Therapeutic Advances in Neurological Disorders最新文献

Background: There are limited data on the real-world healthcare resource use (HCRU) and management costs of myasthenia gravis (MG) in England.

Objective: This study aims to assess the burden of disease for patients with MG in England.

Design: A retrospective, observational cohort study of adult patients diagnosed with MG, using data from the Hospital Episode Statistics data warehouse.

Methods: Patients with a first-ever recorded diagnosis of MG between 30 June 2015 and 30 June 2020 were followed up until 30 June 2021 or death, whichever occurred first. Post-diagnosis patient characteristics, treatment patterns, HCRU, and costs were described. Costs were evaluated using National Health Service reference costs.

Results: A total of 9087 patients with a median follow-up time of 2.9 years (range, 1.7-4.3 years) were included. The mean age at diagnosis was 66.5 years and 53% of the patients were male. A large proportion of patients (72.8%) were admitted as inpatients during follow-up with a mean number of 1.3 admissions. Patients hospitalized for MG-related complications spent a mean of 9.7 days per patient-year in the hospital. During follow-up, 599 (6.6% of the total cohort) and 163 (1.8%) patients had a record of rescue therapy with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX), respectively. Rituximab was administered to 81 (0.9%) patients and 268 (2.9%) patients underwent thymectomy. In those patients receiving rescue therapy or rituximab, >10% received at least three cycles of the same treatment. The average annual cost of hospital admissions across all patients treated with IVIg, PLEX, and rituximab were £907,072, £689,979, and £146,726, respectively.

Conclusion: A majority of MG patients required hospitalization or accident and emergency attendance, resulting in high HCRU and costs. A subset of patients required rescue therapy (including IVIg and PLEX), rituximab administration, ventilation, or thymectomy.

Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon β was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.

Background: The consideration of patient preference for a certain drug route of administration (RoA) plays an important role in promoting patient adherence in chronic diseases. Natalizumab is an established treatment for relapsing-remitting multiple sclerosis (RRMS) and can be administered as intravenous (IV) infusion or subcutaneous (SC) injection developed to enable a shorter and easier administration versus IV RoA.

Study objectives: Primary objective is to compare patients' preference for RoA and satisfaction with SC versus IV natalizumab at baseline and subsequent visits up to 12 months. Secondary objectives include drug utilization, clinical outcomes, safety, and treatment satisfaction in a usual care setting.

Design and methods: SISTER (Subcutaneous: Non-Interventional Study for Tysabri Patient Preference - Experience from Real World) is an ongoing, prospective, observational study where natalizumab is utilized according to local label. RRMS patients are included in three natalizumab cohorts: Patients switching from current IV to SC administration (switcher) and patients newly starting natalizumab on either SC or IV route (starter SC/IV). This interim analysis includes 262 patients (184 switchers, 39 SC starters, and 39 IV starters), median observation period was 9 months.

Results: 80.8% IV starters and 93.9% SC starters reported at baseline that they prefer the assigned RoA. Although initial satisfaction with chosen RoA was maintained over time from baseline through Month 12 in all three cohorts, the wish for change of the current RoA after 6 and 12 months was more frequently expressed among IV starters than in either SC cohort. Consistently, six patients (23.1%) starting with IV changed their RoA from IV to SC route.Mean global treatment satisfaction according to TSQM-II score at baseline remained high in the switcher group and increased through Month 12 in both IV and SC starter cohorts.

Conclusion: Based on current data, there is a trend toward patients' preference for the natalizumab SC route over the IV route, which provides valuable insights into patients' preference for natalizumab RoA in routine care and complements available data from clinical studies with real-world data on SC natalizumab.

Trial registration: This observational (non-interventional) study was registered in the local German PEI register for non-interventional studies (NIS-No. 611) and in the international CTgov register (NCT05304520).

Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental.

Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis.

Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm.

Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%.

Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need.

Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets.

Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS.

Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes.

Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

Background: Stroke misdiagnosis, associated with poor outcomes, is estimated to occur in 9% of all stroke patients.

Objectives: We hypothesized that machine learning (ML) could assist in the diagnosis of ischemic stroke in emergency departments (EDs).

Design: The study was conducted and reported according to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines. We performed model development and prospective temporal validation, using data from pre- and post-COVID periods; we also performed a case study on a small cohort of previously misdiagnosed stroke patients.

Methods: We used structured and unstructured electronic health records (EHRs) of 56,452 patient encounters from 13 hospitals in Pennsylvania, from September 2003 to January 2021. ML pipelines, including natural language processing, were created using pre-event clinical data and provider notes in the EDs.

Results: Using pre-event information, our model's area under the receiver operating characteristics curve (AUROC) ranged from 0.88 to 0.92 with a similar range accuracy (0.87-0.90). Using provider notes, we identified five models that reached a balanced performance in terms of AUROC, sensitivity, and specificity. Model AUROC ranged from 0.93 to 0.99. Model sensitivity and specificity reached 0.90 and 0.99, respectively. Four of the top five performing models were based on the post-COVID provider notes; however, no performance difference between models tested on pre- and post-COVID was observed.

Conclusion: This study leveraged pre-event and at-encounter level EHR for stroke prediction. The results indicate that available clinical information can be used for building EHR-based stroke prediction models and ED stroke alert systems.

Background: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities.

Objective: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database.

Design: Secondary analysis of existing data from the FAERS database.

Methods: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1.

Results: We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132-0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109-0.248), liraglutide (ROR: 0.161; 95% CI: 0.091-0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146-0.377), and metformin (ROR: 0.387; 95% CI: 0.340-0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384-0.806).

Conclusion: Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies.

Background: The spectrum of disease-modifying therapies (DMTs) for people with multiple sclerosis (PwMS) has expanded over years, but data on treatment strategies is largely lacking. DMT switches are common clinical practice.

Objective: To compare switchers and non-switchers, characterize the first DMT switch and identify reasons and predictors for switching the first DMT.

Methods: Data on 2722 PwMS from the German MS Registry were retrospectively analyzed regarding sociodemographic/clinical differences between 1361 switchers (PwMS discontinuing the first DMT) and non-switchers matched according to age, sex, and observation period. Frequencies of first and second DMTs were calculated and switch reasons identified. Predictors for DMT switches were revealed using univariable and multivariable regression models.

Results: Switchers and non-switchers differed significantly regarding time to first DMT, education, calendar period of the first DMT start (2014-2017 versus 2018-2021), first DMT class used [mild-to-moderate efficacy (MME) versus high-efficacy (HE) DMT], time on first DMT, and disease activity at first DMT start or cessation/last follow-up. The majority of PwMS started with MME DMTs (77.1%), with the most common being glatiramer acetate, dimethyl/diroximel fumarate, and beta-interferon variants. Switchers changed treatment more often to HE DMTs (39.6%), most commonly sphingosine-1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, and natalizumab. Fewer PwMS switched to MME DMTs (35.9%), with the most common being dimethyl/diroximel fumarate, teriflunomide, or beta-interferon. Among 1045 PwMS with sufficient data (76.8% of 1361 switchers), the most frequent reasons for discontinuing the first DMT were disease activity despite DMT (63.1%), adverse events (17.1%), and patient request (8.3%). Predictors for the first DMT switch were MME DMT as initial treatment [odds ratio (OR) = 2.83 (1.76-4.61), p < 0.001; reference: HE DMT], first DMT initiation between 2014 and 2017 [OR = 11.55 (6.93-19.94), p < 0.001; reference: 2018-2021], and shorter time on first DMT [OR = 0.22 (0.18-0.27), p < 0.001].

Conclusion: The initial use of MME DMTs was among the strongest predictors of DMT discontinuation in a large German retrospective MS cohort, arguing for the need for prospective treatment strategy trials, not only but also on the initial broad use of HE DMTs in PwMS.

Background: In REFLEX, subcutaneous interferon beta-1a (sc IFN β-1a) delayed the onset of multiple sclerosis (MS) in patients with a first clinical demyelinating event (FCDE).

Objectives: This post hoc analysis aimed to determine whether baseline serum neurofilament light (sNfL) chain can predict conversion to MS and whether correlations exist between baseline sNfL and magnetic resonance imaging (MRI) metrics.

Methods: sNfL was measured for 494 patients who received sc IFN β-1a 44 μg once weekly (qw; n = 168), three times weekly (tiw; n = 161), or placebo (n = 165) over 24 months. Median baseline sNfL (26.1 pg/mL) was used to define high/low sNfL subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard model to determine factors influencing the risk of conversion to MS. Kaplan-Meier estimates calculated median time-to-conversion to MS (McDonald 2005 criteria) or clinically definite MS (CDMS; Poser criteria). Correlations between sNfL and MRI findings were assessed using Spearman's rank correlation coefficient (r).

Results: Multivariable models indicated that high baseline sNfL was associated with the likelihood of converting to MS and inversely to time-to-conversion (HR = 1.3, 95% CI: 1.03-1.64; p = 0.024). Significant additional factors affecting conversion to McDonald MS were on-study treatment (sc IFN β-1a/placebo; qw: HR = 0.59, 95% CI: 0.46-0.76; tiw: HR = 0.45, 95% CI: 0.34-0.59), classification of FCDE (monofocal/multifocal; HR = 0.69, 95% CI: 0.55-0.85), and most baseline imaging findings (T2 and T1 gadolinium-enhancing [Gd+] lesions; HR = 1.02, 95% CI: 1.01-1.03 and HR = 1.07, 95% CI: 1.03-1.11); all p ⩽ 0.001. Conversion to CDMS showed similar results. At month 24, sNfL was strongly correlated with a mean number of combined unique active (r = 0.71), new T2 (r = 0.72), and new T1 Gd+ (r = 0.60) lesions; weak correlations were observed between sNfL and clinical outcomes for all treatment groups.

Conclusion: Higher baseline sNfL was associated with an increased risk of MS conversion, a risk that was mitigated by treatment with sc IFN β-1a tiw.

Trial registration: ClinicalTrials.gov identifier: NCT00404352. Date registered: 28 November 2006.

Background: Reporting of sex-specific analyses in multiple sclerosis (MS) is sparse. Disability accrual results from relapses (relapse-associated worsening) and independent thereof (progression independent of relapses).

Objectives: A population of MS patients during relapse treated per standard of care was analyzed for sex differences and short-term relapse outcome (3-6 months) as measured by Expanded Disability Status Scale (EDSS) change.

Design: Single-center retrospective study.

Methods: We analyzed 134 MS relapses between March 2016 and August 2020. All events required relapse treatment (steroids and/or plasma exchange). Demographic, disease, and paraclinical characteristics [cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI)] were displayed separated by sex. Multivariable linear regression was run to identify factors associated with short-term EDSS change.

Results: Mean age at relapse was 38.4 years (95% confidence interval: 36.3-40.4) with a proportion of 71.6% women in our cohort. Smoking was more than twice as prevalent in men (65.8%) than women (32.3%). In- and after-relapse EDSSs were higher in men [men: 3.3 (2.8-3.9), women: 2.7 (2.4-3.0); men: 3.0 (1.3-3.6); women: 1.8 (1.5-2.1)] despite similar relapse intervention. Paraclinical parameters revealed no sex differences. Our primary model identified female sex, younger age, and higher EDSS at relapse to be associated with EDSS improvement. A higher immunoglobulin G (IgG) quotient (CSF/serum) was associated with poorer short-term outcome [mean days between first relapse treatment and last EDSS assessment 130.2 (79.3-181.0)].

Conclusion: Sex and gender differences are important in outcome analyses of MS relapses. Effective treatment regimens need to respect putative markers for a worse outcome to modify long-term prognosis such as clinical and demographic variables, complemented by intrathecal IgG synthesis. Prospective trials should be designed to address these differences and confirm our results.