University education facilitates uptake of disease-modifying therapies for multiple sclerosis: A community-based study using the UK MS Register.

BACKGROUND: Higher education is associated with better job opportunities and higher income. OBJECTIVES: Herein, the impact of education on the uptake of disease-modifying therapies (DMTs) for multiple sclerosis (MS) in a publicly funded health care system was examined using the UK MS Register. METHODS: All adult participants with relapsing remitting MS diagnosed between 2008 and 2021 were included. Those without data regarding their education levels were excluded. Binary, multinomial and Cox regression models were used to examine the association between education levels and uptake of DMTs. RESULTS: A total of 6317 participants fulfilled all inclusion and exclusion criteria. A total of 1826/2923 (62%) participants with a university education were treated with DMTs, compared to 1788/3394 (53%) participants with school/diploma received DMTs with an odds ratio of 1.318 (1.178-1.473). Participants with a university education were more likely to be treated with both moderate- and high-efficacy DMTs, compared to others, with odds ratios of 1.227 (1.087-1.385) and 1.545 (1.325-1.802), respectively. University education was also a positive predictor for faster initiation of DMTs, and, importantly, higher-efficacy DMTs. CONCLUSION: In a publicly funded health care system, despite intended equality of access, university education was associated with a higher uptake of DMTs.

Ethnic disparities in the epidemiological and clinical characteristics of multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a neuroinflammatory disorder which affects 2.8 million people world-wide. A growing body of evidence shows ethnic disparities in MS. This review aims to evaluate differences, based upon ethnic background, in the incidence, prevalence, disease course, and efficacy of disease-modifying therapies (DMTs) among people with MS (PwMS). METHOD: Ethnicities were classified as White, Black, Hispanic, Asian, and Middle Eastern and North African (MENA). A literature search was conducted using the PubMed search engine to identify articles on MS and ethnicity that were published in the English language between 01/01/2005 and 31/05/2022. RESULTS: 101 studies met all inclusion criteria. Although the incidence and prevalence of MS varied among ethnicities, findings were inconsistent and depended on the continent of the study. Ethnicity may have an impact on the disease course. PwMS from Black, Hispanic, and MENA, but not Asian ethnicities, appeared to accumulate physical disability at a faster rate than those from White ethnicity. Although there was a lack of studies evaluating the relative safety and efficacy of DMTs among various ethnicities, interferon-beta was found to be less efficacious in PwMS from Black ethnicity. CONCLUSIONS: Further studies, with more uniform definitions of ethnicity are required to comprehensively understand ethnic disparities in MS, in particular to identify underlying causes, to facilitate the delivery of personalised medical care and avoid inequity.

Correlates and trajectories of relapses in relapsing-remitting multiple sclerosis.

BACKGROUND AND AIMS: In people with relapsing-remitting multiple sclerosis (pwRRMS), data from studies on non-pharmacological factors which may influence relapse risk, other than age, are inconsistent. There is a reduced risk of relapses with increasing age, but little is known about other trajectories in real-world MS care. METHODS: We studied longitudinal questionnaire data from 3885 pwRRMS, covering smoking, comorbidities, disease-modifying therapy (DMT), and patient-reported outcome measures, as well as relapses during the past year. We undertook Rasch analysis, group-based trajectory modelling, and multilevel negative binomial regression. RESULTS: The regression cohort of 6285 data sets from pwRRMS over time showed that being a current smoker was associated with 43.9% greater relapse risk; having 3 or more comorbidities increased risk and increasing age reduced risk. Those diagnosed within the last 2 years showed two distinct trajectories, both reducing in relapse frequency but 25.8% started with a higher rate and took 4 years to reduce to the rate of the second group. In the cohort with at least three data points completed, there were three groups: 73.7% followed a low stable relapse rate, 21.6% started from a higher rate and decreased, and 4.7% had an increasing then decreasing pattern. These different trajectory groups showed significant differences in fatigue, neuropathic pain, disability, health status, quality of life, self-efficacy, and DMT use. CONCLUSIONS: These results provide additional evidence for supporting pwRRMS to stop smoking and underline the importance of timely DMT decisions and treatment initiation soon after diagnosis with RRMS.

Multiple Sclerosis vision questionnaire (MSVQ-7): Reliability, validity, precision and discrimination.

BACKGROUND: Visual dysfunction is common in people with Multiple Sclerosis (pwMS), associated with a variety of visual symptoms. Capturing the patient experience of these complex patterns of visual pathology is challenging. A valid and reliable patient reported measure, capable of detecting clinically significant change, would have considerable research and clinical benefits. We examined the properties of the MS Vision Questionnaire (MSVQ-7) in a large MS population. METHODS: Data were collected from participants in the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study: MS subtype and Expanded Disability Status Scale (EDSS) band from the clinical team, as well as serial packs including the MSVQ-7 and questionnaires on depression, anxiety and stigma. A calibration sample of 1000 pwMS contributing several years of follow-up were split into training and validation samples for a Confirmatory Factor Analysis and Rasch analysis. The Minimal Detectable Change (MDC) was computed as well as the Minimal Clinically Important Change (MIC), by an anchor-based method, for different MS subtypes. RESULTS: The MSVQ-7 is unidimensional and can be fit to the Rasch model with a solution discarding 3% of variance. Providing all 7 items are answered, the total can be converted to an interval-level metric for calculation of change scores and other parametric analyses. The % of missing values did not exceed 1.7%. Among 5478 pwMS, 80% reported visual problems. MSVQ-7 scores were categorised as mild for 36.1%, moderate for 33.6% and severe for 10.3%, and varied by MS subtype. In the follow-up sample of 2227 pwMS, 42.5% changed MSVQ-7 category between baseline and first follow-up (mean 22.6 months). The MIC exceeded the MDC so clinically significant change exceeds measurement error. While MDC was identical for relapsing and progressive MS, MIC varied by MS subtype, with smaller MIC in relapsing MS. Over one-quarter of the follow-up sample reported a clinically significant change in MSVQ-7: 12.2% improved and 13.5% deteriorated. For pwMS recruited within 2 years of diagnosis, 17.3% reported significant change on follow-up, all improving. MSVQ-7 scores showed strong associations with anxiety, depression and stigma (effect sizes>0.8). Duration, EDSS band and MS subtype all had effect sizes 0.2-0.49. A multinomial logistic regression exploring vision disturbance and depression, adjusted for age, gender, MS subtype, duration and disability, showed vision is the strongest significant predictor of depression. Each unit increase in interval MSVQ-7 increases risk by 10% of 'possible' and by 17% of 'probable' depression. CONCLUSIONS: The MSVQ-7 is a brief self-report measure of visual problems for pwMS. It can easily be converted to interval-level measurement for change scores or power calculations and has good precision and discrimination. Visual problems were reported by 80% of pwMS and changed over time, evidencing the need for regular monitoring. MIC varied by MS subtype, indicating that perception of impact changes over the disease course. Visual dysfunction significantly affects depression risk and perceived stigma, highlighting the importance of routine assessment of visual problems in comprehensive care. The MSVQ-7 has strong psychometric properties for adoption as a measure for vision in clinical and research settings.

Measuring disability in multiple sclerosis: the WHODAS 2.0.

INTRODUCTION: Reliable measurement of disability in multiple sclerosis (MS) using a comprehensive, patient self-reported scale, such as the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, would be of clinical and research benefit. METHODS: In the Trajectories of Outcome in Neurological Conditions-MS study, WHODAS 2.0 (WHODAS-36 items for working, WHODAS-32 items if not working, WHODAS-12 items short-form) was examined using Rasch analysis in 5809 people with MS. RESULTS: The 36- and 32-item parallel forms, and the cognitive and physical domains, showed reliability consistent with individual or group use. The 12-item short-form is valid for group use only. Interval level measurement for parametric statistics can be derived from all three scales which showed medium to strong effect sizes for discrimination across characteristics such as age, subtype, and disease duration. Smallest detectable difference for each scale was < 6 on the standardised metric of 0-100 so < 6% of the total range. There was no substantial differential item functioning (DIF) by age, gender, education, working full/part-time, or disease duration; the finding of no DIF for time or sample supports the use of WHODAS 2.0 for longitudinal studies, with the 36- and 32-item versions and the physical and cognitive domains valid for individual patient follow-up. CONCLUSIONS: Disability in MS can be comprehensively measured at interval level by the WHODAS 2.0, and validly monitored over time. Routine use of this self-reported measure in clinical and research practice would give valuable information on the trajectories of disability of individuals and groups.

Measuring coping in multiple sclerosis: The Coping Index-MS.

BACKGROUND: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. Existing generic and disease-specific coping scales do not meet modern guidelines for scale development and cannot produce interval-level metrics to allow for change scores. OBJECTIVE: The main aim of this study was to develop a brief patient-reported outcome measure for coping in MS, capable of interval-level measurement. METHODS: Qualitative work in 43 people with MS leads to a draft scale which was administered to 5747 participants, with longitudinal collection in 2290. A calibration sample of 1000 subjects split into development and validation sets was used to generate three scales consistent with Rasch model expectations. RESULTS: The total Coping Index-MS (CI-MS-T), CI-MS-Internal (CI-MS-I) and CI-MS-External (CI-MS-E) cover total, internal and externally focused coping. All three scales are capable of interval-level measurement. Trajectory analysis of 9000 questionnaires showed two trajectories in CI-MS-T: Group 1 showed a low level of coping with slight decline over 40 months, while Group 2 had a better and stable level of coping due to improving CI-MS-I which compensated for the deteriorating CI-MS-E over time. CI-MS-T < 30 identified group membership at baseline. CONCLUSION: The CI-MS-T, CI-MS-I and CI-MS-E, comprising 20 items, provide interval-level measurement and are free-for-use in not-for-profit settings.

The association between deprivation and the access to disease modifying therapies for multiple sclerosis: An England wide community-based study in the UK MS Register.

BACKGROUND: Deprivation can impact the access to health interventions in publicly funded health systems where cost is not the dominant barrier. In this study we examined whether deprivation affected the access to disease modifying therapies (DMTs) for multiple sclerosis (MS). METHODS: All English adults on the UK MS register with relapsing remitting MS who were diagnosed between 2010 and 2017, and after the age of 29 years were included. Deprivation was measured using postcode-based 2015 English index of multiple deprivation (IMD), which was divided into quintiles. RESULTS: A total of 1449 participants were eligible and 531/1449 (36.6%) received DMTs. Participants who lived in more deprived areas, based on their IMD scores, were significantly less likely to receive DMTs (odds ratio = 0.69, 95% Confidence interval = 0.49 to 0.98); barriers to housing and services contributed to this disparity. The Nagelkerke R2 value of these models showed that 2% of variation in accessing DMTs were dependant on deprivation. CONCLUSIONS: Deprivation, as measured by IMD, negatively influences the access to DMTs in England. Our findings also suggest that the lack of access to local MS DMT clinics in deprived areas may contribute to this disparity.

Cannabis-based medicines in multiple sclerosis--a review of clinical studies.

For some years a mixture of anecdotal report and data from animal models have implied a potential role for cannabis-based medicines in ameliorating a variety of symptoms of multiple sclerosis. Only recently however have large randomised controlled trials (RCTs) examined these potential effects rigorously. At present the results of RCTs have lacked a coherent message to the prescribing clinician and reasons for such heterogeneity in cannabinoid trials are discussed.

Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial.

BACKGROUND: Central neuropathic pain (CNP), pain initiated or caused by a primary lesion or dysfunction of the central nervous system, occurs in ~28% of patients with multiple sclerosis (MS). Delta(9)-Tetrahydrocannabinol/cannabidiol (THC/CBD), an endocannabinoid system modulator, has demonstrated efficacy for up to 4 weeks in randomized controlled trials in the treatment of CNP in patients with MS. OBJECTIVE: The purpose of this extension was to establish long-term tolerability and effectiveness profiles for THC/CBD (Sativex (R), GW Pharmaceuticals plc, Salisbury, United Kingdom) oromucosal spray in CNP associated with MS. METHODS: This uncontrolled, open-label trial was an indefinite-duration extension of a previously reported 5-week randomized study in patients with MS and CNP. In the initial trial, patients were randomized to placebo or THC/CBD. Patients were only required to maintain their existing analgesia in the randomized study. In the open-label trial they could vary their other analgesia as required. All patients (placebo and THC/CBD) who completed the randomized trial commenced the open-label follow-up on THC/CBD (27 mg/mL: 25 mg/mL). Patients titrated their dosage, maintaining their existing analgesia. The primary end point of the trial was the number, frequency, and type of adverse events (AEs) reported by patients. Secondary end points included changes from baseline in 11-point numerical rating scale (NRS-11) neuropathic pain score, hematology and clinical chemistry test results, vital signs, trial drug usage, and intoxication visual analogue scale scores. RESULTS: Sixty-six patients were enrolled in the randomized trial; 64 (97%) completed the randomized trial and 63 (95%) entered the open-label extension (race, white, 100%; sex, male, 14 [22%]; mean [SD] age, 49 [8.4] years [range, 27-71 years[). The mean (SD) duration of open-label treatment was 463 (378) days (median, 638 days; range, 3-917 days), with 34 (54%) patients completing >1 year of treatment with THC/CBD and 28 (44%) patients completing the open-label trial with a mean (SD) duration of treatment of 839 (42) days (median, 845 days; range, 701-917 days). Mean NRS-11 pain scores in the final week of the randomized trial were 3.8 in the treatment group and 5.0 in the placebo group. In the 28 (44%) patients who completed the 2-year follow up, the mean (SD) NRS-11 pain score in the final week of treatment was 2.9 (2.0) (range, 0-8.0). Fifty-eight (92%) patients experienced > or =1 treatment-related AE. These AEs were rated by the investigator as mild in 47 (75%) patients, moderate in 49 (78%), and severe in 32 (51%). The most commonly reported AEs were dizziness (27%), nausea (18 %), and feeling intoxicated (11%). Two treatment-related serious AEs (ventricular bigeminy and circulatory collapse) were judged to be treatment-related. Both serious AEs occurred in the same patient and resolved completely following a period of discontinuation. Eleven (17%) patients experienced oral discomfort, 4 persistently. Regular oral examinations revealed that 7 (11%) patients developed white buccal mucosal patches and 2 (3%) developed red buccal mucosal patches; all cases were deemed mild and resolved. Seventeen (25%) patients withdrew due to AEs. The mean number of sprays and patients experiencing intoxication remained stable throughout the follow-up trial. CONCLUSIONS: THC/CBD was effective, with no evidence of tolerance, in these select patients with CNP and MS who completed approximately 2 years of treatment (n = 28). Ninety-two percent of patients experienced an AE, the most common of which were dizziness and nausea. The majority of AEs were deemed to be of mild to moderate severity by the investigators.

Validation and reliability of the Neuropathic Pain Scale (NPS) in multiple sclerosis.

OBJECTIVE: Central neuropathic pain occurs in around 28% of patients with multiple sclerosis (MS). The Neuropathic Pain Scale (NPS) has received preliminary validation in peripheral neuropathic pain conditions. The aim of this study was to validate its use in MS central pain syndromes. METHODS: We administered the NPS to 141 patients with MS, together with the Short Form McGill Pain Questionnaire (SFMPQ), the Hospital Anxiety and Depression Scale (HADS), and Short Form 36 Health Survey (SF-36). RESULTS: Cronbach's alpha was 0.78 (95% CI 0.69; 0.83), implying a high degree of internal consistency. Three factors, "Familiar," "Superficial," and "Alien Perception," were extracted, accounting for 64% of the variance. The NPS 10-item total correlates with: the SFMPQ 15-item total score, rho=0.63 (95% CI 0.49; 0.74), its Visual Analog Scale, rho=0.49 (95% CI 0.33; 0.64), the transformed Pain domain of the SF-36 rho=-0.49 (95% CI -0.63; -0.32), but not with its remaining seven health domains, or with either the HADS anxiety or the depression scores. Limits of agreement for short-term test or re-test reliability of the 100 point NPS total (median 2 days, range 1 to 7) were -12 to 14 and when administered to 78 patients who rated their neuropathic pain the "Same" [median interval 33 days (range 19 to 126), the long-term test or re-test correlation coefficient was 0.71 (95% CI 0.6; 0.79)]. DISCUSSION: The NPS appears a useful tool in the assessment of neuropathic pain in MS patients and possibly in measuring outcomes of therapeutic interventions.

Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis.

BACKGROUND: Central pain in multiple sclerosis (MS) is common and often refractory to treatment. METHODS: We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic, seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment. Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours. RESULTS: Sixty-four patients (97%) completed the trial, 34 received CBM. In week 4, the mean number of daily sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1 to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale. CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change -2.7, 95% CI: -3.4 to -2.0, placebo -1.4 95% CI: -2.0 to -0.8, comparison between groups, p = 0.005) and sleep disturbance (CBM mean change -2.5, 95% CI: -3.4 to -1.7, placebo -0.8, 95% CI: -1.5 to -0.1, comparison between groups, p = 0.003). CBM was generally well tolerated, although more patients on CBM than placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-term memory storage. CONCLUSIONS: Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.