BACKGROUND:Although gastrointestinal (GI) adverse reactions (ARs) were commonly observed in registrational clinical trials of fumarate acid ester (FAE) drugs for the treatment of multiple sclerosis, serious GI reactions were uncommon. OBJECTIVE:The objective of the study is to describe the serious GI ARs that supported the post-market safety labeling change for FAE drugs. METHODS:Review of the FDA Adverse Events Reporting System (FAERS) database and published medical literature was conducted to identify cases of serious GI events in patients taking FAE drugs. RESULTS:Forty-nine cases of GI ARs with clinical events of perforation, ulceration, hemorrhage, or obstruction causally associated with FAE drug use were identified. Most cases occurred within 4 months of FAE drug initiation and required hospitalization. Ten of the cases required red blood cell transfusions, nine cases required surgical intervention, and two cases resulted in a fatal outcome. CONCLUSION:Review of postmarketing reports supported the identification of a class association between FAE drugs and serious GI ARs. As these reactions have implications for prescribing decisions and patient management, a safety labeling change was issued to add serious GI reactions to the Warnings and Precautions section of the prescribing information for FAE drugs.

BACKGROUND:Immediate post-injection reactions were commonly observed in registrational trials of glatiramer acetate (GA) for the treatment of multiple sclerosis. Immediate post-injection reactions, characterized by a constellation of symptoms that may occur immediately after injection, can involve signs and symptoms that resemble those of anaphylaxis. OBJECTIVE:The objective of this study is to describe cases of serious anaphylaxis that supported the postmarketing safety labeling change for GA in the United States. METHODS:A review of the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database and published medical literature was conducted. RESULTS:We identified 82 cases of anaphylaxis with GA in FAERS and the medical literature. Six cases reported a fatal outcome (3 anaphylaxis, 3 sudden death). These cases reported anaphylaxis occurring in patients 1 week to 72 months following initiation of GA, including 19 cases that reported anaphylaxis more than 1 year following initiation of GA. CONCLUSION:As these reactions have implications for prescribing decisions and patient management, the FDA issued a labeling change notification to update the WARNINGS AND PRECAUTIONS section and add a BOXED WARNING to the United States prescribing information for GA. A Drug Safety Communication was also issued to inform the public about this update.

BACKGROUND:Risk factors for progressive multifocal leukoencephalopathy (PML) associated with sphingosine-1-phosphate receptor (S1PR) modulators are not as well-characterized as for natalizumab. We characterized S1PR modulator-associated PML cases and risk factors for PML using spontaneous adverse event reports. METHODS:We reviewed case reports from the FDA Adverse Event Reporting System database and the medical literature. RESULTS:We identified 57 PML cases encompassing all marketed S1PR modulators approved for multiple sclerosis, the majority (n = 53) associated with fingolimod. Ten cases reported a fatal outcome. Length of S1PR modulator exposure (≥18 months) appears to be a robust risk factor for PML. Patient age ≥50 years was identified as a potential risk factor, although this may be the result of several biases. We propose that prior immunosuppressant exposure should be considered as a potential risk factor for further validation. No conclusions could be drawn regarding JC virus serology and lymphopenia severity. CONCLUSIONS:Spontaneous adverse event reports support the observation that extended S1PR modulator exposure appears to be a robust PML risk factor. As a result, the U.S. Prescribing Information for each product in the S1PR modulator class was updated. Validation of other potential risk factors would support efforts to stratify and mitigate the risk of S1PR modulator-associated PML.

Background:An association between certain immunomodulatory therapies (rituximab, ipilimumab, and other immune checkpoint inhibitors) and inflammatory (non-ischemic and non-infectious) colitis in oncologic and non-oncologic patient populations is well documented in the medical literature.Objective:The purpose of this case series is to describe adverse event reports of new onset, inflammatory colitis in association with ocrelizumab in patients with multiple sclerosis submitted to U.S. Food and Drug Administration (FDA) or published in the medical literature.Methods:The FDA Adverse Event Reporting System (FAERS) and medical literature were searched.Results:A review of postmarketing cases from FAERS and published medical literature identified 38 cases consistent with inflammatory, non-ischemic, and non-infectious colitis in association with ocrelizumab. The median time-to-onset was 8 months. Cases were reported using the following diagnostic terms: Crohn's disease (13), unspecified colitis (11), microscopic colitis (5), ulcerative colitis (5), medication-induced colitis (3), and autoimmune colitis (2).Conclusions:This case series highlights ocrelizumab induced immune-mediated colitis that can be clinically severe and potentially life-threatening. Based on the findings of this review, the ocrelizumab Prescribing Information was amended to include immune-mediated colitis in the Warnings and Precautions section.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.

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.

Wednesday, April 29April 14, 2020Free AccessComparison of Tolerability Between Rituximab and Ocrelizumab (1478)Brandon Moss, Thomas Love, Laura Baldassari, Sarah Planchon, Jeffrey Cohen, and Daniel OntanedaAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1478 Letters to the Editor

Background and purposeTo analyze the relationship between cognitive processing speed, patient‐reported outcome measures (PROMs), employment and magnetic resonance imaging (MRI) metrics in a large multiple sclerosis cohort.MethodsCross‐sectional clinical data, PROMs, employment and MRI studies within 90 days of completion of the Processing Speed Test (PST), a technology‐enabled adaptation of the Symbol Digit Modalities Test, were collected. MRI was analyzed using semi‐automated methods. Correlations of PST score with PROMs and MRI metrics were examined using Spearman’s rho. Wilcoxon rank sum testing compared MRI metrics across PST score quartiles and linear regression models identified predictors of PST performance. Effects of employment and depression were also investigated.ResultsIn 721 patients (mean age 47.6 ± 11.4 years), PST scores were significantly correlated with all MRI metrics, including cord atrophy and deep gray matter volumes. Linear regression demonstrated self‐reported physical disability, cognitive function, fatigue and social domains (adjusted R2 = 0.44, P < 0.001) as the strongest clinical predictors of PST score, whereas that of MRI variables included T2 lesion volume, whole‐brain fraction and cord atrophy (adjusted R2 = 0.42, P < 0.001). An inclusive model identified T2 lesion volume, whole‐brain fraction, self‐reported upper extremity function, cognition and social participation as the strongest predictors of PST score (adjusted R2 = 0.51, P < 0.001). There was significant effect modification by depression on the relationship between self‐reported cognition and PST performance. Employment status was associated with PST scores independent of age and physical disability.ConclusionThe PST score correlates with PROMs, MRI measures of focal and diffuse brain injury, and employment. The PST score is a feasible and meaningful measure for routine multiple sclerosis care.

Background: Objective and longitudinal measurements of disability in patients with multiple sclerosis (MS) are desired in order to monitor disease status and response to disease-modifying and symptomatic therapies. Technology-enabled comprehensive assessment of MS patients, including neuroperformance tests (NPTs), patient-reported outcome measures (PROMs), and MRI, is incorporated into clinical care at our center. The relationships of each NPT with PROMs and MRI measures in a real-world setting are incompletely studied, particularly in larger datasets. Objectives: To demonstrate the utility of comprehensive neurological assessment and determine the association between NPTs, PROMs, and quantitative MRI measures in a large MS clinical cohort. Methods: NPTs (processing speed [PST], contrast sensitivity [CST], manual dexterity [MDT], and walking speed [WST]) and physical disability-related PROMs (Quality of Life in Neurological Disorders [Neuro-QoL], Patient Determined Disease Steps [PDDS], and Patient-Reported Outcomes Measurement Information System Global-10 [PROMIS-10] physical) were collected as part of routine clinical care. Fully-automated MRI analysis calculated T2-lesion volume (T2LV), whole brain fraction (WBF), thalamic volume (TV), and cervical spinal cord cross-sectional area (CA) for brain MRIs completed within 3 months of a clinic visit during which NPTs and PROMs were assessed. Spearman's rank correlation coefficients evaluated the cross-sectional associations of NPTs with PROMs and MRI measures. Linear regression was utilized to determine which combination of clinical characteristics, patient demographics, MRI measures, and PROMs best cross-sectionally explained each NPT result. Results: 997 unique patients (age 47.7 +/- 11.4 years, 71.8% female) who underwent assessments over a 2-year period were included. Correlations among NPTs and PROMs were moderate. PST correlations were strongest for Neuro-QoL upper extremity (NQ-UE) (Spearman's rho = 0.43) and lower extremity (NQ-LE) (0.47). CST correlations were strongest for NQ-UE (0.33), NQ-LE (0.36), and PDDS (-0.31). MDT correlations were strongest for NQ-UE (-0.53), NQ-LE (-0.54), and PDDS (0.53). WST correlations were strongest for PDDS (0.64) and NQ-LE (-0.65). NPTs also had moderate correlations with MRI metrics, the strongest of which were observed with PST (with T2LV (-0.44) and WBF (0.49)). Spearman's rho for other NPT-MRI correlations ranged from 0.23 to 0.36. Linear regression identified age, disease duration, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV and WBF as significant cross-sectional explanatory variables for PST (adjusted R-2 = 0.46). For CST, significant variables included age and NQ-LE (adjusted R-2 = 0.30). For MDT, significant variables included PDDS, PROMIS-10 physical, NQ-UE, NQ-LE, T2LV, and WBF (adjusted R-2 = 0.37). For WST, significant variables included sex, PDDS, NQ-LE, T2LV, and CA (adjusted R-2 = 0.39). Conclusions: Impaired performance on NPTs correlated with worse physical disability-related PROMs and MRI disease severity, but the strongest cross-sectional explanatory variables for each NPT component varied. This study supports the use of comprehensive, objective quantification of MS status in clinical and research settings. Future longitudinal analyses can determine predictors of treatment response and disability worsening.

May 7, 2019April 9, 2019Free AccessSerum Neurofilament Light Chain in a Phase 1/2 Trial of Autologous Mesenchymal Stem Cell Transplantation in Multiple Sclerosis (P3.2-039)Laura Baldassari, Sarah Planchon Pope, Peter Imrey, Robert Bermel, Kunio Nakamura, Elizabeth Fisher, Jenny Feng, Ken Sakaie, Daniel Ontaneda, and Jeffrey CohenAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P3.2-039 Letters to the Editor

Background Tuberculosis screening is recommended in multiple sclerosis patients starting certain disease-modifying therapies. Disease-modifying therapies may affect interferon-gamma release assay results. Objective To determine the effects of multiple sclerosis disease-modifying therapies on interferon-gamma release assay results. Methods Indeterminate interferon-gamma release assay results among multiple sclerosis patients were compared across disease-modifying therapies by Fisher’s exact test. Logistic regression evaluated the effects of lymphopenia on interferon-gamma release assay results. Results A total of 1058 patients underwent interferon-gamma release assay: 2.0% (21) positive, 6.1% (65) indeterminate, with 59.4% (628) on disease-modifying therapies. Results were significantly different across disease-modifying therapies ( P = 0.002). Absolute lymphocyte count less than 0.5 k/μL had 9.39 times (95% confidence interval 5.2–17.0) increased odds of indeterminate interferon-gamma release assay results. Conclusions Disease-modifying therapies affecting lymphocytes had a higher risk of indeterminate interferon-gamma release assay results.

Background: Tuberculosis screening is recommended in multiple sclerosis patients starting certain disease-modifying therapies. Disease-modifying therapies may affect interferon-gamma release assay results. Objective: To determine the effects of multiple sclerosis disease-modifying therapies on interferon-gamma release assay results. Methods: Indeterminate interferon-gamma release assay results among multiple sclerosis patients were compared across disease-modifying therapies by Fisher's exact test. Logistic regression evaluated the effects of lymphopenia on interferon-gamma release assay results. Results: A total of 1058 patients underwent interferon-gamma release assay: 2.0% (21) positive, 6.1% (65) indeterminate, with 59.4% (628) on disease-modifying therapies. Results were significantly different across disease-modifying therapies (P = 0.002). Absolute lymphocyte count less than 0.5 k/lL had 9.39 times (95% confidence interval 5.2-17.0) increased odds of indeterminate interferon-gamma release assay results. Conclusions: Disease-modifying therapies affecting lymphocytes had a higher risk of indeterminate interferon-gamma release assay results.

Background Serum neurofilament light chain concentration is a proposed biomarker of axonal injury in multiple sclerosis. Mesenchymal stem cells have anti-inflammatory and repair-promoting activities, making them of interest for potential multiple sclerosis treatment. Objectives The purpose of this study was to assess correlation of serum neurofilament light chain concentration and measures of multiple sclerosis disease activity/severity, longitudinal stability of serum neurofilament light chain concentration, and treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration. Methods Twenty-four multiple sclerosis patients underwent intravenous infusion of autologous mesenchymal stem cells. Clinical assessments, serum collection, and brain magnetic resonance imaging were performed at months –1, 0 (transplant), 1, 3, and 6. Matched control serum was collected once ( n = 10). Serum neurofilament light chain concentration was measured by single-molecule array. Serum neurofilament light chain concentration correlations with disease measures were analyzed by Spearman correlations and linear mixed effect models. Pre-post transplant serum neurofilament light chain concentration was compared by Wilcoxon signed rank testing. Results There were significant ( p<0.01) correlations between serum neurofilament light chain concentration and gadolinium-enhancing lesion number (rho = 0.55) and volume (rho = 0.65), and new/enlarging T2 lesions (rho = 0.65). Patients without disease activity had lower fluctuation in serum neurofilament light chain concentration ( p = 0.01). Mean pre- versus post-treatment serum neurofilament light chain concentration values were not significantly different. Conclusions Serum neurofilament light chain concentration correlated with magnetic resonance imaging measures of disease activity cross sectionally and longitudinally, and was stable in patients without disease activity. There was no clear treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.

Introduction: Approved disease-modifying therapies for multiple sclerosis (MS) lessen inflammatory disease activity that causes relapses and MRI lesions. However, chronic inflammation and demyelination lead to axonal degeneration and neuronal loss, for which there currently is no effective treatment. There has been increasing interest in developing repair-promoting strategies, but there are important unanswered questions regarding the mechanisms and appropriate methods to evaluate these treatments. Areas covered: The rationale for remyelinating agents in MS is discussed, with an overview of both myelin physiology and endogenous repair mechanisms. This is followed by a discussion of the identification and development of potential remyelinating drugs. Potential biomarkers of remyelination are reviewed, including considerations regarding measuring remyelination in clinical trials. Information and data were obtained from a search of recent literature through PubMed. Peer-reviewed original articles and review articles were included. Expert opinion: There are several obstacles to the translation of potential remyelinating agents to clinical trials, particularly uncertainty regarding the most appropriate study population and method to monitor remyelination. Refinements in clinical trial design and outcome measurement, potentially via advanced imaging techniques, are needed to optimize detection of repair in patients with MS.

Multiple sclerosis (MS) is a chronic, disabling, immune-mediated, demyelinating and degenerative disease of the central nervous system. Approved disease-modifying therapies may be incompletely effective in some patients with highly active relapsing disease and high risk of disability. The use of immunoablative or myeloablative therapy followed by autologous hematopoietic cell transplantation (AHCT) has been investigated in retrospective studies, clinical trials, and meta-analyses/systematic reviews as an approach to address this unmet clinical need. On behalf of the American Society for Blood and Bone Marrow Transplantation (ASBMT), a panel of experts in AHCT and MS convened to review available evidence and make recommendations on MS as an indication for AHCT. A review of recent literature identified 8 retrospective studies, 8 clinical trials, and 3 meta-analyses/systematic reviews. In aggregate, these studies indicate that AHCT is an efficacious and safe treatment for active relapsing forms of MS to prevent clinical relapse, magnetic resonance imaging-detectable lesion activity, and worsening disability and to reverse disability without unexpected adverse events. Based on the available evidence, the ASBMT recommends that treatment-refractory relapsing MS with high risk of future disability be considered a "standard of care, clinical evidence available" indication for AHCT. Collaboration of neurologists with expertise in treating MS and transplantation physicians with experience performing AHCT for autoimmune disease is crucial for ensuring appropriate patient selection and optimizing transplantation procedures to improve patient outcomes. Transplantation centers in the United States and Canada are strongly encouraged to report baseline and outcomes data on patients receiving AHCT for multiple sclerosis to the Center for International Blood and Marrow Transplant Research.

A 53-year-old man with an 18-year history of multiple sclerosis (MS) was treated with natalizumab for 7 years. Two years prior to presentation, natalizumab treatment interval was increased to every 6 weeks in attempt to reduce the risk of PML. Medical history was notable for cutaneous T-cell lymphoma status-post CHOP chemotherapy. JCV serology was positive (index 2.8). He presented to our tertiary referral center for consultation due to 8 months of progressive left-sided paresthesias, 4 months of right arm clumsiness, and several weeks of expressive aphasia. Neurologic examination was consistent with these symptoms. Serial brain MRIs demonstrated progressive development of a subcortical, multifocal T2/fluid-attenuated inversion recovery hyperintensity in the left frontoparietal white matter (figure 1). Subtle but definite MRI abnormalities were present in the same area 12 months prior. His clinical course and MRI findings prompted urgent evaluation for PML.