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PURPOSE OF REVIEW: Long-term use of multiple sclerosis (MS) disease-modifying therapies (DMTs) is standard practice to prevent accumulation of disability. Immunosenescence and other age-related changes lead to an altered risk-benefit ratio for older patients on DMTs. This article reviews recent research on the topic of de-escalation and discontinuation of MS DMTs. RECENT FINDINGS: Observational and interventional studies have shed light on what happens to patients who de-escalate or discontinue DMTs and the factors, such as age, treatment type, and presence of recent disease activity, that influence outcomes. Though many questions remain, recent findings have been valuable for the development of an evidence-based approach to making de-escalation and discontinuation decisions in MS.
Subject(s)
Multiple Sclerosis , Humans , Multiple Sclerosis/drug therapy , Immunologic Factors/therapeutic useABSTRACT
Neuroimmunology is rapidly evolving field extending from well-known, but incompletely understood conditions like multiple sclerosis, to novel antibody-mediated disorders, of which dozens have been described in the past 10 years. The ongoing expansion in knowledge needed to effectively diagnose and treat these patients presents myriad challenges for clinicians. Here, we discuss six informative cases from our institution. By highlighting these challenging cases, we hope to instill fundamental points on the nuances of diagnosis and management for conditions including tumefactive multiple sclerosis, antibody-mediated encephalitis, antiphospholipid antibody syndrome, neuromyelitis optica, and myelin oligodendrocyte glycoprotein IgG-associated disease.
Subject(s)
Multiple Sclerosis , Neuromyelitis Optica , Humans , Myelin-Oligodendrocyte Glycoprotein , Autoantibodies , Immunoglobulin GABSTRACT
BACKGROUND: Therapeutic research in multiple sclerosis (MS) has focused on the development of treatments with little investigation regarding the possibility of discontinuation of disease-modifying therapies (DMTs). OBJECTIVE: To understand the opinion of individuals with MS concerning stopping DMTs and the factors that influence the decision-making process. METHODS: A mixed method approach was used starting with three focus groups from which a survey was developed. This survey was sent to 1000 participants in the North American Research Committee on Multiple Sclerosis registry who met inclusion criteria (age ⩾45 years; on most recent DMT for ⩾5 years). Descriptive analysis and structural equation modeling were used. RESULTS: Of 1000 participants receiving the survey, 377 provided complete responses and met inclusion criteria. Only 11.9% of participants reported that if their disease was considered stable, they would consider coming off medications. A high level of external locus of control in influential others such as physicians significantly decreased the likelihood of considering discontinuation. CONCLUSIONS: Most individuals with MS report being unlikely to consider stopping MS therapy if their disease was considered "non-active." As the results of studies concerning DMT discontinuation are obtained, information from providers will be an important part of individuals' decision-making process.
Subject(s)
Multiple Sclerosis , Humans , Multiple Sclerosis/drug therapy , Surveys and QuestionnairesABSTRACT
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.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Multiple Sclerosis/therapy , Salvage Therapy/methods , Canada , Humans , Multiple Sclerosis/complications , Patient Care Team , Societies, Medical , Transplantation, Autologous , Treatment Outcome , United StatesABSTRACT
BACKGROUND: Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices. OBJECTIVE: To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician-industry conflicts of interest created by clinical trials and how such disclosures may influence study participation METHODS: An anonymous online instrument was developed. RESULTS: 597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients' decisions to participate in these studies. CONCLUSIONS: Findings from this study support a call for uniform guidelines regarding disclosure of physician-industry relationships to prospective research participants for industry-sponsored clinical trials.
Subject(s)
Clinical Trials as Topic/ethics , Conflict of Interest , Drug Industry/economics , Ethics, Medical , Multiple Sclerosis/drug therapy , Patient Selection/ethics , Physicians/ethics , Adult , Female , Humans , Male , Middle Aged , Patient ParticipationABSTRACT
Objectives: Disease-modifying therapy (DMT) for multiple sclerosis (MS) after natalizumab-associated progressive multifocal leukoencephalopathy (PML) is controversial due to concern for recurrent PML. We describe DMT utilization for over a decade in a patient with MS who survived PML. Methods: Case report. Results: A 36-year-old woman was diagnosed with MS in 2002 and treated with interferon beta-1a until 2006, when she transitioned to natalizumab due to relapses. She presented in 2012 with 2 months of progressive cognitive and gait concerns and was diagnosed with PML by positive CSF JC virus testing with concordant clinical and MRI findings. She was treated with plasma exchange and then corticosteroids for PML immune reconstitution inflammatory syndrome before starting glatiramer acetate for DMT. She transitioned to dimethyl fumarate in 2013 after MS activity on MRI with negative CSF JC virus testing. Owing to worsening footdrop consistent with progression, she transitioned to ocrelizumab in 2017 and then to ofatumumab in 2020 due to logistics of medication administration. There has been no clinicoradiographic or CSF evidence of recurrent PML. Discussion: DMT selection is challenging for patients with MS who survive PML. We used an escalation approach extending to ocrelizumab and ofatumumab due to MS progression. Anti-CD20 DMTs are a high-efficacy option post-PML. Classification of Evidence: This provides Class IV evidence. It is a single observational study without controls.
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OBJECTIVE: Our objectives were to (1) obtain the prevalence and demography of people with multiple sclerosis (MS) in a representative Colorado population, and (2) to assess the utilization of disease-modifying therapy within this prevalent cohort. METHODS: This is a retrospective, observational study of patients that had contact with the University of Colorado Health System from 2012 to 2020. We queried Health Data Compass, a data warehouse, for patient data and applied the MS Prevalence Workgroup Algorithm to generate a prevalent cohort. We calculated prevalence as of 31 December 2020, and stratified by age, sex, race, and ethnicity. Payer information and treatment exposure were obtained from linked claims from the Colorado All Payers Claim Database. Disease-modifying therapies were classified as highly effective and moderately effective based on the clinical trial, TREAT-MS (NCT03500328). RESULTS: From a population of 1,382,821 individuals, 8557 people with MS were captured. Age-adjusted prevalence of MS as of 31 December 2020 was 572.3 per 100,000 with a mean age of 47.36. Prevalence varied between demographic subgroups, with the lowest prevalence in Hispanic men (215.6) and highest in White (824.1) and Black women (820.1). Overall disease-modifying therapy exposure was 62.4%, with increased highly effective therapy use and a corresponding decrease in moderately effective therapy use on a yearly basis. INTERPRETATION: MS is highly prevalent in a representative Colorado cohort. Overall treatment and proportion of highly effective therapy exposure increased significantly during a critical period of MS therapeutic advances, indicating a shift in disease management driven sharply by the availability of on-label anti-CD20 therapy.
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Multiple Sclerosis , Humans , Male , Multiple Sclerosis/epidemiology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/therapy , Female , Adult , Middle Aged , Prevalence , Retrospective Studies , Colorado/epidemiology , Young Adult , Aged , Adolescent , United States/epidemiologyABSTRACT
The primary purpose of this study was to test the hypothesis that multiple sclerosis (MS) patients have impaired acquisition rather than a retrieval deficit. Verbal memory impairment in MS was examined in 53 relapsing-remitting MS patients and 31 healthy controls (HC), and in a meta-analysis of studies that examined memory functioning in MS with list-learning tasks. The MS group demonstrated significantly lower acquisition and delayed recall performance than the HC group, and the meta-analysis revealed that the largest effect sizes were obtained for acquisition measures relative to delayed recall and recognition. Our data argue against a retrieval deficit as the sole explanation for verbal memory impairment in MS, and make a consistent case for the position that deficient acquisition contributes to the memory dysfunction of MS patients. Deficient acquisition may result from demyelination in relevant white matter tracts that reduces encoding efficiency as a result of impaired speed of information processing.
Subject(s)
Memory Disorders/etiology , Multiple Sclerosis/complications , Verbal Learning/physiology , Adult , Female , Humans , Male , Mental Recall , Middle Aged , Neuropsychological Tests , Reference Values , Retention, PsychologyABSTRACT
BACKGROUND: Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. METHODS: DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov, NCT03073603, and is completed. FINDINGS: 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6-15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. INTERPRETATION: We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. FUNDING: Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.
Subject(s)
Multiple Sclerosis , Young Adult , Humans , Aged , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/drug therapy , Single-Blind Method , Magnetic Resonance Imaging , Neuroimaging , Treatment Outcome , Double-Blind MethodABSTRACT
During inflammatory, demyelinating diseases such as multiple sclerosis (MS), inflammation and axonal damage are prevalent early in the course. Axonal damage includes swelling, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise neuronal integrity. The clearance of damaged cell components is important to maintain normal turnover and restore homeostasis. In this study, we used mass spectrometry to identify insoluble proteins within high-speed/mercaptoethanol/sarcosyl-insoluble pellets from purified white matter plaques isolated from the brains of individuals with relapsing-remitting MS (RRMS). We determined that the transmembrane protein 106B (TMEM106B), normally lysosome-associated, is insoluble in RRMS plaques relative to normal-appearing white matter from individuals with Alzheimer's disease and non-neurologic controls. Relative to wild-type mice, hypomorphic mice with a reduction in TMEM106B have increased axonal damage and lipid droplet accumulation in the spinal cord following myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis. Additionally, the corpora callosa from cuprizone-challenged hypomorphic mice fail to clear lipid droplets efficiently during remyelination, suggesting that when TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, further exploration of these sites is warranted.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Mice , Animals , Spinal Cord/metabolism , Myelin-Oligodendrocyte Glycoprotein/metabolism , Lipids/adverse effectsABSTRACT
Emerging evidence is encouraging and suggests that a substantial proportion of patients without antibody responses (due to anti-CD20 therapy or other etiologies) to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines develop T cell responses. However, antigen-specific T cellular responses are notoriously difficult to assess clinically, given the lack of such assays under satisfactory CAP/CLIA regulation, and the laborious nature of the flow cytometric assessment. To evaluate the ability to apply a clinically feasible assay to measure T cellular responses to SARS-CoV-2 mRNA vaccination, we compared flow cytometric and enzyme-linked immunosorbent assay (ELISA) based assays in 24 participants treated with anti-CD20 therapy. T cellular activation (CD69 + CD137+ surface expression, i.e., activation induced markers [AIM]) and intracellular interferon gamma (INFγ) production via flow cytometry was compared to plasma Interferon Gamma Release Assay (IGRA) via ELISA. Plasma INFγ production measured by IGRA correlated with the percent of INFγ-producing AIM positive T cells, supporting the use of IGRA assay as a robust assessment of T cellular response to the SARS-CoV-2 vaccine for B-cell depleted patients that is clinically feasible, time efficient, and cost effective.
Subject(s)
COVID-19 Vaccines , COVID-19 , Interferon-gamma , T-Lymphocytes , Humans , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Interferon-gamma/immunology , SARS-CoV-2 , T-Lymphocytes/immunology , B-LymphocytesABSTRACT
OBJECTIVE: This study aimed to evaluate safety (infusion-related reactions [IRRs]) and patient satisfaction (patient-reported outcomes [PROs]) for at-home ocrelizumab administration for patients with multiple sclerosis (MS). METHODS: This open-label study included adult patients with an MS diagnosis who had completed a ≥ 600-mg ocrelizumab dose, had a patient-determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600-mg ocrelizumab home-based infusion over 2 h, followed by 24-h and 2-week post-infusion follow-up calls. IRRs and adverse events (AEs) were documented during infusions and follow-up calls. PROs were completed before and 2 weeks post infusion. RESULTS: Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)-similar to other shorter ocrelizumab infusion studies-and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at-home infusion process and confidence in the care provided. Patients also reported a significant preference for at-home infusion compared with prior infusion center experiences. INTERPRETATION: IRRs and AEs occurred at acceptable rates during in-home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home-based ocrelizumab infusion over a shorter infusion period.
Subject(s)
Multiple Sclerosis , Adult , Female , Humans , Male , Antibodies, Monoclonal, Humanized , Infusions, Intravenous , Multiple Sclerosis/drug therapy , Multiple Sclerosis/etiology , Patient Outcome AssessmentABSTRACT
Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.
Subject(s)
Multiple Sclerosis , Humans , Multiple Sclerosis/diagnosis , Diagnosis, Differential , Consensus , Magnetic Resonance Imaging , SyndromeABSTRACT
BACKGROUND: Ocrelizumab and rituximab are frequently used treatments for multiple sclerosis (MS). Data on switching from rituximab to ocrelizumab is limited. OBJECTIVES: To assess the frequency, severity, and factors of infusion related reactions (IRRs) in patients with MS who switch from rituximab to ocrelizumab, compared to those who stay on rituximab. METHODS: Prospective study on MS patients aged 18-65, on rituximab for at least 2 cycles, who either switched to ocrelizumab (switch group) or stayed on rituximab (comparator group) (n = 100 each). Participants were followed for IRRs, safety, and tolerability over 12 months. RESULTS: The proportion of IRRs in patients who continue on rituximab (14%) were similar to those who switched to ocrelizumab on Day 1 (14%; p = 1.000) and Week 24 (12%; p = 0.647) but higher than at Day 15 (4%; 0.005). The risk of IRRs for the switch group was associated with the presence of B cells (CD19 and/or CD20 counts ≥1%) increasing by 5.01 (1.49, 16.82) times on Day 1 (p = 0.007). Antidrug antibodies to ocrelizumab were not associated with IRRs. No other safety concerns were identified in switching to ocrelizumab. CONCLUSION: IRRs are similar between both groups, which suggests that it is safe to switch from rituximab to ocrelizumab.
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Introduction and Problem Statement: Neuroimmunology is a rapidly evolving subspecialty. At this time, fellowship training is not standardized. Discrepancies exist in fellowship programs across the United States, including in faculty expertise in rarer neuroimmunologic conditions. Many graduating fellows feel uncomfortable managing the full spectrum of diseases within neuroimmunology. Objectives: To evaluate the feasibility and efficacy of a series of live, virtual, interinstitutional seminars educating neuroimmunology fellows on topics that may be infrequently encountered by trainees. Methods and Curriculum Description: A steering committee of 6 neuroimmunology and multiple sclerosis fellowship program directors selected 18 topics felt to be high yield but representing unique areas of expertise. A live, interactive seminar series was organized. Recognized experts on each topic led seminars using a teleconferencing platform over the 2020-2021 academic year. Recordings were subsequently made available for asynchronous learning. Trainees were surveyed before and after the seminar series and comfort levels with each topic were recorded. Results and Assessment Data: An average of 41 trainees participated in each live seminar and an additional average of 17 trainees viewed each seminar on demand. Trainee comfort levels with each topic increased after the seminar series was completed. An average of 72% of trainees self-identified as at least "comfortable" with each topic after the series compared with 26% beforehand (p < 0.0001). Discussion and Lessons Learned: A year-long series of live, interactive, interinstitutional seminars focusing on unique topics within a single subspecialty represents an effective way to increase trainee comfort levels with such topics.
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BACKGROUND: Strategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation. OBJECTIVE: To provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients. METHODS: We reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation. RESULTS: Younger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity. CONCLUSION: In a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients.
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BACKGROUND: Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs). METHODS: MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms. RESULTS: Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups. CONCLUSION: Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.
Subject(s)
Multiple Sclerosis , Adolescent , Adult , Atrophy/pathology , Brain/diagnostic imaging , Brain/pathology , Humans , Magnetic Resonance Imaging , Middle Aged , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/drug therapy , Multiple Sclerosis/pathology , Natalizumab/adverse effects , Quality of Life , Young AdultABSTRACT
INTRODUCTION: Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist. METHODS: Clinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator. RESULTS: A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX. INTERPRETATION: RTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort.
Subject(s)
Dimethyl Fumarate/pharmacology , Fingolimod Hydrochloride/pharmacology , Immunologic Factors/pharmacology , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Natalizumab/pharmacology , Outcome Assessment, Health Care , Rituximab/pharmacology , Adult , Dimethyl Fumarate/administration & dosage , Dimethyl Fumarate/adverse effects , Female , Fingolimod Hydrochloride/administration & dosage , Fingolimod Hydrochloride/adverse effects , Follow-Up Studies , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Chronic Progressive/pathology , Multiple Sclerosis, Chronic Progressive/physiopathology , Multiple Sclerosis, Relapsing-Remitting/pathology , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Natalizumab/administration & dosage , Natalizumab/adverse effects , Recurrence , Retrospective Studies , Rituximab/administration & dosage , Rituximab/adverse effectsABSTRACT
INTRODUCTION: Studies investigating rates and risk factors for serious safety events (SSEs) during rituximab treatment of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and related disorders are limited. METHODS: Rituximab-treated patients with MS, NMOSD, or related disorders at the Rocky Mountain and New York University MS Care Centers were included. The follow-up period was defined as the time from the initial dose of rituximab up to 12 months of last dose of rituximab or ocrelizumab (in patients who switched). Clinician-reported and laboratory data were retrospectively collected from electronic medical records. RESULTS: One-thousand patients were included comprising 907 MS, 77 NMOSD, and 16 related disorders. Patients had a mean follow-up of 31.1 months and a mean cumulative rituximab dose of 4012 mg. Of the 169 patients who switched to ocrelizumab, the mean ocrelizumab dose was 1141 mg. Crude incidence rate per 1000 person-years (PY) for lymphopenia was 19.2, neutropenia 5.6, and hypogammaglobulinemia 17.8. Infections resulting in either hospitalization, IV antibiotics, or using antibiotics ≥14 days occurred at a rate of 38.6/1000 PY. Risk factors for infection were duration of therapy, male gender, increased disability, prior exposure to immunosuppression/chemotherapy, lymphopenia, and hypogammaglobulinemia. Particularly, wheelchair-bound patients had 8.56-fold increased odds of infections. Crude incidence rates of malignant cancer were 3.5, new autoimmune disease 2.3, thromboembolic event 3.1, and mortality of 5.4 per 1000 PY. INTERPRETATION: Rates of SSEs in patients with MS, NMOSD, and related disorders were low. Through properly assessing risk:benefit of B-cell depleting therapy in neuroinflammatory disorders and continual monitoring, clinicians may decrease the risk of serious infections.