Natalizumab reduces loss of gray matter and thalamic volume in patients with relapsing-remitting multiple sclerosis: A post hoc analysis from the randomized, placebo-controlled AFFIRM trial.

BACKGROUND: Loss of brain gray matter fractional volume predicts multiple sclerosis (MS) progression and is associated with worsening physical and cognitive symptoms. Within deep gray matter, thalamic damage is evident in early stages of MS and correlates with physical and cognitive impairment. Natalizumab is a highly effective treatment that reduces disease progression and the number of inflammatory lesions in patients with relapsing-remitting MS (RRMS). OBJECTIVE: To evaluate the effect of natalizumab on gray matter and thalamic atrophy. METHODS: A combination of deep learning-based image segmentation and data augmentation was applied to MRI data from the AFFIRM trial. RESULTS: This post hoc analysis identified a reduction of 64.3% (p = 0.0044) and 64.3% (p = 0.0030) in mean percentage gray matter volume loss from baseline at treatment years 1 and 2, respectively, in patients treated with natalizumab versus placebo. The reduction in thalamic fraction volume loss from baseline with natalizumab versus placebo was 57.0% at year 2 (p < 0.0001) and 41.2% at year 1 (p = 0.0147). Similar findings resulted from analyses of absolute gray matter and thalamic fraction volume loss. CONCLUSION: These analyses represent the first placebo-controlled evidence supporting a role for natalizumab treatment in mitigating gray matter and thalamic fraction atrophy among patients with RRMS. CLINICALTRIALS.GOV IDENTIFIER: NCT00027300URL: https://clinicaltrials.gov/ct2/show/NCT00027300.

Technology-enabled assessments to enhance multiple sclerosis clinical care and research.

BACKGROUND: Comprehensive and efficient assessments are necessary for clinical care and research in chronic diseases. Our objective was to assess the implementation of a technology-enabled tool in MS practice. METHOD: We analyzed prospectively collected longitudinal data from routine multiple sclerosis (MS) visits between September 2015 and May 2018. The MS Performance Test, comprising patient-reported outcome measures (PROMs) and neuroperformance tests (NPTs) self-administered using a tablet, was integrated into routine care. Descriptive statistics, Spearman correlations, and linear mixed-effect models were used to examine the implementation process and relationship between patient characteristics and completion of assessments. RESULTS: A total of 8022 follow-up visits from 4199 patients (median age 49.9 [40.2-58.8] years, 32.1% progressive course, and median disease duration 13.6 [5.9-22.3] years) were analyzed. By the end of integration, the tablet version of the Timed 25-Foot Walk was obtained in 89.0% of patients and the 9-Hole Peg Test in 94.8% compared with 74.2% and 64.3%, respectively before implementation. The greatest increase in data capture occurred in processing speed and low-contrast acuity assessments (0% prior vs 78.4% and 36.7%, respectively, following implementation). Four PROMs were administered in 41%-98% of patients compared with a single depression questionnaire with a previous capture rate of 70.6%. Completion rates and time required to complete each NPT improved with subsequent visits. Younger age and lower disability scores were associated with shorter completion time and higher completion rates. CONCLUSIONS: Integration of technology-enabled data capture in routine clinical practice allows acquisition of comprehensive standardized data for use in patient care and clinical research.

Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 24-month follow-up.

BACKGROUND: Dimethyl fumarate and fingolimod are oral disease-modifying therapies approved to treat relapsing multiple sclerosis. Prior observational studies and our previous 12-month investigation showed comparable clinical efficacy. OBJECTIVE: The purpose of this study was to assess real-world efficacy and discontinuation of dimethyl fumarate and fingolimod over 24 months in patients with multiple sclerosis. METHODS: Patients treated with dimethyl fumarate (n = 395) or fingolimod (n = 264) completed 24-month follow-up in a large academic multiple sclerosis center. Discontinuation rates and measures of disease activity were compared after propensity score weighting. The primary outcome was on-treatment annualized relapse rate ratio. Other measures included rate of drug discontinuation and brain magnetic resonance imaging activity defined as new T2 and/or gadolinium-enhancing lesions. RESULTS: Propensity score weighting showed excellent covariate balance. At 24 months, dimethyl fumarate demonstrated comparable annualized relapse rate (rate ratio = 1.45, 95% confidence interval 0.53-3.99) and brain magnetic resonance imaging activity (odds ratio = 1.38, 95% confidence interval 0.83-2.32). Dimethyl fumarate patients discontinued therapy earlier compared to fingolimod (hazard ratio = 1.40, 95% confidence interval 1.11-1.77) and were more likely to discontinue therapy due to intolerability (odds ratio = 1.98, 95% confidence interval 1.18-3.23). CONCLUSION: Dimethyl fumarate and fingolimod had similar reductions in annualized relapse rate in clinical trials, and our real-world experience supports this observation. Dimethyl fumarate-treated patients had higher likelihood of early discontinuation, and this was mostly due to intolerability.

Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 12-month follow-up.

BACKGROUND: Dimethyl fumarate (DMF) and fingolimod (FTY) are approved oral disease modifying therapies (DMT) for relapsing multiple sclerosis (MS). Phase 3 trials established these agents as effective and generally well tolerated, though comparative efficacy and discontinuation remain unknown. OBJECTIVE: To assess real-world efficacy and discontinuation of DMF and FTY over 12 months in patients with MS. METHODS: We identified 458 DMF-treated and 317 FTY-treated patients in a large academic MS center. Measures of disease activity and discontinuation were compared using propensity score (PS) weighting. Covariates in the PS model included demographics and baseline clinical and MRI characteristics within 12 months of DMT initiation. The primary outcome measure was on-treatment annualized relapse rate (ARR) ratio, which was analyzed using a Poisson regression model. Other measures included time to first relapse, drug discontinuation, time to discontinuation, and new brain MRI lesions at 12 months. RESULTS: The on-treatment ARR for DMF was 0.16 (95% CI (0.12, 0.18)) and 0.13 (95% CI (0.08, 0.16)) for FTY. PS weighting, which demonstrated excellent covariate balance, showed no differences between groups on ARR (rate ratio=1.56, 95% CI (0.78, 3.14)), overall brain MRI activity defined as new T2 and/or gadolinium enhancing (GdE) lesions (OR=1.38, 95% CI (0.78, 2.42)), new T2 lesions (OR=1.33, 95% CI (0.71, 2.49)), and discontinuation (OR=1.30, 95% CI (0.84, 1.99)). DMF had higher odds of GdE lesions (OR=2.19, 95% CI (1.10, 4.35)), earlier time to discontinuation (HR=1.35, 95% CI (1.05, 1.74)), and earlier relapses (HR=1.64, 95% CI (1.10, 2.46)) compared to FTY. CONCLUSION: Assessment in our clinical practice cohort showed comparable clinical efficacy, overall brain MRI activity, and discontinuation between DMF and FTY at 12 months. DMF had increased GdE lesions and intolerability early after treatment initiation.

Experience with fingolimod in clinical practice.

AIM: To report experience with fingolimod in clinical practice. DESIGN/METHODS: Patients in an academic medical center who were prescribed fingolimod from October 2010 to August 2011 were identified through the electronic medical record and followed for 12 months after fingolimod initiation. Adverse effects (AEs), clinical measures, MRI data, and quality of life measures were assessed. RESULTS: Three hundred seventeen patients started fingolimod. Eleven patients were treatment naïve (3.5%) and 76 (24.0%) had remote disease modifying therapy (DMT) use prior to fingolimod. One hundred fifty-one (47.6%) switched because of patient preference and 79 (24.9%) switched because of breakthrough disease. About 11.6% transitioned from natalizumab. Follow-up data were available for 306 patients (96.5%) with mean follow-up time 332 days. Fingolimod was discontinued in 76 of 306 patients (24.8%) at mean 248 days after fingolimod start. Discontinuation most often was due to AEs (n = 40) or breakthrough disease (n = 22). Among patients who started fingolimod with available 12 month follow-up data, 267 (87.3%) remained relapse free and 256 (83.7%) had no relapses or gadolinium enhancement. Time to first relapse occurred at mean 282 days after fingolimod initiation. Quality of life measures remained stable at follow-up. CONCLUSIONS: Fingolimod was discontinued at a higher rate in clinical practice than in clinical trials. Discontinuation was primarily due to AEs or breakthrough disease. Disease activity was adequately controlled in most patients who started fingolimod. This clinical practice cohort is consistent with efficacy data from phase 3 trials and describes the most common tolerability issues in clinical practice.

Reliability of classifying multiple sclerosis disease activity using magnetic resonance imaging in a multiple sclerosis clinic.

OBJECTIVE: To assess the reliability of new magnetic resonance imaging (MRI) lesion counts by clinicians in a multiple sclerosis specialty clinic. DESIGN: An observational study. SETTING: A multiple sclerosis specialty clinic. PATIENTS: Eighty-five patients with multiple sclerosis participating in a National Institutes of Health­supported longitudinal study were included. INTERVENTION: Each patient had a brain MRI scan at entry and 6 months later using a standardized protocol. MAIN OUTCOME MEASURES: The number of new T2 lesions, newly enlarging T2 lesions, and gadolinium-enhancing lesions were measured on the 6-month MRI using a computer-based image analysis program for the original study. For this study, images were reanalyzed by an expert neuroradiologist and 3 clinician raters. The neuroradiologist evaluated the original image pairs; the clinicians evaluated image pairs that were modified to simulate clinical practice. New lesion counts were compared across raters, as was classification of patients as MRI active or inactive. RESULTS: Agreement on lesion counts was highest for gadolinium-enhancing lesions, intermediate for new T2 lesions, and poor for enlarging T2 lesions. In 18% to 25% of the cases, MRI activity was classified differently by the clinician raters compared with the neuroradiologist or computer program. Variability among the clinical raters for estimates of new T2 lesions was affected most strongly by the image modifications that simulated low image quality and different head position. CONCLUSIONS: Between-rater variability in new T2 lesion counts may be reduced by improved standardization of image acquisitions, but this approach may not be practical in most clinical environments. Ultimately, more reliable, robust, and accessible image analysis methods are needed for accurate multiple sclerosis disease-modifying drug monitoring and decision making in the routine clinic setting.

Early tolerability and safety of fingolimod in clinical practice.

BACKGROUND: Fingolimod is approved by the U.S. Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. Several screening studies and a first-dose observation (FDO) period are recommended due to adverse effects observed in clinical trials. OBJECTIVE: The objective of this study is to describe the early experience with fingolimod, including startup, tolerability and safety in a large academic multiple sclerosis (MS) center. METHODS: Patients prescribed fingolimod from September 2010 to July 2011 were identified through electronic medical records. Demographics, MS disease history, pre-treatment screening studies, FDO experience during shared medical visits and three month follow-up data were analyzed. RESULTS: Three hundred ninety-one patients were prescribed fingolimod of whom 317 started the medication and were included in the analysis. Fingolimod was most frequently used in relapsing remitting MS (n=256, 80.8%) and was prescribed as a first-line agent in 11 cases (3.5%). FDO was uneventful in 308 patients (96.8%). Adverse events during FDO were self limited and included symptomatic bradycardia (n=3), chest tightness (n=2) and hypertension (n=1). Fingolimod was discontinued in 30 patients (9.5%) at three months. Adverse effects leading to discontinuation by more than one patient included headache (n=4), macular edema (n=3), nausea (n=3) and hypertension (n=2). CONCLUSIONS: Fingolimod was well tolerated during FDO and adverse events were self limited. The shared medical visit is an appropriate setting for FDO. Adverse effects were similar to those described in clinical trials but the discontinuation rate was higher.

Validation of a self-report comorbidity questionnaire for multiple sclerosis.

BACKGROUND/AIMS: Researchers increasingly recognize the high frequency of comorbidity in multiple sclerosis (MS) and the negative impact on quality of life and disability, but little work has evaluated methods of comorbidity measurement in MS. We aimed to validate a self-report questionnaire for assessing comorbidity in MS. METHODS: Patients with MS were recruited from the MS Clinic in Winnipeg, Canada and the Mellen Center (Cleveland Clinic, Cleveland, Ohio, USA) from October 2008 to 2009. Using a questionnaire, participants reported the presence or absence of 36 comorbidities, sociodemographic characteristics, and disability status. Abstractors blinded to questionnaire results collected data regarding the comorbidities of interest and their treatments. Using the medical record as the gold standard, we determined the sensitivity, specificity, positive and negative predictive values of the questionnaire data. To measure agreement we calculated kappa (kappa) statistics. RESULTS: We enrolled 404 participants. Agreement between self-report and medical records was high (kappa >0.82) for diabetes and hypertension; substantial (kappa = 0.62-0.80) for hyperlipidemia, thyroid disease, glaucoma, and lung disease; moderate (kappa = 0.43-0.56) for osteoporosis, irritable bowel syndrome, migraine, depression, heart disease, and anxiety disorders. Agreement was slight to fair for the remaining comorbidities. CONCLUSIONS: Self-report is a valid way to capture comorbidities affecting MS patients.