Oral Disease-modifying Treatment Research Articles

Interplay between age and disease-modifying treatments in influencing infection risk in multiple sclerosis.

Disease-modifying treatments (DMTs) can increase the risk of infections in multiple sclerosis (MS). Aged individuals are usually excluded from clinical trials, and there is uncertainty regarding safety of immunosuppressive DMTs in these patients. To investigate the association of DMTs, ageing and other clinical variables with risk of infections in MS patients. Prospective single-centre observational study collecting information on occurrence, type and grade of infections in patients followed at the MS centre, Lugano (Switzerland). Associations with infection risk were tested using multivariable Poisson and Cox regressions. A total of 503 patients were included (injectables/untreated, n = 127; orals, n = 139; monoclonal antibodies (MAB), n = 237) and 326 infections recorded over 12.6 (11.6-14.0) months. As compared to injectable DMTs/no treatment, MAB and oral DMTs were positively associated with infection incidence (IRR = 2.32, 95% confidence interval (CI) = 1.39-3.89, p = 0.001; IRR = 2.04, 95% CI = 1.19-3.49, p = 0.009, respectively). After excluding COVID-19, the effect of MAB was stronger among patients <50 years (IRR = 5.90, 95% CI = 2.80-12.45, p < 0.001) than >50 years (IRR = 1.95, 95% CI = 0.91-4.15, p = 0.084). Higher disability and male sex were the only variables associated with severe infections. Treatment with MAB and oral DMTs is associated with higher incidence of infections, with a stronger effect in young MS patients. Disability appears the main predictor of severe infections regardless of treatment.

Current Status of Oral Disease-Modifying Treatment Effects on Cognitive Outcomes in Multiple Sclerosis: A Scoping Review.

Cognitive impairment represents one of the most hidden and disabling clinical aspects of multiple sclerosis (MS). In this regard, the major challenges are represented by the need for a comprehensive and standardised cognitive evaluation of each patient, both at disease onset and during follow-up, and by the lack of clear-cut data on the effects of treatments. In the present review, we summarize the current evidence on the effects of the available oral disease-modifying treatments (DMTs) on cognitive outcome measures. In this systematised review, we extract all the studies that reported longitudinally acquired cognitive outcome data on oral DMTs in MS patients. We found 29 studies that evaluated at least one oral DMT, including observational studies, randomised controlled trials, and their extension studies. Most of the studies (n = 20) evaluated sphingosine-1-phosphate (S1P) modulators, while we found seven studies on dimethyl fumarate, six on teriflunomide, and one on cladribine. The most frequently used cognitive outcome measures were SDMT and PASAT. Most of the studies reported substantial stability or mild improvement in cognitive outcomes in a short-time follow-up (duration of most studies ≤2 years). A few studies also reported MRI measures of brain atrophy. Cognitive outcomes were evaluated only in a minority of prospective studies on oral DMTs in MS patients with variable findings. More solid and numerous data are present for the S1P modulators. A standardised cognitive evaluation remains a yet unmet need to better clarify the possible positive effect of oral DMTs on cognition.

Comparative effectiveness of natalizumab on cognition in multiple sclerosis: A cohort study

Background: Cognitive impairment occurs in 40%–70% of persons with multiple sclerosis (MS). Objective: To examine the effectiveness of natalizumab compared with other disease-modifying treatments (DMTs) on improving cognition as measured by the Symbol Digit Modalities Test (SDMT). Methods: Data were collected as part of Swedish nationwide phase IV surveillance studies (2007–2020). An increase in SDMT score by ⩾10% of the difference between maximum score possible (110) and the baseline value was defined as cognitive improvement. The likelihood of improvement was compared between natalizumab-treated individuals and individuals treated with other DMTs using mixed effect logistic regression. Trend in odds of improvement was investigated using slope analyses. Results: We included 2100 persons with relapsing-remitting MS treated with natalizumab and 2622 persons treated with other DMTs. At 6 months, 45% reached improvement. The natalizumab group showed largest odds of improvement during follow-up (odds ratio: 2.3, 95% confidence interval (CI): 1.5–3.5). The odds of improvement increased by 7% (95% CI: 6–7) per month of natalizumab treatment. The equivalent estimate was 4% (95% CI: 2–5) for other monoclonal antibodies and nonsignificant for oral or platform therapies. Conclusion: Treatment with natalizumab or other monoclonal antibodies is associated with a significantly faster likelihood of cognitive improvement than platform or oral DMTs.

Gut Microbiota Changes during Dimethyl Fumarate Treatment in Patients with Multiple Sclerosis.

The gut microbiota is involved in the development of the immune system and can modulate the risk for immune-mediated disorders such as multiple sclerosis (MS). Dysbiosis has been demonstrated in MS patients and its restoration by disease-modifying treatments (DMTs) is hypothesized. We aimed to study the changes in gut microbiota composition during the first 6 months of treatment with dimethyl fumarate (DMF), an oral DMT, and to identify the microorganisms associated with DMF side effects. We collected and analyzed the gut microbiota of 19 MS patients at baseline and after 1, 3, and 6 months of DMF treatment. We then cross-sectionally compared gut microbiota composition according to the presence of gastrointestinal (GI) symptoms and flushing. Overall, the gut microbiota biodiversity showed no changes over the 6-month follow-up. At the genus level, DMF was associated with decreased Clostridium abundance after 6 months. In subjects reporting side effects, a higher abundance of Streptococcus, Haemophilus, Clostridium, Lachnospira, Blautia, Subdoligranulum, and Tenericutes and lower of Bacteroidetes, Barnesiella, Odoribacter, Akkermansia, and some Proteobacteria families were detected. Our results suggest that gut microbiota may be involved in therapeutic action and side effects of DMF, representing a potential target for improving disease course and DMT tolerability.

Real-life outcomes for oral disease-modifying treatments of relapsing-remitting multiple sclerosis patients: Adherence and adverse event profiles from Marmara University.

Disease-modifying treatments (DMT) are used to prevent future relapses and disability. High long-term adherence to treatment is important to achieve disease control. This study aims to investigate and compare adherence, adverse event (AE) profiles, and frequencies, main reasons for treatment discontinuation under Teriflunomide (TERI), Dimethyl Fumarate (DMF), and Fingolimod (FNG) for relapsing-remitting MS (RRMS) patients. This study is designed to explore patient-reported experiences in real-life settings. Patients who were older than 18 years with a definite diagnosis of RRMS and no history of stem-cell transplantation were included. Outpatient clinic data files at the Neurology Department of Marmara University from June 2012 to June 2019 were examined retrospectively. One hundred and ninety MS patients were enrolled. 118 FNG, 51 DMF, 44 TERI treatment cycles were recorded. Time sincedisease onset, time since diagnosis, and treatment duration were significantly longer for FNG (p = 0.012, p = 0.004, p < 0.001). 72.8% of all the treatment cycles were continued. There was no significant difference in treatment continuity between the 3 DMT groups. The most common reasons for treatment discontinuation in order of frequency were adverse events, the progression of the disease, and the persistence of relapses. No significant difference was found for treatment discontinuation reasons. 32% of the patients reported at least one AE. 28% FNG, 49 % DMF, and 27.3% TERI using patients reported AEs. AEs were much more frequently reported for DMF (p = 0.015). The most common adverse events for each DMT were alopecia (n = 6, 13.6%) for TERI, flushing for DMF (n = 20, 39.2%), and persistent lymphopenia for FNG (n = 9, 7.6%). No severe or life-threatening AE was reported for DMF, one patient experienced pancreatitis under TERI, and 11 (9.3%) patients using FNG had to stop treatment due to serious or life-threatening AEs including cardiac adverse events, opportunistic infections, and dysplasia. Overall treatment discontinuation because of AEs is as low as 10.3% in this study. However, AEs are still the main reason for treatment drop-out.

Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry

Background: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. Objectives: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. Methods: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). Results: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54–6.32), 7.04 (4.16–11.93), and 6.52 (3.79–11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. Conclusion: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.

Real-world Comparative Effectiveness and Persistence of Cladribine Tablets and Other Oral Disease-Modifying Treatments for Multiple Sclerosis from GLIMPSE: Results from the MSBase Registry (P12-4.003)

Real-world Comparative Effectiveness and Persistence of Cladribine Tablets and Other Oral Disease-Modifying Treatments for Multiple Sclerosis from GLIMPSE: Results from the MSBase Registry (P12-4.003)

Prescription trends of disease-modifying treatments for multiple sclerosis in Iran over the past 30 years

BackgroundIran, as a middle income country, is one of the places with high and rising prevalence of multiple sclerosis (MS). Regarding the substantial economic burden, reviewing the trend in prescribed disease modifying treatments (DMTs) could be of help. Here we studied the DMT information of nearly 14000 MS cases and its trends change for 30 years to improve health services to patients. MethodsThe population base of this descriptive-analytical (cross-sectional) study consisted of all MS patients in the nationwide MS registry of Iran (NMSRI), up to August 1, 2021. Registrars from 15 provinces, 24 cities, 13 hospitals,8 MS associations, 16 private offices, and 7 clinics had entered the data. ResultsOverall, 14316 cases were enrolled. The majority (76.1%) were female. The youngest and eldest patients were 5 and 78 years old, respectively. Diagnosis delay was under one year in most cases (median: 0, IQR: 0 – 1). Most (61.4%) had RRMS. Generally, platform injectables (IFN beta, glatiramer acetate) were the most used DMTs until 2010. It seems that introduction of newer agents (antiCD20s and oral DMTs) resulted in a decrease in the use of former drugs since around 2015. Some unusual practices are prominent such as using not approved DMTs for PPMS over the years, or administering high efficacy drugs like natalizumab for CIS. The results indicate the remaining popularity of first line injectable DMTs in female and pediatric patients. DiscussionMean age (SD) at onset in our study (29 ± 8.8) is near the statistics in Asia and Oceania (28 ± 0.7). Concerns about COVID-19 had a noticeable impact on administering high efficacy drugs like rituximab and fingolimod. However, in male patients this approach has not been the case. It may be related to more aggressive disease course in this group. The other possible explanation could be planning for pregnancy in female cases. The popularity of platform injectable drugs in pediatric MS may be related to its favorable safety profile over the years. Another point in this group, is the superiority of rituximab over other highly efficient medications.

Rational Design of Highly Potent, Selective, and Bioavailable SGK1 Protein Kinase Inhibitors for the Treatment of Osteoarthritis.

The serine/threonine kinase SGK1 is an activator of the β-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today, no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic, and safety profile. We describe the identification of a highly selective druglike 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor 17a that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 co-crystal structure, and multiple ligand-based computer models were applied to guide the chemical optimization of the compound ADMET and selectivity profiles. Compounds were selected for subchronic proof of mechanism studies in the mouse femoral head cartilage explant model, and compound 17a emerged as a druglike SGK1 inhibitor, with a highly optimized profile suitable for oral dosing as a novel, potentially disease-modifying agent for osteoarthritis.

Comparative analysis of dimethyl fumarate and fingolimod in relapsing\u2013remitting multiple sclerosis

BackgroundDimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing–remitting multiple sclerosis (RRMS).ObjectiveTo compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.MethodsWe identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.ResultsOf the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8–1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6–1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6–1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.ConclusionDimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.

Changing therapeutic strategies and persistence to disease-modifying treatments in a population of multiple sclerosis patients from Veneto region, Italy

BackgroundThe availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy. MethodsDemographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence. ResultsOf 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among second-line DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation. ConclusionThe use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors.

Summarizing Patient Preferences for the Competitive Landscape of Multiple Sclerosis Treatment Options.

Objective. Quantitatively summarize patient preferences for European licensed relapsing-remitting multiple sclerosis (RRMS) disease-modifying treatment (DMT) options. Methods. To identify and summarize the most important RRMS DMT characteristics, a literature review, exploratory physician interviews, patient focus groups, and confirmatory physician interviews were conducted in Germany, the United Kingdom, and the Netherlands. A discrete choice experiment (DCE) was developed and executed to measure patient preferences for the most important DMT characteristics. The resulting DCE data (n=799 and n=363 respondents in the United Kingdom and Germany, respectively) were analyzed using Bayesian mixed logit models. The estimated individual-level patient preferences were subsequently summarized using 3 additional analyses: the quality of the choice data was assessed using individual-level R2 estimates, individual-level preferences for the available DMTs were aggregated into DMT-specific preference shares, and a principal component analysis was performed to explain the patients' choice process. Results. DMT usage differed between RRMS patients in Germany and the United Kingdom but aggregate patient preferences were similar. Across countries, 42% of all patients preferred oral medications, 38% infusions, 16% injections, and 4% no DMT. The most often preferred DMT was natalizumab (26%) and oral DMT cladribine tablets (22%). The least often preferred were mitoxantrone and the beta-interferon injections (1%-3%). Patient preferences were strongly correlated with patients' MS disease duration and DMT experience, and differences in patient preferences could be summarized using 8 principle components that together explain 99% of the variation in patients' DMT preferences. Conclusion. This study summarizes patient preferences for the included DMTs, facilitates shared decision making along the dimensions that are relevant to RRMS patients, and introduces methods in the medical DCE literature that are ideally suited to summarize the impact of DMT introductions in preexisting treatment landscapes.

ND3 SHORT- AND LONG-TERM DISABILITY BURDEN AMONG EMPLOYED PATIENTS RECEIVING DISEASE-MODIFYING TREATMENT FOR MULTIPLE SCLEROSIS

This study examined the short-term disability (STD) and long-term disability (LTD) burden (as measures of severe productivity loss) among employees with multiple sclerosis (MS) initiating disease-modifying treatments (DMTs). Using the IBM MarketScan Commercial Claims and Health and Productivity Management Database, patients with ≥2 new MS claims (≥1 and <365 days apart) between January 1, 2009, and January 1, 2017, and 1 subsequent claim for a DMT (index date) were identified. Patients had ≥12 months of continuous enrollment pre-index, ≥1 full calendar year of STD and/or LTD eligibility (accessible to active employees only), and no evidence of pregnancy or malignancy during the study period. The number and duration of all STD and/or LTD claims were captured during all calendar years of follow-up. A total of 3,023 patients initiating orals (25.5%), injectables (64.1%), or infusions (6.1%) were identified (mean age: 41.4 years; female: 62.1%). In the first year, the percentage of patients with STD claims was generally similar across routes of administration (total: 23.2%; orals: 21.7%; injectables: 23.4%; infusions: 27.7%), as were STD days per patient with a claim (68.8, 69.9, 68.8, and 64.6 days, respectively). Percentages of patients with LTD claims were low (total: 3.1%; orals: 3.7%; injectables: 2.9%; infusions: 2.8%). Oral DMT initiators had the lowest number of LTD days per patient (31.7 days), with a numerically lower number of days compared with infusions (45.8 days) and a significantly lower difference compared with injectables (76.3 days; P=0.0307). Productivity loss burden was high in the first year in MS patients. Oral DMT initiators had the lowest percentage of short-term disability claims and days per long-term disability claim, suggesting productivity benefits in severe productivity loss with early access to orals. Additional research is needed to better quantify this benefit.

Nocebo in multiple sclerosis trials: A meta-analysis on oral and newer injectable disease-modifying treatments

BackgroundNocebo phenomena are linked to decreased adherence to treatments in clinical practice as well as difficulty in assessing the adverse effect profile in clinical trials. ObjectiveTo estimate the incidence and severity of nocebo responses in clinical trials of oral and newer injectable disease-modifying treatments (DMTs) for relapsing multiple sclerosis (MS). MethodsMeta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events (AEs) in randomized, placebo-controlled MS trials published between 2005 and 2018. Nocebo severity was estimated as a percentage of placebo-treated patients who discontinued the treatment due to drug-related AEs. ResultsThe pooled incidence of nocebo was 89% (95% CI: 88%–90%) in trials for oral DMTs (cladribine, fingolimod, teriflunomide and dimethyl fumarate) and 66% (95% CI: 51%–80%) in trials of newer injectable DMTs (biosimilar glatiramer acetate 20 mg, innovator glatiramer acetate 40 mg and pegylated interferon beta). The pooled nocebo severity was 8% (95% CI: 5%–12%) for oral treatments and 2% (95% CI: 0–2%) for newer injectable DMTs. ConclusionsOral DMTs may be associated with a higher incidence and greater nocebo severity than newer injectables.

Preclinical discovery and development of fingolimod for the treatment of multiple sclerosis

ABSTRACTIntroduction: Fingolimod, the first oral disease-modifying treatment (DMT) in multiple sclerosis (MS), is a sphingosine 1-phosphate receptor (S1PR) ligand. Approved in 2010, fingolimod has been extensively studied and has been credited with several mechanisms of actions that contribute to its efficacy in MS, among which is the regulation of lymphocyte circulation between the central nervous system and the periphery. Concerns about toxicity, off-target effects, and real-life performance have been raised over time in post-marketing studies of such that next-generation sphingosine-1 phosphate receptor ligands are now being developed.Areas covered: Herein, the authors expand upon previous systematic reviews obtained via PubMed and through their expert opinion on fingolimod use in clinical practice. Long-term data including long-term efficacy, safety, tolerability, and management especially within growing DMT options and pre-treatment constellation in MS patients are discussed, together with the results of an increased understanding of the chemistry underlying the structure–activity relationship.Expert opinion: Despite the limitations illustrated in this article, fingolimod still constitutes a paradigm shift in MS treatment. However, although immunomodulation via S1PRs on lymphocytes has represented a major breakthrough in the clinical management of MS, modifying the evolution of progressive MS will likely require the development of approaches other than merely targeting S1PRs.

PSY132 - Patterns of Use of Disease Modifying Treatments Among Patients with Relapsing Remitting Multiple Sclerosis in Europe Between 2012 and 2016

To assess the patterns of use of Disease Modifying Treatments (DMTs) between 2012 and 2016 among Relapsing Remitting Multiple Sclerosis (RRMS) patients in Europe (EU). Data are from an ongoing multi-center retrospective chart-review study of RRMS patients in 5-EU (5EU: UK/Germany/France/Italy/Spain). Data on diagnosis, clinical status, and treatment patterns are collected from health care providers (HCPs) with practice duration (≥3yrs) and patient volume (≥15 MS patients/month). Each HCP collects de-identified data from next 10 consecutive MS patients within the respective study windows. RRMS patients taking injectable (INJ), ORAL, or infusible (INF) DMTs were analyzed across five time-periods since 2012: Q42012/Q42013/Q42014/Q42015/Q42016. In total, 1395(Q42012)/1465(Q42013)/1601(Q42014)/1586(Q4015)/1591(Q416) eligible RRMS patient charts were included in the analyses. Over the 2012-2016 time period, top-4 reasons for choosing DMTs were: efficacy factors (74.2%/55.6%), convenience factors (8.0%/13.6%), benefit vs risk profile (2.6%/10.5%) and patient decision (5.5%/5.9%). Overall % patients on INJ decreased from 73.5% (Q42012) to 38.8% (Q42016), and those on ORAL increased from 11.3% (Q42012) to 43.2% (Q42016). INF use showed only slight increase (14.6%/17.5% in Q42012/Q42016). Within 1st-line, changes in drug utilization from Q42012/Q42016 were: INJ:93.5%/53.5%, ORAL:2.0%/35.7%, INF:4.2%/10.3%; within 2nd-line, INJ:51.8%/23.7%, ORAL:18.9%/53.5%, INF:28.6%/22.7%; within 3rd and later lines, INJ:17.8%/9.4%, ORAL:44.1%/51.1%, INF:36.2%/37.8%. Among the overall cohort, mean EDSS scores at the time of study data collection remained stable from Q42012/Q42016 for INJ (2.08/1.99) & INF (3.63/3.26), while EDSS scores decreased for ORAL (3.18/2.16). In this study cohort, adoption of oral DMTs increased dramatically; displacing the use of injectables as preferred treatment and corresponding to a shift in prescription driver trends. Most recent EDSS scores indicated lower disease severity among users of oral DMTs, a likely consequence of their 1st line penetration. Impact of observed treatment patterns and treatment sequencing strategies on patient outcomes warrant further scrutiny.

Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study

ObjectiveLittle is known about disease-modifying treatments (DMTs) for multiple sclerosis (MS) and infection risk in clinical practice. We examined the association between DMTs and infection-related medical encounters.MethodsUsing population-based administrative data...

A multicentRE observational analysiS of PErsistenCe to Treatment in the new multiple sclerosis era: the RESPECT study.

In this independent, multicenter, retrospective study, we investigated the short-term persistence to treatment with first-line self-injectable or oral disease-modifying treatments (DMTs) in patients with relapsing-remitting multiple sclerosis. Data of patients regularly attending 21 Italian MS Centres who started a self-injectable or an oral DMT in 2015 were collected to: (1) estimate the proportion of patients discontinuing the treatment; (3) explore reasons for discontinuation; (3) identify baseline predictors of treatment discontinuation over a follow-up period of 12months. We analyzed data of 1832 consecutive patients (1289 women, 543 men); 374 (20.4%) of them discontinued the prescribed DMT after a median time of 6 months (range 3days to 11.5months) due to poor tolerability (n = 163; 43.6%), disease activity (n = 95; 25.4%), adverse events (n = 64; 17.1%), convenience (i.e. availability of new drug formulations) and pregnancy planning (n = 21; 1.1%). Although the proportion of discontinuers was higher with self-injectable (n = 107; 22.9%) than with oral DMT (n = 215; 16.4%), the Cox regression model revealed no significant between-group difference (p = 0.12). Female sex [hazard ratio (HR) = 1.39, p = 0.01] and previous exposure to ≥ 3 DMTs (HR = 1.71, p = 0.009) were two independent risk factors for treatment discontinuation, regardless of prescribed DMTs. Our study confirms that persistence to treatment represents a clinical challenge, irrespective of the route of administration.

A Longitudinal, Observational Study of the Effect of Dimethyl Fumarate on Hippocampal Metabolites in RRMS using 1H-MR Spectroscopy

Background: Dimethyl fumarate (DMF), an oral diseasemodifying treatment for Multiple Sclerosis (MS), displays anti-oxidative properties, thought to be via modulation of glutathione (GSH). However, to date, the effect of DMF on the metabolic profile of MS brains has not been evaluated. The aim of this study was to measure cross-sectional changes in hippocampal neurometabolites in Relapsing- Remitting MS (RRMS) patients, compared to Healthy Controls (HCs) and then evaluate the metabolic impact of DMF treatment longitudinally over 24 months. Methods: 1H-MRS was undertaken on 20 RRMS patients prior to and up to 24 months post-inception of DMF treatment and 20 age sex-matched HCs. Spectroscopic data was acquired from the hippocampus using single voxel spectroscopy (6.75 mL, PRESS, TE 30 ms) at 3T. Results: We identified a significant reduction in hippocampal N-acetylaspartate (NAA, -13%, p=0.0001) and increased myoinositol (mI, +9%, p=0.02) in RRMS patients, before starting DMF, compared to HCs. Following treatment onset, GSH levels differed significantly over 24 months in the RRMS group (F=3.5, p<0.05). There was a reduction in GSH from baseline to 1 month of treatment (p=0.014). This reduction remained statistically significant after 6 months of treatment (p=0.04), but slightly increased after 12 and 24 months of treatment (p=0.15 and 0.18, respectively), approaching levels seen in HCs. Conclusions: The trend for the rebound effect of GSH following 24 months of DMF treatment is suggestive of recovery from the inflammatory event and is the first demonstration of an anti-oxidative effect in the MS brain following DMF treatment.

Teriflunomide for multiple sclerosis in real-world setting.

Teriflunomide 14mg is a once-daily oral disease-modifying treatment for relapsing-remitting multiple sclerosis. We examined adverse event (AE) profile and efficacy in real life. In this observational cohort study, we retrospectively examined 1521 blood samples and data of 102 patients followed for up to 28months. The number of female patients starting teriflunomide peaked in the fifth decade, 10years later compared to male patients (P<.001), reflecting pregnancy concerns. Seventy-six percentages of patients shifted to teriflunomide from treatment with interferon-beta. Expanded disability status scale improved in 11% of patients (18.2±3.6months follow-up) and remained constant in 67.5% (15±5.3months follow-up). Of ten relapses, three occurred within 6months after starting treatment. Seventeen patients (16.5%) discontinued teriflunomide: 53% because of AEs and 29% because of relapse. Levels of alanine aminotransferase (ALT) remained normal in 95.3% of the blood samples and remained below 1.5 times the upper limit of normal in 91% of the 4.7% abnormal samples. One-third of the patients had abnormal ALT values at least once. Haematological abnormalities were found in <4% of the blood samples, but at least one abnormal value was observed in up to 21% of the patients. Efficacy and safety of teriflunomide in real-life setting support data obtained by the pivotal trials. Laboratory abnormalities are rare among the large number of samples, but patients may commonly have a single mild, abnormal value if frequently tested.