NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study

Background Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilament and longterm outcome in MS (NaloMS) cohort. Methods The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204). Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated. Findings During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs. 7.2 pg/ml (4.5-12.5), p<0.017). In a multivariable logistic regression model, increased sNfL levels at BL (Odds Ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04, p=0.012) remained an independent risk factor for RFP and predicted individual RFP risk with an accuracy of 82% (NaloMS) and 83% (validation cohort) as revealed by support vector machine. In addition, the sNfL FU/BL ratio was increased in SPMS-converters (1.16 (0.89-1.70) vs. 0.96 (0.75-1.23), p=0.011). This was confirmed by a multivariable logistic regression model, as sNfL FU/BL ratio remained in the model (OR 1.476, 95%CI 1.078-2,019, p=0.015) and individual sNfL FU/BL ratios showed a predictive accuracy of 72% in NaloMS (63% in the validation cohort) as revealed by machine learning. Interpretation sNfL levels at baseline predict relapse-free disability progression in a prospective longitudinal cohort study 6 years later. While prediction was confirmed in an independent cohort, sNfL further discriminates patients with SPMS at follow-up and supports early identification of patients at risk for later SPMS conversion. Funding This work was supported by the German Research Council (CRC-TR-128), Else Kröner Fresenius Foundation and Hertie-Stiftung

Anti-EBNA1 IgG titre is not associated with fatigue in multiple sclerosis patients

Introduction. Fatigue is the most frequent symptom in multiple sclerosis (MS), although it is still poorly understood due to its complexity and subjective nature. There is an urgent need to identify reliable biomarkers to improve disease prognosis and therapeutic strategies. Epstein-Barr virus (EBV) is the major environmental risk factor associated with MS aetiology, and trials with EBV-targeted T cell therapies have reduced fatigue severity in MS patients. Aim of the study. We investigated whether the serum amount of immunoglobulin (Ig)G-specific for EBV antigens could be a suitable prognostic marker for the assessment of MS-related fatigue. Material and methods. A total of 194 MS patients were enrolled. We quantified EBV nuclear antigen 1 (EBNA1) and EBV viral capsid antigen (VCA) immunoglobulin (Ig) G levels and B cell-activating factor of the tumour necrosis factor family (BAFF) concentration in the serum of patients with relapsing-remitting MS (RRMS) and chronic progressive MS (CPMS), and we analysed their correlation with aspects of fatigue and other clinical disease parameters. Results. A complete EBV seropositivity could be detected in our cohort. After adjusting for confounding variables and covariates, neither EBNA1 nor VCA antibody titres were associated with levels of fatigue, sleepiness, depression, or with any of the clinical values such as expanded disability status scale, lesion count, annual relapse rate, or disease duration. However, patients with RRMS had significantly higher EBNA1 IgG titre than those with CPMS, whereas this was not the case under therapies targeting CD20+ cells. BAFF levels in serum were inversely proportional to anti-EBNA1 IgG. Conclusions and clinical implications. Our results show that EBNA1 IgG titre is not associated with the presence or level of fatigue. Whether the increased EBNA1 titre in RRMS plays a direct role in disease progression, or is only a consequence of excessive B cell activation, remains to be answered in future studies

Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis

BACKGROUND: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing–remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. METHODS: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. RESULTS: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. CONCLUSION: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s42466-022-00219-3

Absence of Regulatory T Cells Causes Phenotypic and Functional Switch in Murine Peritoneal Macrophages

Tissue macrophages are important components of tissue homeostasis and inflammatory pathologies. In the peritoneal cavity, resident macrophages interact with a variety of immune cells and can exhibit broad range of phenotypes and functions. Forkhead-box-P3 (FOXP3)+ regulatory T cells (Tregs) play an indispensable role in maintaining immunological tolerance, yet whether, and how the pathological condition that results from the lack of functional Tregs affects peritoneal macrophages (PM) is largely unknown. We used FOXP3-deficient scurfy (Sf) mice to investigate PM behavior in terms of the missing crosstalk with Tregs. Here, we report that Treg deficiency induced a marked increase in PM numbers, which was reversed after adoptive transfer of CD4+ T cells or neutralization of macrophage colony-stimulating factor. Ex vivo assays demonstrated a pro-inflammatory state of PM from Sf mice and signs of excessive activation and exhaustion. In-depth immunophenotyping of Sf PM using single-cell chipcytometry and transcriptome analysis revealed upregulation of molecules involved in the initiation of innate and adaptive immune responses. Moreover, upon transfer to non-inflammatory environment or after injection of CD4+ T cells, PM from Sf mice reprogramed their functional phenotype, indicating remarkable plasticity. Interestingly, frequencies, and immune polarization of large and small PM subsets were dramatically changed in the FOXP3-deficient mice, suggesting distinct origin and specialized function of these subsets in inflammatory conditions. Our findings demonstrate the significant impact of Tregs in shaping PM identity and dynamics. A better understanding of PM function in the Sf mouse model may have clinical implication for the treatment of immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and other forms of immune-mediated enteropathies

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment. By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients. Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME

Immunotherapies in chronic adhesive arachnoiditis - A case series and literature review

Chronic spinal adhesive arachnoiditis (CSAA) is a rare condition with limited therapeutic options. Surgical treatment proves effective in approximately 60% of cases. Conservative treatment options have not been extensively investigated. Here, we report the course of the disease, analyze the effect of immune treatments in patients with CSAA who were treated in the University Hospital Essen between 2015 and 2020, and conduct a literature review. Three out of four patients showed no improvement after treatment with corticosteroids, methotrexate, or plasmapheresis. All non-responders suffered from CSAA for several years, while one patient who had a disease duration of less than one month fully recovered. It is necessary to verify whether treatment at an early stage of the disease is better than treatment after chronic adhesion manifestation, as it interrupts the development of adhesions and all subsequent complications

Disease Activity and Conversion into Multiple Sclerosis after Optic Neuritis Is Treated with Erythropoietin

Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU of recombinant human erythropoietin (IV) daily for three days, or a placebo, as an add-on to methylprednisolone. Of 35 patients, we investigated changes in cerebral lesion load in MRIs obtained at baseline and at weeks 4, 8, and 16. In 5 of the 35 patients, we found conversion into multiple sclerosis (MS) based on MRI progression only. These five patients had received the placebo. Another five patients showed MRI progression together with relapses. Three of these patients had received erythropoietin, and two the placebo. Yet, analyzing the change in absolute numbers of periventricular, juxtacortical, and infratentorial lesions including gadolinium-enhancing lesions, there were no significant differences between the groups. Although effective in terms of retinal nerve fiber layer protection, erythropoietin treatment of acute isolated optic neuritis did not influence further evolution of MRI lesions in the brain when comparing absolute numbers. However, early conversion from clinically isolated syndrome to MS assessed by MRI activity seemed to occur more frequently in the placebo-treated group