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Jagadeswara R Earla,1 George J Hutton,2 J Douglas Thornton,1 Hua Chen,1 Michael L Johnson,1 Rajender R Aparasu1 1Pharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Houston, TX, USA; 2Department of Neurology, Baylor College of Medicine, Houston, TX, USACorrespondence: Rajender R AparasuPharmaceutical Health Outcomes and Policy, College of Pharmacy, University of Houston, Texas Medical Center, 4849 Calhoun Road, Houston, TX 77204-5047, USATel +1 832-842-8374Email rraparasu@uh.eduBackground: Oral fingolimod is convenient to use than injectable disease modifying agents (DMAs) in patients with multiple sclerosis (MS). However, the existing literature regarding the comparative adherence trajectories between oral fingolimod and injectable DMAs is limited.Objective: To compare the adherence trajectories between oral DMA, fingolimod, and injectable DMAs in patients with MS.Methods: A retrospective longitudinal study was conducted using adults (≥ 18 years) with MS (ICD-9-CM: 340 and a DMA prescription) from the IBM MarketScan Commercial Claims and Encounters Database between 2010 and 2012. Patients were grouped into oral fingolimod or injectable DMA users based on the index DMA among patients with MS. The annual DMA adherence trajectories, based on the proportion of days covered (PDC), were examined using group-based trajectory modeling (GBTM) during the one-year follow-up period after treatment initiation. Multivariable multinomial logistic regression using stabilized inverse probability treatment weights (IPTW) was performed to assess the association between the DMA route of administration (Oral vs Injectable) and the adherence trajectory groups. The balance of covariates between oral and injectable DMAs before and after IPTW was checked against a standardized difference threshold of 0.25.Results: The study cohort consisted of 1,700 MS patients who were initiated with oral (15.8%) or injectable (84.2%) DMAs between 2010 and 2012. The adherence rates (PDC≥ 0.8) in oral fingolimod and injectable DMA users were found to be 64.7% and 50.8%, respectively. The GBTM grouped individuals in the study cohort into three adherence trajectories – rapid discontinuers (23.5%), complete adherers (49.9%), and slow decliners (26.6%). The multinomial logistic regression model with stabilized IPTW revealed that oral fingolimod users had higher odds to be a complete adherer (adjusted odds ratio [AOR]: 2.78, 95% CI: 1.85– 4.16) or a slow discontinuer (AOR: 2.62, 95% CI: 1.70– 4.05) than injectable DMA users.Conclusions: Oral DMA fingolimod was associated with better adherence than injectable DMAs across group-based trajectories. Further research is warranted to evaluate the adherence trajectories with newer oral DMAs introduced in the last decade for MS.Keywords: group based trajectory modelling, GBTM, adherence trajectory, multiple sclerosis, disease modifying agent, DMA, fingolimod, injectable DMA

Objective: The optimal treatment strategy for the management of multiple sclerosis is widely discussed due to the increasing availability of high-efficacy disease-modifying agents (heDMAs). This study evaluated the comparative effectiveness of heDMA and moderate-efficacy disease-modifying agents (meDMAs) use in reducing annualized relapse rate (ARR) among multiple sclerosis patients., Methods: A retrospective cohort study was conducted using the 2015-2019 United States Merative MarketScan Commercial Claims Data. Adult (18-64 years) patients with incident disease-modifying agents (DMA) use were included. Claim-based relapse algorithms were applied to measure relapse events. The inverse probability treatment weighting (IPTW) based negative binomial regression model with the offset of the follow-up period was used to compare the ARR. The moderation effect of sex on ARR was also examined., Results: This study included 10,003 incident DMA users, with 22.9 % initiated heDMAs. The average ARR during follow-up among heDMA users was lower than meDMA users (0.25 vs. 0.28, p < 0.01). The IPTW-based regression found that sex moderated the relationship between the types of DMAs and ARR. Stratified analyses revealed that heDMAs were associated with a lower ARR in males (adjusted incidence rate ratio [aIRR] 0.74; 95 % confidence interval [CI] 0.59-0.94) compared with meDMAs. No significant differences were noted among females (aIRR 0.99; 95 % CI: 0.88-1.21)., Conclusion: The study found that sex moderated the effect of heDMAs, with male multiple sclerosis patients using heDMAs associated with a 26 % decreased risk of relapse than those with meDMAs. However, there was no difference in comparative effectiveness for females., Competing Interests: Declaration of competing interest Dr. Aparasu has received research funding from Astellas Inc., Incyte Corp., Gilead, and Novartis Inc. for projects unrelated to the current work. Dr. Hutton reports grants from Biogen, Novartis, MedImmune, Hoffman-LaRoche, E.M.D. Serono, Sanofi, and personal fees from Novartis, Sanofi, and Celgene outside the submitted work. The other authors declare no conflicts of interest for this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In patients with multiple sclerosis (MS), infections represent a significant concern, particularly given the immunomodulatory effects of disease-modifying agents (DMAs). High-efficacy DMAs (heDMAs) play a pivotal role in delaying MS progression, yet their use also raises concerns regarding the risk of infection. This study aimed to compare the infection risk with the use of heDMA and moderate-efficacy disease-modifying agents (meDMAs) in MS patients. This retrospective cohort study involved adult (18-64 years) MS patients with incident DMA use based on the 2015-2019 MarketScan Commercial Claims and Encounters Database. Patients initiating heDMAs (natalizumab, alemtuzumab, and ocrelizumab) or meDMAs (interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and glatiramer acetate) were included. The outcomes of interest were comparative risk of overall infection, serious infection, and frequently reported types of infection. Adjusted hazard ratios (aHR) were estimated in inverse probability treatment weighting (IPTW) based on Cox proportional hazard models. Among 10,003 eligible incident DMA users, 22.92% of patients initiated heDMAs. The IPTW-CPH model revealed that patients with heDMAs were associated with a higher risk of serious infection (aHR: 1.24, 95% confidence interval (CI): 1.06-1.44) and urinary tract infection (UTI; aHR: 1.21, 95% CI: 1.14-1.30). Sensitivity analyses with different follow-up periods yielded consistent findings with the main analyses. In MS, heDMAs were associated with a greater risk of serious infection and UTI compared with meDMAs. These findings suggest the need to carefully monitor and manage the infection risk to optimize the use of heDMAs in MS., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: With multiple treatment options, choosing the initial disease-modifying agent (DMA) could be crucial to managing multiple sclerosis (MS). Common treatment strategies recommend starting patients with moderate-efficacy disease-modifying agents (meDMAs), while others advocate initiating high-efficacy disease-modifying agents (heDMAs). However, limited real-world evidence exists regarding the factors associated with utilizing differing treatment strategies in the MS., Objective: This study evaluated the factors associated with the initiation of heDMAs in comparison to meDMAs among patients with MS., Methods: A retrospective cohort study was conducted using the Merative MarketScan Commercial Claims Database. Adult (18-64 years) MS patients with ≥1 DMA prescription were identified from 2016 to 2019. Patients were classified as incident heDMA or meDMA users based on their earliest DMA prescription, with a 12-month washout period. All covariates were measured during the 12-month baseline before the index DMA date. A multivariable logistic regression model, guided by the Andersen Behavioral Model, was applied to examine the predisposing, enabling, and need factors associated with using heDMAs over meDMAs., Results: There were 10,003 eligible MS patients, with the majority of users being female (74.92 %), middle-aged adults (35-54 years, 58.97 %), and enrolled in the Preferred Provider Organization (PPO, 53.10 %) healthcare plan. Overall, 2293 (22.92 %) MS patients initiated heDMAs. The multivariable logistic regression model revealed that male patients (adjusted odds ratio [aOR]: 1.46, 95 % Confidence Interval [CI]: 1.30-1.64) had higher odds of initiating heDMAs. Meanwhile, patients with bladder dysfunction medications (aOR: 1.39, 95% CI: 1.21-1.61), fatigue medications (aOR: 1.77, 95 %CI: 1.44-2.17), and impaired walking (aOR: 1.62, 95 %CI: 1.42-1.86) were more likely to initiate treatment with heDMAs. In contrast, patients with higher Elixhauser comorbidities scores, sensory symptoms (aOR: 0.47, 95 %CI: 0.42-0.53), visual symptoms (aOR: 0.63, 95 %CI: 0.54-0.73), and brainstem symptoms (aOR: 0.81, 95 %CI: 0.67-0.97) were less likely to be prescribed with heDMAs., Conclusion: The study found that approximately one in four MS patients initiated heDMAs. Both demographic and clinical factors influenced the selection of heDMA. More work is needed to understand the differential value of selecting heDMAs over meDMAs for personalizing DMA treatment., Competing Interests: Declaration of competing interest Dr. Aparasu has received research funding from Astellas Inc., Incyte Corp., Gilead, and Novartis Inc. for projects unrelated to the current work. Dr. Hutton reports grants from Biogen, Novartis, MedImmune, Hoffman-LaRoche, E.M.D. Serono, Sanofi, and personal fees from Novartis, Sanofi, and Celgene outside the submitted work. Dr. Varisco reports personal fees from Healix Infusion Therapy. The other authors declare no conflicts of interest for this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have a monophasic or relapsing disease course. To date, factors that may predict a relapsing disease course remain largely unknown and only limited data exist regarding the efficacy of different utilized immunotherapy regimens at preventing or reducing relapses., Objectives: To assess the characteristics, predictors, and immunotherapy of relapsing MOGAD., Methods: This multicenter retrospective analysis included all MOGAD cases at the University of Florida, Baylor College of Medicine and the University of California San Diego with minimum follow-up time of 6 months. Cox proportional hazards regression analyses, corrected for age and sex, were performed to evaluate hazard ratios (HR) of predictors of a relapsing disease course and to compare relapse hazards for utilized immunotherapies., Results: The majority of included participants (51/79 [64.6 %]) had a relapsing course, and of these individuals, 68.6 % (35/51) experienced their first relapse within the first year. However, 10/51 (19.6 %) participants experienced their first relapse ≥5 years (5-15 years) after the initial presentation. Predictors of a relapsing course were CSF pleocytosis (>150 cells/mm 3 ; HR 3.3 [1.18 - 9.24]; p = 0.023), a pediatric disease onset at age < 9 years (HR 2.69 [1.07-6.75]; p = 0.035), and an initial presentation with the clinical syndrome of meningoencephalitis (HR 3.42 [1.28 - 9.17]; p = 0.015),. In participants with a relapsing course, 13/24 (54.2 %) patients remained relapse-free on rituximab, 4/8 (50 %) on mycophenolate mofetil, and 11/14 (78.6 %) on scheduled immunoglobulins. Patients treated with immunoglobulins had significantly fewer relapses compared to patients treated with other immunotherapies (HR: 0.1 [0.2 - 0.63]; p = 0.014)., Conclusions: In our cohort, the majority of MOGAD patients relapsed. The initial relapse occurred most frequently within the first year, but first relapses also took place over a decade after the initial presentation. Prepubertal onset, severe CSF pleocytosis, and the clinical syndrome of meningoencephalitis may be predictors of a relapsing course. Of the currently available off-label steroid-sparing treatments, scheduled immunoglobulins may be the most effective in relapse prevention., Competing Interests: Declaration of competing interest Dr. Rempe received grant funding from the National Multiple Sclerosis Society. He served on advisory boards for Genentech, Sanofi-Genzyme, Alexion, and Amgen. He receives contract research support from EMD Serono, Genentech, Sanofi-Genzyme, Celgene, and Novartis. Dr. Elfasi has nothing to disclose. Dr. Alkabie has nothing to disclose. Dr. Rodriguez has nothing to disclose. Dr. Montalvo served on an advisory board for Horizon Therapeutics. Dr. Castrodad-Molina has no disclosures. Dr. Cuascut reports participation in scientific advisory boards for Horizon, Biogen, and Novartis as well as receiving speaker fees from Biogen. Dr. Hutton reports participation in scientific advisory boards for Novartis, Genentech, Genzyme, Bristol Myers Squibb, and Autoimmunity Biologic Solution, Inc and has also received research funding/commercial entities from Genzyme, Biogen, Novartis, Hoffmann La Roche, and MedImmune. Dr. Kinkel has received honoraria for non-promotional educational activity from Biogen and received speaker fees from Alexion, Biogen, BMS, Genentech and Sanofi-Genzyme. Dr. Graves has received research support from NMSS, Octave, Biogen, EMD Serono, Novartis, ATARA Biotherapeutics, and ABM. She has served on an advisory board for TG therapeutics and a pediatric clinical trial steering committee for Novartis. She has consulted for Google., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs., Objectives: This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS., Methods: This retrospective observational cohort study based on the 2015-2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18-64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model., Results: The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1-2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups., Conclusions: Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS., Competing Interests: Declaration of competing interest Dr. Aparasu has received research funding from Astellas Inc., Incyte Corp., Gilead, and Novartis Inc. for projects unrelated to the current work. Dr. Hutton reports grants from Biogen, Novartis, MedImmune, Hoffman-LaRoche, E.M.D. Serono, Sanofi, and personal fees from Novartis, Sanofi, and Celgene outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Patients with multiple sclerosis (MS) frequently switch their Disease-Modifying Agents (DMA) for effectiveness and safety concerns. This study aimed to develop and compare the random forest (RF) machine learning (ML) model with the logistic regression (LR) model for predicting DMA switching among MS patients., Methods: This retrospective longitudinal study used the TriNetX data from a federated electronic medical records (EMR) network. Between September 2010 and May 2017, adults (aged ≥18) MS patients with ≥1 DMA prescription were identified, and the earliest DMA date was assigned as the index date. Patients prescribed any DMAs different from their index DMAs were considered as treatment switch. . The RF and LR models were built with 72 baseline characteristics and trained with 70% of the randomly split data after up-sampling. Area Under the Curves (AUC), accuracy, recall, G-measure, and F-1 score were used to evaluate the model performance., Results: In this study, 7258 MS patients with ≥1 DMA were identified. Within two years, 16% of MS patients switched to a different DMA. The RF model obtained significantly better discrimination than the LR model (AUC = 0.65 vs. 0.63, p  < 0.0001); however, the RF model had a similar predictive performance to the LR model with respect to F- and G-measures (RF: 72% and 73% vs. LR: 72% and 73%, respectively). The most influential features identified from the RF model were age, type of index medication, and year of index., Conclusions: Compared to the LR model, RF performed better in predicting DMA switch in MS patients based on AUC measures; however, judged by F- and G-measures, the RF model performed similarly to LR. Further research is needed to understand the role of ML techniques in predicting treatment outcomes for the decision-making process to achieve optimal treatment goals., Competing Interests: Dr. Aparasu has received research funding from Astellas Inc., Incyte Corp., Gilead, and Novartis Inc. for projects unrelated to the current work. Dr. Hutton reports grants from Biogen, Novartis, MedImmune, Hoffman-LaRoche, E.M.D. Serono, Sanofi, and personal fees from Novartis, Sanofi, Celgene outside the submitted work. The other authors declare no conflicts of interest for this article., (© 2023 The Author(s).)

Study Objective: This study compared the adherence trajectories of fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users with multiple sclerosis (MS) as there is limited evidence regarding the comparative adherence patterns of different oral disease-modifying agents (DMAs)., Design: A retrospective cohort study DATA SOURCE: 2015-2019 IBM MarketScan Commercial Claims Database., Patients: Adults (≥18 years) with MS (International Classification of Diseases [ICD]-9/10-Clinical Modification [CM]:340/G35) diagnosis and ≥1 DMA prescription., Intervention: Incident FIN-, TER-, or DMF use based on the index DMA with 1 year of washout period., Measurements: The DMA adherence trajectories based on the proportion of days covered (PDC) were examined using the Group-Based Trajectory Modeling (GBTM) one year after the treatment initiation. Generalized boosting models (GBM)-based inverse probability treatment weights (IPTW) were incorporated in multinomial logistic regression to assess the comparative adherence trajectories across oral DMAs with FIN group as a reference category., Measurements and Main Results: The study cohort consisted of 1913 patients with MS who were initiated with FIN (24.2%, n = 462), TER (24.0%, n = 458), and DMF (51.9%, n = 993) during 2016-2018. The adherence rate (PDC ≥ 0.8) among FIN, TER, and DMF users was found to be 70.8% (n = 327), 59.6% (n = 273), and 61.0% (n = 606), respectively. The GBTM grouped patients into three adherence trajectories: Complete Adherers-59.1%, Slow Decliners-22.6%, and Rapid Discontinuers-18.3%. The multinomial logistic regression model involving GBM-based IPTW revealed that DMF (adjusted odds ratio [aOR]: 2.32, 95% confidence interval [CI]:1.57-3.42) and TER (aOR: 2.50, 95% CI: 1.62-3.88) users had higher odds to be rapid discontinuers relative to FIN users. In addition, TER users were more likely (aOR: 1.50, 95% CI: 1.06-2.13) to be slow decliners compared with FIN users., Conclusion: Teriflunomide and DMF were associated with poorer adherence trajectories than FIN. More research is needed to evaluate the clinical implications of these adherence trajectories of oral DMAs to optimize the management of MS., (© 2023 Pharmacotherapy Publications, Inc.)

Multiple sclerosis (MS) is an acquired demyelinating disease of the central nervous system (CNS). Historically, research on MS has focused on White persons with MS. This preponderance of representation has important possible implications for minority populations with MS, from developing effective therapeutic agents to understanding the role of unique constellations of social determinants of health. A growing body of literature involving persons of historically underrepresented races and ethnicities in the field of multiple sclerosis is assembling. Our purpose in this narrative review is to highlight two populations in the United States: Black and Hispanic persons with multiple sclerosis. We will review the current understanding about the patterns of disease presentation, genetic considerations, response to treatment, roles of social determinants of health, and healthcare utilization. In addition, we explore future directions of inquiry as well as practical methods of meeting these challenges.

Multiple sclerosis (MS) is the most prevalent nontraumatic disabling neurologic condition among young adults worldwide. The diagnosis and management of MS is complex. The goal of this review is to provide an updated and practical approach to the diagnosis and treatment approaches in MS, emphasizing current understanding of immunopathogenesis, recent advances, and future directions, for both MS and non-MS clinicians., Competing Interests: Disclosure C.A. Pérez received postgraduate fellowship support from Genentech and has participated in advisory boards for Sanofi. F.X. Cuascut received research funding from Genentech and Biogen and has participated in advisory boards for Genentech, Biogen, Horizon, and Pharma Novartis and Horizon. G.J. Hutton received research funding from Biogen, Hoffman-La Roche, Sanofi, MedImmune, and Novartis and has participated in advisory boards for Novartis and Horizon., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system. Both the physical and mental burden of MS affect patients' health-related quality of life (HRQoL). However, there is limited research at the national level evaluating the humanistic burden among MS patients., Objectives: This study evaluated the HRQoL and functional limitations among MS patients using ten years of national survey data., Methods: Guided by the conceptual framework of the Wilson and Cleary model, this study compared HRQoL between adults diagnosed with MS (Clinical Classification Code= "080″) and non-MS adults using the 2006-2015 Medical Expenditure Panel Survey (MEPS) data. The humanistic burden included HRQoL and functional limitations. The HRQoL was evaluated using physical component summary (PCS) and mental component summary (MCS) based on the Short Form Health Survey (SF-12). The study applied the multivariable Generalized Linear Models (GLM) to estimate the marginal differences in PCS and MCS based on the SF-12. In addition, seeking help for activities of daily living (ADL) and instrumental activities of daily living (IADL) were modeled with multivariable logistic regression., Results: According to the MEPS, the estimated annual prevalence of MS was 0.52 million (95% Confidence Interval [CI]: 0.42-0.60). MS patients were mainly female (71.90%), middle aged (50-64 years, 40.21%), non-Hispanic whites (78.29%), and enrolled in private insurance plans (68.93%). The average PCS scores in MS and non-MS groups were 35.70 and 49.48, respectively. The average MCS scores were 45.58 and 51.25 for MS and non-MS groups, respectively. In addition, 18.26% of MS patients sought help for ADL, and 27.08% sought help for IADL. After adjusting for individual, biological, and environmental characteristics, the multivariable GLM with Poisson distribution indicated that the marginal difference of PCS score was 11.10 (95% CI: 9.50-12.61) units lower, and the MCS score was 4.89 (95% CI: 3.44-6.30) units lower among MS patients. In addition, MS patients were 17.32 (95% CI: 11.61-25.84) and 14.43 (95% CI: 10.09-20.65) times more likely to request assistance for ADL and IADL, respectively., Conclusions: MS was associated with lower physical and mental HRQoL than their non-MS counterparts and MS patients were more likely to request help for ADL and IADL. More work is needed to evaluate the effect of treatment strategies on improving the HRQoL and functional limitations in MS., Competing Interests: Declarations of Competing Interest None, (Copyright © 2022. Published by Elsevier B.V.)

Background: Since the introduction of oral disease-modifying agents (DMA) in 2010, the treatment options for multiple sclerosis (MS) have changed significantly. There is limited information regarding the factors associated with switching to oral DMA among prevalent injectable DMA users., Objective: This study evaluated the factors associated with switching to oral DMAs among prevalent injectable DMA users with MS., Methods: A retrospective observational cohort study using the TriNetX electronic medical records (EMR) data was conducted among patients with MS. The study included prevalent injectable DMA users with at least two injectable DMA (interferon beta-1a, interferon beta-1b, peginterferon beta-1a, or glatiramer acetate) prescription records within 6 months between September 2010 and May 2018. The second injectable DMA prescription date was considered as the index date. Switching was defined as any oral DMA prescription record (fingolimod, dimethyl fumarate, or teriflunomide) within 12 months after the index date. Patients with any infusion DMA prescription after the first injectable DMA prescription, and those less than 18 years of age were excluded from the study. The Andersen Behavioral Model was used as the conceptual framework to identify predisposing, enabling, and need factors measured during the 1-year baseline period before the index date. A multivariable logistic regression model was used to examine the predisposing (age, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, MS-related medication, and healthcare utilization) associated with switching from injectable to oral DMAs., Results: Among 2,943 prevalent injectable users included in this study, 8.09% (n=238) patients switched to oral DMAs. Patients who switched to oral DMAs were primarily younger adults aged 18-44 years (64.29%), females (82.77%), had sensory and visual symptoms, and had corticosteroid utilization during the one-year look-back period compared to non-switchers. Results from multivariable logistic regression model revealed that middle-aged adults (45-64 years, adjusted odds ratio [aOR]: 0.43, 95% Confidence Interval [CI]: 0.32-0.58), old adults (≥65 years, aOR: 0.30, 95% CI: 0.13-0.66) and men (aOR: 0.67, 95% CI: 0.47-0.96) were associated with decreased odds of switching to oral DMAs. Presence of MS-related sensory symptoms (aOR: 1.52, 95% CI: 1.07-2.16), visual symptoms (aOR: 1.59, 95% CI: 1.10-2.31), and corticosteroids usage (aOR: 1.44, 95% CI: 1.04-1.98) were associated with increased odds of switching to oral DMAs., Conclusion: The study found that about one in twelve prevalent injectable DMA users switched to oral DMA. Both demographic and clinical factors were associated with switching to oral DMAs. Further research is needed to evaluate the outcomes of switching to inform treatment decisions for MS management., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We present the case of a 57-year-old man with protein S deficiency and left leg deep vein thrombosis (DVT) 5 years earlier, who developed stepwise progressive bilateral lower limb weakness, numbness/paresthesia, gait imbalance, hesitancy of micturition, and constipation in the setting of recurrent left common femoral DVT treated with apixaban. Symptoms amplified with Valsalva, corticosteroids, and postlumbar puncture, with longitudinally extensive midthoracic T2-hyperintense lesion extending to the conus associated with hazy holocord enhancement on magnetic resonance imaging (MRI), raising suspicion for spinal dural arteriovenous fistula (sDAVF). Initial digital subtraction angiography (DSA) was negative for sDAVF. However, cerebral spinal fluid (CSF) was herpes simplex virus (HSV)-2 positive, and he was treated with antiviral therapy. Unfortunately, he continued to worsen despite treatment. Repeat neuroimaging 12 months after initial presentation demonstrated persistent lower thoracic/conus lesion in addition to cauda equina enhancement and subtle dorsal T2-hypointense flow voids. We raised red flags (e.g., lack of clinical prodrome, no herpetic rash, no CSF pleocytosis, and rostral extent of the lesion) that suggested the HSV2 nucleic acid detection was perhaps unrelated to the neurologic syndrome. Given the high index of suspicion for sDAVF, we repeated spinal vascular imaging. Spinal MRA demonstrated dilated right dorsal perimedullary veins from T10 to T11. Repeat DSA revealed a right T10 sDAVF. Microsurgical treatment rather than embolization of the fistula was successful without complication, with significant improvement in motor, sphincter, and to a lesser extent sensory function, with residual gait imbalance after inpatient rehabilitation 3 weeks postoperatively., (© 2021 American Academy of Neurology.)

Background: The use of disease-modifying agents (DMAs) to treat Multiple Sclerosis (MS) in older adults is debated as the disease activity decreases with aging. However, limited data exist regarding prescribing patterns of DMAs among older adults with MS., Objective: To examine prescribing patterns of DMAs and the factors associated with DMA prescribing practices among older adults with MS using electronic medical records (EMR) data., Methods: A retrospective longitudinal cohort study was conducted using the TriNetX, a federated EMR network from the US, data from 2016 to 2019. The study included older adults (≥60 years) with MS diagnosis and at least one prescription record during the study period. Patients with DMA prescriptions were identified and further classified into injectable, oral, or infusion users based on their last DMA prescription. A multivariable logistic regression model was used to evaluate the factors associated with prescribing of DMAs. A multinomial logistic regression model was also used to determine the factors associated with prescribing a particular dosage form of DMA., Results: The study cohort consisted of 12,922 older adults with MS, with 2,455 (18.99%) receiving DMA prescriptions. The commonly prescribed DMAs were injectables (10.46%), followed by orals (6.06%) and infusions (2.40%). Multivariable logistic regression revealed that older adults between 60- to 64 years (Adjusted Odds Ratio [aOR]= 2.38) and 65-69 years (aOR=1.60) had higher odds of receiving DMA compared to older adults of 70 years and above. African Americans (aOR=1.71) had higher odds of receiving DMA prescriptions compared to Caucasians. The presence of symptoms (pain, fatigue, speech, walking difficulty) and use of symptomatic medication (anti-fatigue medication, bladder dysfunction medication, antispasmodics, antidepressants, and relapse medication) increased the odds of being prescribed DMAs. Multinomial logistic regression found that patients 60-64 years of age had higher odds of being prescribed infusion (aOR, 95% Confidence Interval [CI] =2.06, 1.35-3.15) and oral (65-69 years: aOR=1.60, 1.24-2.07) over injectable DMAs compared to the older adults aged 70 years and above.Older males (aOR=1.68, 95% CI: 1.23-2.30) were associated with increased odds of being prescribed infusion DMA over injectable DMA compared to females. The presence of comorbidities such as coagulopathy and peripheral vascular disorders decreased the odds of being prescribed oral DMA over injectable DMA. Patients with cerebellar symptoms had an increased likelihood of being prescribed with an infusion DMA over injectable DMA. Patients using drugs for treating relapses had higher odds of being prescribed an infusion DMA over an injectable DMA. In terms of healthcare utilization, older adults with outpatient visits had higher odds of being prescribed an infusion DMA over an injectable DMA, while older adults with inpatient visits had lower odds of being prescribed an infusion DMA over an injectable DMA., Conclusion: Nearly one in five older adults with MS are prescribed DMAs, with a majority receiving injectable DMAs. Several demographic and clinical factors were associated with DMA prescribing . This study fills the data gap regarding the utilization of DMAs in older adults with MS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Brain volume loss (BVL) is commonly observed after high-dose immunosuppression and autologous hematopoietic cell transplantation (HDIT/HCT) for treatment of multiple sclerosis (MS). To better understand the mechanisms of underlying BVL associated with this treatment, we characterized the time courses of whole-brain (WB), grey-matter (GM) and white-matter (WM) volume loss in relapsing-remitting MS (RRMS) patients who received BEAM-based HDIT/HCT., Methods: We used Jacobian integration to measure MRI-based WB, GM and WM volume changes up to 5 years after transplant in twenty-four RRMS participants who underwent BEAM-based HDIT/HCT. Using a two-piecewise mixed-effects model, we estimated the short-term (baseline to 1 year) and long-term (beyond 1 year) rates of BVL after HDIT/HCT. We also compared the rates based on the presence of gadolinium-enhancing lesions at baseline, and the maintenance of event-free survival during follow-up., Results: On average, accelerated short-term BVL of -1.37% (SE: 0.21), -0.86% (SE: 0.28) and -2.18% (SE: 0.26) occurred in WB, GM and WM, respectively. Baseline T1-weighted MRI WM lesion volume was a significant predictor in the WB (short-term) and the WM (short-term and long-term). The average rates of BVL after the initial acceleration were -0.22%/y (SE: 0.10), -0.13%/y (SE: 0.11) and -0.36%/y (SE: 0.11) in the WB, GM and WM, respectively. Participants with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM (-1.56% vs. -0.27%, p = 0.01) and WB volume loss (-1.94% vs. -0.81%, p = 0.006) at 1 year follow-up as compared to those without gadolinium-enhancing lesions. WM volume loss was not significantly different (-2.59% vs. -1.66%, p = 0.16). Participants who maintained event-free survival had similar rates of BVL compared to those who did not., Conclusions: BVL may accelerate for months after HDIT/HCT. However, over the long-term, adequate HDIT/HCT may reduce BVL rates to those similar to normal aging at the WB level., (Copyright © 2021. Published by Elsevier B.V.)

Background: Fingolimod is the first approved oral disease-modifying agent (DMA) in 2010 to treat Multiple Sclerosis (MS). There is limited real-world evidence regarding the determinants associated with fingolimod use in the early years., Objective: The objective of this study was to examine the factors associated with fingolimod prescribing in the initial years after the market approval., Methods: A retrospective, longitudinal study was conducted involving adults (≥18 years) with MS from the 2010-2012 IBM MarketScan. Individuals with MS were selected based on ICD-9-CM: 340 and a newly initiated DMA prescription. Based on the index/first DMA prescription, patients were classified as fingolimod or injectable users. All covariates were measured during the six months baseline period prior to the index date. Multivariable logistic regression was performed to determine the predisposing, enabling, and need factors, conceptualized as per the Andersen Behavioral Model (ABM), associated with prescribing of fingolimod versus injectable DMA for MS., Results: The study cohort consisted of 3118 MS patients receiving DMA treatment. Of which, 14.4% of patients with MS initiated treatment with fingolimod within two years after the market entry, while the remaining 85.6% initiated with injectable DMAs. Multivariable regression revealed that the likelihood of prescribing oral DMA increased by 2-3 fold during 2011 and 2012 compared to 2010. Patients with ophthalmic (adjusted odds ratio [aOR]-2.60), heart (aOR-2.21) and urinary diseases (aOR-1.37) were more likely to receive fingolimod. Patients with other neurological disorders (aOR-0.50) were less likely to receive fingolimod than those without neurological disorders. Use of symptomatic medication (for impaired walking (aOR-2.60), bladder dysfunction (aOR-1.54), antispasmodics (aOR-1.48), and neurologist consultation (aOR-1.81) were associated with higher odds of receiving fingolimod. However, patients with non-MS associated emergency visits (aOR-0.64) had lower odds of receiving fingolimod than those without emergency visits., Conclusions: During the initial years after market approval, patients with highly active MS were more likely to receive oral fingolimod than injectable DMAs. More research is needed to understand the determinants of newer oral DMAs., Competing Interests: None., (© 2021 The Author(s).)

Study Objective: To compare the effectiveness of oral fingolimod and conventional injectable disease-modifying agents (DMAs) using the composite endpoint of relapse or DMA treatment switch in patients with multiple sclerosis (MS)., Design: A retrospective longitudinal cohort study., Data Source: IBM MarketScan Commercial Claims and Encounters Database from 2010-2012., Patients: Adults (≥18 years) with MS diagnosis (ICD-9-CM:340) who newly initiated DMAs., Intervention: Oral fingolimod and conventional injectable DMAs (interferon beta and glatiramer acetate)., Measurements: Composite endpoint of time to relapse or DMA treatment switch., Main Results: The incident study cohort consisted of 1997 MS patients who initiated oral fingolimod (15.6%) or injectable (84.4%) DMAs. The proportion of patients who had a composite endpoint (relapse/DMA treatment switch) in oral fingolimod and injectable DMA users was found to be 16.72% and 27.16%, respectively. The Cox PH regression model with stabilized IPTW revealed that fingolimod is equally effective as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint of relapse or DMA switch (adjusted hazard ratio [aHR]: 0.67, 95% CI: 0.43-1.03). Additional analysis among patients who were adherent also found no significant difference in the composite endpoint (aHR: 0.70, 95% CI 0.49-1.15) between oral fingolimod and injectable DMA users., Conclusions: Oral fingolimod has similar effectiveness as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint (relapse or DMA treatment switch). In addition, when assessed independently, oral fingolimod showed no difference in reducing the time to relapse or DMA treatment switch compared to injectable DMAs., (© 2021 Pharmacotherapy Publications, Inc.)

Background: Disease modifying agents (DMAs) are used to reduce relapses and decrease disability progression in Multiple Sclerosis (MS) patients. However, limited national level data exists regarding the prescribing patterns for MS, especially after the introduction of oral DMAs., Objective: This study examined the prescribing patterns and trends of DMAs using national level data and determined the factors associated with prescribing DMAs among MS patients in the United States., Methods: This cross-sectional study utilized 2006-2015 National Ambulatory Medical Care Survey (NAMCS) data to examine office-based visits involving MS (ICD-9-CM code 340). Descriptive weighted analyses were performed to assess the prescribing patterns of DMAs. Multivariable logistic regression model within the conceptual framework of Andersen Behavioral Model was used to determine the factors associated with prescribing of DMAs among MS patients., Results: An estimated 8.5 million (95% Confidence Interval [CI] 7.01-10.09 million) MS patient visits were identified from 2006 to 2015. During the ten-year study period, 3.84 million (45%) MS visits involved prescribing of DMAs. The majority of DMA prescriptions were injectables (78%), followed by infusions (11%) and orals (11%). Oral DMAs use increased (from 11% in 2010-2011 to 40% in 2014-2015), whereas the use of injectable DMAs decreased (from 96% in 2006-2007 to 52% in 2014-2015) during the study period. Multivariable analyses revealed that predisposing (age and region) and enabling (physician specialty) factors were significantly associated with prescribing of DMAs among MS patients. Visits to neurologists (Odds Ratio [OR] 6.61, 95% CI 3.66-11.93) were associated with higher odds of being prescribed with DMAs., Conclusion: During the ten-year study period, increasing use of oral DMAs and declining use of injectable DMAs was observed. Both predisposing and enabling factors influenced the prescribing of DMAs. With increasing availability of oral DMAs, the DMAs use is likely to increase among MS patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Multiple Sclerosis (MS) is a progressive neurodegenerative disease that affects more than 2 million people worldwide. Increasing knowledge about MS in different populations has advanced our understanding of disease epidemiology and variation in the natural history of MS among White and minority populations. In addition to differences in incidence, African American (AA) and Hispanic patients have greater disease burden and disability in earlier stages of disease compared to White patients. To further characterize MS in AA and Hispanic populations, we conducted a retrospective chart analysis of 112 patients treated at an MS center in Houston, Texas. Here, we describe similarities and differences in clinical presentation, MRI findings, treatment regimens, disability progression, and relapse rate. While we found several similarities between the groups regarding mean age, disability severity, and degree of brain atrophy at diagnosis, we also describe a few divergences. Interestingly, we found that patients who were evaluated by a neurologist at symptom onset had significantly decreased odds of greater disability [defined as Expanded Disability Status Scale (EDSS) > 4.5] at last presentation compared to patients who were not evaluated by a neurologist (OR: 0.04, 95% CI: 0.16-0.9). We also found that active smokers had significantly increased odds of greater disability both at diagnosis and at last clinical encounter compared to nonsmokers (OR: 2.44, 95% CI: 1.10-7.10, OR= 2.44, 95% CI: 1.35-6.12, p = 0.01, respectively). Additionally, we observed significant differences in treatment adherence between groups. Assessment of the degree of brain atrophy and progression over time, along with an enumeration of T1, T2, and gadolinium-enhancing brain lesions, did not reveal differences across groups.

Background: Little is known about the factors associated with the selection of Disease Modifying Agents (DMA) for the management of Multiple Sclerosis (MS) since the introduction of oral DMAs in 2010., Objectives: To examine the factors associated with initiation of oral DMAs in patients with MS using data from electronic medical records (EMR)., Methods: A retrospective longitudinal study was conducted using TriNetX, a federated EMR network of over 38 million patients from the US, from 2009-2019. Adult (≥18 years) patients with MS from the United States were identified using a MS diagnosis (ICD-9-CM: 340 or ICD-10-CM: G35) and a newly prescribed DMA with a one-year baseline period. Patients with new DMA prescriptions were classified as oral or injectable users based on their index medication. A multivariable logistic regression model was used to determine the predisposing (age category, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, symptomatic medication, and healthcare utilization) associated with initiation of an oral versus injectable DMA., Results: The study cohort consisted of 7,511 MS patients with a newly prescribed DMA, of whom most were 18-44 years old (48.33%), female (75.18%), and white (80.92%). About 42.32% of MS patients were diagnosed with at least one comorbidity (mean±SD: 0.86±1.37). Two thirds (66.32%) of the patients with MS started injectable DMAs, and the remaining one third (33.68%) started oral DMAs. Multivariable regression revealed that middle-aged (45-64 years; Adjusted Odds Ratio [aOR]=0.88; 95% Confidence Interval [CI]: 0.79-0.98) and older adults (≥65 years; aOR=0.67, 95% CI: 0.53-0.84) were associated with a decreased likelihood of receiving oral DMAs. The presence of general symptoms (aOR=1.26, 95% CI: 1.10-1.45) and cerebellar symptoms (aOR=1.56, 95% CI: 1.26-1.93) was associated with an increased likelihood of an oral DMA. However, the presence of sensory symptoms (aOR: 0.72, 95% CI: 0.59-0.88) was associated with a decreased likelihood of an oral DMA. Comorbidities such as renal failure (aOR=0.16, 95%% 0.04-0.62), obesity (aOR=0.60, 95% CI: 0.45-0.80), drug abuse (aOR=0.61, 95% CI: 0.38-0.99), and other neurological disorders (aOR=0.82, 95% CI: 0.69-0.96) were associated with a decreased likelihood of receiving an oral DMA prescription. While the use of analgesics (aOR=0.78, 95% CI: 0.69-0.88) was associated with decreased likelihood, the use of antispasmodics (aOR=1.14, 95% CI: 1.01-1.28) was associated with an increased likelihood of receiving an oral DMA. Relative to the time-period when first oral DMAs entered into the market (2010-11), with time, the likelihood of prescribing oral DMA increased by multiple folds (2012-13, aOR=4.30, 95% CI: 3.08-6.00; 2014-15, aOR=19.34, 95% CI: 14.10-26.54; 2016-17, aOR=17.63, 95% CI: 12.76-24.35; and 2018-19, aOR=20.73, 95% CI: 14.64-29.37)., Conclusions: Oral DMA use steadily increased over the years, with one in three MS patients receiving oral agents. Both demographic and clinical factors were associated with the initiation of oral DMA over injectable DMA., Competing Interests: Declaration of Competing Interest George J Hutton reports grants from Biogen, Novartis, MedImmune, Hoffman-LaRoche, EMD Serono, Sanofi,and Mallinckrodt, and personal fees from Novartis, Sanofi, Celgene, outside the submitted work. Rajender R Aparasu reports grants from Incyte, Novartis, and Astellas outside the submitted work. We wish to confirm that there are no other known conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years., Methods: We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety., Results: As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively., Conclusion: Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses., Competing Interests: Declaration of Competing Interest The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. JO has received consulting and/or speaking fees from Biogen Idec, Celgene, EMD Serono, Sanofi, Novartis, and Roche, and grant/research support from Biogen, Roche, and Sanofi. AA has received consulting and/or speaking fees from Biogen, Roche, and Sanofi, and grant/research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Roche, and Sanofi. EGC has received honoraria for advisory boards and/or speaking from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, and Teva, and unrestricted research grants from Genzyme and Novartis. CC was compensated for serving as editor, associate editor, or member of an editorial advisory board for Birth Defects Research Part A: Clinical and Molecular Teratology, and received grant/research support from AAAAI/VAMPS, AbbVie Laboratories, Amgen, Apotex, AstraZeneca, Barr Laboratories, Bristol-Myers Squibb, California Department of Public Health, CDC, Celgene, Hoffmann-La Roche, Genentech, GlaxoSmithKline, HRSA, IHC, Janssen Biotech, NIAAA, NIH/HIGM, Pfizer, Regeneron, Sanofi, Segirus, the State of California, and UCB Pharma. JD reports receiving speaking and consulting fees from Biogen, Celgene, EMD Serono, Genentech, Genzyme, Novartis, and Teva. VD has received consulting and/or speaking fees from Biogen, EMD Serono, Sanofi, Novartis, Roche, and Teva. KH received speaker honoraria and research support from Almirall, Bayer, Biogen, Merck, Novartis, Sanofi, and Teva. GJH has received research support from Adamas, Biogen, EMD Serono, Hoffman-La Roche, Mallinckrodt, MedImmune, Novartis, and Sanofi, and consulting fees from Biogen, Celgene, Novartis, and Sanofi. PM has received consulting and speaker fees from Biogen, Novartis, Sanofi, and Teva. MM has received speaking fees from Genzyme and fees for participating in advisory boards for Celgene. DR has received consulting fees from Bayer-Schering Pharma, Biogen, MedDay, Merck Serono, Novartis, Roche, Sanofi, and Teva Neuroscience, and research support from Actelion, Biogen, GW Pharma, Merck Serono, Mitsubishi, MedDay, Novartis, Sanofi, Teva Neuroscience, and TG Therapeutics. JRS and LS have nothing to disclose. RFS has received fees for advisory boards and consulting from Biogen and Sanofi, and lecture fees from Biogen, Merck, Novartis, and Roche. SGV reports receiving consulting and speaking fees from Sanofi, speaking fees from Genentech, consulting fees from EMD Serono, and fees as a study monitor for Millennium Pharmaceuticals, Inc. LC, ND, and CM are employees of Sanofi. DASC has received consulting fees and grant/research support from Sanofi, and lecture fees from Bayer-Schering Pharma and Sanofi., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disorder with significant health care burden. However, little is known about health care expenditures since the introduction of oral agents for MS after 2010., Objective: To analyze health care expenditures in individuals with MS using Medical Expenditure Panel Survey (MEPS) data from 2010-2015., Methods: This retrospective cross-sectional study included adults (≥ 18 years) with MS (Clinical Classification Code 080) and those without MS based on the 2010-2015 full year consolidated MEPS Household Component and Medical Provider Component data files. Descriptive weighted analyses were performed to compare health care expenditures between individuals with MS and without MS. The 2-part model involving probit and generalized linear models was used to estimate the marginal increase in total health care expenditures for MS patients., Results: There were 0.61 million patients (95% CI = 0.50-0.72) diagnosed with MS annually, accounting for a prevalence of 0.25%. The 2-part model revealed that the marginal total health care expenditures in patients diagnosed with MS were $20,103.49 (95% CI = $14,516.24-$25,690.73) more compared with those without MS. Further, the mean adjusted prescription medication expenditures for the MS group were $13,092.16 (95% CI = $9,452.20-$16,732.12) higher than the non-MS group and accounted for 65.12% of total health care expenditures in MS., Conclusions: MS is an expensive neuroinflammatory disease with a majority of the burden attributable to prescription medications. High prescription expenditure burden can be a barrier to optimal patient care in MS., Disclosures: No funding was received for this study. Hutton reports grants from Adamas, Biogen, EMD Serono, Genzyme, Hoffman-LaRoche, MedImmune, Mallinckrodt, and Novartis and fees from Biogen, Celgene, Genzyme, Genentech, and Novartis, outside the submitted work. Aparasu reports grants from Novartis, Incyte, and Astellas, outside the submitted work. Earla and Thornton have nothing to disclose. Part of the study findings was presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2019 National Conference; May 18-22, 2019; New Orleans, LA.

Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system leading to demyelination. MS in the pediatric population is rare, but has been shown to lead to significant disability over the duration of the disease. As we have learned more about pediatric MS, there has been a development of improved diagnostic criteria leading to earlier diagnosis, earlier initiation of disease-modifying therapies (DMT), and an increasing number of DMT used in the treatment of pediatric MS. Over time, treatment with DMT has trended towards the initiation of higher efficacy treatment at time of diagnosis to help prevent further disease progression and accrual of disability over time, and there is evidence in current literature that supports this change in treatment patterns. In this review, we discuss the current knowledge in diagnosis, treatment, and clinical outcomes in pediatric MS.

Purpose: This study evaluates the diagnostic performance of apparent diffusion coefficient (ADC) and T2 fluid-attenuation inversion recovery (T2 FLAIR) in discriminating between new white matter (WM) enhancing lesions (ELs) and non-enhancing lesions (NELs) in multiple sclerosis (MS) patients., Methods: Thirty MS patients with a new solitary WM lesion on brain MRI were analyzed. A region-of-interest was drawn on all lesions and the contralateral normal-appearing WM (NAWM) on T2 FLAIR and ADC maps. Normalized ratios of T2 FLAIR and ADC were calculated by dividing lesion value by the contralateral NAWM. Histogram analysis was performed on the T2 FLAIR, ADC values, and their normalized ratios. Mann-Whitney U test was used to compare histogram parameters and receiver operating characteristic (ROC) analysis determined the area under the curve (AUC)., Results: T2 FLAIR histogram parameters were not significantly different between ELs and NELs. Several EL ADC histogram parameters, including maximum and mean, were significantly higher than NELs (p = 0.006 to p = 0.031). There was a trend toward significantly higher maximum ADC in ELs after adjusting for multiple comparisons (p = 0.054). The standard deviation of T2 FLAIR (AUC 0.70), maximum ADC (AUC 0.79), and normalized maximum ADC ratio (AUC 0.75) were among histogram parameters with the highest diagnostic performance. A maximum ADC cutoff of 1274 × 10 -6  mm 2 /s provided a 0.86 sensitivity and 0.75 specificity., Conclusion: In patients with contraindications to gadolinium or concerns with gadolinium brain deposition, consideration may be given to ADC and T2 FLAIR as potential noncontrast methods for the evaluation of active MS lesions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing⁻remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell-based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS.

Objective: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT)., Methods: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE)., Results: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12-72). EFS was 69.2% (90% confidence interval [CI] 50.2-82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of -0.5 (interquartile range -1.5 to 0.0; p = 0.001) among participants who survived and completed the study., Conclusion: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years., Clinicaltrialsgov Identifier: NCT00288626., Classification of Evidence: This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg., Methods: Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test., Results: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported., Conclusions: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.

Importance: Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS., Objective: To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT., Design, Setting, and Participants: Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled., Interventions: Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT., Main Outcomes and Measures: The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events., Results: Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores., Conclusions and Relevance: At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

Background: Fingolimod is used to reduce the rates of relapse and slow the progression of disability in relapsing-remitting multiple sclerosis (RRMS). In-office monitoring of patients for 6h after the first dose of fingolimod is currently recommended due to rare cardiac rhythm disturbances. The objective of this paper is to describe our experience with continuous electrocardiographic monitoring of patients with RRMS starting on fingolimod., Methods: Since changes to the FDA recommendations for first dose observation, a total of 59 patients with RRMS began treatment with fingolimod. After the first dose, all patients were observed for 6h with continuous electrocardiographic telemetry, vital signs were checked every hour, and 12 lead ECG performed before and after the 6-h period., Results: Three out of 59 (5%) patients developed arrhythmia that led to discontinuation of fingolimod. The first patient had a sinus bradycardia with idioventricular escape rhythm that lasted 45s and two patients developed second-degree atrio-ventricular block Mobitz type I. None of the patients had a history of prior cardiacc disease or was taking other medications that may cause arrhythmia or bradycardia., Conclusion: Continuous on-line electrocardiographic telemetry may detect abnormal rhythms in a small number of patients started on fingolimod. The clinical significance of these is unclear and warrants further study., (© 2013 Elsevier B.V. All rights reserved.)

IFN-β is a major disease-modifying agent used for the treatment of multiple sclerosis (MS). Its mechanisms are complex and it has broad immunomodulatory effects on many types of immune cells. It was observed clinically that the quantity of CD4(+)CD25(+)Foxp3(+) regulatory T cells increases in some MS patients treated with IFN-β. In this study, we show that IFNAR engagement by IFN-β expands naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T cell population through the modulation of dendritic cells (DCs). IFN-β has no effect on the conversion of CD4(+)CD25(-) T cells to adaptive Treg cells. The IFN-β-induced upregulation of GITRL on DC and downregulation of CTLA-4 on Treg cell work together to facilitate the proliferation of anergic Treg cells. In MS patients treated with Avonex or Rebif (IFN-β), it was found that GITRL expression is markedly upregulated on peripheral CD14(+) cells. Our findings help the better understanding of the complex effects of IFN-β in the treatment of MS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is most prevalent in women of childbearing age. It is well established that the relapse rate decreases during pregnancy but increases significantly during the first postpartum trimester. The objective of this retrospective study was to evaluate the effectiveness of the administration of 1 g of intravenous methylprednisolone (IVMP) after delivery in the prevention of MS relapses. The study involved 47 women with one or more documented pregnancies; each pregnancy was treated as a separate case. There were 50 cases with relapsing-remitting MS and 2 with secondary progressive MS. The cases were divided into two groups: the IVMP group (those who received 1 g of IVMP after delivery) and the no-IVMP group (those who did not receive IVMP after delivery). There were 39 cases in the IVMP group and 13 in the no-IVMP group. During the first postpartum trimester, relapses occurred in 17.9% of the IVMP group, compared with 46.2% of the no-IVMP group (P = .0448). The difference in relapse percentage between the two groups during the second and third postpartum trimesters was not statistically significant. Our study shows a statistically significant benefit of postpartum IVMP administration in reducing MS relapses.

In multiple sclerosis (MS) functional changes in connectivity due to cortical reorganization could lead to cognitive impairment (CI), or reflect a re-adjustment to reduce the clinical effects of widespread tissue damage. Such alterations in connectivity could result in changes in neural activation as assayed by executive function tasks. We examined cognitive function in MS patients with mild to moderate CI and age-matched controls. We evaluated brain activity using functional magnetic resonance imaging (fMRI) during the successful performance of the Wisconsin card sorting (WCS) task by MS patients, showing compensatory maintenance of normal function, as measured by response latency and error rate. To assess changes in functional connectivity throughout the brain, we performed a global functional brain network analysis by computing voxel-by-voxel correlations on the fMRI time series data and carrying out a hierarchical cluster analysis. We found that during the WCS task there is a significant reduction in the number of smaller size brain functional networks, and a change in the brain areas representing the nodes of these networks in MS patients compared to age-matched controls. There is also a concomitant increase in the strength of functional connections between brain loci separated at intermediate-scale distances in these patients. These functional alterations might reflect compensatory neuroplastic reorganization underlying maintenance of relatively normal cognitive function in the face of white matter lesions and cortical atrophy produced by MS.

Multiple sclerosis (MS) is a demyelinating disease characterized by autoimmune inflammation in the central nervous system. Despite over a decade of use of interferon-&#x03B2; (IFN-&#x03B2;) in the treatment of MS, its mechanisms of action are still not fully elucidated. New data now demonstrate that the 2 important proinflammatory cytokines involved in the pathogenesis of MS, osteopontin (OPN) and interleukin-17 (IL-17), are regulated by IFN-&#x03B2;. This review discusses the role of OPN and IL-17 in the development of MS and how the downregulation of the levels of OPN and interleukin-17 contributes to the therapeutic effects of IFN-&#x03B2; in MS.

Objective: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy., Methods: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center., Results: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers., Conclusions: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Objective: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNbeta-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM IFNbeta-1a monotherapy., Methods: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >or=1 relapse or gadolinium-enhancing MRI lesion in the prior year while on IM IFNbeta-1a monotherapy. Subjects continued IFNbeta-1a 30 mcg IM weekly and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without IVMP 1,000 mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center., Results: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNbeta neutralizing antibodies. ACT's management and operational structures functioned well., Conclusion: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.

Interferon beta (IFN beta) has complex immune regulatory properties that contribute to its treatment effect on multiple sclerosis (MS). In this study, we investigated the role of IFN beta in differentiation and functional properties of monocytes and monocyte-derived dendritic cells that are critical to the inflammatory process in MS. The results revealed that IFN beta inhibited intracellular production of interleukin (IL)-1b (P<0.01) in both monocytes exposed to in vitro treatment of IFN beta and monocytes analysed ex vivo from MS patients treated with IFN beta. IFN beta was shown to modulate differentiation of monocytes into dendritic cells in the presence of IL-4 and GM-CSF, which resulted in a delayed differentiation process. Furthermore, it characteristically altered the phenotypic features of differentiated dendritic cells by inhibiting the expression of CD1a, CD11b, CD11c, CD123 and CD209 while upregulating costimulatory molecules, such as CD86. The selective regulatory properties of IFN beta appeared to render the function of differentiated dendritic cells to produce an increased amount (P<0.01) while their ability to secrete proinflammatory IL-12 and TGF beta was significantly reduced. The observed collective effects of IFN beta seemed to correlate with Th2 immune deviation. The study has provided new insights into the regulatory mechanisms of IFN beta in the treatment of MS.