Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis.

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.

Treatment patterns and persistence on disease modifying therapies for multiple sclerosis and its associated factors.

BACKGROUND: Effective interventions for Multiple Sclerosis require timely treatment optimization which usually involves switching disease modifying therapies. The patterns of prescription and the reasons for changing treatment in people with MS, especially in low prevalence populations, are unknown. OBJECTIVES: To describe the persistence, reasons of DMT switches and prescription patterns in a cohort of Colombian people with MS. METHODS: We conducted a retrospective observational study including patients with confirmed MS with at least one visit at our centre. We estimated the overall incidence rate of medication changes and assessed the persistence on medication with Kaplan-Meier survival estimates for individual medications and according to efficacy and mode of administration. The factors associated with changing medications were assessed using adjusted Cox proportional-hazards models. The reasons for switching medication changes were described, and the prescription patterns were assessed using network analysis, with measures of centrality. RESULTS: Seven hundred one patients with MS were included. Mean age was 44.3 years, and 67.9% were female. Mean disease duration was 11.3 years and 84.5% had relapsing MS at onset, with median EDSS of 1.0. Treatment was started in 659 (94%) of the patients after a mean of 3 years after MS symptom onset. Among them, 39.5% maintained their initial DMT, 29.9% experienced a single DMT change, while 18.7% went through two, and 11.9% had three or more DMT changes until the final follow-up. The total number of treatment modifications reached 720, resulting in an incidence rate of 1.09 (95% confidence interval: 1.01-1.17) per patient per year The median time to change after the first DMT was 3.75 years, and was not different according to the mode of administration or efficacy classification. The main reasons for changing DMT were MS activity (relapses, 56.7%; MRI activity, 18.6%), followed by non-serious adverse events (15.3%) and disability (11.1%). Younger age at MS onset, care under our centre and insurer status were the main determinants of treatment change. Network analysis showed that interferons and fingolimod were the most influential DMTs. CONCLUSIONS: A majority of patients switch medications, mostly due to disease activity, and in association with age and insurer status.

Neutrophil Membrane-Camouflaged Polyprodrug Nanomedicine for Inflammation Suppression in Ischemic Stroke Therapy.

Neuroinflammation has emerged as a major concern in ischemic stroke therapy because it exacebates neurological dysfunction and suppresses neurological recovery after ischemia/reperfusion. Fingolimod hydrochloride (FTY720) is an FDA-approved anti-inflammatory drug which exhibits potential neuroprotective effects in ischemic brain parenchyma. However, delivering a sufficient amount of FTY720 through the blood-brain barrier into brain lesions without inducing severe cardiovascular side effects remains challenging. Here, a neutrophil membrane-camouflaged polyprodrug nanomedicine that can migrate into ischemic brain tissues and in situ release FTY720 in response to elevated levels of reactive oxygen species. This nanomedicine delivers 15.2-fold more FTY720 into the ischemic brain and significantly reduces the risk of cardiotoxicity and infection compared with intravenously administered free drug. In addition, single-cell RNA-sequencing analysis identifies that the nanomedicine attenuates poststroke inflammation by reprogramming microglia toward anti-inflammatory phenotypes, which is realized via modulating Cebpb-regulated activation of NLRP3 inflammasomes and secretion of CXCL2 chemokine. This study offers new insights into the design and fabrication of polyprodrug nanomedicines for effective suppression of inflammation in ischemic stroke therapy.

A case of early disease rebound after fingolimod discontinuation in a patient with multiple sclerosis and SARS-CoV-2 infection.

Fingolimod is approved in Italy as a second-line therapy for relapsing-remitting multiple sclerosis (RRMS). Discontinuation of fingolimod may elevate the risk of relapses, typically manifesting after a relatively prolonged drug-free interval and often necessitating high doses of intravenous steroids for management. Similar to other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can act as a trigger for MS relapses. In this context, we present a case of rebound following fingolimod discontinuation during a SARS-CoV-2 infection. Notably, the rebound occurred shortly after stopping the medication and responded effectively to low doses of oral steroids. Our case is discussed in light of existing literature, with speculation on potential mechanisms governing this unconventional disease course rebound. We also consider the possibility that SARS-CoV-2 infection might have contributed to or even triggered the MS relapse.

Fingolimod improves diffuse brain injury by promoting AQP4 polarization and functional recovery of the glymphatic system.

BACKGROUND: Diffuse brain injury (DBI) models are characterized by intense global brain inflammation and edema, which characterize the most severe form of TBI. In a previous experiment, we found that fingolimod promoted recovery after controlled cortical impact injury (CCI) by modulating inflammation around brain lesions. However, it remains unclear whether fingolimod can also attenuate DBI because of its different injury mechanisms. Furthermore, whether fingolimod has additional underlying effects on repairing DBI is unknown. METHODS: The impact acceleration model of DBI was established in adult Sprague-Dawley rats. Fingolimod (0.5 mg/kg) was administered 0.5, 24, and 48 h after injury for 3 consecutive days. Immunohistochemistry, immunofluorescence analysis, cytokine array, and western blotting were used to evaluate inflammatory cells, inflammatory factors, AQP4 polarization, apoptosis in brain cells, and the accumulation of APP after DBI in rats. To evaluate the function of the glymphatic system (GS), a fluorescent tracer was injected into the cistern. The neural function of rats with DBI was evaluated using various tests, including the modified neurological severity score (mNSS), horizontal ladder-crossing test, beam walking test, and tape sensing and removal test. Brain water content was also measured. RESULTS: Fingolimod administration for 3 consecutive days could reduce the levels of inflammatory cytokines, neutrophil recruitment, microglia, and astrocyte activation in the brain following DBI. Moreover, fingolimod reduced apoptotic protein expression, brain cell apoptosis, brain edema, and APP accumulation. Additionally, fingolimod inhibited the loss of AQP4 polarization, improved lymphatic system function, and reduced damage to nervous system function. Notably, inhibiting the GS weakened the therapeutic effect of fingolimod on the neurological function of rats with DBI and increased the accumulation of APP in the brain. CONCLUSIONS: In brief, these findings suggest that fingolimod alleviates whole-brain inflammation and GS system damage after DBI and that inhibiting the GS could weaken the positive effect of fingolimod on nerve function in rats with DBI. Thus, inhibiting inflammation and regulating the GS may be critical for the therapeutic effect of fingolimod on DBI.

High-Efficacy Therapy Discontinuation vs Continuation in Patients 50 Years and Older With Nonactive MS.

Importance: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. Objective: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. Design, Setting, and Participants: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. Exposures: Natalizumab, fingolimod, rituximab, and ocrelizumab. Main Outcomes and Measures: Time to first relapse. Results: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P < .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. Conclusion and Relevance: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

Evidence of disease activity during pregnancy and post-partum in MS patients treated with high-efficacy therapies.

BACKGROUND: Multiple sclerosis (MS) predominantly affects women of childbearing age. Due to the risk of teratogenicity, women with active multiple sclerosis (MS) who require high-efficacy therapies (HET) may need to discontinue treatment during pregnancy. Fingolimod and Natalizumab withdrawal increases the risk of disease reactivation, a risk not commonly associated with anti-CD20 therapies. However, comparative data are limited during pregnancy and post-partum. Our aim was to compare evidence of disease activity during pregnancy and post-partum in women treated with HET (anti-CD20 therapies, Natalizumab or Fingolimod) before conception, whether or not exposed during pregnancy. METHODS: In this single-center retrospective study, we included consecutive pregnancies of relapsing-remitting MS patients and classified them in three groups according to the last HET used before conception: « anti-CD20 ¼ « Natalizumab (NTZ) ¼ and « Fingolimod (FGD) ¼. The main outcome was annualized relapse rate (ARR) during pregnancy and post-partum. RESULTS: We included 66 pregnancies: 21, 24 and 21 in anti-CD20, NTZ and FGD groups respectively. Overall, mean ARR (SD) increased from 0.36 (0.6) during the preconception year to 0.60 (1.3) during pregnancy and to 1.03 (2.0) in the first 3 months post-partum. Mean ARR in anti-CD20 group (0.09 (0.3)) during pregnancy and the first 3 months post-partum was lower compared with NTZ (0.48 (0.6); p = 0,09) and FGD (1.50 (1.8); p = 0.001) groups. Proportion of pregnancies with radiological activity during pregnancy and post-partum in anti-CD20 group (5.2 %) was lower compared with NTZ (63.1 %; p < 0.001) and FGD (72.2 %; p < 0.001) groups. There was no significant difference in the evolution of EDSS score from conception to post-partum between each group (p = 0.75). CONCLUSION: Evidence of disease activity was significantly lower in patients exposed to anti-CD20 therapies before conception. This study suggests that use of anti-CD20 therapies is an efficient option to prevent disease reactivation during pregnancy and post-partum.

Immunosenescence and vaccine efficacy revealed by immunometabolic analysis of SARS-CoV-2-specific cells in multiple sclerosis patients.

Disease-modifying therapies (DMT) administered to patients with multiple sclerosis (MS) can influence immune responses to SARS-CoV-2 and vaccine efficacy. However, data on the detailed phenotypic, functional and metabolic characteristics of antigen (Ag)-specific cells following the third dose of mRNA vaccine remain scarce. Here, using flow cytometry and 45-parameter mass cytometry, we broadly investigate the phenotype, function and the single-cell metabolic profile of SARS-CoV-2-specific T and B cells up to 8 months after the third dose of mRNA vaccine in a cohort of 94 patients with MS treated with different DMT, including cladribine, dimethyl fumarate, fingolimod, interferon, natalizumab, teriflunomide, rituximab or ocrelizumab. Almost all patients display functional immune response to SARS-CoV-2. Different metabolic profiles characterize antigen-specific-T and -B cell response in fingolimod- and natalizumab-treated patients, whose immune response differs from all the other MS treatments.

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries.

BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. FINDINGS: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. INTERPRETATION: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. FUNDING: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. METHODS: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. RESULTS: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DISCUSSION: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

An integrative mechanistic model of thymocyte dynamics.

Background: The thymus plays a central role in shaping human immune function. A mechanistic, quantitative description of immune cell dynamics and thymic output under homeostatic conditions and various patho-physiological scenarios are of particular interest in drug development applications, e.g., in the identification of potential therapeutic targets and selection of lead drug candidates against infectious diseases. Methods: We here developed an integrative mathematical model of thymocyte dynamics in human. It incorporates mechanistic features of thymocyte homeostasis as well as spatial constraints of the thymus and considerations of age-dependent involution. All model parameter estimates were obtained based on published physiological data of thymocyte dynamics and thymus properties in mouse and human. We performed model sensitivity analyses to reveal potential therapeutic targets through an identification of processes critically affecting thymic function; we further explored differences in thymic function across healthy subjects, multiple sclerosis patients, and patients on fingolimod treatment. Results: We found thymic function to be most impacted by the egress, proliferation, differentiation and death rates of those thymocytes which are most differentiated. Model predictions also showed that the clinically observed decrease in relapse risk with age, in multiple sclerosis patients who would have discontinued fingolimod therapy, can be explained mechanistically by decreased thymic output with age. Moreover, we quantified the effects of fingolimod treatment duration on thymic output. Conclusions: In summary, the proposed model accurately describes, in mechanistic terms, thymic output as a function of age. It may be further used to perform predictive simulations of clinically relevant scenarios which combine specific patho-physiological conditions and pharmacological interventions of interest.

Distinct disease-modifying therapies are associated with different blood immune cell profiles in people with relapsing-remitting multiple sclerosis.

Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of action. However, there is a lack of a comprehensive assessment of their effects on the immune system in comparison to treatment-naïve pwRRMS. Herein, we evaluated the numbers of circulating B cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in pwRRMS who were treatment-naïve or treated with different DMTs. Compared to treatment-naïve pwRRMS, common and divergent effects on immune system cells were observed on pwRRMS treated with different DMTs, with no consistent pattern across all therapies in any of the cell populations analysed. PwRRMS treated with fingolimod, dimethyl fumarate (DMF), or alemtuzumab have reduced numbers of CD4+ and CD8+ T cells, as well as Treg subsets, with fingolimod causing the most pronounced decrease in T cell subsets. In contrast, teriflunomide and interferon (IFN) ß have minimal impact on T cells, and natalizumab marginally increases the number of memory T cells in the blood. The effect of DMTs on the B cell, NKT and NK cell subsets is highly variable with alemtuzumab inducing a strong increase in the number of the most immature NK cells and its subsets. This study comprehensively evaluates the magnitude of the effect of different DMTs on blood immune cells providing a better understanding of therapy outcome. Furthermore, the lack of a discernible pattern in the effects of DMTs on blood immune cells suggests that multiple immune cells can independently modulate the disease.

Incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease in patients with multiple sclerosis initiating disease-modifying therapies: Retrospective cohort study using a frequentist model averaging statistical framework.

Researchers are increasingly using insights derived from large-scale, electronic healthcare data to inform drug development and provide human validation of novel treatment pathways and aid in drug repurposing/repositioning. The objective of this study was to determine whether treatment of patients with multiple sclerosis with dimethyl fumarate, an activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, results in a change in incidence of type 2 diabetes and its complications. This retrospective cohort study used administrative claims data to derive four cohorts of adults with multiple sclerosis initiating dimethyl fumarate, teriflunomide, glatiramer acetate or fingolimod between January 2013 and December 2018. A causal inference frequentist model averaging framework based on machine learning was used to compare the time to first occurrence of a composite endpoint of type 2 diabetes, cardiovascular disease or chronic kidney disease, as well as each individual outcome, across the four treatment cohorts. There was a statistically significantly lower risk of incidence for dimethyl fumarate versus teriflunomide for the composite endpoint (restricted hazard ratio [95% confidence interval] 0.70 [0.55, 0.90]) and type 2 diabetes (0.65 [0.49, 0.98]), myocardial infarction (0.59 [0.35, 0.97]) and chronic kidney disease (0.52 [0.28, 0.86]). No differences for other individual outcomes or for dimethyl fumarate versus the other two cohorts were observed. This study effectively demonstrated the use of an innovative statistical methodology to test a clinical hypothesis using real-world data to perform early target validation for drug discovery. Although there was a trend among patients treated with dimethyl fumarate towards a decreased incidence of type 2 diabetes, cardiovascular disease and chronic kidney disease relative to other disease-modifying therapies-which was statistically significant for the comparison with teriflunomide-this study did not definitively support the hypothesis that Nrf2 activation provided additional metabolic disease benefit in patients with multiple sclerosis.

Microvascular Network Remodeling in the Ischemic Mouse Brain Defined by Light Sheet Microscopy.

BACKGROUND: Until now, the analysis of microvascular networks in the reperfused ischemic brain has been limited due to tissue transparency challenges. METHODS: Using light sheet microscopy, we assessed microvascular network remodeling in the striatum from 3 hours to 56 days post-ischemia in 2 mouse models of transient middle cerebral artery occlusion lasting 20 or 40 minutes, resulting in mild ischemic brain injury or brain infarction, respectively. We also examined the effect of a clinically applicable S1P (sphingosine-1-phosphate) analog, FTY720 (fingolimod), on microvascular network remodeling. RESULTS: Over 56 days, we observed progressive microvascular degeneration in the reperfused striatum, that is, the lesion core, which was followed by robust angiogenesis after mild ischemic injury induced by 20-minute middle cerebral artery occlusion. However, more severe ischemic injury elicited by 40-minute middle cerebral artery occlusion resulted in incomplete microvascular remodeling. In both cases, microvascular networks did not return to their preischemic state but displayed a chronically altered pattern characterized by higher branching point density, shorter branches, higher unconnected branch density, and lower tortuosity, indicating enhanced network connectivity. FTY720 effectively increased microvascular length density, branching point density, and volume density in both models, indicating an angiogenic effect of this drug. CONCLUSIONS: Utilizing light sheet microscopy together with automated image analysis, we characterized microvascular remodeling in the ischemic lesion core in unprecedented detail. This technology will significantly advance our understanding of microvascular restorative processes and pave the way for novel treatment developments in the stroke field.

A comparison of clinical, utilization, and cost outcomes between oral treatments for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) affects nearly 1 million people in the United States and causes significant disability and economic loss. Among the first available oral MS treatment options, clinical outcome comparisons and associated health care resource utilization are not clearly defined. OBJECTIVE: To compare MS outcomes, health care resource utilization, and relative costs across treatment with dimethyl fumarate (DMF), fingolimod (FG), or teriflunomide (TERI) among Medicare Advantage Prescription Drug (MAPD) plan and commercially insured beneficiaries. METHODS: This retrospective cohort study used the Humana Research Database. Eligible study patients had their first MS medication claim for oral DMG, FG, or TERI between January 1, 2013, and December 31, 2018. Patients were followed for a minimum of 12 months (mean follow-up = 3.8 years), until the earliest of the following occurred: health plan disenrollment, the end of the study period, or death. Study cohorts were balanced with inverse probability of treatment weighting. All-cause and MS-related health care resource utilization, time on therapy, and time after therapy were compared using inverse probability of treatment-adjusted multivariate generalized linear models across treatment groups. Relative costs were compared using a generalized linear model with a gamma distribution and log link. RESULTS: We identified 1,442 patients in 3 medication groups: DMF (n = 843), FG (n = 213), and TERI (n = 386). After weighting, there were no significant differences between the medication groups on demographic and clinical characteristics. Time on therapy (days) was significantly different across medication groups (P < 0.001). Time on therapy was longest for FG compared with the DM and TERI groups (644 vs 462 vs 521). The number discontinuing the index medication was significantly different for FG vs DMF vs TERI (74.7% vs 85.3% vs 80.7%; P < 0.001). FG had the lowest discontinuation rate. The mean (SD) annualized relapse rates (ARRs) were 0.47 (0.80), 0.42 (1.3), and 0.53 (1.3) (P = 0.037) for DMF, FG, and TERI, respectively. The percentage of those experiencing inpatient stays and the number of stays (mean [SD]) were significantly different among the FG group vs DMF vs TERI (29.9% vs 34.1% vs 40.9%; P < 0.001) and (0.57 [2.9] vs 0.74 [1.9] vs 0.91 [3.5]; P = 0.007), respectively. All-cause emergency department visits and the number of visits (mean [SD]) were significantly different for the FG cohort vs DMF vs TERI (46% vs 54.3% vs 61%; P < 0.001) and (1.84 [7.7] vs 2.38 [5.9] vs 2.87 [8.8]; P = 0.002), respectively. FG had the lowest impatient stays and emergency department visits of the 3 groups. CONCLUSIONS: Patients with MS initiated on FG used fewer health care resources and experienced lower ARR compared with patients on DMF and TERI.

Response to Fingolimod in Multiple Sclerosis Patients Is Associated with a Differential Transcriptomic Regulation.

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (five responders and five non-responders) at baseline and at 12 months of fingolimod therapy. Fingolimod exerted a vast impact at the transcriptional level, identifying 7155 differentially expressed genes (DEGs) compared to baseline that affected the regulation of numerous signaling pathways. These DEGs were predominantly immune related, including genes associated with S1P metabolism, cytokines, lymphocyte trafficking, master transcription factors of lymphocyte functions and the NF-kB pathway. Responder and non-responder patients exhibited a differential transcriptomic regulation during treatment, with responders presenting a higher number of DEGs (6405) compared to non-responders (2653). The S1P, NF-kB and TCR signaling pathways were differentially modulated in responder and non-responder patients. These transcriptomic differences offer the potential of being exploited as biomarkers of a clinical response to fingolimod.

Author's addendum to the article: Fingolimod: Assay analysis of US generic capsule products reveals variation in fingolimod content beyond the recommended acceptance criteria.

Our article "Fingolimod: Assay analysis of US generic capsule products reveals variation in fingolimod content beyond the recommended acceptance criteria" highlighted the variation of active ingredient in generic fingolimod capsule products. This analysis was prompted by reports of clinical adverse events and/or multiple sclerosis relapse in patients following transition from Gilenya® fingolimod capsules (Novartis) to generic fingolimod capsule products. Further assay analysis functioned to both confirm previous out-of-specification findings, and to identify an additional generic product that failed to comply with United States Pharmacopeia (USP) recommendations.

Quantifying the administration and monitoring time burden of several disease-modifying therapies for relapsing multiple sclerosis in the United Kingdom: A time and motion study.

BACKGROUND: The treatment landscape for relapsing multiple sclerosis (MS) has changed dramatically in recent decades, including an increasing number of high-efficacy disease-modifying therapies (DMTs) with varied administration and monitoring requirements. Coupled with greater focus on earlier treatment, these factors have resulted in stretching of the capacity of MS specialist services and allied healthcare professionals (HCPs). To assist with the effective planning of MS services in the UK NHS, this study quantified the administration and monitoring time burden associated with high-efficacy DMTs (alemtuzumab, cladribine tablets, fingolimod, natalizumab, and ocrelizumab) for relapsing MS. METHODS: A Time and Motion (T&M) study was conducted across four MS centres in the UK, over 3-4 months per centre (Aug 2019-Feb 2021). Time dedicated by HCPs (including but not limited to neurologists, MS specialist nurses, infusion nurses, and healthcare assistants) to pre-specified drug administration and monitoring activities, elicited during pre-study interviews at each centre, was assessed for each of the selected DMTs. Administration activities included: installing peripheral access; pre-medication administration (if needed); preparing drug for infusion; infusion initiation, monitoring, and disconnection; and patient monitoring post-infusion. Monitoring activities included: booking appointments for blood draws; blood draw; retrieval and review of blood results; maintaining blood records and follow-up with the patient; checking availability of MRI results and follow-up with the patient; booking appointments for neurologist or nurse consultations; and checking patient files prior to clinic visits. A T&M model was built using observational T&M study results, data obtained through pre-study interviews, as well as stipulated monitoring intervals from relevant Summaries of Product Characteristics for the selected DMTs, to estimate active HCP time with each DMT, extrapolated over a period of 4 years per-patient. RESULTS: For oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 14.7 h for cladribine tablets and 19.2 h for fingolimod. For infused DMTs, total time (administration and monitoring) for alemtuzumab was 37.7 h (6.0 and 31.6 h, respectively), 48.1 h for natalizumab (17.4 and 30.8 h, respectively), and 23.5 h for ocrelizumab (6.1 and 17.4 h, respectively). CONCLUSIONS: While active HCP time varied across centres, infused DMTs were projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs. These findings may assist MS-specific HCPs in planning and delivering the equitable provision of DMT services for patients with relapsing MS.