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Background: Predictive and prognostic biomarkers for multiple sclerosis (MS) remain a significant gap in MS diagnosis and treatment monitoring. Currently, there are no timely markers to diagnose the transition to secondary progressive MS (SPMS)., Objective: This study aims to evaluate the discriminatory potential of the High temperature requirement serine protease (HTRA1)/Macrophage migration inhibitory factor (MIF) cerebrospinal fluid (CSF) ratio in distinguishing relapsing-remitting (RRMS) patients from SPMS patients., Methods: The MIF and HTRA1 CSF levels were determined using ELISA in healthy controls (n = 23), RRMS patients before (n = 22) and after 1 year of dimethyl fumarate treatment (n = 11), as well as in SPMS patients before (n = 11) and after 2 years of mitoxantrone treatment (n = 7). The ability of the HTRA1/MIF ratio to discriminate the different groups was determined using receiver operating curve (ROC) analyses., Results: The ratio was significantly increased in treatment naïve RRMS patients while decreased again in SPMS patients at baseline. Systemic administrated disease modifying treatment (DMT) only significantly affected the ratio in RRMS patients. ROC analysis demonstrated that the ratio could discriminate treatment naïve RRMS patients from SPMS patients with 91% sensitivity and 100% specificity., Conclusion: The HTRA1/MIF ratio is a strong candidate as a MS biomarker for SPMS conversion., Competing Interests: Declaration of competing interest MZ, ÅFS, EB, MA, LN, SH declare that they have no competing interest. ZI and JL have served on scientific advisory boards, as a consultant, received support for conference participation, received speaker honoraria, and as a member of Clinical Endpoint Committee of phase 3 trials. They have both received research support from companies as Biogen, Merck-Serono, Sanofi-Genzyme, Novartis, Roche, Bristol-Myers-Squibb and Alexion. TS has received honoraria for lectures and advisory boards from several of the companies mentioned above., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: While kappa free light chain (KFLC) index has become a useful diagnostic biomarker in multiple sclerosis (MS), its prognostic properties are less explored. B cells play a crucial role in MS pathogenesis, but the impact from increased intrathecal production of immunoglobulins and KFLC remains to be determined. Recently, it has become evident that insidious worsening is not confined to progressive MS but is also common in relapsing-remitting MS (RRMS), a feature known as progression independent of relapse activity (PIRA)., Methods: We retrospectively identified 131 patients with clinically isolated syndrome or early RRMS who had determined KFLC index as part of their diagnostic workup. Demographic and clinical data were extracted from the Swedish MS registry. Associations of baseline KFLC index with evidence of disease activity (EDA) and PIRA were investigated in multivariable cox proportional hazards regression models., Results: KFLC index was significantly higher in PIRA (median 148.5, interquartile range [IQR] 106.9-253.5) compared with non-PIRA (78.26, IQR 28.93-186.5, p = 0.009). In a multivariable cox regression model adjusted for confounders, KFLC index emerged as an independent risk factor for PIRA (adjusted hazard ratio [aHR] 1.005, 95% confidence interval [CI] 1.002-1.008, p = 0.002). Dichotomized by the cut-off value KFLC index > 100, patients with KFLC index > 100 had an almost fourfold increase in the risk for developing PIRA. KFLC index was also predictive of evidence of disease activity during follow-up., Conclusions: Our data indicate that high KFLC index at baseline is predictive of PIRA, EDA-3, and overall worse prognosis in MS., (© 2023. The Author(s).)

Background: Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system. The glycosphingolipid sulfatide, a lipid particularly enriched in the myelin sheath, has been shown to be involved the maintenance of this specific membrane structure. Sulfatide in cerebrospinal fluid (CSF) may reflect demyelination, a dominating feature of MS. We investigated the diagnostic utility of CSF sulfatide isoform levels to separate different courses or phenotypes of MS disease., Material and Methods: This was a mono-center, cross-sectional study of relapsing-remitting MS (RRMS) (n = 45) and progressive MS (PMS) (n = 42) patients (consisting of primary PMS (n = 17) and secondary PMS (n = 25)) and healthy controls (n = 19). In total, 20 sulfatide isoforms were measured in CSF by liquid chromatography-mass spectrometry., Results: CSF total sulfatide concentrations, as well as CSF sulfatide isoform distribution, did not differ across the study groups, and their levels were independent of disease course/phenotype, disease duration, time to conversion to secondary PMS, age, and disability in MS patients., Conclusion: CSF sulfatide isoforms lack diagnostic and prognostic utility as a biomarker for progressive MS., Competing Interests: Declaration of Competing Interest JL reported receiving honoraria for lectures and for advisory boards from Biogen, Novartis, Merck, Alexion, Roche, Sanofi, and BMS; and unconditional grants from Biogen and Novartis; and is serving on the editorial board of the Acta Neurologica Scandinavica outside the submitted work. LN has received honoraria for lectures from Biogen, Novartis, Teva and Merck, and for advisory boards from Merck, Janssen and Sanofi. MS, EB, MA, JB, IR, SC and MB report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS)., Objectives: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue., Methods: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database., Results: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly lower in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia., Conclusion: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease., Objective: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue., Methods: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map., Results: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons., Conclusion: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Cerebrospinal fluid (CSF) levels of neurofilament light (NFL), a biomarker of axonal damage, and CXCL13, a chemokine involved in B-cell regulation, are both associated with disease activity in multiple sclerosis (MS)., Objective: To explore the potential of NFL and CXCL13 to detect residual disease activity in patients with no signs of clinical or ongoing radiological activity and to study the clinical relevance of such activity., Methods: NFL and CXCL13 concentrations were determined with ELISA in CSF obtained from 90 relapsing-remitting (RR) MS and 47 Progressive (Pr) MS (including primary and secondary PrMS) at baseline and after 12 months of follow-up. The patients were assessed at baseline, before initiating or switching disease modifying therapy (DMT) and again after 12 and 27 months of follow-up., Results: All patients with ongoing disease activity (relapse or contrast-enhancing lesions on MRI) had increased NFL or CXCL13. The proportion of RRMS and PrMS patients without ongoing disease activity with elevation of either NFL or CXCL13 (residual disease activity) was 39% and 50%, respectively, and both were increased in 11% and 16%, respectively. The treatment with DMTs decreased the proportion with residual disease activity in both RRMS and PrMS significantly. We could not show any significant association between residual disease activity and clinical or MRI measures at 12 or 27 months of follow-up., Conclusions: Although most of this real-world study population had been treated with second-line DMTs and achieved clinical and radiological stability, a significant proportion of patients still displayed increased CSF levels of both NFL and CXCL13, indicating residual disease activity. Thus, these markers seemed considerably more sensitive to disease activity than clinical and MRI measures. However, the long-term clinical significance of such activity remains to be determined., (Copyright © 2020. Published by Elsevier B.V.)

Neurodegeneration in multiple sclerosis (MS) correlates with disease progression and reparative processes may be triggered. Growth-associated protein 43 (GAP-43) exhibits induced expression during axonal growth and reduced expression during MS progression. We aimed to evaluate if GAP-43 can serve as a biomarker of regeneration in relapsing-remitting MS (RRMS) and whether disease-modifying therapies (DMTs) influence GAP-43 concentration in cerebrospinal fluid (CSF). GAP-43 was measured using an enzyme-linked immunosorbent assay in 105 MS patients (73 RRMS, 12 primary progressive MS, 20 secondary progressive MS) and 23 healthy controls (HCs). In 35 of the patients, lumbar puncture, clinical assessment, and magnetic resonance imaging was performed before initiation of therapeutic intervention, and at follow-up. CSF GAP-43 concentration was significantly lower in progressive MS compared with HCs (p = 0.004) and RRMS (p =  < 0.001) and correlated negatively with disability (p = 0.026). However, DMTs did not alter CSF GAP-43. Interestingly, in RRMS CSF GAP-43 levels were higher in patients with signs of active inflammatory disease than in patients in remission (p = 0.042). According to CSF GAP-43 concentrations, regeneration seems reduced in progressive MS, increased during disease activity in RRMS but is unaffected by treatment of highly active DMTs.

Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS)., Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded., Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected., Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS., Classification of Evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective., (© 2016 American Academy of Neurology.)

Background: Microglia-mediated proteolysis of the triggering receptor expressed on myeloid cells-2 (TREM-2) produces soluble TREM-2 (sTREM-2) that can be measured in cerebrospinal fluid (CSF) samples. Loss-of-function mutations in TREM2 or in the gene encoding its adaptor protein cause the rare Nasu-Hakola disease (NHD). Multiple sclerosis (MS) is an autoimmune disease that in common with NHD is characterized by demyelination and microglial activation., Objective: To investigate the potential utility of sTREM-2 as a biomarker for MS and to follow treatment effects., Methods: sTREM-2 was analyzed in CSF samples from subjects with MS (N = 59); relapsing-remitting MS (RRMS) (N = 36), secondary progressive MS (SPMS) (N = 20) and primary progressive MS (PPMS) (N = 3), and controls (N = 27). CSF levels of sTREM-2 were also assessed before and after treatment of patients with natalizumab or mitoxantrone., Results: CSF levels of sTREM-2 were significantly increased in patients with RRMS, SPMS, and PPMS compared with controls. After natalizumab treatment, the levels of sTREM-2 were normalized to control levels. The levels of sTREM-2 were also reduced after mitoxantrone treatment., Conclusion: Increased CSF levels of sTREM-2, a new marker of microglial activation, in MS and normalization upon treatment with either natalizumab or mitoxantrone support a role for microglial activation in active MS., (© The Author(s), 2016.)