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

No abstract available [ABSTRACT FROM AUTHOR]

Background: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. Objective: To characterize long-term safety and efficacy of ozanimod. Methods: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. Results: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. Conclusions: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity. [ABSTRACT FROM AUTHOR]

Background: There is a lack of studies on the association between obesity and conversion from a clinically isolated syndrome (CIS) to multiple sclerosis (MS). Objective: The aim of this study was to determine whether obesity predicts disease activity and prognosis in patients with CIS. Methods: Body mass index (BMI) at baseline was available for 464 patients with CIS in BENEFIT. Obesity was defined as BMI ⩾ 30 kg/m2 and normal weight as 18.5 ⩽ BMI < 25. Patients were followed up for 5 years clinically and by magnetic resonance imaging. Hazard of conversion to clinically definite (CDMS) or to 2001 McDonald criteria (MDMS) MS, annual rate of relapse, sustained progression on Expanded Disability Status Scale (EDSS), change in brain and lesion volume, and development of new brain lesions were evaluated. Results: Obese individuals were 39% more likely to convert to MDMS (95% CI: 1.02–1.91, p = 0.04) and had a 59% (95% CI: 1.01–2.31, p = 0.03) higher rate of relapse than individuals with normal weight. No associations were observed between obesity and conversion to CDMS, sustained progression on EDSS or magnetic resonance imaging (MRI) outcomes, except for a larger reduction of brain volume in obese smokers as compared to normal weight smokers (−0.82%; 95% CI: −1.51 to −0.12, p = 0.02). Conclusion: Obesity was associated with faster conversion to MS (MDMS) and a higher relapse rate. [ABSTRACT FROM AUTHOR]

Background: Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Objective: Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. Methods: In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). Results: A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24—end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. Conclusion: Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged. [ABSTRACT FROM AUTHOR]

Background: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. Objective: To validate the proposed genetic markers and to identify new markers. Methods: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. Results: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10−4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10−3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10−15). Conclusion: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies. [ABSTRACT FROM AUTHOR]

Objective: To assess whether a high-salt diet, as measured by urinary sodium concentration, is associated with faster conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and MS activity and disability.Methods: BENEFIT was a randomized clinical trial comparing early versus delayed interferon beta-1b treatment in 465 patients with a CIS. Each patient provided a median of 14 (interquartile range = 13-16) spot urine samples throughout the 5-year follow-up. We estimated 24-hour urine sodium excretion level at each time point using the Tanaka equations, and assessed whether sodium levels estimated from the cumulative average of the repeated measures were associated with clinical (conversion to MS, Expanded Disability Status Scale [EDSS]) and magnetic resonance imaging (MRI) outcomes.Results: Average 24-hour urine sodium levels were not associated with conversion to clinically definite MS over the 5-year follow-up (hazard ratio [HR] = 0.91, 95% confidence interval [CI] = 0.67-1.24 per 1g increase in estimated daily sodium intake), nor were they associated with clinical or MRI outcomes (new active lesions after 6 months: HR = 1.05, 95% CI = 0.97-1.13; relative change in T2 lesion volume: -0.11, 95% CI = -0.25 to 0.04; change in EDSS: -0.01, 95% CI = -0.09 to 0.08; relapse rate: HR = 0.78, 95% CI = 0.56-1.07). Results were similar in categorical analyses using quintiles.Interpretation: Our results, based on multiple assessments of urine sodium excretion over 5 years and standardized clinical and MRI follow-up, suggest that salt intake does not influence MS disease course or activity. Ann Neurol 2017;82:20-29. [ABSTRACT FROM AUTHOR]

The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening ( n = 175) were randomized 1:1:2 to continue natalizumab ( n = 45), switch to placebo ( n = 42), or switch to other therapies ( n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during natalizumab interruption did not exceed pre-natalizumab levels or levels seen in historical control patients. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the possible use of a scoring system based on magnetic resonance imaging (MRI) to relapsing-remitting multiple sclerosis (RRMS) patients receiving glatiramer acetate (GA). The study was conducted to 151 patients and their scores were taken on clinical and MRI activity after a year of treatment, while response variables were analysed through regression analysis. Findings reveal that the total possible score range for patients was between 0 to 3.

Objective To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy. Methods The presence or absence of both immunoglobulin (Ig) G and IgM oligoclonal bands (OCB) was blindly examined in paired cerebrospinal fluid (CSF) and serum samples from a large PPMS patient cohort, and related to clinical and imaging evidence of focal inflammatory disease activity. Results Using both cross-sectional samples and serial sampling in a subgroup of patients followed prospectively as part of the placebo-controlled OLYMPUS study of rituximab in PPMS, we found that the presence of CSF-restricted IgM OCB (but not of IgG OCB) is associated with an active inflammatory disease phenotype in PPMS patients. This finding was confirmed in an independent, multicenter validation cohort. Interpretation The presence of CSF IgM OCB may be a biomarker for a subset of PPMS patients with more active inflammatory disease, who may benefit from immune-directed treatments. Ann Neurol 2014;76:231-240 [ABSTRACT FROM AUTHOR]

Objective Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25( OH)D) on multiple sclerosis ( MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25( OH)D. Methods This study measured serum 25( OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b ( IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging ( MRIs). Results The number of gadolinium-enhancing lesions was highly significantly associated with 25( OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25( OH)D regulates expression dynamics of a large gene-gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25( OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25( OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25( OH)D effects on MS activity were additively enhanced by IFNB-1b. Interpretation Here, we provide mechanistic evidence that an unbalanced 25( OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b. [ABSTRACT FROM AUTHOR]

Background: Cognitive dysfunction occurs at the earliest stages of multiple sclerosis (MS), including the stage of clinically isolated syndrome (CIS).Methods: We evaluated the impact of interferon beta-1b (IFNβ-1b) 250 µg on cognitive performance during the CIS stage in the BENEFITstudy. Cognition was assessed by Paced Auditory Serial Addition Test-3” (PASAT-3”) scores.Results: Improvement in PASAT-3” score from baseline to year two was greater for IFNβ-1b treatment than placebo in patients not reaching clinically definite MS (CDMS) by year two. The treatment effect was maintained at year five and was statistically significant.Conclusions: To conclude, early IFNβ-1b treatment had a sustained positive effect on PASAT-3” score over the 5-year BENEFIT study. [ABSTRACT FROM PUBLISHER]

Summary: Background: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. Methods: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 μg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. Findings: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0·63, 95% CI 0·48–0·83; p=0·003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0·76, 0·52–1·11; p=0·177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. Interpretation: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. Funding: Bayer Schering Pharma. [Copyright &y& Elsevier]

The objective in this paper is to compare the cumulative incidence and incidence density of therapy-related acute myeloid leukaemia in two cohorts of patients with multiple sclerosis treated with mitoxantrone, and with previously reported data in the literature. Six new cases of acute myeloid leukaemia were observed by prospectively following two Spanish series of 142 and 88 patients with worsening relapsing multiple sclerosis and secondary-progressive disease treated with mitoxantrone. A literature review shows 32 further cases of acute myeloid leukaemia reported, 65.6% of which are therapy-related acute promyelocytic leukaemia. Five cases in the cohorts fulfilled the diagnostic criteria for acute promyelocytic leukaemia, and one patient was diagnosed with pre-B-acute lymphoblastic leukaemia. Acute myeloid leukaemia latency after mitoxantrone discontinuation was 1 to 45 months. The accumulated incidence and incidence density was 2.82% and 0.62%, respectively, in the Valencian cohort, and 2.27% and 0.44% in the Catalonian cohort. In the only seven previously reported series, the accumulated incidence varied from 0.15% to 0.80%. The real incidence of acute myeloid leukaemia after mitoxantrone therapy in the multiple sclerosis population could be higher as evidenced by the growing number of cases reported. Haematological monitoring should continue for at least 5 years after the last dose of mitoxantrone. These data stress the necessity of re-evaluating this risk. [ABSTRACT FROM AUTHOR]

The BENEFIT study examined interferon beta (IFNB)-1b treatment in patients with clinically isolated syndrome (CIS) and ≥ 2 clinically silent brain MRI lesions. Subgroups of 468 patients (IFNB-1b: n = 292; placebo: n = 176) were created for demographics, clinical, laboratory, and MRI findings at onset. The 'natural' risk of clinically definite MS (CDMS) over 2 years was estimated by Kaplan Meier statistics in placebo-treated patients; the IFNB-1b treatment effect was analysed by Cox proportional hazards regression. The risk of CDMS was increased in placebotreated patients (overall 45 %) if they were younger (< 30 years: 60%), were cerebrospinal fluid (CSF)-positive (49 %), or had received steroid treatment (48 %). MRI parameters implied a higher risk in placebo-treated patients with ≥ 9 T2-lesions (48%) or ≥ 1 gadolinium (Gd)-enhancing lesions (52 %). The CDMS risk was highest (75 %) in placebo-treated patients with monofocal disease onset displaying MRI disease activity (≥ 1 Gd-lesion) and dissemination (≥ 9 T2-lesions). Treatment effects were significant across almost all subgroups including patients with less disease dissemination/activity at onset (monofocal: 55%; < 9 T2-lesions: 60%; no Gd-lesions: 57%) and patients without steroid treatment for the CIS (62 %). Monofocal patients had greater treatment effects if they had ≥ 9 T2-lesions (61 %), Gd-lesions (58 %), or both (65 %). This study confirms the impact of age of onset, CSF and MRI findings on risk of conversion from CIS to CDMS. IFNB-1b treatment effect was robust across the study population including patients without MRI disease activity and less clinical or MRI disease dissemination at onset and patients not receiving steroids for the CIS. [ABSTRACT FROM AUTHOR]

This article presents the results of a trial on the effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis (MS). Several studies have provided evidence that treatment with interferon beta delays conversion to clinically definite MS (CDMS). This study was to determine if early initiation of treatment prevents development of confirmed disability in MS. The study followed patients in the trial for a period of three years and concluded that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability which supports its use after the first manifestation of relapsing-remitting MS.

Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research. [ABSTRACT FROM AUTHOR]

Background: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression.Methods: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211.Findings: 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0.63, 95% CI 0.48-0.83; p=0.003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, 0.52-1.11; p=0.177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b.Interpretation: Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes.Funding: Bayer Schering Pharma. [ABSTRACT FROM AUTHOR]