Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

Real-world annualized relapse rates from contemporary multiple sclerosis clinics in the UK: a retrospective multicentre cohort study.

BACKGROUND: Annualized relapse rate (ARR) is used as an outcome measure in multiple sclerosis (MS) clinical trials. Previous studies demonstrated that ARR has reduced in placebo groups between 1990 and 2012. This study aimed to estimate real-world ARRs from contemporary MS clinics in the UK, in order to improve the feasibility estimations for clinical trials and facilitate MS service planning. METHODS: A multicentre observational, retrospective study of patients with MS from 5 tertiary neuroscience centres in the UK. We included all adult patients with a diagnosis of MS that had a relapse between 01/04/2020 and 30/06/2020. RESULTS: One hundred thirteen out of 8783 patients had a relapse during the 3-month study period. Seventy-nine percent of the patients with a relapse were female, the mean age was 39 years, and the median disease duration was 4.5 years; 36% of the patients that had a relapse were on disease-modifying treatment. The ARR from all study sites was estimated at 0.05. The ARR for relapsing remitting MS (RRMS) was estimated at 0.08, while the ARR for secondary progressive MS (SPMS) was 0.01. CONCLUSIONS: We report a lower ARR compared to previously reported rates in MS.

Is the assumption of waning of treatment effect applied consistently across NICE technology appraisals? A case-study focusing on disease-modifying therapies for treatment of multiple sclerosis.

OBJECTIVES: Whether the effects of therapies may wane over time is a matter of debate, especially when considering their long-term cost-effectiveness. Here, we examined how the assumption of the waning of treatment effect was applied across the National Institute for Health and Care Excellence (NICE) appraisals for disease-modifying therapies (DMTs) used in multiple sclerosis. METHODS: We undertook a document analysis following a search of the NICE website. The inclusion criteria of the study were as follows: all publicly available documents related to completed appraisals for DMTs (period: January 2000 to July 2021). The exclusion criteria of the study were as follows: all documents that did not meet the inclusion criteria, especially pertaining to drugs used in other disease areas. We extracted information about the waning of treatment effect assumption as considered by companies, assessment groups, and appraisal committees, and we analyzed trends over time. RESULTS: We reviewed fifteen appraisals that reported guidance on sixteen DMTs. Irrespective of the drugs' mechanism of action or their pharmaceutical nature, there was substantial variation in the modalities when the assumption of waning was implemented. We noted the recent preference to use all-cause discontinuation as a proxy. This heterogeneity did not appear to affect acceptance of the DMTs (all but one were recommended for use across the National Health System (NHS)). CONCLUSIONS: Modeling the long-term effect of therapies is challenging, especially given the limited follow-up duration of related trials. This generates recurrent debates on the presence of waning of treatment efficacy and heterogeneity across appraisals. More refined recommendations obtained by consensus among stakeholders could help to achieve greater consistency in decision making.

Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride.

Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1)-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, we showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis.

Treatment continuation with cladribine at 5 years after initiation in people with multiple sclerosis: A case series and literature review.

BACKGROUND: Cladribine is an oral disease-modifying drug approved for the treatment of highly active relapsing multiple sclerosis (MS). The recommended number of treatment courses is two, with the courses given 1 year apart (i.e., in year 1 and year 2), followed by 2 years without treatment. Pivotal clinical trials showed that, compared with placebo, cladribine significantly reduced relapse rates, risk of disability progression and magnetic resonance imaging measures of disease activity for up to 4 years in treatment-naïve or -experienced adults with relapsing-remitting MS (RRMS). The management of patients and requirement for retreatment with cladribine beyond year 4 is unclear. METHODS: We describe the treatment history and outcomes of three people with MS retreated with cladribine, given as a third course 5 years after treatment initiation. We also include a review of evidence on retreatment with cladribine from year 3 onwards and a discussion of patient selection criteria for retreatment. RESULTS: The cases included a 53-year-old female patient with RRMS, a 43-year-old female patient with RRMS, and a 42-year-old male patient with RRMS. Six months after the third course of cladribine, all three patients were relapse-free and stable on magnetic resonance imaging, with no evidence of disease activity. At 11-12 months follow-up, all patients had clinical and radiological stability (i.e., no evidence of disease activity). CONCLUSION: Continuation of oral cladribine treatment may be considered for people with MS beyond year 5 following completion of the initial two courses. Our real-world experience is ongoing and additional data are required to obtain insight into patient phenotypes which predict response to cladribine treatment.

Literature review and meta-analysis of natalizumab therapy for the treatment of highly active relapsing remitting multiple sclerosis in the 'suboptimal therapy' patient population.

BACKGROUND: Highly active (HA) relapsing remitting multiple sclerosis (RRMS) is associated with frequent relapses and high burden of disease/disability. Natalizumab is licensed for HA RRMS, including rapidly evolving severe (RES) (≥2 relapses in previous year) and sub-optimally treated (SOT) (≥1 relapse in previous year despite treatment) populations. However, there is limited RCT evidence in the SOT subpopulation. OBJECTIVE: To review the non-RCT evidence for natalizumab in SOT HA RRMS. METHODS: Databases were searched to January 2023 for non-randomised studies of natalizumab in HA RRMS. Studies in patients with ≥1 relapse during previous treatment were eligible for inclusion. Meta-analyses were conducted to compare natalizumab with platform and higher efficacy disease-modifying therapies, with sensitivity analysis restricted to studies of low risk of bias. RESULTS: Included comparative studies (n = 16) showed natalizumab had lower relapse rates, disease activity and MRI (radiological) outcomes compared with platform and higher efficacy therapy. Case series (n = 11) showed natalizumab was associated with high rates of freedom from relapse and clinical/radiological disease activity and reductions in annualised relapse rate and disability progression. CONCLUSIONS: Literature reviewed indicates that natalizumab is more effective than other included treatments for SOT patients. Findings were consistent with studies in the broad HA RRMS population, suggesting that natalizumab may have similar efficacy for SOT and RES HA RRMS.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

Virtual Flavor: High-fidelity simulation of real flavor experiences.

Food and drink are a key part of our lives. While Virtual Reality has the potential to provide high-fidelity simulation of real experiences in virtual worlds, the incorporation of flavor appreciation within these virtual experiences has largely been ignored. This paper introduces a virtual flavor device to simulate real flavor experiences. The goal is to provide virtual flavor experiences, using food safe chemicals for the three components of a flavor (taste, aroma, mouthfeel), which are perceived as "indistinguishable" from the equivalent real experience. Furthermore, because we are delivering a simulation, the same device can be used to take a user on a "flavor discovery journey" from a start flavor to a new, preferred flavor by adding or removing any amount of the components. In the first experiment, participants (N = 28) were exposed to real and virtual samples of orange juice, and the health product, rooibos tea, and asked to rate their similarity. The second experiment investigated how participants (N = 6) could move within "flavor space" from one flavor to another. The results show that it is possible to simulate, with a high degree of precision, a real flavor experience, and precisely controlled "flavor discovery journeys" can be undertaken using virtual flavors.

Influence of physicians' risk perception on switching treatments between high- efficacy and non-high-efficacy disease­modifying therapies in multiple sclerosis.

BACKGROUND: The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians. OBJECTIVE: Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching. METHODS: Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021. RESULTS: Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%). CONCLUSIONS: Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs.

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK.

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries.

Effects of immunotherapies and clinical outcomes in neurosarcoidosis: a retrospective cohort study.

INTRODUCTION: Neurosarcoidosis is associated with a significant degree of morbidity and mortality and its treatments are varied and complex. There is a paucity of information in current literature on patterns of treatment and long term outcomes. This study aimed to evaluate the clinical outcomes and responses to immunosuppressive therapy in a large cohort of neurosarcoidosis patients . METHODS: We enrolled 80 patients with a diagnosis of neurosarcoidosis. Prescription patterns and clinical outcomes before and after treatment and differences between the treatment groups were compared using Kruskal-Wallis and Mann-Witney U tests. RESULTS: Patients with cranial mononeuropathy other than optic neuropathy were more likely to be treated with steroids alone whereas patients with other presentations were likely to require second and third level treatments. These included azathioprine, methotrexate, mycophenolate, infliximab, and cyclophosphamide often used in combination. Prednisolone alone at onset failed in 67% of patients but appeared most effective in those with isolated facial nerve palsy. Patients treated with prednisolone plus a standard immunosuppression first line generally did well except for those with brain parenchymal disease and /or hydrocephalus who responded better to the addition of infliximab, or cyclophosphamide. Triple therapy with prednisolone + azathioprine + infliximab was associated with significantly greater improvement on the Modified Rankin Scale than prednisolone alone whether used first line (p = 0.001 corrected) or subsequently (p = 0.021 corrected). Overall favourable outcomes in the form of improvement of MRS were reported in 87%, CONCLUSIONS: Our results provides evidence that early immunosuppressive treatments, with azathioprine, methotrexate and infliximab could effectively improve clinical outcomes in many patients with neurosarcoidosis.

Distinguishing neurosarcoidosis from multiple sclerosis based on CSF analysis: A retrospective study.

OBJECTIVE: To characterize a cohort of patients with neurosarcoidosis with particular focus on CSF analysis and to investigate whether CSF values could help in distinguishing it from multiple sclerosis (MS). METHODS: This retrospective cohort study enrolled 85 patients with a diagnosis of neurosarcoidosis (possible, probable, or definite). CSF total protein, white cell count, and angiotensin-converting enzyme levels were measured. CSF and serum oligoclonal immunoglobulin G (IgG) patterns were analyzed with the use of odds ratios and binary logistic regression. RESULTS: Eighty patients had a probable (nonneural positive histology) or definite (neural positive histology) diagnosis of neurosarcoidosis. Most frequent findings on MRI were leptomeningeal enhancement (35%) and white matter and spinal cord involvement (30% and 23%). PET scan showed avid areas in 74% of cases. CSF analysis frequently showed lymphocytosis (63%) and elevated protein (62%), but CSF-selective oligoclonal bands were rare (3%). Serum ACE levels were elevated in 51% of patients but in only 14% of those with isolated neurosarcoidosis. Elevated CSF ACE was not found in any patient. CONCLUSIONS: Large elevations in total protein, white cell count, and serum ACE occur in neurosarcoidosis but are rare in MS. The diagnostic use of these tests is, however, limited because minimal changes may occur in both. MS clinical mimics in neurosarcoidosis are not common, and intrathecal synthesis of oligoclonal IgG is a powerful discriminator because it is rare in neurosarcoidosis but occurs in 95% to 98% cases of MS. We suggest caution in making a diagnosis of neurosarcoidosis when intrathecal oligoclonal IgG synthesis is found.

Gleaning multicomponent T1 and T2 information from steady-state imaging data.

The driven-equilibrium single-pulse observation of T(1) (DESPOT1) and T(2) (DESPOT2) are rapid, accurate, and precise methods for voxelwise determination of the longitudinal and transverse relaxation times. A limitation of the methods, however, is the inherent assumption of single-component relaxation. In a variety of biological tissues, in particular human white matter (WM) and gray matter (GM), the relaxation has been shown to be more completely characterized by a summation of two or more relaxation components, or species, each believed to be associated with unique microanatomical domains or water pools. Unfortunately, characterization of these components on a voxelwise, whole-brain basis has traditionally been hindered by impractical acquisition times. In this work we extend the conventional DESPOT1 and DESPOT2 approaches to include multicomponent relaxation analysis. Following numerical analysis of the new technique, renamed multicomponent driven equilibrium single pulse observation of T(1)/T(2) (mcDESPOT), whole-brain multicomponent T(1) and T(2) quantification is demonstrated in vivo with clinically realistic times of between 16 and 30 min. Results obtained from four healthy individuals and two primary progressive multiple sclerosis (MS) patients demonstrate the future potential of the approach for identifying and assessing tissue changes associated with several neurodegenerative conditions, in particular those associated with WM.