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Background: Mechanisms underlying neurodegeneration in multiple sclerosis (MS) remain poorly understood but mostly implicate molecular pathways that are not unique to MS. Recently detected tau seeding activity in MS brain tissues corroborates previous neuropathological reports of hyperphosphorylated tau (p-tau) accumulation in secondary and primary progressive MS (PPMS). We aimed to investigate whether aberrant tau phosphorylation can be detected in the cerebrospinal fluid (CSF) of MS patients by using novel ultrasensitive immunoassays for different p-tau biomarkers., Methods: CSF samples of patients with MS (n = 55) and non-inflammatory neurological disorders (NIND, n = 31) were analysed with in-house Single molecule array (Simoa) assays targeting different tau phosphorylation sites (p-tau181, p-tau212, p-tau217 and p-tau231). Additionally, neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were measured with a multiplexed Simoa assay. Patients were diagnosed with clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS, n = 21) and PPMS (n = 24) according to the 2017 McDonald criteria and had MRI, EDSS and basic CSF analysis performed at the time of diagnosis., Results: Patients with progressive disease course had between 1.4-fold (p-tau217) and 2.2-fold (p-tau212) higher p-tau levels than relapsing MS patients (PPMS compared with CIS + RRMS, p < 0.001 for p-tau181, p-tau212, p-tau231 and p = 0.042 for p-tau217). P-tau biomarkers were associated with disease duration (ρ=0.466-0.622, p < 0.0001), age (ρ=0.318-0.485, p < 0.02, all but p-tau217) and EDSS at diagnosis and follow-up (ρ=0.309-0.440, p < 0.02). In addition, p-tau biomarkers correlated with GFAP (ρ=0.517-0.719, p ≤ 0.0001) but not with the albumin quotient, CSF cell count or NFL. Patients with higher MRI lesion load also had higher p-tau levels p ≤ 0.01 (<10 vs. ≥ 10 lesions, all p ≤ 0.01)., Conclusion: CSF concentrations of novel p-tau biomarkers point to a higher degree of tau phosphorylation in PPMS than in RRMS. Associations with age, disease duration and EDSS suggest this process increases with disease severity; however, replication of these results in larger cohorts is needed to further clarify the relevance of altered tau phosphorylation throughout the disease course in MS., Competing Interests: Declaration of competing interest AE has participated in meetings sponsored by Novartis and received travel grants or research support from Novartis. GBJ participated as a clinical investigator and/or received consultation and/or speaker fees from Biogen, Janssen, Lek, Merck, Novartis, Pliva/Teva, Roche, Sanofi Genzyme and Swixx. UR participated as a clinical investigator and/or received consultation and/or speaker fees from Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Pliva/Teva, Roche. AHL participated as a clinical investigator and/or received consultation and/or speaker fees from Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Pliva/Teva, Roche. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant and at advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics. HZ and KB are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors declare no competing interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that particularly affects people in their 30s. Oral disease-modifying therapy (DMT) offers a simple dosage form, good efficacy and safety. Dimethyl fumarate (DMF) is a frequently prescribed oral DMT medication worldwide. The aim of this study was to evaluate the impact of medication adherence on health outcomes in Slovenian persons with MS treated with DMF., Methods: Our retrospective cohort study included persons with relapsing-remitting MS on DMF treatment. The medication adherence was evaluated by AdhereR software package using the proportion of days covered (PDC) measure. The threshold was set at 90%. Health outcomes after treatment initiation were represented by relapse occurrence, disability progression and occurrence of active (new T2 and T1/Gadolinium (Gd) enhancing) lesions between first two outpatient visits and first two brain magnetic resonance imaging (MRI), respectively. For each health outcome a separate multivariable regression model was built., Results: The study included 164 patients. Their mean age (SD) was 36.7 (8.8) years, and the majority of patients were women (114 or 70%). Eighty-one patients were treatment naive. The mean (SD) PDC value was 0.942 (0.08) and 82% of patients were considered adherent above the 90% threshold. Older age (OR 1.06 per one year, P = 0.017, 95% CI (1.01-1.11)) and treatment naivety (OR 3.93, P = 0.004, 95% CI (1.64-10.4)) were related to higher adherence. In the 6-year follow-up period after DMF treatment initiation, 33 patients experienced a relapse. Among those, 19 required an emergency visit. Sixteen patients had a 1-point disability progression on the Expanded Disability Status Scale (EDSS) score between two consecutive outpatient visits. Thirty-seven patients were found to have active lesions between first and second brain MRI. Medication adherence showed no impact on relapse occurrence or disability progression. Lower medication adherence (10% lower PDC) was associated with higher occurrence of active lesions (OR 1.25, P=0.038, 95% CI: 1.01-1.56). Higher disability prior to DMF initiation was related to a higher risk for relapse occurrence and EDSS progression., Conclusion: Our study showed high medication adherence among Slovenian persons with relapse-remitting MS on DMF treatment. Higher adherence was associated with lower incidence of the radiological progression of MS. Interventions for improving medication adherence should be intended for younger patients with higher disability prior treatment with DMF and those switching from alternative DMTs., Competing Interests: Declaration of Competing Interest MJ: None declared IL: received consultation and/or speaker fees from: Novartis. GBJ: participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Janssen, Lek, Merck, Novartis, Pliva/Teva, Roche, Sanofi Genzyme, Swixx. MK: Research contracts with Krka, Vizera, Clinres, Phamalinea with the aim of statistical analysis and a grant from AstraZeneca as a support to developments of sustainability and resilience of the healthcare system after COVID-19 pandemic. UR: participated as a clinical investigator and/or received consultation and/or speaker fees from: Bayer, Biogen, Sanofi Genzyme, Merck, Novartis, Pliva/Teva, Roche., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Secondary progressive multiple sclerosis (SPMS) is a debilitating condition characterized by gradual worsening after an initial relapsing disease course. Despite the recent advances in our understanding of the disease, the diagnosis and treatment of SPMS continue to be challenging in routine clinical practice. The aim of this review article is to present the views of leading MS experts on the challenges in the diagnosis and management of SPMS and clinicians' perspectives in Central and Eastern Europe. This article also provides recommendations of MS experts to improve the situation with diagnosis and management of SPMS. Many countries within Central and Eastern Europe have high prevalence of MS (>100 per 100,000 population). Consistent with the global trend, in the absence of reliable tests or biomarkers, SPMS at early stage remains undiagnosed. Due to diagnostic uncertainty and lack of a universally accepted disease definition, clinicians rely more on retrospective analysis of the clinical symptoms to confirm the diagnosis. With the lack of awareness and poor understanding of the timing of the onset of SPMS, clinicians may tend to direct attention to relapses than the symptoms of progression, which leads to underestimation of SPMS. Although several predictors of progression to SPMS have been identified, their predictive value is highly variable. Therefore, defining the transitioning period as a separate stage of MS is essential. According to experts' opinion, frequent follow-up of patients and periodic assessment of progression are recommended for the timely identification of patients transitioning from RRMS to SPMS. MSProDiscuss Tool is an example of a quick assessment tool for identifying patients progressing from RRMS to SPMS. MS progression is usually assessed by changes in Expanded Disability Status Scale (EDSS) scores. As EDSS scores tend to fluctuate when measured in the short term (3-6 months), a longer period (≥12 months) may be needed to confirm the progression. Assessment of cognitive function is also important for evaluating secondary progression. Compartmentalization of inflammation within the central nervous system is an important reason behind the limited success of disease-modifying therapies (DMTs) for treating SPMS. Most of the DMTs fail to cross the blood-brain barrier; only 38% of the tested DMTs achieved their primary endpoint in SPMS. In Europe, siponimod is the first oral treatment for adults with active SPMS. Particularly, in Central and Eastern Europe, patients with SPMS are still being prescribed less efficacious DMTs and interferons. The absence of alternative treatments in SPMS supports the use of new products (siponimod and others); however the decision to initiate siponimod therapy in more severe patients (EDSS score of 7 or higher) should be individualized in consultation with the payers. The focus should be on early treatment initiation to delay disease progression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the effect of intravenous immunoglobulins (IVIG) on prevention of postpartum relapses in women with relapsing-remitting multiple sclerosis (RRMS)., Methods: This was a retrospective study performed in Ljubljana, Slovenia where the practice for all pregnant women with RRMS is to receive IVIG after the delivery (10 g monthly, during first 6 months after delivery) and in Zagreb, Croatia where no such practice exists. The following data were collected: date of delivery, maternal age at delivery, year of the RRMS diagnosis, EDSS, disease modifying therapy prior to pregnancy, relapses in the year prior, during and in the period of one year after pregnancy., Results: Data on 132 pregnancies from 112 women (mean age at delivery 31.70±4.10, average disease duration 6.34±4.33) were analyzed. There was no association between the IVIG treatment and annualized relapse rate one year after the delivery (0.27 vs 0.38, rate ratio 1.409, 95% CI 0.764-2.598, p = 0.272). No risk factors for the postpartum relapse were identified (age at delivery, duration of RRMS, EDSS prior pregnancy, disease modifying therapy prior pregnancy, relapses in the year prior pregnancy, IVIG)., Conclusion: This study provides no evidence of benefit for postpartum administration of IVIG in women with RRMS., (Copyright © 2019 Elsevier B.V. All rights reserved.)