Multiple Sclerosis Research Articles

A Qualitative Exploration of the Socioecological Influences Shaping the Diagnostic Experience and Self-Management Practices Among People Newly Diagnosed With Multiple Sclerosis.

People newly diagnosed with multiple sclerosis (MS) often pursue 'health-related' behaviour changes to feel in control of their diagnosis. However, little is known about the specific factors that may influence behaviour change during this crucial time. Therefore, we conducted an in-depth exploration of the socioecological influences impacting the diagnostic experience and self-management practices following an MS diagnosis. We followed a qualitative study design using a phenomenological approach to explore the lived experiences of people newly diagnosed with MS. Analysis was conducted via an iterative process, starting with deductive open coding to map onto the socioecological model, followed by inductive focused coding to extract key themes from participants' reported experiences. Eight participants diagnosed with MS within the past 12 months were interviewed. Four themes were reported across the MS journey, reflecting the different levels of the socioecological model: (1) taking control of a new diagnosis to retain a sense of personal identity-individual level; (2) grief and acceptance guided by community-social connection, community and social environment; (3) practical management of MS in the wider society-policy and government regulation; and (4) global events that greatly upheave the MS journey-natural disasters and societal conflicts, such as a pandemic. These themes highlighted the complex interrelationship between socioecological factors and self-management abilities in people living with MS. The diagnostic experience of those with MS is highly complex. Although it varies for each person living with MS, there are shared experiences that often reflect a common cycle of grief. An MS diagnosis provides an opportunity for self-rediscovery, which can both influence and be influenced by socioecological factors. The social and technical nature of self-managing MS strongly shapes the diagnostic experience, underpinning many aspects of daily living, social interaction and physical and psychological well-being. The research team worked closely with an MS-specific consumer panel for the study design. This project was raised with this group, and preliminary results were shared at a national conference for MS during a lived-experience consumer stream to gain additional insights.

Analysis of Concentrations of Monomethyl Fumarate in Patients with Multiple Sclerosis: Result from Routine Health Care

Dimethyl fumarate is used to treat patients with relapsing-remitting multiple sclerosis. After ingestion, it is rapidly hydrolyzed to the active primary metabolite monomethyl fumarate. The main objective of our study was to analyze serum concentrations of monomethyl fumarate during routine health care in patients with multiple sclerosis treated with a fixed dose of dimethyl fumarate. In the pilot cross-sectional study, data from 42 patients treated with dimethyl fumarate at a dose of 240 mg twice daily were collected. Concentrations of the active metabolite monomethyl fumarate were determined at 1-8 h (median, 3 h) or 10-14 h (median, 13 h) after taking the dose. The relationship between monomethyl fumarate concentrations and absolute lymphocyte count was evaluated. Concentrations of monomethyl fumarate ranged from 2.5-3177.9 μg/L, with most concentrations being undetectable approximately 10 hours after administration. In the 1-8 h (median, 3 h) post-dose subgroup, the concentration/dose ratio ranged widely from 0.04-6.62. The median concentration of monomethyl fumarate in the group with the absolute lymphocyte count <0.8 x 10^9/l was more than four times higher than in the group with the absolute lymphocyte count ≥0.8 x 10^9/l (median 440.1 μg/L versus 98.4 μg/L). The wide interindividual variability in monomethyl fumarate pharmacokinetics could contribute to the differential response to dimethyl fumarate in multiple sclerosis patients. A nonsignificant but noticeable trend was observed in the relationship of higher serum monomethyl fumarate concentrations to absolute lymphocyte counts.

Development and Psychometric Evaluation of the Treatment Management Adherence Scale for Children with Multiple Sclerosis

BackgroundPediatric multiple sclerosis (pMS) is a chronic inflammatory, demyelinating, and neurodegenerative disease affecting the central nervous system in children and adolescents The aim of this correlational, comparative study was to develop an assessment scale for adherence to treatment management in pMS. MethodsTwo measurement tools were used to develop a scientifically sound tool to assess adherence in pediatric patients (12-18 years) diagnosed with multiple sclerosis (MS). Cases of pMS (n=120) in 7 hospitals in Turkey were included between August 2021-February 2022. The tools were a "Sociodemographic and Disease-Related Information" and a newly developed "Treatment Management Adherence Scale for Children with Multiple Sclerosis”. The form and questionnaire were completed by the children through online using the Zoom platform in approximately 10 minutes. The questionnaire on adherence contains 16 items related to the disease and treatment, scored in a 5-point Likert type. Face validity was established by pretesting with 20 children, and construct validity was established using the statistical methods of exploratory factor analysis and confirmatory factor analysis. For the reliability of the scale, Cronbach's Alpha and omega coefficients, item test correlation values, split-half, test-retest techniques were used. ResultsThere were 120 eligible patients, 71.2% girls, with mean age (±SD) 13,6±2,2 years at disease onset and 15,7±1,5 at the time of the study, all under disease-modifying therapy. The sample size and items were sufficient to conduct a factor analysis. The Cronbach's Alpha and Omega value was 0.75, indicating participants’ opinions were consistent across items. The mean content validity index was 0.93, showing the scale represented the measured data, and the exploratory factor analysis showed the scale measures adherence in 55% of patients (desired figures: >0.80 and 40-60% respectively). The 16 items of the questionnaire were grouped into 4 dimensions. These dimensions were termed 'physiological', 'self-concept', 'role function' and 'interdependence', in line with different styles of adaptation. The total score can be between 16-80, with higher scores indicating strong adherence to treatment. The mean total score of 54,3 ±9,53 (min=31, max= 75) in this study was in the “moderate adherence” range. ConclusionsThis new scale is the first to assess adherence in pMS. The study supports its validity, reliability, and likelihood to address adjustment issues in children and adolescents with MS accurately and can be recommended for clinical use.

A qualitative study on the experiences of autologous haematopoietic stem cell transplant for Multiple Sclerosis

AimAutologous haematopoietic stem cell transplant (HSCT) is an effective treatment for people with highly-active relapsing multiple sclerosis (MS), who are not adequately responding to disease-modifying therapies. To date, research has predominantly focused on disease-specific outcome measures. There is a lack of research exploring patient experiences of this complex treatment. The study aims to explore the experience of considering and receiving HSCT treatment for MS. MethodsSemi-structured interviews were conducted online with 12 adults with MS who had undergone HSCT treatment. Interview topics covered the experience of deciding on the treatment, the HSCT process itself, and the patient-reported outcomes following HSCT. Interviews were audio-recorded and transcribed verbatim. A thematic analysis approach was employed. ResultsThree main themes were identified: (1) Balancing hope and fear explores the decision-making experience when considering HSCT as a treatment; (2) Distinct emotional experience, highlights the unique challenges faced on all stages of the treatment journey; and (3) Adjusting to outcomes, explores how participants make sense of the aftermath of the treatment, including managing the ongoing uncertainty of MS and complications arising from HSCT. DiscussionHSCT is a complex treatment, both physically and psychologically for pwMS. A comprehensive and holistic care pathway is required to support people with MS at all stages of the treatment process, to ensure patient-centred planning and care.

Real world experience with cladribine tablets in the management of relapsing multiple sclerosis in Qatar

ObjectivesTo study the 30-month safety and effectiveness of Cladribine tablets (CladT) in relapsing multiple sclerosis (RMS) months in a real-world setting. MethodsRetrospective single-centre observational study in Qatar (January 2018–Feb 2023). Clinical and MRI data, lymphocyte counts and adverse events (AE) were recorded for patients with RMS who received at least one course of CladT. ResultsForty-six patients were included (mean follow-up 22 months); 34 (74%) were female, 22 (48%) were disease-modifying therapy (DMT) naïve, 16 (35%) had switched from platform DMT and 8 (17%) from high efficacy (HE) DMD. Mean age was 26.7±7.2y, mean disease duration was 7.2±6.0y. Common reasons for treatment with CladT were MS activity (91%), pregnancy planning (17%), AE (20%), compliance (9%). 44/46 ( 96%) received the year 2 course of CladT. Annualised relapse rate (ARR) fell from 1.02 (baseline) to 0.1, 0, 0.1, 0.1 and 0.1 for years 1–5 post-treatment, respectively; 87.5–100% were free of relapses at these times, vs. 21% at baseline. There were no relapses in year 2; 78%, 100%, 84%, 80% and 100%, respectively, were free of GD+ MRI lesions at years 1–5, vs. 31% at baseline. Most clinical AE were mild (1 moderate, no severe AE); 12 contracted Covid-19 (no hospitalisations). Grade 3 lymphopenia occurred in 5 patients. ConclusionsCladT appeared to be effective and safe in our retrospective study, irrespective of prior treatments, consistent with other real world data that support the early use of CladT in the management of RRMS.

Vitamin D and Cardiovascular Outcomes in Multiple Sclerosis

Background: Vitamin D (25(OH)D) deficiency is linked to increased cardiovascular disease (CVD) risk in the general population, but its implications for people with multiple sclerosis (pwMS) remain unexplored. This study aimed to evaluate the association of 25(OH)D with long-term CVD outcomes in pwMS and the impact of vitamin D supplementation. Methods: This observational cohort study analysed anonymised medical records from 70 healthcare organisations following pwMS for 5-years (2019-2024). PwMS and deficient or inadequate 25(OH)D levels were 1:1 propensity-score matched with pwMS and adequate 25(OH)D levels, for demographics, comorbidities, and cardiovascular care. Cox proportional hazard models analysed the incidence of all-cause mortality, stroke, acute myocardial infarction, heart failure, angina, atrial fibrillation/flutter, and a composite measure of major adverse cardiovascular events (MACE). Propensity-matched pwMS who had deficient or inadequate 25(OH)D levels taking cholecalciferol were compared to pwMS and adequate 25(OH)D levels (not taking supplementation). Results: Amongst 74,372 pwMS, 9% had deficient 25(OH)D levels, 18% inadequate, and 73% adequate. Deficient, or inadequate 25(OH)D levels were associated with an increased rate of MACE (HR, 1.32 [95%CI: 1.19, 1.46], HR, 1.29 [95%CI: 1.20, 1.40], respectively) compared to those with adequate levels. Cholecalciferol supplementation in pwMS and deficient or inadequate 25(OH)D levels did not alleviate the higher CVD rate (HR, 1.39 [95%CI: 1.21,1.60], HR, 1.31 [95%CI: 1.17, 1.47], respectively) in comparison to those with adequate 25(OH)D levels taking no vitamin D supplementation. Conclusions: Deficient or inadequate 25(OH)D levels in pwMS were associated with an increased rate of MACE, which may not be mitigated by vitamin D supplementation.

Effects of Psychological Stress on Multiple Sclerosis via HPA Axis-mediated Modulation of Natural Killer T Cell Activity.

The involvement of psychological stress and Natural Killer T (NKT) cells in the pathophysiology of multiple sclerosis has been identified in the progression of this disease. Psychological stress can impact disease occurrence, relapse, and severity through its effects on the Hypothalamic- Pituitary-Adrenal (HPA) axis and immune responses. NKT cells are believed to play a pivotal role in the pathogenesis of multiple sclerosis, with recent evidence suggesting their distinct functional alterations following activation of the HPA axis under conditions of psychological stress. This review summarizes the associations between psychological stress, NKT cells, and multiple sclerosis while discussing the potential mechanism for how NKT cells mediate the effects of psychological stress on this disease.

Which experimental factors govern successful animal-to-human translation in multiple sclerosis drug development? A systematic review and meta-analysis

Despite successes in multiple sclerosis (MS) drug development, the effectiveness of animal studies in predicting successful bench-to-bedside translation is uncertain. Our goal was to identify predictors of successful animal-to-human translation for MS by systematically comparing animal studies of approved disease-modifying therapies (DMTs) with those that failed in clinical trials due to efficacy or safety concerns. Systematic review of animal studies testing MS DMTs, identified from searches in PubMed and EMBASE. A random effect meta-analysis was fitted to the data to compare outcome effect sizes for approved versus failed DMTs. Effect sizes and testing under diverse experimental conditions were assessed as potential predictors for successful translation. We included 497 animal studies, covering 15 approved and 11 failed DMTs, tested in approximately 30'000 animals. DMTs were tested in a small repertoire of experimental parameters: about 86% of studies used experimental autoimmune encephalomyelitis (EAE), 80% used mice, and 76% used female animals. There was no association between animal study outcomes or testing DMTs under varied conditions (e.g., different laboratories or models) and successful approval. Surprisingly, 91% of animal studies were published after first-in-MS trial and 91% after official regulatory approval. Our findings emphasize the complexity in carrying drugs from animals to clinical practice. Specific challenges include limited experimental methods in animal research and a disconnect between preclinical and clinical research. We advocate for efforts to streamline drug development for MS to improve animal research's relevance for patients. NIH, Swiss National Science Foundation, Universities Federation for Animal Welfare.

Progress in the mechanisms of pain associated with neurodegenerative diseases.

Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.

Cognitive Impairment, Associated Clinical Factors, and MR Volumetric Measures in Myelin Oligodendrocyte Glycoprotein-IgG-Associated Disease.

Cognitive impairment is a common and challenging symptom in multiple sclerosis and neuromyelitis optica spectrum disease; however, data in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) remain scarce. In this cross-sectional study, we investigated the frequency of cognitive impairment, associated clinical factors, and MRI volumetric measures in MOGAD. Participants were investigated in a single center by certified psychologists and underwent a standardized 3-T-MRI protocol. MRI data were processed with FreeSurfer for gray and white matter volume estimation, presented as a fraction of total intracranial volume. Sera screening for antineural antibodies has been conducted using cell-based assays. The following clinical factors were included in the multivariate logistic regression analysis: sex, age, overall number of previous relapses, and specifically the history of acute disseminated encephalomyelitis (ADEM)/ADEM-like episodes and other brain relapses. Thirty-two patients with MOGAD (19 female, median age 29.4 years) after a median of 2 relapses with a median EDSS of 1.0 were recruited. Seven patients (21.9%) demonstrated cognitive impairment with the most prevalent deficits in mental flexibility (16.7%), attention (11.1%-14.8%), and verbal working memory (10.3%). 72.4% suffered from fatigue and 42.9% from signs of depression, moderate to severe in 28.6%. The overall number of previous relapses (odds ratio [OR] 1.789, 95% CI 1.041-3.074) and specifically ADEM/ADEM-like episodes (OR 16.929, 95% CI 1.228-233.427) were the only clinical factors associated with cognitive impairment in a multivariate logistic regression model. Screening for antineuronal antibodies remained negative. Cerebral white matter (WM) (0.300 vs 0.317, p = 0.003) and deep gray matter (DGM) (0.036 vs 0.038, p = 0.002) volumes were reduced in patients with MOGAD compared with healthy controls (n = 32). Both cognitive impairment (0.031 vs 0.036, p = 0.003) and history of ADEM/ADEM-like episodes (0.032 vs 0.036, p = 0.006) were associated with reduced DGM volume compared with unaffected patients with MOGAD. Despite a low overall disability, every 5th patient with MOGAD experiences cognitive impairment. Cognitive impairment is associated with a higher number of relapses and particularly ADEM/ADEM-like attacks. Although both WM and DGM atrophies are apparent in MOGAD, the latter only seems to have an association with cognitive impairment.

The multiple-action allosteric inhibition of TYK2 by deucravacitinib: insights from computational simulations

Participating in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, TYK2 emerges as a promising therapy target in controlling various autoimmune diseases, including psoriasis and multiple sclerosis. Deucravacitinib (DEU) is a novel oral TYK2-specific inhibitor approved in 2022 that is clinically effective in moderate to severe psoriasis trials. Upon the AlphaFold2 predicted TYK2 pseudokinase domain (JH2) and kinase domain (JH1), we explored the details of the underlined allosteric inhibition mechanism on TYK2 JH2-JH1 with the aid of molecular dynamics simulation. Our results suggest that the allosteric inhibition of DEU on TYK2 is accomplished by affecting the JH2-JH1 interface and hampering the state transition and ATP binding in JH1. Particularly, DEU binding stabilized the autoinhibitory interface between JH2 and JH1 while disrupting the formation of the activation interface. As a result, the negative regulation of JH2 on JH1 was greatly enhanced. These findings offer additional details on the pseudokinase-dependent autoinhibition of the JAK kinase domain and provide theoretical support for the JH2-targeted drug discovery in JAK members.

The Current Landscape in the Development of Small-molecule Modulators Targeting Sphingosine-1-phosphate Receptors to Treat Neurodegenerative Diseases.

Sphingosine 1-phosphate (S1P) is extensively researched as a lysophospholipid and is crucial in various physiological and pathological processes. It achieves this via signalling through five different subtypes of G protein-coupled receptors (GPCRs), namely S1PR1 to S1PR5. S1PR modulators possess the ability to traverse the blood-brain barrier, potentially leading to direct ac-tions within the Central Nervous System (CNS). S1PR modulators specifically bind to receptors located on the surface of naive and central memory lymphocytes, causing these cells to be trapped or confined within the lymph node. The investigation of the S1P pathway has resulted in the ap-proval of three S1PR modulators, namely fingolimod, siponimod, and ozanimod, as medications for the treatment of patients suffering from Multiple Sclerosis (MS). Additionally, new S1PR modulators, such as ponesimod and etrasimod, are currently being developed and tested in clini-cal trials. Research on the creation of S1P modulators in neurodegenerative illnesses is ongoing as scientists continue to explore novel possibilities for selective S1P modulators. This study provides a concise overview of sphingolipid metabolism, the mechanism by which S1P receptors are af-fected, and the structural characteristics of several small molecule S1P modulators, with a particu-lar focus on their structure-activity connections.

Advances in Research on Adropin: Potential Implications for Clinical Diagnosis and Possible Treatment – A Mini-Review

: Adropin is 76-amino acids protein. It was discovered in 2008. Adropin expression was found in the liver, brain, heart, kidneys, pancreas, testis and ovary, umbilical vein, coronary artery endothelial cells, aortic smooth muscle cells and monocytes/macrophages. Adropin is involved in energy balance, and it has an endothelial protective effect. Changes in adropin content have been found in many diseases and disorders, such as obesity, diabetes mellitus type 1 and 2, coronary artery disease, myocardial infarction, rheumatoid arthritis, primary Sjögren's syndrome, multiple sclerosis, nonalcoholic fatty liver disease, polycystic ovary syndrome and preeclampsia. This mini-review focuses on those papers that have potential implications for clinical diagnosis or possible treatment. It can be assumed that adropin can be useful in the diagnosis of certain diseases. It seems to be a promising candidate for the treatment of diabetes, atherosclerosis, polycystic ovary syndrome and diseases of the nervous system associated with cognitive decline.

Access to Care and Health-Related Quality of Life in Multiple Sclerosis.

Despite their high health care use, it is unclear whether the health care needs of people with MS are being met and what their priorities are. We assessed priorities for access to, and affordability of care, by people living with MS in the United States. We also tested the association between perceived inadequate access to care and health-related quality of life (HRQoL). In Fall 2022, we conducted a cross-sectional survey of participants in the North American Research Committee on Multiple Sclerosis Registry about access to care and HRQoL (Health Utilities Index Mark III). We used multivariable polytomous logistic regression to test sociodemographic and clinical factors associated with access to care. We used multivariable linear regression analysis to test the association between access to care and HRQoL. We included 4,914 respondents in the analysis, of whom 3,974 (80.9%) were women, with a mean (SD) age 64.4 (9.9) years. The providers who were most reported as needed but inaccessible were complementary providers (35.5%), followed by allied health providers (24.2%), occupational therapists (22.7%), and mental health providers (20.7%). Over 80% of participants reported that it was important or very important to be able to get an appointment with their primary MS health care provider when needed, to have sufficient time in their appointments to explain their concerns, to see their neurologist if their status changed, and that their health care providers communicated to coordinate their care. Participants who reported needing to see the provider but not having access or seeing the provider but would like to see them more often had lower HRQOL (ranging from -0.059 to -0.176) than participants who saw the provider as much as needed. Gaps in access to care persist for people with MS in the United States and substantially affect HRQoL. Improving access to care for people with MS should be a health system priority.

EBNA-1 and VCA-p18 immunoglobulin markers link Epstein-Barr virus immune response and brain’s myelin content to fatigue in a community-dwelling cohort

Given the association of Epstein-Barr virus (EBV) with subjective perception of fatigue and demyelination in clinical conditions, the question about potential subclinical effects in the adult general population remains open. We investigate the association between individuals’ EBV immune response and perceived fatigue in a community dwelling cohort (n=864, age 62 ± 10 years old; 49% women) while monitoring brain tissue properties. Fatigue levels are assessed with the established fatigue severity scale, the EBNA-1 and VCA p18 immunoglobulin G (IgG) chronic response – with multiplex serology and the estimates of local brain volume, myelin content, and axonal density - using relaxometry- and multi-shell diffusion-based magnetic resonance imaging (MRI). In our analysis we adjust for the effects of demographic and cardiovascular risk factors, sleep apnea, depression, and polygenic risk score for multiple sclerosis. We demonstrate that EBNA-1 IgG levels are positively associated with perceived levels of fatigue, whilst VCA p18 IgG levels show a positive correlation with myelin content and a negative one with an estimate of axonal g-ratio in male participants. In the context of EBVs immune response, the polygenic risk for multiple sclerosis is not associated with increased fatigue levels, brain myelination or atrophy. Our findings bring empirical evidence about the potential role of EBVs chronic immune response in perceived fatigue and hint towards a protective role of myelination specific for men. They underscore the added value of advanced assessment of brain tissue microstructure in uncovering the mechanisms behind frequent fatigue complaints associated with EBV infection and multiple sclerosis.

Utility of icobrain for brain volumetry in multiple sclerosis clinical practice

BackgroundFew studies on multiple sclerosis (MS) have explored the variability of percentage brain volume change (PBVC) measurements obtained from different clinical MRIs. In a retrospective multicentre cohort study, we quantified the variability of annualised PBVC in clinical MRIs. MethodsClinical MRIs of relapse-onset MS patients were assessed by icobrain. Volumetric data were analysed on same-scanner and different-scanner MRI pairs if they passed quality control criteria. Alignment similarity between two images had to be comparable to same-scanner scan-rescan images. ResultsOf 6826 MRIs, 85% had appropriate volumetric sequences and 4446 serial MRI pairs were analysed. 3334 (75%) MRI pairs from 1207 patients met the inclusions. The PBVC of included MRI pairs showed variance of 0.78% for same-scanner pairs and 0.80% for different-scanner pairs. Further selection of included MRI pairs with the best variance resulted in 1885 (42%) MRI pairs with PBVC variance of 0.34%. Excluded MRI pairs with poor alignment similarity had variances of 2.97% for same-scanner pairs and 20.79% for different-scanner pairs. ConclusionIcobrain should be utilised for PBVC determination only on selected MRIs with the best alignment similarity. Applying strict selection criteria for the included MRI pairs and longitudinal imaging on the same scanner remain mandatory to reduce PBVC variability.

Pharmacokinetics and Pharmacodynamics of Natalizumab 6-Week Dosing vs Continued 4-Week Dosing for Relapsing-Remitting Multiple Sclerosis.

Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical efficacy was maintained in the majority of patients switched to every-6-week (Q6W) dosing in the phase 3b NOVA clinical trial. In this article, we report pharmacokinetics (PK) and pharmacodynamics (PD) of Q6W vs Q4W dosing in NOVA. In NOVA study Part 1, participants with RRMS (aged 18-60 years) and Expanded Disability Status Scale score <5.5, who were stable on IV natalizumab Q4W dosing for ≥12 months, were randomized to continue IV Q4W dosing or switched to IV Q6W dosing of natalizumab and followed for 72 weeks. Exploratory outcomes were measurements of trough serum natalizumab concentration, α4-integrin saturation, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration. A mixed model of repeated measures was used to estimate mean treatment differences between groups. Patient-level PK and PD data were examined in those with relapse or radiologic disease activity. In NOVA, 486 (Q6W, n = 245; Q4W, n = 241) and 487 (Q6W, n = 246; Q4W, n = 241) participants were included in the PK and PD populations, respectively. Mean trough natalizumab concentrations ranged from 10 to 21 μg/mL (Q6W) and 33-38 μg/mL (Q4W), and mean α4-integrin saturation remained above 65.5% (Q6W) and above 77.9% (Q4W). In the Q6W group, mean sVCAM-1 levels increased 23.6% by week 24 and remained elevated throughout the study, while mean sVCAM-1 levels remained generally stable in the Q4W group. Most participants with T2 lesion activity or relapse activity, in either treatment arm, maintained trough natalizumab levels >10 μg/mL and trough α4-integrin saturation >50%. Compared with Q4W dosing, Q6W dosing was associated with a 60%-70% decrease in mean trough natalizumab levels and a 9%-16% decrease in mean α4-integrin saturation. At the patient level, neither natalizumab concentration nor α4-integrin saturation was consistently predictive of lesion or relapse activity, suggesting that trough natalizumab and α4-integrin saturation measurements should be interpreted with caution in clinical practice. ClinicalTrials.gov, NCT03689972; EudraCT, 2018-002145-11. Submitted 2018-09-27. First patient enrolled: 2018-12-26. https://clinicaltrials.gov/study/NCT03689972.

Progressive Multifocal Leukoencephalopathy Associated with Sphingosine-1-Phosphate Receptor Modulators: A Large Case Series

Risk factors for progressive multifocal leukoencephalopathy (PML) associated with sphingosine-1-phosphate receptor (S1PR) modulators are not as well-characterized as for natalizumab. We characterized S1PR modulator-associated PML cases and risk factors for PML using spontaneous adverse event reports. We reviewed case reports from the FDA Adverse Event Reporting System database and the medical literature. We identified 57 PML cases encompassing all marketed S1PR modulators approved for multiple sclerosis, the majority (n = 53) associated with fingolimod. Ten cases reported a fatal outcome. Length of S1PR modulator exposure (≥18 months) appears to be a robust risk factor for PML. Patient age ≥50 years was identified as a potential risk factor, although this may be the result of several biases. We propose that prior immunosuppressant exposure should be considered as a potential risk factor for further validation. No conclusions could be drawn regarding JC virus serology and lymphopenia severity. Spontaneous adverse event reports support the observation that extended S1PR modulator exposure appears to be a robust PML risk factor. As a result, the U.S. Prescribing Information for each product in the S1PR modulator class was updated. Validation of other potential risk factors would support efforts to stratify and mitigate the risk of S1PR modulator-associated PML.

Exploring Overlap Syndromes: An Atypical Case of Multiple Sclerosis With Anti-Sjogren’s Syndrome Type B Antibody

Exploring Overlap Syndromes: An Atypical Case of Multiple Sclerosis With Anti-Sjogren’s Syndrome Type B Antibody

Prevalence of, and Disability Due to, Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder in Japan by the Fifth Nationwide Survey.

All 4 previous nationwide surveys of multiple sclerosis (MS) in Japan were conducted before the discovery of anti-aquaporin-4 (AQP4) antibodies; thus, neuromyelitis optica spectrum disorder (NMOSD) was included in MS, as optic-spinal MS. We aimed to clarify the epidemiologic features and trends of MS and NMOSD in Japan separately using a fifth nationwide survey. The primary survey, in which a questionnaire was sent to 3,799 selected departments (including neurology/internal medicine, pediatrics, and ophthalmology), explored the estimated number and prevalence of patients with MS or NMOSD in 2017, and the secondary survey collected detailed characteristics of the patients using a second questionnaire. The response rates for the primary and secondary surveys were 60.1% and 53.9%, respectively. The estimated total number of patients with MS or NMOSD was 24,800, 2.5-fold higher than that in the fourth survey in 2003. The crude prevalence was 19.6 per 100,000 patients (14.2 for MS and 5.4 for NMOSD), compared with 7.7 per 100,000 patients in the fourth survey. Patients with MS showed milder disability (median Expanded Disability Status Scale [EDSS] score: 2.0 [interquartile range 1.0-4.5] vs 2.5 [1.0-6.0]), decreased secondary progression (8.5% vs 15.2%), and increased usage of disease-modifying drugs (63.7% vs 37.2%) compared with those with conventional MS in the fourth survey. The proportions of oligoclonal bands and Barkhof criteria fulfillment on MRI, which are features of classical MS, increased with advancing year of birth. Patients with NMOSD also showed less disability and shorter disease duration than patients with optic-spinal MS in the fourth survey (EDSS score: 3.5 [2.0-5.5] vs 3.8 [2.0-6.0]; disease duration: 8.0 [3.9-14.8] vs 10.0 [5.0-16.0]). Among patients with NMOSD, disability was exacerbated by a history of longitudinally extensive spinal cord lesions and anti-AQP4 antibody positivity, which both decreased with advancing year of birth. The prevalences of MS (particularly with classical features) and NMOSD have been increasing in Japan, suggesting the contribution of environmental factors. However, disabilities in patients with MS and NMOSD have been mitigated. Extensive usage of various disease-modifying drugs could be a factor contributing to this disability mitigation in MS.