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.

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.

Spending on and Use of Clinician-Administered Drugs in Medicare.

Importance: Medicare Part B drug expenditures have increased in recent years. This trend is likely to persist given the increased use and availability of biologics. Objectives: To assess the extent to which Medicare Part B spending growth was associated with changes in price vs quantity, and how these trends interacted with entry of new drugs into the marketplace. Design, Setting, and Participants: This cross-sectional study quantified the degree of spending concentration and the association between price and use of Part B drugs among fee-for-service Medicare beneficiaries. Data on use and spending for separately payable Part B drugs were included. Source data were aggregated to the drug-year level and reported from 2016 to 2020. Descriptive decomposition and index analyses quantified the relative association of price and use changes separately for existing single-source drugs, existing drugs that faced competition, and new drugs that entered the market. Data analysis was performed from June to December 2022. Main Outcomes and Measures: Part B drug spending by the fee-for-service Medicare program and beneficiaries, as well as use, defined as dosage units and beneficiaries using the drugs. Results: The study included 535 unique Part B drug products. From 2016 to 2020, 15 or fewer products comprised half of all Part B drug expenditures. The set of 7 drugs that comprised the top 25% of spending was very consistent over time, and all were biologics. Part B drug products that cost $1.85 or less per administration accounted for more than half of the doses administered in 2020. Spending on Part B drugs increased by $15 billion from 2016 to 2020. The entry of new, nonbiosimilar drugs during this period accounted for $12 billion of this increased spending (80%), while shifts in use and price increases among existing single-source brand drugs accounted for the remaining increase in spending. Part B spending decreased among the subset of existing drugs facing generic or biosimilar competition. Among single-source drugs on the market in 2016, the index that varied dosage units exceeded the index that varied price in all years, confirming that changes in use were associated more with spending growth for those drugs. Conclusions and Relevance: In this cross-sectional study of Medicare Part B drug expenditures, spending was found to be concentrated among a small number of drugs. The entry of new products was a key factor associated with recent increases in Part B drug spending. These findings suggest that policies targeting top-selling drugs may have greater potential to curb Part B drug spending than those targeting price growth.

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.

Biosimilars engage in low levels of direct-to-physician marketing relative to reference biologics.

Biosimilars have the potential to greatly reduce US spending on biologic drugs, but uptake of these competitor products varies. We used Open Payments data from 2014 to 2022 to proxy for direct-to-physician marketing and compared levels of activity between biologic and biosimilar drug manufacturers. Our analysis focused on 6 reference biologics that recently faced competition in the years immediately before and after the launch of the first biosimilar. We used Medicare Part B dosage units to measure market penetration of biosimilars and its relationship with biosimilar marketing activity. Last, we conducted a sensitivity test, comparing payments for primarily office- or hospital-based physicians, using affiliations constructed from Medicare Carrier claims. Reference biologic manufacturers greatly reduced the amount of direct-to-physician marketing in the post-launch period. Biosimilar manufacturers generally engaged in low levels of activity relative to the historic performance of reference biologics. These trends were consistent across office- and hospital-based physicians. The intensity of biosimilars' direct-to-physician marketing also had no apparent relationship with achieved market penetration. Our findings demonstrate that persistently high market shares of reference biologics cannot be explained by ongoing direct-to-physician marketing activities. At the same time, while such activities could educate physicians or induce switching, biosimilar entrants engaged in little direct-to-physician marketing.

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.

The impact of cognitive rehabilitation on quality of life in multiple sclerosis: A pilot study.

BACKGROUND: Cognitive impairment in people with multiple sclerosis (pwMS) negatively impacts daily function and quality of life (QoL). Prior studies of cognitive rehabilitation in pwMS have shown limited benefit but many focused on cognitive function scores rather than QoL measures. Studies using QoL metrics primarily evaluated group cognitive rehabilitation, which may be less appropriate due to variable cognitive profiles in pwMS. This study assesses the impact of an individualized cognitive rehabilitation approach on QoL in MS. METHODS: We performed a retrospective chart review of NeuroQoL assessments done by pwMS (n = 12, mean age 47.9 ± 4.0 years, 75% female, 100% White, 75% RRMS) before and after participation in an individualized compensatory cognitive program. We used a comparison group of pwMS who were candidates for the program but did not participate (n = 9, mean age 48.9 ± 4.4 years, 88.9% female, 100% White, 66.7% RRMS). RESULTS: PwMS who participated in the rehabilitation program saw improvements in Sleep Disturbance (50.5 from 55.5, p = 0.005), Fatigue (52.5 from 57.0, p = 0.024), Anxiety (49.8 from 55.4, p = 0.011), and Cognitive Function (39.3 from 36.7, p = 0.049). CONCLUSIONS: Individualized compensatory cognitive rehabilitation appears effective for improving QoL measures in pwMS with cognitive complaints, supporting the need for further randomized controlled prospective analysis of this intervention.

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.

Harnessing Real-World Data to Inform Decision-Making: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS).

Background: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is the first example of a learning health system in multiple sclerosis (MS). This paper describes the initial implementation of MS PATHS and initial patient characteristics. Methods: MS PATHS is an ongoing initiative conducted in 10 healthcare institutions in three countries, each contributing standardized information acquired during routine care. Institutional participation required the following: active MS patient census of ≥500, at least one Siemens 3T magnetic resonance imaging scanner, and willingness to standardize patient assessments, share standardized data for research, and offer universal enrolment to capture a representative sample. The eligible participants have diagnosis of MS, including clinically isolated syndrome, and consent for sharing pseudonymized data for research. MS PATHS incorporates a self-administered patient assessment tool, the Multiple Sclerosis Performance Test, to collect a structured history, patient-reported outcomes, and quantitative testing of cognition, vision, dexterity, and walking speed. Brain magnetic resonance imaging is acquired using standardized acquisition sequences on Siemens 3T scanners. Quantitative measures of brain volume and lesion load are obtained. Using a separate consent, the patients contribute DNA, RNA, and serum for future research. The clinicians retain complete autonomy in using MS PATHS data in patient care. A shared governance model ensures transparent data and sample access for research. Results: As of August 5, 2019, MS PATHS enrolment included participants (n = 16,568) with broad ranges of disease subtypes, duration, and severity. Overall, 14,643 (88.4%) participants contributed data at one or more time points. The average patient contributed 15.6 person-months of follow-up (95% CI: 15.5-15.8); overall, 166,158 person-months of follow-up have been accumulated. Those with relapsing-remitting MS demonstrated more demographic heterogeneity than the participants in six randomized phase 3 MS treatment trials. Across sites, a significant variation was observed in the follow-up frequency and the patterns of disease-modifying therapy use. Conclusions: Through digital health technology, it is feasible to collect standardized, quantitative, and interpretable data from each patient in busy MS practices, facilitating the merger of research and patient care. This approach holds promise for data-driven clinical decisions and accelerated systematic learning.

Socioeconomic status and race are correlated with affective symptoms in multiple sclerosis.

OBJECTIVE: Investigate the relationship between socioeconomic status (SES) and race with self-reported fatigue, depression, and anxiety levels in multiple sclerosis (MS). METHODS: Cross-sectional review of the MS Partners Advancing Technology and Health Solutions (MS PATHS) database for adults with MS in the United States. We evaluated race and socioeconomic status (available markers: insurance, employment status, or level of education) as predictors of fatigue, depression, and anxiety sub-scores of the Neuro-QoL (Quality of life in neurological disorders), with particular interest between Caucasians/whites (CA) and African Americans/blacks (AA). Multivariate linear regression models included as covariates age, sex, disability status, smoking status, body mass index, and disease-modifying therapy. RESULTS: 7,430 individuals were included; compared to CA, AA tended to be younger, more female-predominant, and had a higher level of disability. AA had completed slightly less education, had a higher level of Medicaid coverage or uninsured status, and had higher rates of unemployed or disabled status. In the univariate model, markers of lower SES, by whichever definition we used, correlated with worse affective symptoms. In the multivariate model stratified by race, CA showed similar trends. In contrast, in AA, only lower SES by employment status was correlated with worse affective symptoms. In both CA and AA, moderate and severe level of disability correlated with worse affective symptoms. CONCLUSION: SES and race may influence affective symptoms reported by individuals with MS. The reasons for the correlation are likely multifactorial. Longitudinal studies should strive to identify factors associated with risk of affective symptoms in MS that may be modifiable.

Comparison of telemedicine versus in-person visits for persons with multiple sclerosis: A randomized crossover study of feasibility, cost, and satisfaction.

BACKGROUND: Telemedicine, the remote delivery of health care services, increases access to care for patients with mobility or geographic limitations. Virtual house calls (VHCs) are one type of telemedicine in which clinical visits are conducted remotely using an audio-visual connection with the patient at home. Use of VHCs is more established in other neurologic disorders but is only recently being formally evaluated in multiple sclerosis (MS). This randomized crossover study systematically assessed VHCs compared with in-clinic visits in persons with MS. METHODS: Recruitment occurred in a university based MS clinic. Each subject completed one VHC and one in-clinic follow-up visit. A 1:1 randomization determined whether the VHC or in-clinic follow-up visit occurred first. Baseline surveys included demographics and MS history; post-visit surveys elicited subject responses regarding each visit type to assess feasibility, satisfaction, and cost differences. Outcomes were compared using t-tests for continuous variables and Fisher's exact test for proportions. RESULTS: Thirty-six participants completed both study visits and both post-visit surveys. VHC feasibility was demonstrated by a lack of statistically significant difference in the number of completed VHCs as compared with in-clinic visits. VHCs provided both cost and time savings to participants. The majority of participants reported that they would recommend telemedicine visits to others (97.1%) and rated it easy to connect via telemedicine (94.3%). In qualitative comments, participants expressed appreciation for VHCs due to convenience and similarity to in-clinic visits. CONCLUSIONS: VHCs were found to be feasible, cost-effective, and appealing to persons with MS and physicians, supporting their utility as a care delivery method for MS.

Restricted diffusion preceding gadolinium enhancement in large or tumefactive demyelinating lesions.

Although restricted diffusion without coincident contrast enhancement is most commonly associated with cerebral ischemia, large or tumefactive multiple sclerosis (MS) lesions may demonstrate this pattern initially, followed by subsequent gadolinium (Gd) enhancement. The clinical and MRI characteristics of 3 patients with MS with this imaging pattern are reviewed. All patients had brain MRI lesions >1 cm in diameter, in locations consistent with new neurologic symptoms, and with prominent restricted diffusion but no Gd enhancement. Demyelinating lesion etiologies were supported by CSF findings, laboratory exclusion of alternative diagnoses, lesion evolution, or additional lesions characteristic of MS on brain MRI. Follow-up imaging within 2-4 weeks showed decreased restricted diffusion with patchy Gd enhancement which resolved on subsequent imaging. This imaging evolution may reflect early demyelination prior to inflammation-associated blood-brain barrier disruption.

Multiple sclerosis: new insights in pathogenesis and novel therapeutics.

Concepts of multiple sclerosis (MS) have shifted from the traditional view of a T cell-mediated, demyelinating disease of the white matter to include a broad range of immunopathogenic mechanisms, axonal damage, and widespread gray matter pathology. The cause of MS remains unknown, but recent epidemiological work has focused on genetic factors; environmental factors such as vitamin D, sunlight, and Epstein-Barr virus; and the controversial theory of chronic cerebrospinal venous insufficiency. Revised criteria facilitate making the diagnosis of MS. Emerging therapies are rapidly expanding treatment options, including both parenterally administered and oral medications. Strategies to preserve tissue, promote repair, and restore function are under development, and it is anticipated that they will provide better options for patients with progressive disease.

Challenges to clinical trials in multiple sclerosis: outcome measures in the era of disease-modifying drugs.

PURPOSE OF REVIEW: This review summarizes standard and evolving outcome measures in multiple sclerosis (MS) clinical trials. RECENT FINDINGS: Progress in the development of MS treatments has led to an increasing number of clinical trials and a need for sensitive, timely, and clinically relevant outcome measures. Relapse rate and the Expanded Disability Status Scale remain the standard clinical outcome measures, but the MS Functional Composite continues to gain additional validation as a meaningful outcome measure. The uncertain relationship between MRI outcome measures and clinical disability has been a persistent challenge in MS clinical trials, but there is increasing evidence supporting a correlation between MRI changes and disability in relapsing-remitting MS patients. Additionally, new imaging techniques are being developed to further increase the sensitivity of MRI as a tool in MS clinical trials. Optical coherence tomography is another outcome measure gaining influence in clinical trials. Some of the greatest challenges remain in the subset of primary progressive MS clinical trials in which brain atrophy appears to be the most promising imaging outcome measure, but the optimal clinical measures and study durations are still uncertain. SUMMARY: Progress in MS clinical trials requires critical evaluation of existing and future outcome measures and their relationships to one another.

Fingolimod.

Fingolimod is the first oral disease therapy approved for relapsing-remitting multiple sclerosis (MS). Patients can be switched directly from interferon-ß or glatiramer acetate to fingolimod without a washout period. Fingolimod's potent efficacy, oral route of administration, and generally good safety and tolerability make it appealing to patients and clinicians. However, several adverse effects have already been identified, overall experience with its use is limited compared to other agents, and its novel and complex mechanism of action make predicting adverse effects challenging. Fingolimod's place in the MS treatment algorithm is evolving. We anticipate that once centers have solved the logistical issues associated with fingolimod initiation and if the experience in clinical practice parallels the efficacy, safety, and tolerability demonstrated in the phase 3 trials, fingolimod's routine use will increase.