Neurofilament light chain as a biomarker in multiple sclerosis

Due to the unpredictable course and heterogenous treatment response in multiple sclerosis (MS), there is a clear need for biomarkers that reflect disease activity in the clinical follow-up of these patients. Neurofilaments are neuron-specific components of the cytoskeleton that can be assayed in different body compartments. They have been explored as potential biomarkers for many years. Neurofilament light chain (NF-L) appears the most promising biomarker in MS patients, and there is now little doubt that NF-L should have a role in the follow-up of MS patients. Newer assays and techniques for NF-L detection available in serum samples confirms the usefulness of NF-L as a biomarker. Nevertheless, there is still a need for prospective studies, and studies to determine clinical useful cut-off values. This review evaluates the strengths and weaknesses of NF-L as a biomarker in patients with MS.publishedVersio

Wearing-off at the end of natalizumab dosing interval and risk of MS disease activity: A prospective 1-year follow-up study

Natalizumab effectively prevents disease activity in relapsing-remitting multiple sclerosis by binding α4 integrin and inhibiting leukocyte migration to the central nervous system. We recently reported an association between low natalizumab receptor occupancy and subjective wearing-off symptoms at the end of the 4-week dosing interval. Here, we aimed to evaluate the short-term risk of disease activity in a 1-year prospective follow-up of the same patient cohort (n = 40). We found that all patients available for follow-up after one year (n = 35) fulfilled the criteria for no evidence of disease activity (NEDA). Thus, wearing-off symptoms were not associated with increased short-term risk of disease activity. Longer follow-up in a larger patient cohort is required to establish whether therapeutic efficacy is maintained in patients with wearing-off symptoms.publishedVersio

Neurofilament Light Chain as a Biomarker in Multiple Sclerosis

Due to the unpredictable course and heterogenous treatment response in multiple sclerosis (MS), there is a clear need for biomarkers that reflect disease activity in the clinical follow-up of these patients. Neurofilaments are neuron-specific components of the cytoskeleton that can be assayed in different body compartments. They have been explored as potential biomarkers for many years. Neurofilament light chain (NF-L) appears the most promising biomarker in MS patients, and there is now little doubt that NF-L should have a role in the follow-up of MS patients. Newer assays and techniques for NF-L detection available in serum samples confirms the usefulness of NF-L as a biomarker. Nevertheless, there is still a need for prospective studies, and studies to determine clinical useful cut-off values. This review evaluates the strengths and weaknesses of NF-L as a biomarker in patients with MS

Safety of breast feeding during rituximab treatment in multiple sclerosis

Background There are limited data on the safety of breast feeding during rituximab therapy. Our objective is to determine exposure from breast feeding and biological effects of rituximab in breastfed infants. Methods In our case series of six mother–infant pairs, the nursing mothers with relapsing-remitting multiple sclerosis received rituximab during breast feeding. As part of clinical follow-up, six serial breast milk samples, and blood samples from both mothers and infants, were collected and analysed. Results The median average rituximab concentration (Cavg) in breast milk was 0.04 µg/mL and the estimated relative infant dose (RID) was 0.07%. The highest measured concentration of rituximab in the breast milk samples was 0.25 µg/mL, giving an estimated RID of 0.26%. All infant serum rituximab concentrations were below 0.01 µg/mL. The CD19 +B cell count values were within the 10th– 90th percentiles of reported normal ranges in healthy infants. Conclusions We found minimal transfer of rituximab into breast milk and could not reliably detect levels of rituximab in infant serum. B cell counts in infants were unaffected.publishedVersio

Comorbidity in multiple sclerosis patients from Nordland County, Norway - validated data from the Norwegian Patient Registry

Postponed access: the file will be available after 2021-12-21Background: Knowledge of comorbid disorders is important to optimize therapy for multiple sclerosis (MS), but data are limited. The aim of this study was to assess comorbidity in persons with MS living in Nordland County on January 1, 2017. Methods: Data were retrieved from the Norwegian Patient Registry (2008-2017) and validated through review of electronic hospital charts (1970-2017). Comorbidity was defined as any distinct disorder, classified in the International Classification of Diseases (ICD-10), that had existed or occurred after the diagnosis of MS was established. Results: Data from 637 subjects were reviewed, and 97.5% were registered with at least one comorbid condition. Malignant melanoma was found in 0.5%, and non-melanoma skin cancers in 1.9%. In female subjects, breast cancer was found in 3.3%. Hypothyroidism was confirmed in 3.1%, type-1 diabetes in 0.3%, type-2 diabetes in 3.9%, psychosis in 0.6%, epilepsy in 2.8%, myocardial infarction in 1.7%, subarachnoid hemorrhage in 0.2%, cerebral infarction in 0.6%, pulmonary embolism in 0.9%, inflammatory bowel disease in 1.3%, and rheumatoid arthritis in 0.6%. Conclusion: Compared to reports from other Norwegian epidemiological studies, a higher proportion of inflammatory bowel disease and epilepsy was found. This is in accordance with findings from other studies. The prevalence of non-melanoma skin cancers was significantly higher than in the general Norwegian population as they were reported by The Cancer Registry of Norway.acceptedVersio

Brief international cognitive assessment for MS (BICAMS) and global brain volumes in early stages of MS – A longitudinal correlation study

Background Cognitive impairment is common in patients with multiple sclerosis, even in the early stages of the disease. The Brief International Cognitive Assessment for multiple sclerosis (BICAMS) is a short screening tool developed to assess cognitive function in everyday clinical practice. Objective To investigate associations between volumetric brain measures derived from a magnetic resonance imaging (MRI) examination and performance on BICAMS subtests in early stages of multiple sclerosis (MS). Methods BICAMS was used to assess cognitive function in 49 MS patients at baseline and after one and two years. The patients were separated into two groups (with or without cognitive impairment) based on their performances on BICAMSs subtests. MRI data were analysed by a software tool (MSMetrix), yielding normalized measures of global brain volumes and lesion volumes. Associations between cognitive tests and brain MRI measures were analysed by running correlation analyses, and differences between subgroups and changes over time with independent and paired samples tests, respectively. Results The strongest baseline correlations were found between the BICAMS subtests and normalized whole brain volume (NBV) and grey matter volume (NGV); processing speed r = 0.54/r = 0.48, verbal memory r = 0.49/ r = 0.42, visual memory r = 0.48 /r = 0.39. Only the verbal memory test had significant correlations with T2 and T1 lesion volumes (LV) at both time points; T2LV r = 0.39, T1LV r = 0.38. There were significant loss of grey matter and white matter volume overall (NGV p<0.001, NWV p = 0.003), as well as an increase in T1LV (p = 0.013). The longitudinally defined confirmed cognitively impaired (CCI) and preserved (CCP) patients showed significant group differences on all MRI volume measures at both time points, except for NWV. Only the CCI subgroup showed significant white matter atrophy (p = 0.006) and increase in T2LV (p = 0.029). Conclusions The present study found strong correlations between whole brain and grey matter volumes and performance on the BICAMS subtests as well as significant changes in global volumes from baseline to follow-up with clear differences between patients defined as cognitively impaired and preserved at both baseline and follow-up.publishedVersio

Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis – A cohort study

Background Rituximab is increasingly used as off-label therapy in multiple sclerosis (MS). More data are needed on safety and efficacy of rituximab, particularly in cohorts of de novo patients and patients in early therapy escalation. Objective To investigate the safety and efficacy of off-label treatment with rituximab in an MS-cohort of predominantly de novo patients or as therapy escalation. Methods We retrieved safety and efficacy data from the Norwegian MS-registry and biobank for all MS-patients treated with rituximab at Haukeland University Hospital, Bergen, Norway, during a four year period. Results In the 365 MS-patients (320 relapsing-remitting MS (RRMS), 23 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS)), the overall annualized relapse rate (ARR) was 0.03 and annualized drug discontinuation rate (ADDR) was 0.05. NEDA-3 was achived in 79% of patients with available data (n=351). Sixty-one patients experienced infusion-related adverse events of which two were serious (CTCAE grade 3–4). Eighteen patients experienced serious non-infusion related adverse events, of which 16 were infections. Infections (n = 34; 9.3%, CTCAE grade 2-5), hypogammaglobulinemia (n = 19, 5.2%) and neutropenia (n = 16; 4.4%) were the most common non-infusion-related adverse events. Conclusion Rituximab was a safe and highly efficient disease modifying therapy in this cohort of MS-patients; however, infections and neutropenia need to be monitored.publishedVersio

Strong tuberculin response after BCG vaccination is associated with low multiple sclerosis risk: a population-based cohort study

Background: Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette–Guerin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk. Methods: Using data from a Norwegian tuberculosis screening programme (1963–1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship. Results: Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76–0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST. Conclusion: A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades.publishedVersio

CSF neurofilament light chain predicts 10-year clinical and radiologic worsening in multiple sclerosis

Background Neurofilament light chain (NfL) is an attractive biomarker of disease activity and progression in MS, but there is a lack in long-term prognostic data. Objective To test the long-term clinical and radiological prognostic value of cerebrospinal fluid (CSF)-NfL among newly diagnosed patients with MS. Methods Newly diagnosed MS patients where followed prospectively with baseline CSF-NfL and repeated MRI and clinical assessments for up to 10 years. Associations between baseline CSF-NfL and longitudinal MRI and clinical assessments were found by Generalized Estimating Equations analysis. Results Forty-two participants were included. CSF-NfL at baseline was significantly associated with the rate of atrophy in globus pallidus (p = 0.009) and hippocampus (p = 0.001) as evaluated by MRI. Baseline volumes of thalamus (β −0.33; 95% CI −0.57 to −0.10, p = 0.006), T1 (β 0.28; 95% CI 0.11 to 0.44, p = 0.001) and T2 (β 0.16; 95% CI 0.04 to 0.27, p = 0.008) lesions and baseline levels of CSF-NfL (β 0.9; 95% CI 0.3 to 1.5, p = 0.002) significantly predicted EDSS worsening over 10 years. Baseline CSF-NfL gave a comparable prediction to the best MRI volumetric predictors. Conclusion CSF-NfL predicted the clinical and radiological course of newly diagnosed patients with MS over a 10-year period, underlining its prognostic role.publishedVersio

Brain atrophy and clinical characteristics predicting SDMT performance in multiple sclerosis: A 10-year follow-up study

Objectives To identify Magnetic Resonance Imaging (MRI), clinical and demographic biomarkers predictive of worsening information processing speed (IPS) as measured by Symbol Digit Modalities Test (SDMT). Methods Demographic, clinical data and 1.5 T MRI scans were collected in 76 patients at time of inclusion, and after 5 and 10 years. Global and tissue-specific volumes were calculated at each time point. For the primary outcome of analysis, SDMT was used. Results Worsening SDMT at 5-year follow-up was predicted by baseline age, Expanded Disability Status Scale (EDSS), SDMT, whole brain volume (WBV) and T2 lesion volume (LV), explaining 30.2% of the variance of SDMT. At 10-year follow-up, age, EDSS, grey matter volume (GMV) and T1 LV explained 39.4% of the variance of SDMT change. Conclusion This longitudinal study shows that baseline MRI-markers, demographic and clinical data can help predict worsening IPS. Identification of patients at risk of IPS decline is of importance as follow-up, treatment and rehabilitation can be optimized.publishedVersio