Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold.

PURPOSE OF REVIEW: Research in multiple sclerosis (MS) has long been predicated on clinical groupings that do not reflect the underlying biologic heterogeneity apparent within patient populations. This review explicates the various levels of explanation through which the spectrum of disease is described and investigated both above and below the clinical threshold of detection, as framed by the topographical model of MS, to help advance a cogent mechanistic framework. RECENT FINDINGS: Contemporary evidence has amended the view of MS as consisting of sequential disease phases in favor of a spectrum of disease with an admixture of interdependent and dynamic pathobiological axes driving tissue injury and progression. Recent studies have shown the presence of acute and compartmentalized inflammation and mechanisms of neurodegeneration beginning early and evolving throughout the disease continuum. Still, the gap between the understanding of immunopathologic processes in MS and the tools used to measure relevant molecular, laboratory, radiologic, and clinical metrics needs attention to enable better prognostication of disease and monitoring for changes along specific pathologic axes and variable treatment outcomes. SUMMARY: Aligning on a consistently-applied mechanistic framework at distinct levels of explanation will enable greater precision across bench and clinical research, and inform discourse on drivers of disability progression and delivery of care for individuals with MS.

Immunoglobulin G immune response to SARS-CoV-2 vaccination in people living with multiple sclerosis within Multiple Sclerosis Partners Advancing Technology and Health Solutions.

BACKGROUND: The impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on SARS-CoV-2 vaccination response is uncertain. METHODS: Post-SARS-CoV-2 vaccination blood samples across multiple DMTs were tested for SARS-CoV-2 immunoglobulin G (IgG) response. RESULTS: Three hundred twenty-two people with MS were included; 91.9% received an mRNA vaccine. Post-vaccination reactive IgG rates (IgG index > 1) were 40% for anti-CD20 (32/80 patients); 41% for sphingosine 1-phosphate receptor modulators (S1PRM, 16/39); and 100% for all other classes, including the no DMT group. CONCLUSION: Anti-CD20 therapies and S1PRMs reduce IgG response to SARS-CoV-2 vaccination; IgG response is preserved with other DMTs.

Multiple Sclerosis Progression Discussion Tool Usability and Usefulness in Clinical Practice: Cross-sectional, Web-Based Survey.

BACKGROUND: A digital tool, Multiple Sclerosis Progression Discussion Tool (MSProDiscuss), was developed to facilitate discussions between health care professionals (HCPs) and patients in evaluating early, subtle signs of multiple sclerosis (MS) disease progression. OBJECTIVE: The aim of this study is to report the findings on the usability and usefulness of MSProDiscuss in a real-world clinical setting. METHODS: In this cross-sectional, web-based survey, HCPs across 34 countries completed an initial individual questionnaire (comprising 7 questions on comprehensibility, usability, and usefulness after using MSProDiscuss during each patient consultation) and a final questionnaire (comprising 13 questions on comprehensibility, usability, usefulness, and integration and adoption into clinical practice to capture the HCPs' overall experience of using the tool). The responses were provided on a 5-point Likert scale. All analyses were descriptive, and no statistical comparisons were made. RESULTS: In total, 301 HCPs tested the tool in 6974 people with MS, of whom 77% (5370/6974) had relapsing-remitting MS, including those suspected to be transitioning to secondary progressive MS. The time taken to complete MSProDiscuss was reported to be in the range of 1 to 4 minutes in 97.3% (6786/6974; initial) to 98.2% (269/274; final) of the cases. In 93.54% (6524/6974; initial) to 97.1% (266/274; final) of the cases, the HCPs agreed (4 or 5 on the Likert scale) that patients were able to comprehend the questions in the tool. The HCPs were willing to use the tool again in the same patient, 90.47% (6310/6974; initial) of the cases. The HCPs reported MSProDiscuss to be useful in discussing MS symptoms and their impact on daily activities (6121/6974, 87.76% initial and 252/274, 92% final) and cognitive function (5482/6974, 78.61% initial and 271/274, 79.2% final), as well as in discussing progression in general (6102/6974, 87.49% initial and 246/274, 89.8% final). While completing the final questionnaire, 94.9% (260/274) of the HCPs agreed that the questions were similar to those asked in regular consultation, and the tool helped to better understand the impact of MS symptoms on daily activities (249/274, 90.9%) and cognitive function (220/274, 80.3%). Overall, 92% (252/274) of the HCPs reported that they would recommend MSProDiscuss to a colleague, and 85.8% (235/274) were willing to integrate it into their clinical practice. CONCLUSIONS: MSProDiscuss is a usable and useful tool to facilitate a physician-patient discussion on MS disease progression in daily clinical practice. Most of the HCPs agreed that the tool is easy to use and were willing to integrate MSProDiscuss into their daily clinical practice.

Optic Neuropathy and Stroke Secondary to Invasive Aspergillus in an Immunocompetent Patient.

Angioinvasive aspergillosis is an aggressive fungal infection that is potentially life threatening without prompt treatment. Optic nerve involvement of Aspergillus can mimic optic neuritis commonly seen in demyelinating and other inflammatory conditions. Treatment of Aspergillus infection with steroids may worsen the clinical course. We describe a unique case of disseminated central nervous system aspergillosis, initially presenting as an optic neuropathy, with subsequent stroke in multiple vascular territories.

Experience with fingolimod in clinical practice.

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

Comparison of time to clinically meaningful improvement in quality of life in neurological disorders in patients treated with natalizumab versus ocrelizumab.

Aim: To assess time to improvement in Quality of Life in Neurological Disorders (Neuro-QoL) domains for patients treated with natalizumab versus ocrelizumab. Methods: Patients enrolled in the MS PATHS network who initiated treatment with either natalizumab or ocrelizumab rated the Neuro-QoL domains of physical function, symptoms, emotional health, cognitive function and social ability. Results: Time to clinically meaningful improvement was significantly shorter with natalizumab versus ocrelizumab for cognitive function (event time ratio [95% CI]: 0.37 [0.24-0.57]; p < 0.001), sleep disturbance (0.45 [0.28-0.72]; p = 0.001), social role participation (0.37 [0.21-0.66]; p = 0.001) and social role satisfaction (0.5 [0.31-0.8]; p = 0.004). Conclusion: Natalizumab had shorter time to clinically meaningful improvement in cognitive, sleep, and social role Neuro-QoL domains versus ocrelizumab.

Knowledge of treatment-related benefits associated with medication choices, including improvement of quality of life (QoL), are strong influential factors for patients to start and continue their therapies. Little is known about patient-reported time to onset of functional improvement upon the initiation of medications for multiple sclerosis (MS). The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network, a repository of collaborative international data on routine MS management, includes patient-reported information on the health-related QoL using the Quality of Life in Neurological Disorders (Neuro-QoL) measure. This study included data from 883 eligible patients enrolled in MS PATHS, with the aim of assessing and comparing the time to improvement in physical, mental and social health for patients treated with natalizumab versus ocrelizumab using Neuro-QoL. Natalizumab and ocrelizumab are both high-efficacy treatment options for relapsing forms of MS. The results demonstrated that, compared with ocrelizumab, natalizumab treatment led to faster effect on mental and social health, as well as quicker improvements in physical functioning in the arms and hands. Overall, it took shorter time for natalizumab-treated patients to achieve better QoL compared with ocrelizumab. These findings highlight the importance of QoL in disease management and provide a patient perspective for healthcare providers when making decisions about high-efficacy treatments for their patients with MS.

Updates and advances in multiple sclerosis neurotherapeutics.

The multiple sclerosis (MS) neurotherapeutic landscape is rapidly evolving. New disease-modifying therapies (DMTs) with improved efficacy and safety, in addition to an expanding pipeline of agents with novel mechanisms, provide more options for patients with MS. While treatment of MS neuroinflammation is well tailored in the existing DMT armamentarium, concerted efforts are currently underway for identifying neuropathological targets and drug discovery for progressive MS. There is also ongoing research to develop agents for remyelination and neuroprotection. Further insights are needed to guide DMT initiation and sequencing as well as to determine the role of autologous stem cell transplantation in relapsing and progressive MS. This review provides a summary of these updates.

The range of treatment options available for multiple sclerosis (MS) is growing, with the aim of developing safer and more effective therapies. There are ongoing efforts to discover additional mechanisms of MS and create drugs that can target these pathways. A more tailored approach will allow better personalization of drug selection for patients. There is currently a special focus on identifying treatment targets for progressive MS, where there are only a limited number of therapeutic options available to date. In addition, there is ongoing research aimed at developing stem cell therapies, drugs that provide neuroprotection and agents that can potentially reverse the damage caused by MS through remyelination. In this review, these topics are summarized.

Leadership Inequity, Burnout, and Lower Engagement of Women in Medicine.

Gender parity has been reached in graduation rates from medical school, yet women in medicine continue to face obstacles in promotion, compensation and opportunities, leading to leadership inequity, higher burnout and lower engagement. These complex issues with gender are just one aspect of the wide challenges related to diversity, equity and inclusion among medical professionals. While there are no "one size fits all" approaches, psychologists are well positioned to lead efforts related to promoting leadership equity, reducing burnout and raising engagement because of their training in communication skills, programmatic development and empathetic listening. This paper details several evidence-based efforts in which psychologists can lead in these ongoing issues for women in medicine.

Secondary hypogammaglobulinemia in patients with multiple sclerosis on anti-CD20 therapy: Pathogenesis, risk of infection, and disease management.

Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.

Diversity, Equity, and Inclusion in the Multiple Sclerosis Community: A Call to Action.

Many medical organizations have begun to confront the longstanding problem of inequalities in health care delivery and the undeniable effect of disparities on health outcomes. The Consortium of Multiple Sclerosis Centers (CMSC) recognizes that disparities affect the lives of many people with multiple sclerosis (MS) and acknowledges the need to address this as an organization. The CMSC recently (1) appointed a task force, (2) conducted a survey of its membership, (3) commissioned this review article and call to action, and (4) formulated a mission statement on diversity, equity, and inclusion (DEI), which was adopted by the CMSC's Board of Governors in March 2023. This paper summarizes recent literature on health care disparities in MS, particularly those relating to race/ethnicity, sexual orientation, and gender identity. It presents findings from CMSC's survey of members' awareness of DEI issues, the need for education and resources for MS care providers, and existing institutional policies on DEI in the members' practice settings. It also presents the task force's recommendations for next steps, which includes the goal of greater diversity in the MS workforce of the future. The CMSC will continue to revisit DEI policies and practices over time with the goal of motivating greater awareness, momentum, and positive changes within the MS community.

Agreement Between Published Reference Resources for Neurofilament Light Chain Levels in People With Multiple Sclerosis.

OBJECTIVES: To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS). METHODS: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z-scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z-score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z-scores could be derived for 4 of 6 reference resources. RESULTS: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m2, and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z-scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89. DISCUSSION: Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes.

Associations of sNfL with clinico-radiological measures in a large MS population.

OBJECTIVE: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. METHODS: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. RESULTS: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. INTERPRETATION: Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

Racial disparities in hypertension management among multiple sclerosis patients.

BACKGROUND: Hypertension adversely impacts the multiple sclerosis (MS) disease course and is more common among Black Americans. Disparities in care due to structural racism may lead to suboptimal hypertension detection and control in Black American MS patients. OBJECTIVES: To determine if uncontrolled hypertension is more common in Black or White Americans with MS and whether race impacts the likelihood of receiving anti-hypertensive treatment. METHODS: A retrospective cohort study was conducted using longitudinal data from American participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) multi-institutional registry. Data was collected from 7 sites in the United States between May 2015 and November 2020. Patients with uncontrolled hypertension, defined as ≥2 blood pressure measurements ≥140/90 mmHg, were identified in the dataset. Racial differences in uncontrolled hypertension and odds of anti-hypertensive treatment were evaluated using logistic regression. Predictors of anti-hypertensive treatment in those with uncontrolled hypertension were determined by race. RESULTS: The analysis included 10,673 MS patients, of whom 1,442 (13.5%) were Black Americans. Despite a lower mean age (45.7 vs. 49.2 years), Black Americans had a 31% increased odds of uncontrolled hypertension compared to White Americans. After adjustment for relevant covariates, mean systolic blood pressure was 1.84 mmHg (95% confidence interval=1.07-2.61) higher in Black Americans than White Americans, and mean diastolic blood pressure was 1.28 mmHg (95% confidence interval=0.74-1.82) higher. Black Americans were also more likely to be on anti-hypertensive therapy (OR=1.68, 95% confidence interval=1.30-2.18) and were exposed to an adjusted average of 0.61 (95% confidence interval=0.45-0.78) more anti-hypertensive treatments than White Americans (p<0.001). Age, comorbid diabetes mellitus, and comorbid hyperlipidemia were positively associated with use of anti-hypertensive treatments in all patients with uncontrolled hypertension. CONCLUSION: Black American MS patients have significantly increased odds of uncontrolled hypertension, but also higher odds of receiving anti-hypertensive treatment.

Real-world effectiveness of dimethyl fumarate versus fingolimod in a cohort of patients with multiple sclerosis using standardized, quantitative outcome metrics.

BACKGROUND: Prior studies suggest comparable effectiveness of dimethyl fumarate (DMF) and fingolimod (FTY) in multiple sclerosis (MS) using relapse, Expanded Disability Status Score (EDSS), and magnetic resonance imaging (MRI) lesion metrics. OBJECTIVE: Compare the real-world effectiveness of DMF versus FTY using quantitative, validated neuroperformance tests, MRI, and serum neurofilament light chain (sNfL) outcomes while controlling for between-group differences. METHODS: Patients were eligible if on DMF or FTY when first enrolled in the MS Partners Advancing Technology and Health Solutions (MS PATHS) network and had ≥1-year follow-up in MS PATHS. Sensitivity analysis included a subgroup who started DMF/FTY ≤2 years from enrolment. After propensity score weighting, differences in means and in mean 1-year change of neuroperformance and MRI outcomes were compared. sNfL levels were assessed. This was a non-randomized comparison. RESULTS: In the overall cohort, no significant differences were observed between DMF (n = 702) and FTY (n = 600) in neuroperformance or MRI outcomes including brain volume loss; mean time (SD) since treatment initiation was 1.98 (0.68) years for DMF and 2.02 (0.75) years for FTY. A sensitivity analysis controlling for DMF and FTY treatment duration yielded similar results. CONCLUSION: In this study, DMF and FTY demonstrated similar effects on physical and cognitive neuroperformance and MRI outcomes. Direct comparisons to other fumarates and S1P receptor modulators were not conducted.

How the COVID-19 Pandemic has changed multiple sclerosis clinical practice: Results of a nationwide provider survey.

BACKGROUND: The COVID-19 crisis has created unanticipated changes in health care delivery for people living with multiple sclerosis (MS). The pandemic's rapid evolution has resulted in a knowledge gap in how COVID-19 has affected MS clinical practice. Our objective was to understand how the COVID-19 pandemic has affected clinical practice patterns in a nationwide cohort of MS clinicians across the United States. METHODS: In collaboration with the National Multiple Sclerosis Society (NMSS), we developed a 28-item SurveyMonkeyTM electronic questionnaire exploring MS specialists' perceptions of how COVID-19 has altered how they prescribe MS disease-modifying therapies (DMTs), provide telehealth and other services, and view issues affecting their own well-being including re-deployment to the front lines of COVID-19 care and availability of personal protective equipment (PPE). NMSS staff sent a recruitment email containing the electronic survey link to 188 clinicians who serve on regional NMSS Healthcare Provider Councils across the US, 86 (45.7%) of whom were MS specialist physicians. RESULTS: Eighty-six of 188 potential respondents (45.7%) from 32 US states completed the survey including 45 physicians (41 neurologists, 3 physiatrists and 1 family physician), 18 rehabilitation therapists, 7 psychologists, 6 nurse practitioners, 4 social workers, 2 physician assistants, 2 nurses and 2 health professionals from other disciplines. More than 80% of all respondents working on-site in a health care setting believed they had adequate PPE. More than 41% were able to distance safely from others at work. Nearly 10% of respondents reported they had been re-deployed to the front lines of COVID-19 patient care, and an additional 16.9% anticipated being re-deployed. Among the MS specialist physician subgroup, nearly one-third reported using telemedicine to provide over 75% of their clinical care. Only 16.7% believed COVID-19 had not changed how they prescribe DMTs. Therapies prescribed more often during the pandemic included ß-IFNs (28.6% of prescribers), natalizumab (23.8%), glatiramer acetate (21.4%) and teriflunomide (19%). DMTs prescribed less often included alemtuzumab (64.3% of prescribers), cladribine (54.8%), ocrelizumab and rituximab (50%), and fingolimod and siponimod (40.5%). For at least some of their patients during the pandemic, some MS specialists reported suspending certain DMTs including alemtuzumab (21.4% of prescribers), ocrelizumab and rituximab (16.7%) and cladribine (11.9%). Others reported extending DMT dosing intervals for natalizumab (38.1%), fingolimod and siponimod (11.9%). CONCLUSIONS: In this nationwide survey, MS specialist physicians and other clinicians serving on regional NMSS Healthcare Provider Councils across the US reported profound changes in how they are delivering MS care during the COVID-19 pandemic.

Clinical characteristics of a large multi-center cohort of people with multiple sclerosis over age 60.

BACKGROUND: As the peak prevalence of multiple sclerosis (MS) shifts due to an aging patient population, understanding the characteristics that define this older cohort to improve overall management is critical. We sought to determine the clinical characteristics of people with MS over age 60. METHODS: Demographics, clinical characteristics, MS disease history, and Multiple Sclerosis Performance Test (MSPT) patient-reported outcomes and neuroperformance tests (NPTs) were collected from 10 academic MS centers in the US and Europe participating in the MS Partners Advancing Technology Health Solutions (MS PATHS) system. We characterized demographic and disease characteristics of included participants using descriptive statistics. We characterized prevalence of comorbidities and compared with estimated prevalences from the National Health and Nutrition Examination Survey (NHANES) respondents aged ≥60 years in 2017-2018. RESULTS: We identified 2738 individuals over age 60 from MS PATHS, with 58.1% relapsing-remitting (RR) and 41.9% progressive. Our results showed median age (RR=65.7 years, progressive=66.0 years), age of symptom onset (RR and progressive=40.9 years), and disease duration (RR=22.8 years, progressive=23.3 years). Over two-thirds of individuals in our cohort were treated with DMTs. The most common DMT used in RR patients were interferons (17.6%) and glatiramer acetate (16.3%), while glatiramer acetate was the most common (12.0%) in progressive patients. Progressive patients had higher disability (higher median PDDS scores, worse Neuro-Qol T-scores, and worse NPTs) compared to the RR group. Pain was the most common comorbidity, followed by cardiac disease, depression, hypertension, dyslipidemia, and obesity. Compared to older NHANES participants, older people with MS were more likely to have depression (MS PATHS: 51.5% [95% CI: 49.5% to 53.5%] vs. NHANES: 21.7% [95% CI: 1619.3% to 22.2%]) and osteoporosis (MS PATHS: 12.7% [95% CI: 11.3% to 14.1%] vs. NHANES: 8.2% [95% CI: 6.2% to 10.3%]); they were less likely to be obese (MS PATHS: 29.4% [95% CI: 27.7% to 31.2%] vs. NHANES: 45.1% [95% CI: 38.9% to 51.3%]) and have diabetes (MS PATHS: 12.3% [95% CI: 11.1% to 13.6%] vs. NHANES: 22.5% [95% CI: 18.8% to 25.7%]). CONCLUSIONS: Our study characterizes a large multi-center international cohort of people with MS over age 60. This contemporary cohort appears less disabled than prior studies, which may reflect long term impact of DMT availability on the natural history of MS. The burden of comorbidity in this population was generally high. Information on DMT use, comorbidity, and disability outcome measures will be beneficial in future studies evaluating the impact of therapeutic interventions in older individuals.

The implications of suboptimal year-1 outcomes with disease-modifying therapy in employees with multiple sclerosis.

AIM: Multiple sclerosis (MS) poses a substantial employer burden in medically related absenteeism and disability costs due to the chronic and debilitating nature of the disease. Although previous studies have evaluated relapse, nonadherence, discontinuation, and switching individually, little is known about their overall collective prevalence and implications in employees with MS treated with disease-modifying therapies (DMTs). This study evaluated the proportion of employees with MS with suboptimal DMT year-1 outcomes and to quantify the clinical and economic burden of suboptimal year-1 outcomes from a US employer perspective. MATERIALS AND METHODS: Employees with MS were selected from the Workpartners database. Eligibility criteria were: ≥2 MS diagnosis claims (ICD-9-CM 340.xx/ICD-10-CM G35) from January 1, 2010-March 31, 2019, ≥1 once-/twice-daily oral or self-injectable DMT claim (first claim = index), continuous eligibility 6-months pre-/1-year post-index, no baseline DMT, and age 18-64 years. Suboptimal year-1 outcomes included: non-adherence (proportion of days covered <80%), discontinuation (gap >60 days), switch, or relapse (MS-related hospitalization, emergency room visit, or outpatient visit with corticosteroid). A two-part logistic-generalized linear model evaluated costs. RESULTS: Of 488 eligible patients, half (n = 247; 50.6%) had suboptimal year-1 outcomes (39.5% non-adherence, 9.8% discontinuation, 10.9% switching, 20.7% relapse; not mutually exclusive). Employees with suboptimal year-1 outcomes had higher all-cause medical ($12,730 vs. $6,428; p < 0.0001), MS-related medical ($5,444 vs. $2,652; p < 0.0001), non-DMT pharmacy ($2,920 vs. $2,169; p = 0.0199), sick leave ($1247 vs. $908; p = 0.0274), and short-term disability ($934 vs. $146; p = 0.0001) costs. Long-term disability ($751 vs. $0; p = 0.1250) and Workers' Compensation ($56 vs. $24; p = 0.1276) did not significantly differ. LIMITATIONS: Administrative claims lack clinical information. Results may not be generalizable to other patients or care settings. CONCLUSIONS: Half of the employees with MS in this sample had suboptimal year-1 outcomes (i.e. non-adherence, discontinuation, switching, or relapse). These suboptimal year-1 outcomes were associated with greater medical, sick leave, and short-term disability costs.

Impact of natalizumab on quality of life in a real-world cohort of patients with multiple sclerosis: Results from MS PATHS.

BACKGROUND: Optimizing multiple sclerosis treatment warrants understanding of changes in physical, mental, and social health. OBJECTIVE: To assess the impact of natalizumab on Quality of Life in Neurological Disorders (Neuro-QoL) scores. METHODS: Annualized change in T-scores and likelihood of ≥5-point improvement over baseline were calculated for each Neuro-QoL domain after natalizumab initiation. Comparisons with ocrelizumab-treated patients were conducted after propensity score weighting and adjustment for relevant co-medications, year, and drug-year interaction. RESULTS: Among 164 natalizumab patients analyzed, 8 of 12 Neuro-QoL domains improved significantly, with greater improvement in patients with abnormal baseline Neuro-QoL. In the subgroup comparison of natalizumab-treated (n = 145) and ocrelizumab-treated (n = 520) patients, significant improvement occurred in 9 of 12 and 4 of 12 domains, respectively. The difference between groups was statistically significant for positive affect and well-being (p = 0.02), sleep (p = 0.003), and satisfaction with social roles and activities (SRA) (p = 0.03) in the overall population and for emotional and behavioral dyscontrol (p = 0.01), participation in SRA (p = 0.0001), and satisfaction with SRA (p = 0.02) in patients with abnormal baseline Neuro-QoL. CONCLUSIONS: Natalizumab can produce clinically meaningful improvements in mental and social health. Such improvements are unlikely to be primarily driven by expectation bias, as their magnitude exceeded improvements with another high-efficacy therapy, ocrelizumab.

Effect of switching from natalizumab to moderate- vs high-efficacy DMT in clinical practice.

OBJECTIVE: To assess the real-world comparative effectiveness of switching from natalizumab (NTZ) to a moderate-efficacy (Mod) disease-modifying therapy (DMT) vs high-efficacy therapy (HET) in patients with multiple sclerosis (MS). METHODS: Patients discontinuing NTZ at two MS centers (n = 556) who switched to Mod DMT (n = 270) vs HET (n = 130) were assessed using propensity score (PS) weighting. PS model covariates included demographics and baseline clinical and MRI characteristics. All outcomes were reported as Mod DMT vs HET. RESULTS: Of the patients included in the study, 48.6% switched to Mod DMT (dimethyl fumarate, n = 130; fingolimod, n = 140) vs 23.4% who switched to HET (ocrelizumab, n = 106; rituximab, n = 17; alemtuzumab, n = 7). Within the first 6 months post-NTZ, switchers to Mod DMT experienced comparable relapses (odds ratio [OR] = 1.36, 95% confidence interval [CI] [0.72-1.66], p = 0.724), although they had increased MRI activity on treatment (OR = 2.59, 95% CI [1.09-3.57], p = 0.037). By 24 months post-NTZ, there was no difference in the annualized relapse rate (OR = 1.44, 95% CI [0.69-1.59], p = 0.334) or time to first clinical relapse (HR = 2.12, 95% CI [0.87-5.17], p = 0.090), although switchers to Mod DMT had higher gadolinium-enhancing (GdE) lesions (OR = 3.62, 95% CI [1.56-5.21], p = 0.005), earlier time to first GdE lesion (HR = 6.67, 95% CI [2.06-9.16], p = 0.002), lower proportion with the absence of disease activity (OR = 0.41, 95% CI [0.21-0.71], p = 0.004), and higher risk of disability progression on T25FW (OR = 1.83, 95% CI [1.06-3.02], p = 0.043) and 9-HPT (OR = 1.81, 95% CI [1.05-3.56], p = 0.044). CONCLUSION: Patients switching from NTZ to Mod DMT vs HET were at relatively increased risk of disease activity within the first 6 months of NTZ withdrawal that was sustained at 24 months, yielding greater disability progression.

Effect of tobacco use on disease activity and DMT discontinuation in multiple sclerosis patients treated with dimethyl fumarate or fingolimod.

BACKGROUND: Tobacco exposure is a modifiable risk factor for multiple sclerosis (MS). Studies evaluating the relationship between tobacco, disease activity, and disease modifying therapy (DMT) persistence yielded conflicting results. We sought to address this issue with data from clinical practice. OBJECTIVE: To compare 24-month disease outcomes in tobacco versus non-tobacco users treated with dimethyl fumarate (DMF) or fingolimod (FTY) in clinical practice. METHODS: We retrospectively identified 659 MS patients treated with DMF or FTY, stratified by patient-reported tobacco use. DMT discontinuation and measures of disease activity at 24 months were assessed using propensity score (PS) weighting. Outcome estimates were calculated as tobacco vs non-tobacco use. RESULTS: 164 tobacco users (DMF n = 101; FTY n = 63) and 495 non-tobacco users (DMF n = 294; FTY n = 201) were identified. Tobacco (39.4%) and non-tobacco (34.4%) users were equally likely to discontinue DMT (OR = 1.17, 95% CI 0.79, 1.75), but tobacco users discontinued therapy earlier (HR = 1.53, 95% CI 1.06, 2.43). There were no differences in ARR (rate ratio = 1.39, 95% CI 0.97, 1.96). However, tobacco users had decreased odds of NEDA-2 (OR = 0.61, 95% CI 0.44, 0.83). CONCLUSION: Our findings suggest that tobacco is a negative risk factor for inflammatory disease activity and earlier DMF and FTY discontinuation.