), nine-hole peg test (9-HPT), and paced auditory serial addition test (PASAT) results were relatively stable before and after treatment. Conclusion: Medium- to long-term MS disease activity, as indicated by NEDA-3 status, is well controlled in patients treated with continuous teriflunomide treatment in real-world settings. [ABSTRACT FROM AUTHOR]

Abstract Introduction The real-world data on the medium- to long-term effectiveness and safety of teriflunomide in Chinese patients with relapsing multiple sclerosis (MS) is limited. Therefore, this study aims to assess the treatment outcomes of teriflunomide in Chinese patients with MS over a medium- to long-term period. Methods This cohort study was carried out in three tertiary hospitals and regional MS centers located in the Greater Bay Area of China. We obtained the historical clinical data of patients who underwent teriflunomide treatment for at least 6 months. The primary objective was to evaluate the proportion of patients achieving no evidence of disease activity (NEDA)-3 status, which is characterized by the absence of relapses, confirmed disability worsening, and new or enlarging MRI lesions, over time. Secondary objectives included assessing the proportion of patients meeting each NEDA-3 criterion, changes in motor and cognitive function, as well as the incidence of adverse events and treatment discontinuations. Results A total of 160 patients with MS were enrolled, including 125 patients treated with teriflunomide for at least 1 year (≥ 1-year completers) and 71 patients treated for at least 2 years (≥ 2-year completers). A total of 85.63% of the overall population achieved clinical NEDA-3 status at 6 months of teriflunomide treatment, and 71.20% of ≥ 1-year completers achieved NEDA-3 status at 12 months of teriflunomide treatment. The median timed 25-foot walk test (T25FW), nine-hole peg test (9-HPT), and paced auditory serial addition test (PASAT) results were relatively stable before and after treatment. Conclusion Medium- to long-term MS disease activity, as indicated by NEDA-3 status, is well controlled in patients treated with continuous teriflunomide treatment in real-world settings.

Background: This study investigates clinical and biomarker differences between standard interval dosing (SID) and extended interval dosing (EID) of ocrelizumab therapy in multiple sclerosis (MS). Methods: This is a prospective, double-arm, open-label, multi-center study in Denmark. Participants diagnosed with MS on ocrelizumab therapy >12 months were included (n = 184). Clinical, radiological, and blood-based biomarker outcomes were evaluated. MRI disease activity, relapses, worsening of neurostatus, and No Evidence of Disease Activity-3 (NEDA-3) were used as a combined endpoint. Results: Out of 184 participants, 107 participants received EID (58.2%), whereas 77 participants received SID (41.8%). The average extension was 9 weeks with a maximum of 78 weeks. When comparing EID to SID, we found higher levels of B-cells, lower serum concentrations of ocrelizumab, and similar levels of age-adjusted NFL and GFAP in the two groups. No difference in NEDA-3 between EID and SID was demonstrated (hazard ratio: 1.174, p = 0.69). Higher levels of NFL were identified in participants with disease activity. Body mass index correlated with levels of ocrelizumab and B-cells. Conclusion: Extending one treatment interval of ocrelizumab on average 9 weeks and up to 78 weeks did not result in clinical, radiological, or biomarker evidence of worsening compared with SID. [ABSTRACT FROM AUTHOR]

The emergence of high-efficacy therapies for multiple sclerosis (MS), which target inflammation more effectively than traditional disease-modifying therapies, has led to a shift in MS management towards achieving the outcome assessment known as no evidence of disease activity (NEDA). The most common NEDA definition, termed NEDA-3, is a composite of three related measures of disease activity: no clinical relapses, no disability progression, and no radiological activity. NEDA has been frequently used as a composite endpoint in clinical trials, but there is growing interest in its use as an assessment tool to help patients and healthcare professionals navigate treatment decisions in the clinic. Raising awareness about NEDA may therefore help patients and clinicians make more informed decisions around MS management and improve overall MS care. This review aims to explore the potential utility of NEDA as a clinical decision-making tool and treatment target by summarizing the literature on its current use in the context of the expanding treatment landscape. We identify current challenges to the use of NEDA in clinical practice and detail the proposed amendments, such as the inclusion of alternative outcomes and biomarkers, to broaden the clinical information captured by NEDA. These themes are further illustrated with the real-life perspectives and experiences of our two patient authors with MS. This review is intended to be an educational resource to support discussions between clinicians and patients on this evolving approach to MS-specialized care. Plain Language Summary: Recent progress in multiple sclerosis (MS) has led to the development of new treatments, known as high-efficacy therapies. Compared with previous treatments, high-efficacy therapies are better at managing visible inflammation of the central nervous system, a main cause of worsening symptoms early on in people living with MS. Treatment with high-efficacy therapies means many people with MS may achieve better outcomes than previously possible. One such outcome is the set of criteria known as no evidence of disease activity (NEDA). Achieving NEDA-3, the most commonly used NEDA criteria, means that people exhibit no clinical relapses, no worsening of physical symptoms, and no visible disease activity on a magnetic resonance imaging scan. Researchers have studied NEDA as an outcome in MS clinical trials, but it may be useful in clinical practice as a tool for doctors to measure a person's disease progression and response to treatment. This could help to inform important decisions around treatment selection and improve overall care for people with MS. This review explores the available information about NEDA to understand its potential to support clinical decision-making and patient evaluations. We discuss the barriers to NEDA being used in clinical practice and the ways the criteria may change to capture a broader range of clinical information from the patient. These topics are presented alongside the real-life perspectives and experiences of our two patient authors with MS. This review is meant to be an educational resource to assist conversations about NEDA between clinicians and patients in everyday clinical practice. [ABSTRACT FROM AUTHOR]

Abstract The emergence of high-efficacy therapies for multiple sclerosis (MS), which target inflammation more effectively than traditional disease-modifying therapies, has led to a shift in MS management towards achieving the outcome assessment known as no evidence of disease activity (NEDA). The most common NEDA definition, termed NEDA-3, is a composite of three related measures of disease activity: no clinical relapses, no disability progression, and no radiological activity. NEDA has been frequently used as a composite endpoint in clinical trials, but there is growing interest in its use as an assessment tool to help patients and healthcare professionals navigate treatment decisions in the clinic. Raising awareness about NEDA may therefore help patients and clinicians make more informed decisions around MS management and improve overall MS care. This review aims to explore the potential utility of NEDA as a clinical decision-making tool and treatment target by summarizing the literature on its current use in the context of the expanding treatment landscape. We identify current challenges to the use of NEDA in clinical practice and detail the proposed amendments, such as the inclusion of alternative outcomes and biomarkers, to broaden the clinical information captured by NEDA. These themes are further illustrated with the real-life perspectives and experiences of our two patient authors with MS. This review is intended to be an educational resource to support discussions between clinicians and patients on this evolving approach to MS-specialized care.

Abstract Background Multiple sclerosis (MS) is a disabling autoimmune demyelinating disorder affecting young people and causing significant disability. In the last decade, different microRNA (miRNA) expression patterns have been associated to several treatment response therapies such as interferon and glatiramer acetate. Nowadays, there is increasing interest in the potential role of miRNA as treatment response biomarkers to the most recent oral and intravenous treatments. In this study, we aimed to evaluate serum miRNAs as biomarkers of No Evidence of Disease Activity (NEDA-3) at 2 years in patients with relapsing remitting MS (RRMS) treated with fingolimod. Main body A Discovery cohort of 31 RRMS patients treated with fingolimod were identified from the CLIMB study and classified as No Evidence of Disease Activity (NEDA-3) or Evidence of Disease Activity (EDA-3) after 2 years on treatment. Levels of miRNA expression were measured at 6 months using human serum miRNA panels and compared in EDA-3 and NEDA-3 groups using the Wilcoxon rank sum test. A set of differentially expressed miRNA was further validated in an independent cohort of 22 fingolimod-treated patients. We found that 548a-3p serum levels were higher levels in fingolimod-treated patients classified as NEDA-3, compared to the EDA-3 group in both the Discovery (n = 31; p = 0.04) and Validation (n = 22; p = 0.03) cohorts 6 months after treatment initiation; miR-548a-3p provided an AUC of 0.882 discriminating patients with NEDA-3 at 2 years in the Validation cohort. Conclusion Our results show differences in miR-548a-3p expression at 6 months after fingolimod start in patients with MS with NEDA-3 at 2 years. These results provide class III evidence of the use of miR-548a-3p as biomarker of NEDA-3 in patients with fingolimod.

Introduction: Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of central nervous system that can be diagnosed in pediatric age (<18 years) in 3-5% of the cases. This early onset is associated with higher relapse rates and earlier progression to neurological disability. By using NEDA-3 (No Evidence of Disease Activity-3) criteria, we aimed to identify clinical predictors associated with absence of disease activity and control of disease progression 12 months after the diagnosis, in a cohort of pediatric-onset MS (POMS) patients regularly followed-up in our center. Methods: We analyzed demographic, clinical, laboratorial and imaging variables of patients with POMS identified in our center, between 2010 and 2021, in two moments: at the diagnosis and 12 months after it. Statistical tests were applied to compare the distribution of those variables between groups defined by NEDA-3 status and by each one of its three variable components. Results: We included 27 patients in the study (18 female), with a mean age of 14.8years (± 2.8), being all diagnosed with relapsing-remitting MS and with a median score of 1.5 at the Expanded Disability Status Scale (EDSS). The use of natalizumab (p = 0.017) and the negativity for anti-EBV IgG antibodies (p = 0.018) at diagnosis were associated with a higher achievement of NEDA-3 status 12months after, in our cohort. Prescribed treatment was also associated with statistically significant differences in the "absence of MRI activity" component of NEDA-3 (p = 0.006): patients under treatment with natalizumab had a higher probability of achieving this status, and the opposite was observed in glatiramer acetate-treated children. Discussion and conclusion: Our exploratory results underline the pivotal importance that an early and more effective therapeutical approach may have in the control of disease activity, in POMS. Additionally, they also seem to suggest that the presence of anti-EBV antibodies is not innocent, as it can be related to a less favorable evolution of the disease, even at a very early stage. Further studies are needed to confirm the applicability of these variables as prognostic and personalized tools in this clinical setting. [ABSTRACT FROM AUTHOR]

IntroductionMultiple sclerosis (MS) is an inflammatory and demyelinating disorder of central nervous system that can be diagnosed in pediatric age (

Background: Multiple sclerosis (MS) is a disabling autoimmune demyelinating disorder affecting young people and causing significant disability. In the last decade, different microRNA (miRNA) expression patterns have been associated to several treatment response therapies such as interferon and glatiramer acetate. Nowadays, there is increasing interest in the potential role of miRNA as treatment response biomarkers to the most recent oral and intravenous treatments. In this study, we aimed to evaluate serum miRNAs as biomarkers of No Evidence of Disease Activity (NEDA-3) at 2 years in patients with relapsing remitting MS (RRMS) treated with fingolimod. Main body: A Discovery cohort of 31 RRMS patients treated with fingolimod were identified from the CLIMB study and classified as No Evidence of Disease Activity (NEDA-3) or Evidence of Disease Activity (EDA-3) after 2 years on treatment. Levels of miRNA expression were measured at 6 months using human serum miRNA panels and compared in EDA-3 and NEDA-3 groups using the Wilcoxon rank sum test. A set of differentially expressed miRNA was further validated in an independent cohort of 22 fingolimod-treated patients. We found that 548a-3p serum levels were higher levels in fingolimod-treated patients classified as NEDA-3, compared to the EDA-3 group in both the Discovery (n = 31; p = 0.04) and Validation (n = 22; p = 0.03) cohorts 6 months after treatment initiation; miR-548a-3p provided an AUC of 0.882 discriminating patients with NEDA-3 at 2 years in the Validation cohort. Conclusion: Our results show differences in miR-548a-3p expression at 6 months after fingolimod start in patients with MS with NEDA-3 at 2 years. These results provide class III evidence of the use of miR-548a-3p as biomarker of NEDA-3 in patients with fingolimod. [ABSTRACT FROM AUTHOR]

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Background: Multiple sclerosis (MS) is a chronic autoimmune disease with huge heterogeneity in terms of clinical course, disease severity and treatment response. The need for a tailored treatment approach has emerged over the last few years. The present observational study aims to assess fingolimod (FTY) effectiveness in RRMS patients, stratifying them according to the disease-modifying treatments used before FTY, to identify subjects who could benefit more from this treatment. Methods: We prospectively included 554 RRMS patients who started FTY at San Raffaele Hospital between 2012 and 2018. We classified them into three categories according to previous treatments: naïve patients, subjects previously treated with first-line drugs, and patients previously treated with second-line drugs. We compared disease activity during a 2-years follow-up using No-Evidence-of-Disease-Activity (NEDA-3) and Time-To-First-Relapse (TTFR) outcomes, applying logistic and Cox proportional hazard regression respectively. Results: The proportion of patients who maintained NEDA-3 status was higher in the naïve group despite a higher level of baseline disease activity (naïve versus first-line p = 0.025, naïve versus second-line p < 0.001). In the multivariable analyses, patients switching to FTY from first- and second-line treatments showed a higher risk of disease reactivation (p = 0.041, OR = 1.86 and p = 0.002, OR = 2.92, respectively) and a shorter TTFR (p = 0.017, HR = 4.35 and p = 0.001, HR = 8.19, respectively). Conclusion: Naïve patients showed a better response to FTY compared to patients switching to FTY from other drugs. Our findings support the early use of FTY in patients with active MS. [ABSTRACT FROM AUTHOR]

Introduction: Cladribine administration has been approved for the treatment of relapsing–remitting multiple sclerosis (MS) in 2017; thus, data on cladribine in a real-world setting are still emerging. Methods: We report on cladribine effectiveness, safety profile, and treatment response predictors in 243 patients with MS followed at eight tertiary MS centers. Study outcomes were: (1) No Evidence of Disease Activity-3 (NEDA-3) status and its components (absence of clinical relapses, MRI activity, and sustained disability worsening); (2) development of grade III/IV lymphopenia. The relationship between baseline features and the selected outcomes was tested via multivariate logistic models. Results: Of the 243 subjects included in the study (66.5% female, age 34.2 ± 10 years, disease duration 6.6 ± 9.6 years), 64% showed NEDA-3 at median follow-up (22 months). Patients with higher number of previous treatments had lower probability to retain NEDA-3 [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.41–0.98, p = 0.04] and were more prone to experience clinical relapses (OR 1.6, 95% CI 1–2.6, p = 0.04). The presence of active lesions at baseline was associated with follow-up magnetic resonance imaging (MRI) activity (OR 1.92, 95% CI 1.04–3.55, p = 0.04). Patients with higher rate of relapses in the year prior to cladribine start were at higher risk of developing sustained disability worsening (OR 2.95% CI 1–4.2, p = 0.04). Lymphopenia grade III/IV over the follow-up was associated with baseline lymphocyte count (OR 0.998, 95% CI 0.997–0.999, p = 0.01). Conclusion: In this large cohort, we confirm previous data about cladribine effectiveness on disease activity and disability worsening and provide information on response predictors that might inform therapeutic choices. [ABSTRACT FROM AUTHOR]

In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity. [ABSTRACT FROM AUTHOR]

Background: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS). Objective: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally. Methods: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1–60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria. Results: At baseline, sT1w/T2w (p = 0.152) and cortical thickness (p = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal R 2 = 0.061). The association was modulated by failing NEDA-3 (marginal R 2 = 0.097). Conclusion: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures. [ABSTRACT FROM AUTHOR]

Background: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. Objective: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. Methods: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile). Results: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95]; p = 0.0001) and greater whole brain volume loss during the following year (β = −0.36%; 95% CI = [−0.60, −0.13]; p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). Conclusion: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information. [ABSTRACT FROM AUTHOR]

Background: Comparative effectiveness of natalizumab and fingolimod over a follow-up longer than 2 years has been not addressed yet. Objectives: To compare the effect on no evidence of disease activity (NEDA-3) in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab or fingolimod for at least 4 years. Methods: We included RRMS patients switched from first-line agents to natalizumab or fingolimod. Patients were propensity score (PS)-matched on a 1-to-1 basis. Percentages of patients reaching NEDA-3 status at 2 and 4 years of follow-up were compared using the chi-square test. The risk of not achieving NEDA-3 at 4 years was explored in matched samples by Cox regression models. Results: We evaluated 174 PS-matched patients. Patients receiving natalizumab reached a NEDA-3 status at 2 and 4 years more frequently than those exposed to fingolimod (63% vs 44%, p=0.037; 45.7% vs 25.8%, p=0.015, respectively). Patients receiving natalizumab were at a significant lower risk of not achieving the NEDA-3 status at 4 years compared to those exposed to fingolimod (hazard ratio (95% confidence interval): 0.54 (0.36–0.80), p=0.002). Conclusions: Although both medications were effective in patients non-responding to first-line agents, natalizumab seems to be superior to fingolimod in RRMS in obtaining NEDA-3 status at 4 years. [ABSTRACT FROM AUTHOR]

Background: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years., Methods: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement., Results: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Irene Schiavetti reports a relationship with Roche, Biogen, Horizon, Novartis, Hoya, Hippocrates Research, D.M.G Italia, Eyepharma, DreamsLab that includes: consulting or advisory. Livia Pasquali reports a relationship with Alexion, Biogen, Sanofi, Merck, Novartis, Roche that includes: consulting or advisory and travel reimbursement. Elisabetta Signoriello reports a relationship with Almirall, Biogen, Genzyme, Novartis, Teva that includes: board membership and travel reimbursement. Maria Pia Sormani reports a relationship with Biogen Idec, Merck Serono, Teva, Genzyme, Roche, Novartis, GeNeuro, Medday that includes: consulting or advisory. Jessica Frau reports a relationship with Biogen, Bristol, Novartis, Genzyme, Merck, Teva, Alexion that includes: board membership, consulting or advisory, and speaking and lecture fees. Daniele Caliendo reports a relationship with Merck that includes: funding grants. Alessio Signori reports a relationship with Roche, Horizon, Novartis that includes: speaking and lecture fees. Andrea Surcinelli reports a relationship with Roche, Merck, Biogen, Sanofi, Novartis that includes: travel reimbursement. Simona Bonavita reports a relationship with Novartis, Merck-Serono, Alexion, BMS, Biogen, Roche, Janssen-Cilag, Horizon that includes: speaking and lecture fees and travel reimbursement. Roberta Fantozzi reports a relationship with Novartis, Roche, Merck Serono, Bristol-Myers Squibb that includes: board membership and consulting or advisory. Antonio Carotenuto reports a relationship with Almirall, ECTRIMS- MAGNIMS, Biogen, Roche, Sanofi-Genzyme, Merck, Ipsen, Novartis that includes: funding grants. Doriana Landi reports a relationship with Biogen, Merck Serono, Teva, Bristol Myers Squibb, Mylan, Novartis, Roche, Horizon, Alexion, Sanofi-Genzyme, Novartis, Bayer-Schering that includes: speaking and lecture fees and travel reimbursement. Giacomo Lus reports a relationship with Biogen Idec, Merck Serono, Novartis, Sanofi- Aventis Pharmaceuticals, Teva neuroscience that includes: funding grants. Eleonora Cocco reports a relationship with Biogen, Merck, Novartis, Roche, Genzyme that includes: consulting or advisory and funding grants. Matteo Lucchini reports a relationship with Biogen, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Almirall, Horizon, Bayer that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Girolama Alessandra Marfia reports a relationship with Almirall, Bayer-Schering, Biogen, Sanofi Genzyme, Merck Serono, Novartis, Teva, Mylan, Bristol Mayers Squibb, Roche, Biogen that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Matteo Foschi reports a relationship with Merck, Biogen, Sanofi, Roche, Novartis that includes: consulting or advisory and travel reimbursement. Massimiliano Mirabella reports a relationship with Bayer Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva, Mylan, Almirall, CSL Behring, Roche, Ultragenix that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Diego Centonze reports a relationship with Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Protagon, Sandoz, Bristol-Myers Squibb, Alexion, Mitsubishi, Teva, Celgene that includes: board membership, funding grants, and non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity.

Background and Aims: Interferon beta (IFNb) is a safe first-line drug commonly used for relapsing-remitting (RR)-MS. Nevertheless, a considerable proportion of patients do not respond to IFNb treatment. Therefore, until now, a number of studies have investigated various markers that could predict the patients who would respond to IFNb therapy. The objective of this study was to identify reliable biomarkers to predict the efficacy of IFNb treatment in MS. Methods: In a group of 116 patients with clinically isolated syndrome (CIS) and RR-MS, we explored the association between CSF detectability of a large set of proinflammatory and anti-inflammatory molecules at the time of diagnosis and response to IFNb after the first year of treatment. The absence of clinical relapses, radiological activity and disability progression (NEDA-3) was assessed at the end of 1-year follow up. The results were compared with those obtained in additional groups of CIS and RR-MS patients treated with other first-line drugs (dimethyl fumarate and glatiramer acetate). Results: CSF undetectability of macrophage inflammatory protein (MIP)-1α was the main predictor of reaching NEDA-3 status after 1 year of IFNb treatment. Moreover, detectable platelet-derived growth factor (PDGF) was associated with higher probability of reaching NEDA-3. Conversely, no associations with the CSF molecules were found in the two other groups of patients treated either with dimethyl fumarate or with glatiramer acetate. Conclusion: MIP-1α and PDGF could potentially represent suitable CSF biomarkers able to predict response to IFNb in MS. [ABSTRACT FROM AUTHOR]

A combined endpoint measure to define no evidence of disease activity (NEDA) is becoming increasingly appealing in the treatment of multiple sclerosis (MS). Initial efforts using a 3 parameter NEDA monitored disease activity using clinical and MRI lesion data. Later refinements, introduced more recently, include brain atrophy measurement and cognitive function analysis in defining NEDA-4. Using these stringent criteria clearly differentiated the usefulness of different disease modifying agents (DMDs) in achieving and sustaining NEDA over time. This in turn has changed attitudes and strategies in management of MS.

Background: Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate fingolimod effectiveness in a real-world sample of RRMS patients. Methods: A retrospective, multicentre study in patients treated with fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of fingolimod. Results: Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%). Conclusions: Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up. [ABSTRACT FROM AUTHOR]

Background: One of the most common autoimmune disorder of central nervous system is multiple sclerosis. Fingolimod is the first oral drug approved to treat relapsing multiple sclerosis. 'No evidence of disease activity' 3, a composite measure of clinical and radiological outcomes, provides a comprehensive assessment of disease activity. Aim of study: To estimate the proportion of patients with relapsing remitting multiple sclerosis who have achieved No Evidence of Disease Activity up to one year kept on fingolimod therapy. Methods: A descriptive observational study that was conducted in the multiple sclerosis clinic at Baghdad Teaching Hospital during a period of one year from December 2018 till December 2019 in real world formatting. It included 100 patients diagnosed with multiple sclerosis and shifted from first line directly to second line fingolimod for one year. Expanded Disability Status Scale was calculated for all patients at onset of the year of the study, after six months, and after one year. Brain and cord MRI 1.5 tesla study before and after one year of treatment. The baseline and follow up results compared with the results at the end of the study year while the patients on fingolimod to see the percentage of patients who have achieved no evidence of disease activity. Results: In this study, the most common cause of shift to fingolimod was the failure of the 1st line treatment (64%). No relapse in 79% of cases. means of Expanded Disability Status Scale were significantly decreased after six months and after one year of treatment with fingolimod compared to that before treatment. T2 value and Gadolinium enhancement were significantly decreased after one year of treatment with fingolimod compared to that before treatment. By overall NEDA3, 66% of cases were improved. Prevalence of deteriorated cases was significantly increased with increasing in age and age of diagnosis. Post dose hypertension, fatigue, and lymphopenia were reported in 3% of patients. Conclusion: The No Evidence of Disease Activity parameters are significantly achieved with more doses of fingolimod therapy. [ABSTRACT FROM AUTHOR]

Background and Aims: Interferon beta (IFNb) is a safe first-line drug commonly used for relapsing-remitting (RR)-MS. Nevertheless, a considerable proportion of patients do not respond to IFNb treatment. Therefore, until now, a number of studies have investigated various markers that could predict the patients who would respond to IFNb therapy. The objective of this study was to identify reliable biomarkers to predict the efficacy of IFNb treatment in MS. Methods: In a group of 116 patients with clinically isolated syndrome (CIS) and RR-MS, we explored the association between CSF detectability of a large set of proinflammatory and anti-inflammatory molecules at the time of diagnosis and response to IFNb after the first year of treatment. The absence of clinical relapses, radiological activity and disability progression (NEDA-3) was assessed at the end of 1-year follow up. The results were compared with those obtained in additional groups of CIS and RR-MS patients treated with other first-line drugs (dimethyl fumarate and glatiramer acetate). Results: CSF undetectability of macrophage inflammatory protein (MIP)-1α was the main predictor of reaching NEDA-3 status after 1year of IFNb treatment. Moreover, detectable platelet-derived growth factor (PDGF) was associated with higher probability of reaching NEDA-3. Conversely, no associations with the CSF molecules were found in the two other groups of patients treated either with dimethyl fumarate or with glatiramer acetate. Conclusion: MIP-1α and PDGF could potentially represent suitable CSF biomarkers able to predict response to IFNb in MS. [ABSTRACT FROM AUTHOR]

Affecting 2.5 million people worldwide, multiple sclerosis (MS) is one of the main causes of acquired disability among young adults. In French West Indies (FWI), where MS has arisen from the end of the 80's, a low therapeutic response to interferons beta1 (IFN beta1) in patients of African descent, restrains the therapeutic options. Fingolimod is a Sphingosine-1-Phosphate receptor modulator whose efficacy in the treatment of MS has recently been shown in three phase III studies. Nevertheless, data are currently lacking concerning the use of Fingolimod among populations of African descent, particularly in a real-world setting. Efficacy and safety information collected during the first two years of follow-up have been analysed retrospectively for all patients in whom Fingolimod treatment was introduced in FWI between its marketing date and December 2015. Fifty-two consecutive patients with a relapsing remitting MS started Fingolimod therapy in the FWI, according to the European guidelines. After 24 months, 40 patients were still receiving the treatment. The average Annualized Relapse Rate (ARR) dropped by 81%, and 72.5% of patients remained free from disability progression during the 24 months on Fingolimod. MS remained controlled (according NEDA 3 criteria) for 41% of patients who were still on therapy at 24 months. Nine participants presented with a moderate or major side effect. Unlike IFN beta1 therapy, Fingolimod appears to be effective in Afro-Caribbean patients in a real-world setting with a similar benefit to what has been observed in phase III studies in more selected populations. • First study to assess MS activity in AC patients treated with Fingolimod in real life. • Similar rate of patient reaching NEDA-3 compared to phase III study. • The rate of patients reaching NEDA-3 increases from year 1 to year 2. • No case of PML was observed in this study. [ABSTRACT FROM AUTHOR]

• Cladribine tablets are an immune-reconstitution therapy for relapsing MS (RMS). • Belgian, single-center, retrospective cohort of 84 cladribine-treated RMS patients. • 72.6% of included patients retained NEDA-3 at mean follow-up (22.6 months). • More events in year 1 for patients with ≥2 prior DMTs and switching from FNG. • Valuable real-world insights that might inform treatment decisions. Cladribine tablets are a highly effective immune reconstitution therapy licensed for treating relapsing multiple sclerosis (RMS) in Europe since 2017. Currently, there is a high demand for real-world data from different clinical settings on the effectiveness and safety profile of cladribine in MS. Within this report, we retrospectively evaluated the outcomes of RMS patients who received cladribine between August 2018 and November 2021 at our Belgian institute. Patients with data for three effectiveness endpoints, more specifically, relapses, MRI observations, and confirmed disability worsening were incorporated into the analysis of 'no evidence of disease activity' (NEDA-3) re-baselined at 3 months. Safety endpoints included lymphopenia, liver transaminases, and adverse events (AEs) during follow-up. Descriptive statistics and time-to-event analysis were performed, including subgroup analysis by pre-treatment. Of the 84 RMS patients included in this study (age 42 [33–50], 64.3% female, diagnosis duration 6 [2–11] years, baseline EDSS 2.5 [1.5–3.6]), 14 (16.7%) patients experienced relapses, while disability progression and brain MRI activity occurred in 8.5% (6/71) and 6.3% (5/79). This resulted in 72.6% (n = 69, standard error 6%) retaining NEDA-3 status at the mean follow-up time of 22.6 ± 11.5 months. During the first year after cladribine initiation, disease activity prevailed more in patients with ≥2 prior DMTs and those switching from fingolimod, although both trends were not statistically significant. In terms of safety, 67.9% reported at least one AE during follow-up, the most frequent being fatigue (64.9%) and skin-related problems (38.6%). Overall, our research results confirm cladribine's safety and effectiveness among RMS patients in real-world conditions. After the re-baseline, we observed high rates of NEDA-3-retention, and no new safety signals were noted. [ABSTRACT FROM AUTHOR]

A combined endpoint measure to define no evidence of disease activity (NEDA) is becoming increasingly appealing in the treatment of multiple sclerosis (MS). Initial efforts using a 3 parameter NEDA monitored disease activity using clinical and MRI lesion data. Later refinements, introduced more recently, include brain atrophy measurement and cognitive function analysis in defining NEDA-4. Using these stringent criteria clearly differentiated the usefulness of different disease modifying agents (DMDs) in achieving and sustaining NEDA over time. This in turn has changed attitudes and strategies in management of MS. [ABSTRACT FROM AUTHOR]

The present study aims to describe the evolution of teriflunomide use for multiple sclerosis (MS) in the clinical setting, in particular for naïve patients and young women. Predictors of treatment response were also investigated. This was an independent, retrospective, real-world monocentric study. We analysed the use of teriflunomide from 2016 to 2020 in patients categorized as naïve or switchers, and assessed the variations in its use in men and women by age group. Clinical and MRI data of treated patients were evaluated, and NEDA-3 status at 24 and 36 months was defined. Determinants of therapeutic response were examined using regression analysis. The study included 319 MS patients exposed to teriflunomide [209 women (65.5%)]. Of these, 67 (21%) were naïve and 252 (79%) were switchers. A 20% increase of teriflunomide use in the naïve group in the past two years, particularly in 2020, the first year of global Sars-Cov-2 spread, was observed. An increase of teriflunomide use of more than 10% in young women under age 45 was also reported. NEDA-3 status was calculated for 204 patients after 24 months and was achieved in 120 (58.8%) of these ones. NEDA-3 was also achieved in 92/160 (56.8%) patients at 36 months. A lower ARR in the two years prior to teriflunomide treatment (p = 0.026), lower baseline age (p = 0.05), and lower EDSS score (p = 0.009) were associated with achievement of the NEDA-3. Our study confirms a major evolution in teriflunomide use in clinical settings, particularly for naïve patients and young women. • Teriflunomide use has progressively increased for treatment of Multiple Sclerosis (MS). • In the last two years, we described a 20% and 10% increase of its use in naïve patients and young women. • The efficacy goal of NEDA-3 at 24 and 36 months was achieved in more than 55% patients. • An adequate shared decision-making process is necessary to identify the best candidate patient. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disorder of the central nervous system. Accelerated brain volume loss (BVL) has emerged as a promising magnetic resonance imaging marker (MRI) of neurodegeneration, correlating with present and future clinical disability. We have systematically selected MS patients fulfilling 'no evidence of disease activity-3′ (NEDA-3) criteria under high-efficacy disease-modifying treatment (DMT) from the database of two Belgian MS centers. BVL between both MRI scans demarcating the NEDA-3 period was assessed and compared with a group of prospectively recruited healthy volunteers who were matched for age and gender. Annualized whole brain volume percentage change was similar between 29 MS patients achieving NEDA-3 and 24 healthy controls (−0.25 ± 0.49 versus −0.24 ± 0.20, p = 0.9992; median follow-up 21 versus 33 months; respectively). In contrast, we found a mean BVL increase of 72%, as compared with the former, in a second control group of MS patients (n = 21) whom had been excluded from the NEDA-3 group due to disease activity (p = 0.1371). Our results suggest that neurodegeneration in MS can slow down to the rate of normal aging once inflammatory disease activity has been extinguished and advocate for an early introduction of high-efficacy DMT to reduce the risk of future clinical disability. [ABSTRACT FROM AUTHOR]

Approximately 40% of young-onset multiple sclerosis (MS) patients experience breakthrough disease, which carries a high risk for long-term disability, and requires using therapies beyond traditional first-line agents. Despite the increasing use of newer disease-modifying treatments (DMTs) in this population, data are not available to guide the need for escalating DMTs and there is a scarcity of data on the effects of natalizumab in children and young adults with active disease. We performed a retrospective analysis of the rate of No Evidence of Disease Activity (NEDA), tolerability, and safety of natalizumab in a multi-center cohort of 36 children and young adults with highly active MS. All patients had active disease and initiated treatment with natalizumab. The primary endpoint was the rate of achieving NEDA-3 status, within two years of natalizumab treatment. To examine a possible effect of age on the outcome of treatment, outcomes were also analyzed by pre-pubertal (n = 13 children aged 9–13 years) and pubertal subgroups (n = 23 young adolescents aged 14–20 years). The NEDA-3 status of the pre-pubertal group was 92% in the first and second year and in the pubertal group - 96% in the first year and 92% in the second year. Natalizumab reduced the number and volume of brain lesions in both pre-pubertal and pubertal groups. Treatment was well-tolerated, only 8 patients (22.2%) had adverse events during the 2-year study period. Our analysis shows that natalizumab is effective and well-tolerated in pre-pubertal and pubertal MS patients. • Natalizumab was assessed in 36 prepubertal children and young adults with highly active MS. • Natalizumab reduced the number and volume of brain lesions in pre-pubertal and pubertal patients. • NEDA-3 status was above 92% in the first and second years of study follow-up. • NEDA-3 status in response to natalizumab was similar in pre-pubertal and pubertal patients. [ABSTRACT FROM AUTHOR]

• Alemtuzumab is associated with improved disability and cognitive scores in relapsing multiple sclerosis. • Safety data from our real-world cohort is similar to others, including clinical trials. • Laboratory data reveals long-lasting depletion of lymphocytes and CD4 T-cells. Multiple sclerosis (MS) is a chronic and progressive neurological disease characterized by recurrent episodes of inflammatory demyelination of the brain and spinal cord. Alemtuzumab has been previously shown in large phase III trials to be an effective therapy in reducing MS clinical flares as well as new radiological activity and atrophy rates. The purpose of this study was to examine real-world effectiveness and safety data from a large cohort of people treated with alemtuzumab at an academic medical center, including those who failed B-cell depletion therapy. Over an average of 2.6 years follow-up, there were small but significant improvements in neurological disability scores, and a 61% rate of the composite "No Evidence of Disease Activity" (NEDA-3) outcome at 2-year follow-up. There were no substantial safety issues encountered in our review; rates of adverse events were similar or below those reported in Phase III trials. We compare and contrast our results to other available real-world data using alemtuzumab in multiple sclerosis. [ABSTRACT FROM AUTHOR]

• No evidence of disease activity (NEDA) is considered as a potential outcome measure of DMTs effect. • NEDA-3 is defined by the absence of clinical relapses, disability progression and MRI activity. • NEDA-4 = NEDA-3 components and brain atrophy (predictive marker of disability progression). 'No evidence of disease activity' (NEDA) that has been identified as a potential outcome measure for the evaluation of DMTs effects. The concept has been adopted from other diseases such as cancer where treatment is intended to free the patient from the disease. Disease-free status has been substituted by NEDA in MS, since we are limited when it comes to fully evaluating the underlying disease. In general, NEDA, otherwise termed as NEDA-3, is defined by the lack of disease activity based on the absence of clinical relapses, disability progression with the expanded disability status score (EDSS), and radiological activity. Recently, brain atrophy, a highly predictive marker of disability progression, has been added as a fourth component (NEDA-4). The use of this composite allowed a more comprehensive assessment of the disease activity. Indeed, it has an important role in clinical trials as a secondary outcome in addition to primary endpoints. However, the evidence is insufficient regarding the ability of NEDA to predict future disability and treatment response. Moreover, combining different composites does not eliminate the limitation of each, therefore the use of NEDA in clinical routine is still not implemented. The aim of this review is first to report from the literature the available definitions of NEDA and its different variants, and second, evaluate the importance of its use as a surrogate marker to assess the efficacy of different DMTs. [ABSTRACT FROM AUTHOR]

Aim: The two-year study of the efficacy of Ifnb-1B (infibeta) in patients with relapsing-remitting (RRS) and secondary progressive multiple sclerosis (SPMS) in the Moscow region with the criteria NEDA-3., Material and Methods: Three hundred patients, 81 men and 219 women, aged from 18 to 67 years, including 227 with RRS and 73 with SPMS, were studied. The duration of disease was from 0.5 to 39 years, the level of neurological deficit on EDSS scale was from 1 to 6.5 points. All patients received infibeta., Results and Conclusion: During the treatment with infibeta, the chance of exacerbation decreased by an average of 39.4 times (OR 39.4 95% CI; 16.6-122.7) during the first year, by 35.3 times (OR 35.3; 95% CI 13.5-131,2) during the second year. A statistically significant decrease in the probability of exacerbation is also confirmed in the conditional logistic regression model (p<0.001). MRI revealed the signs of exacerbation and progression of the disease only in 11.5% of patients; 54.9% of the patients met the criteria NEDA-3. The highest efficacy of infibeta is noted in patients with RRS, more than 3 / 4 of them responded to therapy with the absence of both clinical and MRI signs of exacerbation and increase in neurodegeneration. Thus, a good clinical result is achieved in patients with RRS and SPMS treated with infibeta. When using the NEDA-3 criteria, a positive result is achieved in more than half of patients.

Aim: To evaluate the efficacy and safety of the interferon beta-1b bioanalogue 'infibeta' in the treatment of multiple sclerosis (MS) in comparison with other interferon beta bioanalogues and the generic drug glatiramer acetate., Material and Methods: The data of 500 patients with MS treated with different disease-modifying drugs were analyzed. Patients of group 1 (n=95) received infibeta; group 2 (n=108) interferon beta-1b; group 3 (n=83) genfaxon-44; group 4 (n=109) sinnovex; group 5 (n=105) aksoglatiran FS., Results: In all groups, there was a significant decrease in the AARR and an increase in the EDSS score (p<0,05) after 12 and 24 months of treatment (p<0,05) with the best indicators in groups 1-3. After 12 months of treatment, the number of patients without signs of MRI activity was higher in groups 1-3 (48-61%) than in groups 4 and 5 (47, 43%, respectively) (p>0,05). After 24 months of treatment, the number of patients without signs of MRI activity decreased to 41-46% in groups 1-3, and more significantly in group 4 (27%). The percentage of NEDA-3 achieving patients did not significantly differ in the groups (23-32%) after 12 months of treatment. After 24 months of treatment the NEDA-3 declined more in group 4 (19%), least of all in groups 1 and 2 (27, 25%, respectively) (p>0,05). In most cases, the observed adverse events were mild or moderate. Flu-like syndrome was observed rarely in groups 1 and 4 (p<0,05). Injection reactions were observed most commonly in groups 3 and 5 (p<0,05)., Conclusion: Infibeta, while retaining all the advantages of high-dose interferon beta, has the best tolerability profile, which makes it one of the optimal first line disease-modifying therapy for treatment of patients with MS.

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system comprising of inflammation, demyelinisation and neurodegeneration. The natural history of MS is heterogenous. Owing to the vast range and severity of the symptoms MS can cause the effect of the disease on one's cognitive and physical status is unpredictable. According to the new, phenotype based classification two subgroups can be distinguished; relapsing-remitting (RR) and progressive MS. Relapsing-remitting MS can be further divided into active and inactive disease. The activity of the disease can be proven either clinically and/or by radiological means. A patient's disease is considered inactive, if it fulfills the criteriae set in the "no evidence of disease activity-3" (NEDA-3) concept, meaning that no progression can be seen on the MRI scans, the patient is relapse free and there is no worsening on any disability scale. Nowadays a paradigm shift can be seen in the treatment of MS. The aim of this shift is to provide each and every patient with the most potent medication best suiting his/her illness as soon as possible. Alemtuzumab offers a great option as either a first line treatment or as escalation therapy for patients with a highly active disease. The efficacy of alemtuzumab was proven in two phase III trials (CARE-MS I, II), where it was compared to subcutaneous interferon b-1a, administered three times weekly. In both studies alemtuzumab was superior to subcutaneous interferon b-1a in terms of relapse rate reduction, in all scouted MRI parameters. In the CARE-MS II trial it was found superior in terms of progression slowing. In the studies' first 2 years 32% and 39% of the alemtuzumab treated patients managed to achieve the NEDA-3 state (data from CARE-MS II and I respectively). At the end of the 4 year extension of both studies these numbers have increased to 60% and 55% respectively. The aim of our synopsis is to suggest neurologists an evidence based guideline, a therapeutic algorithm to be used when they give their MS patients the very best, personalised treatment, and also to appoint the recently introduced alemtuzumab to its proper place in the algorithm.