Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 ( P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

Human chorionic gonadotropin regulates cytokine production by lymphocytes from patients with multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults, predominantly females. This was partially attributed to sex differences in immunity, which are influenced by changes in sex hormones occurring during women's life, among other factors. Furthermore, MS patients experience significant improvement in their symptoms during pregnancy when levels of female sex-hormones significantly increase. This phenomenon was attributed to immune adaptations occurring during gestation which are regulated by paternal antigens and sex hormones. The human chorionic gonadotropin (hCG) was shown to have strong immunosuppressive abilities. We aimed to analyze here the capacity of the hCG to regulate pro- and anti-inflammatory cytokine production by PBMC from MS patients. PBMC isolated from 17 MS patients receiving IFNß1a treatment were cultured with or without recombinant or urinary hCG. Cytokine production in the supernatants was assessed using a CBA array and cytokine production by lymphocytes and expression of co-stimulatory molecules in B-lymphocytes were evaluated by flow cytometry. hCG reduced the production of TNF by PBMC from MS patients while lowering the percentages of TNF producing T cells and diminishing the production of TNF by B cells. hCG significantly boosted the production of IL-10 by regulatory T cells and CD19high B cells from MS patients. Furthermore, hCG treatment lowered the percentages of CD80+CD86+ expressing B cells within PBMC from MS patients. Overall, our results described a novel and not yet explored mechanisms of action of hCG in the context of MS.

Treatment strategies and responses for attacks of neuromyelitis optica spectrum disorder: A real-world retrospective cohort study.

We aimed to assess the treatment strategies utilized in patients with neuromyelitis optica spectrum disorder (NMOSD) experiencing relapses, including their frequency, types, and response after 6 months based on the Expanded Disability Status Scale (EDSS) score. METHODS: We conducted a retrospective study involving NMOSD patients from the Argentinean MS and NMOSD registry (RelevarEM, NCT03375177). Treatment response at 6 months was categorized as "good" if the EDSS score decreased by ≥1 point after a nadir EDSS score ≤ 3, or by ≥2 points after a nadir EDSS score > 3, "poor" if the EDSS score decrease was slighter, and as "absent" if the EDSS score remained unchanged or worsened. RESULTS: We included 120 NMOSD patients (seropositive N = 75), who experienced 250 NMOSD-related relapses and received 248 treatments. At 6 months, complete recovery was achieved in 70/98 (71.4%) and 15/19 (79%) patients, respectively. Predictors of a "good" response in our regression model were a younger age at disease onset (OR:3.54, CI95% 2.45-5.01, p < 0.0001) and a short delay from onset of relapse to treatment initiation (OR:1.56, CI95% 1.22-2.13, p = 0.004). CONCLUSIONS: Approximately two-thirds of patients experienced complete recovery, and younger age and a short delay to start treatment were independent predictors of a "good" response.

Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina.

OBJECTIVE: The aim was to evaluate patient profiles, effectiveness and safety of cladribine (CLAD) in patients with relapsing-remitting multiple sclerosis in Argentina. METHODS: This was a substudy included in RelevarEM (MS and neuromyelitis optica registry in Argentina, NCT03375177). Patients with MS who received CLAD tablets and were followed up for at least 24 months were included. Clinical evaluations every 3 months collect information about: a) clinical relapses; b) progression of physical disability, evaluated through Expanded Disability Status Scale, and c) new lesions found in the magnetic resonance imaging. Lymphopenia was evaluated during the follow-up and defined as grade 1: absolute lymphocyte count (ALC) 800-999/µL; grade 2: ALC 500-799/µL; grade 3: ALC 200-499/µL and grade 4: ALC <200/µL. RESULTS: A total of 240 patients were included from 19 centers from Argentina. The mean annualized relapse rate during the 12-month pre-CLAD initiation was 1.19 ± 0.56 versus 0.22 ± 0.18 at month 12 and 0.19 ± 0.15 at month 24 (P < 0.001). A total of 142 (59.2%) fulfilled the criteria of disease activity during the 12 months before treatment initiation, whereas 27 (11.3%) fulfilled it at month 12 and 38 (15.8%) at month 24, P < 0.001. Regarding no evidence of disease activity (NEDA), 202 (84.2%) patients achieved NEDA status at month 12 and 185 (77%) at month 24. The most frequent incidence density of lymphopenia for course 2 observed was also for grade 1, 6.1 (95% confidence interval [CI] = 5.5-7.1). The overall incidence density of lymphopenia grade 4 was 0.1 (95% CI = 0.06-0.19). CONCLUSION: This information will help when choosing the best treatment option for Argentinean patients.

Selection of disease modifying therapies in multiple sclerosis based on patient's age and disease activity: Data from a nationwide registry.

BACKGROUND: Knowledge of the safety and efficacy of disease-modifying therapies (DMTs) in older patients with Multiple Sclerosis (pwMS) is limited due to their exclusion from clinical trials. Our purpose is to evaluate the choice of DMTs in pwMS older than 50 years old in a real-world setting. METHODS: Cross-sectional study of pwMS from the Argentine MS and NMOSD Registry. We included patients under 35 and above 50 years old prescribed DMTs. Disease activity was categorized as highly active (HA) or not highly active (NHA), and DMTs were classified as low efficacy therapies (LET) or high efficacy therapies (HET). RESULTS: 1460 patients (65% females) were enrolled. The HA group comprised 241 patients, 198 young (82.2%) and 43 older (17.8%). The NHA group included 1219 patients, 893 young (73%) and 326 older (27%). In the NHA group, older patients received LET more frequently than younger patients (66% versus 44%; p < 0.01). In the HA group, older patients received LET in 61% of cases, whereas younger patients received HET in 71% (p = 0.01). CONCLUSION: The study shows the preference of LET in older patients regardless of disease activity. However it does not demonstrate a difference in disability in older patients based on low vs high efficacy DMTs used, probably due to the design of the study. Further longitudinal studies are warranted to address this issue.

Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Occurrence of area postrema syndrome during follow-up: phenotype and influence over NMOSD activity in LATAM in real-world settings.

INTRODUCTION: We aimed to assess the frequency, duration, and severity of area postrema syndrome (APS) during follow-up in neuromyelitis optica spectrum disorder (NMOSD) patients, as well as its association with inflammatory activity and prognostic factors of APS severity in a real-world setting. METHODS: We conducted a retrospective study on a cohort of Latin American (LATAM) NMOSD patients who had experienced APS during their follow-up. Patients from Mexico, Peru, Brazil, Colombia, Panama, Chile and Argentina patients who met 2015 NMOSD criteria were included. We evaluated data on symptom type (nausea, vomiting and/or hiccups), frequency, duration, severity (measured by APS severity scale), association with other NMOSD core relapses, and acute treatments (symptomatic and immunotherapy or plasmapheresis). Logistic regression was conducted to evaluate factors associated with APS severity (vs. mild-moderate). RESULTS: Out of 631 NMOSD patients, 116 (18.3%) developed APS during their follow-up. The most common APS phenotype was severe. Inflammatory activity (i.e., relapses) significantly decreased after the onset of APS. Half of the patients experienced isolated APS with a median duration of 10 days, and the most frequently used acute treatment was IV steroids. All three symptoms were present in 44.6% of the patients. APS symptoms resolved following immunotherapy. Logistic regression did not identify independent factors associated with the severity of APS. CONCLUSIONS: Our findings indicate that 18.3% of NMOSD patients developed APS during the follow-up period, with most patients fulfilling criteria for severe APS. The inflammatory activity decreased after the onset of APS compared to the previous year.

Clinical impact of gender and age at onset on disease trajectory in primary progressive multiple sclerosis patients.

BACKGROUND AND OBJECTIVES: Primary-progressive multiple sclerosis (PPMS) is characterized by gradual neurological deterioration without relapses. This study aimed to investigate the clinical impact of gender and age at disease onset on disease progression and disability accumulation in patients with this disease phenotype. METHODS: Secondary data from the RelevarEM registry, a longitudinal database in Argentina, were analyzed. The cohort comprised patients with PPMS who met inclusion criteria. Statistical analysis with multilevel Bayesian robust regression modeling was conducted to assess the associations between gender, age at onset, and Expanded Disability Status Scale (EDSS) score trajectories. RESULTS: We identified 125 patients with a confirmed diagnosis of PPMS encompassing a total of 464 observations. We found no significant differences in EDSS scores after 10 years of disease progression between genders (-0.08; credible interval (CI): -0.60, 0.42). A 20-year difference in age at onset did not show significant differences in EDSS score after 10 years of disease progression (0.281; CI: -0.251, 0.814). Finally, we also did not find any clinically relevant difference between gender EDSS score with a difference of 20 years in age at onset (-0.021; CI: -0.371, 0.319). CONCLUSION: Biological plausibility of gender and age effects does not correlate with clinical impact measured by EDSS score.

Clinical characteristics, course and prognosis of Multiple Sclerosis patients with epilepsy. A case control study: MS and epilepsy.

BACKGROUND AND PURPOSE: Although more common than in the general population, seizures are an atypical manifestation of multiple sclerosis (MS) and their pathophysiology is not well understood. This study aims to examine the prevalence, clinical characteristics, brain imaging findings and course of epilepsy, presenting in patients with MS. METHODS: Observational retrospective study of MS patients evaluated at a single MS reference center in Buenos Aires, Argentina, between 2011 and 2022, focusing on those who developed epilepsy (EMS). Clinical, demographic, and prognostic factors were evaluated and compared to a control group of non-epileptic MS patients (NEMS). To analyze specific epilepsy characteristics, a second control group of patients with non-lesional focal epilepsy (FNLE) was also included. RESULTS: Twenty-five patients (18 women), were diagnosed with epilepsy, corresponding to a prevalence of 1.95%. Comparison of brain imaging characteristics between EMS and NEMS patients showed brain atrophy (32% vs 6.1%, p<0.01), as well as cortical (26% vs 4%, p=0.03) and juxtacortical lesions (84% vs 55%, p=0.05), were more frequent in EMS patients. However, after multivariate analysis, cortical atrophy was the only variable linked to a significant increase in risk of epilepsy (OR 24, 95%CI=2.3-200, p<0.01). No significant differences in clinical characteristics, disease activity, disability levels, response to disease modified treatment (DMT) or lack of DMT efficacy were observed between MS patients with or without epilepsy. Most patients received anti-seizure medication (ASM), and seizure control was better in EMS than in FNLE patients (92% vs 58%, p=0.022) with no differences found in drug resistance. We did not find predictors of seizure recurrence in the population studied. CONCLUSION: We observed a lower prevalence of epilepsy in this group of MS patients, compared to other reported cohorts. Although epilepsy seems to have a benign course in MS patients, cortical atrophy appears to be an important contributor to the development of secondary epilepsy in MS patients. Further investigations will be necessary to identify risk factors or biomarkers predicting increased epilepsy risk in MS.

Assessing robustness and generalization of a deep neural network for brain MS lesion segmentation on real-world data.

OBJECTIVES: Evaluate the performance of a deep learning (DL)-based model for multiple sclerosis (MS) lesion segmentation and compare it to other DL and non-DL algorithms. METHODS: This ambispective, multicenter study assessed the performance of a DL-based model for MS lesion segmentation and compared it to alternative DL- and non-DL-based methods. Models were tested on internal (n = 20) and external (n = 18) datasets from Latin America, and on an external dataset from Europe (n = 49). We also examined robustness by rescanning six patients (n = 6) from our MS clinical cohort. Moreover, we studied inter-human annotator agreement and discussed our findings in light of these results. Performance and robustness were assessed using intraclass correlation coefficient (ICC), Dice coefficient (DC), and coefficient of variation (CV). RESULTS: Inter-human ICC ranged from 0.89 to 0.95, while spatial agreement among annotators showed a median DC of 0.63. Using expert manual segmentations as ground truth, our DL model achieved a median DC of 0.73 on the internal, 0.66 on the external, and 0.70 on the challenge datasets. The performance of our DL model exceeded that of the alternative algorithms on all datasets. In the robustness experiment, our DL model also achieved higher DC (ranging from 0.82 to 0.90) and lower CV (ranging from 0.7 to 7.9%) when compared to the alternative methods. CONCLUSION: Our DL-based model outperformed alternative methods for brain MS lesion segmentation. The model also proved to generalize well on unseen data and has a robust performance and low processing times both on real-world and challenge-based data. CLINICAL RELEVANCE STATEMENT: Our DL-based model demonstrated superior performance in accurately segmenting brain MS lesions compared to alternative methods, indicating its potential for clinical application with improved accuracy, robustness, and efficiency. KEY POINTS: • Automated lesion load quantification in MS patients is valuable; however, more accurate methods are still necessary. • A novel deep learning model outperformed alternative MS lesion segmentation methods on multisite datasets. • Deep learning models are particularly suitable for MS lesion segmentation in clinical scenarios.

Remyelinating effect driven by transferrin-loaded extracellular vesicles.

Extracellular vesicles (EVs) are involved in diverse cellular functions, playing a significant role in cell-to-cell communication in both physiological conditions and pathological scenarios. Therefore, EVs represent a promising therapeutic strategy. Oligodendrocytes (OLs) are myelinating glial cells developed from oligodendrocyte progenitor cells (OPCs) and damaged in chronic demyelinating diseases such as multiple sclerosis (MS). Glycoprotein transferrin (Tf) plays a critical role in iron homeostasis and has pro-differentiating effects on OLs in vivo and in vitro. In the current work, we evaluated the use of EVs as transporters of Tf to the central nervous system (CNS) through the intranasal (IN) route. For the in vitro mechanistic studies, we used rat plasma EVs. Our results show that EVTf enter OPCs through clathrin-caveolae and cholesterol-rich lipid raft endocytic pathways, releasing the cargo and exerting a pro-maturation effect on OPCs. These effects were also observed in vivo using the animal model of demyelination induced by cuprizone (CPZ). In this model, IN administered Tf-loaded EVs isolated from mouse plasma reached the brain parenchyma, internalizing into OPCs, promoting their differentiation, and accelerating remyelination. Furthermore, in vivo experiments demonstrated that EVs protected the Tf cargo and significantly reduced the amount of Tf required to induce remyelination as compared to soluble Tf. Collectively, these findings unveil EVs as functional nanocarriers of Tf to induce remyelination.

Incidence of SARS-CoV-2 infection in patients with multiple sclerosis who received SARS-CoV-2 vaccines and are under treatment with high-efficacy therapies in Argentina.

We aimed to evaluate the incidence of SARS-CoV-2 breakthrough infection of SARS-CoV-2 vaccines in people with MS (PwMS) on high-efficacy disease-modifying therapies (HET) included in the national MS registry in Argentina (RelevarEM). METHODS: Non-interventional, retrospective cohort study that collected information directly from RelevarEM. Adult PwMS who had been treated for at least 6 months with a HET (ocrelizumab, natalizumab, alemtuzumab, cladribine) who had received at least two doses of SARS-CoV-2 vaccines available in Argentina were included. Full course of vaccination was considered after the second dose of the corresponding vaccines. Cumulative incidence of SARS-CoV-2 infection was reported for the whole cohort by Kaplan-Meier survival curves (which is expressed in percentage) as well as incidence density (which is expressed per 10.000 patients/day with 95% CI). RESULTS: Two hundred twenty-eight PwMS were included. Most frequent first and second dose received was AstraZeneca vaccine, followed by Sputnik vaccine. Most frequent HETs used in included patients were cladribine in 79 (34.8%). We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina. We described the incidence rate after vaccination for every HET used, it being significantly higher for ocrelizumab compared with other HETs (p = 0.005). Only five patients presented a relapse during the follow-up period with no differences regarding the pre-vaccination period. CONCLUSIONS: We found an incidence density of breakthrough COVID-19 infection of 3.5 × 10.000 patients/day (95% CI 2.3-6.7) after vaccination in Argentina.

Mortality of neuromyelitis optica spectrum disorder patients in an Argentinean population: A study from the RelevarEM registry.

We aimed to evaluate mortality and causes of death among Argentinean neuromyelitis optica spectrum disorder (NMOSD) patients and identify predictors of death. Retrospective study included 158 NMOSD patients and 11 (7%) patients died after 11 years of follow-up for a total exposure time of 53,345 days with an overall incidence density of 2.06 × 10.000 patients/day (95% CI 1.75-2.68). Extensive cervical myelitis with respiratory failure (45%) was the most frequent cause of death. Older age (HR = 2.05, p = 0.002) and higher disability score (HR = 2.30, p < 0.001) at disease onset were independent predictors of death. We found an 11-year mortality rate of 7% in Argentinean NMOSD patients.

A plain language summary on assessing the long-term effectiveness of cladribine tablets in people living with relapsing multiple sclerosis: The CLASSIC-MS study.

WHAT IS THIS SUMMARY ABOUT?: Previous studies have shown that people living with multiple sclerosis (MS) treated with cladribine tablets have fewer relapses (where new symptoms occur or existing symptoms get worse for 24 hours or more) and delayed disability progression (slowing down of the disease getting worse). The CLASSIC-MS study looked at the long-term effectiveness of treatment with cladribine tablets in people living with MS who had taken part in the original CLARITY and CLARITY Extension clinical studies. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets maintained their mobility (the ability to move freely) for longer and experienced other positive effects long after their treatment ended, including being less likely to need further treatment for their MS. WHAT DO THE RESULTS MEAN?: The results obtained from CLASSIC-MS show that the benefits of taking cladribine tablets carry on even when patients stop taking the treatment.

Differential diagnosis of suspected multiple sclerosis: an updated consensus approach.

Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.

Frequency of new asymptomatic MRI lesions during attacks and follow-up of patients with NMOSD in a real-world setting.

BACKGROUND: We aimed to assess the frequency of new asymptomatic lesions on brain and spinal imaging (magnetic resonance imaging (MRI)) and their association with subsequent relapses in a large cohort of neuromyelitis optica spectrum disorder (NMOSD) patients in Argentina. METHODS: We retrospectively reviewed 675 MRI (225 performed during an attack and 450 during the relapse-free period (performed at least 3 months from the last attack)) of NMOSD patients who had at least 2 years of clinical and MRI follow-up since disease onset. Kaplan-Meier (KM) curves were used for depicting time from remission MRI to subsequent relapse. RESULTS: We included 135 NMOSD patients (64.4% were aquaporin-4-immunoglobulin G (AQP4-IgG)-positive). We found that 26 (19.26%) and 66 (48.88%) of patients experienced at least one new asymptomatic MRI lesion during both the relapse-free period and attacks, respectively. The most frequent asymptomatic MRI lesions were optic nerves followed by short-segment myelitis during the relapse-free period and attacks. KM curves did not show differences in the time taken to develop a new relapse. CONCLUSION: Our findings showed that new asymptomatic lesions are relatively frequent. However, the presence of new asymptomatic MRI lesions during the relapse-free period and at relapses was not associated with a shorter time to developing subsequent relapses.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.

Global Barriers to the Diagnosis of Multiple Sclerosis: Data From the Multiple Sclerosis International Federation Atlas of MS, Third Edition.

BACKGROUND AND OBJECTIVES: Recent data suggest increasing global prevalence of multiple sclerosis (MS). Early diagnosis of MS reduces the burden of disability-adjusted life years and associated health care costs. Yet diagnostic delays persist in MS care and even within national health care systems with robust resources, comprehensive registries, and MS subspecialist referral networks. The global prevalence and characteristics of barriers to expedited MS diagnosis, particularly in resource-restricted regions, have not been extensively studied. Recent revisions to MS diagnostic criteria demonstrate potential to facilitate earlier diagnosis, but global implementation remains largely unknown. METHODS: The Multiple Sclerosis International Federation third edition of the Atlas of MS was a survey that assessed the current global state of diagnosis including adoption of MS diagnostic criteria; barriers to diagnosis with respect to the patient, health care provider, and health system; and existence of national guidelines or national standards for speed of MS diagnosis. RESULTS: Coordinators from 107 countries (representing approximately 82% of the world population), participated. Eighty-three percent reported at least 1 "major barrier" to early MS diagnosis. The most frequently reported barriers included the following: "lack of awareness of MS symptoms among general public" (68%), "lack of awareness of MS symptoms among health care professionals" (59%), and "lack of availability of health care professionals with knowledge to diagnose MS" (44%). One-third reported lack of "specialist medical equipment or diagnostic tests." Thirty-four percent reported the use of only 2017 McDonald criteria (McD-C) for diagnosis, and 79% reported 2017 McD-C as the "most commonly used criteria." Sixty-six percent reported at least 1 barrier to the adoption of 2017 McD-C, including "neurologists lack awareness or training" by 45%. There was no significant association between national guidelines pertaining to MS diagnosis or practice standards addressing the speed of diagnosis and presence of barriers to early MS diagnosis and implementation of 2017 McD-C. DISCUSSION: This study finds pervasive consistent global barriers to early diagnosis of MS. While these barriers reflected a lack of resources in many countries, data also suggest that interventions designed to develop and implement accessible education and training can provide cost-effective opportunities to improve access to early MS diagnosis.

Long-term follow-up of patients with relapsing multiple sclerosis from the CLARITY/CLARITY Extension cohort of CLASSIC-MS: An ambispective study.

BACKGROUND: CLASSIC-MS evaluated the long-term efficacy of cladribine tablets in patients with relapsing multiple sclerosis. OBJECTIVE: Report long-term mobility and disability beyond treatment courses received in CLARITY/CLARITY Extension. METHODS: This analysis represents CLASSIC-MS patients who participated in CLARITY with/without participation in CLARITY Extension, and received ⩾1 course of cladribine tablets or placebo (N = 435). Primary objective includes evaluation of long-term mobility (no wheelchair use in the 3 months prior to first visit in CLASSIC-MS and not bedridden at any time since last parent study dose (LPSD), i.e. Expanded Disability Status Scale (EDSS) score <7). Secondary objective includes long-term disability status (no use of an ambulatory device (EDSS < 6) at any time since LPSD). RESULTS: At CLASSIC-MS baseline, mean ± standard deviation EDSS score was 3.9 ± 2.1 and the median time since LPSD was 10.9 (range = 9.3-14.9) years. Cladribine tablets-exposed population: 90.6% (N = 394), including 160 patients who received a cumulative dose of 3.5 mg/kg over 2 years. Patients not using a wheelchair and not bedridden: exposed, 90.0%; unexposed, 77.8%. Patients with no use of an ambulatory device: exposed, 81.2%; unexposed, 75.6%. CONCLUSION: With a median 10.9 years' follow-up after CLARITY/CLARITY Extension, findings suggest the sustained long-term mobility and disability benefits of cladribine tablets.

Transferrin Enhances Neuronal Differentiation.

Although transferrin (Tf) is a glycoprotein best known for its role in iron delivery, iron-independent functions have also been reported. Here, we assessed apoTf (aTf) treatment effects on Neuro-2a (N2a) cells, a mouse neuroblastoma cell line which, once differentiated, shares many properties with neurons, including process outgrowth, expression of selective neuronal markers, and electrical activity. We first examined the binding of Tf to its receptor (TfR) in our model and verified that, like neurons, N2a cells can internalize Tf from the culture medium. Next, studies on neuronal developmental parameters showed that Tf increases N2a survival through a decrease in apoptosis. Additionally, Tf accelerated the morphological development of N2a cells by promoting neurite outgrowth. These pro-differentiating effects were also observed in primary cultures of mouse cortical neurons treated with aTf, as neurons matured at a higher rate than controls and showed a decrease in the expression of early neuronal markers. Further experiments in iron-enriched and iron-deficient media showed that Tf preserved its pro-differentiation properties in N2a cells, with results hinting at a modulatory role for iron. Moreover, N2a-microglia co-cultures revealed an increase in IL-10 upon aTf treatment, which may be thought to favor N2a differentiation. Taken together, these findings suggest that Tf reduces cell death and favors the neuronal differentiation process, thus making Tf a promising candidate to be used in regenerative strategies for neurodegenerative diseases.