Natalizumab promotes anti-inflammatory and repair effects in multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system leading to demyelination and axonal loss. Relapsing-remitting multiple sclerosis (RRMS) is commonly treated by anti-inflammatory drugs, where one of the most effective drugs to date is the monoclonal antibody natalizumab. METHODS: The cerebrospinal fluid (CSF) proteome was analyzed in 56 patients with RRMS before and after natalizumab treatment, using label-free mass spectrometry and a subset of the changed proteins were verified by parallel reaction monitoring in a new cohort of 20 patients, confirming the majority of observed changes. RESULTS: A total of 287 differentially abundant proteins were detected including (i) the decrease of proteins with roles in immunity, such as immunoglobulin heavy constant mu, chitinase-3-like protein 1 and chitotriosidase, (ii) an increase of proteins involved in metabolism, such as lactate dehydrogenase A and B and malate-dehydrogenase cytoplasmic, and (iii) an increase of proteins associated with the central nervous system, including lactadherin and amyloid precursor protein. Comparison with the CSF-PR database provided evidence that natalizumab counters protein changes commonly observed in RRMS. Furthermore, vitamin-D binding protein and apolipoprotein 1 and 2 were unchanged during treatment with natalizumab, implying that these may be involved in disease activity unaffected by natalizumab. CONCLUSIONS: Our study revealed that some of the previously suggested biomarkers for MS were affected by the natalizumab treatment while others were not. Proteins not previously suggested as biomarkers were also found affected by the treatment. In sum, the results provide new information on how the natalizumab treatment impacts the CSF proteome of MS patients, and points towards processes affected by the treatment. These findings ought to be explored further to disclose potential novel disease mechanisms and predict treatment responses.

Antiviral therapy with tenofovir in MS.

Infection by the Epstein-Barr virus (EBV) is implicated as the leading cause of multiple sclerosis (MS). We have previously published a case description of a person with MS (pwMS) who was also HIV positive and treated with a combination of antiretrovirals (ART) containing tenofovir, a potent inhibitor of EBV replication. In the years following this publication, the patient had no new relapses, even though she did not use any MS disease-modifying therapy for nearly five years. After switching to another ART with no known efficacy against EBV, her MS-disease activity gradually re-emerged. This finding further emphasizes that targeting EBV lytic reactivation should be explored further in clinical trials as a potential treatment option for MS.

Ocrelizumab and ofatumumab, but not rituximab, trigger complement induction in vitro.

The clinical and adverse effects of the therapeutic monoclonal antibodies (mAb) ocrelizumab, ofatumumab and rituximab in multiple sclerosis (MS) are presently subject to extensive study. While the two former are approved for MS, the older and less costly rituximab is used off label, and adverse effect profiles are important in their evaluation. The three mAbs all induce B cell depletion, with complement-dependent cytotoxicity (CDC) as one of several mechanisms of action. Complement activation is also postulated to underlie adverse reactions related to infusion/injection. Such administration-related reactions are associated with all three mAbs, but comparisons have so far been indirect, resting on incidence reports from separate clinical trials. The objective of this study was to perform head-to-head comparison of complement activation by ofatumumab, ocrelizumab and rituximab. In vitro experiments were performed in whole blood from healthy donors. The complement-activating potential of the three mAbs was analyzed after 30 min of exposure to 0.3 mg/mL or 0.9 mg/mL of each drug, and compared with those of the well-known TNF inhibitory mAbs adalimumab and infliximab, the latter with recognized potential for infusion reactions. Ofatumumab, ocrelizumab, and infliximab, but not rituximab and adalimumab, triggered statistically significant complement activation measured as increased levels of terminal C5b-9 complement complex (TCC), a sensitive marker of such activation. While results demand careful interpretation, they provide an indication of distinct complement-inducing potential among anti-CD20 mAbs currently used to treat MS.

Humoral response to Epstein-Barr virus in patients with multiple sclerosis treated with B cell depletion therapy.

BACKGROUND: B cell depletion therapy is highly effective in relapsing-remitting multiple sclerosis (RRMS). However, the precise underlying mechanisms of action for its biological effects in MS have still not been clarified. Epstein-Barr virus (EBV) is a known risk factor for MS and seems to be a prerequisite for disease development. EBV resides latently in the memory B cells, and may not only increase the risk of developing MS, but also contribute to disease activity and disability progression. Therefore, the effects of B cell depletion in MS could be associated with the depletion of EBV-infected cells and the altered immune response to the virus. In this study, we investigate the impact of B cell depletion on the humoral immune response specific to EBV in patients with MS. METHODS: Newly diagnosed, treatment-naïve patients with RRMS were followed up to 18 months after initiation of B-cell depletion therapy in the Overlord-MS study, a phase III trial (NCT04578639). We analyzed serum sampled before treatment and after 3, 6, 12 and 18 months for immunoglobulin γ (IgG) against Epstein-Barr nuclear antigen 1 (EBNA1) and Epstein-Barr viral capsid antigen (VCA). We analyzed antibodies to cytomegalovirus (CMV) and total IgG in serum, as controls for viral and overall humoral immunity. The risk allele, HLA-DRB1*15:01, and the protective allele, HLA-A*02:01, were determined in all participants. In addition, polymerase chain reaction (PCR) for circulating EBV-DNA was performed in the first 156 samples drawn. The associations between time on B cell-depletion therapy and serum anti-EBV antibody levels were estimated using linear mixed-effects models. RESULTS: A total of 290 serum samples from 99 patients were available for analysis. After 6, 12 and 18 months, the EBNA1 IgG levels decreased by 12.7 % (95 % CI -18.8 to -6.60, p < 0.001), 12.1 % (95 % CI -19.8 to -3.7, p = 0.006) and 14.6 % (95 % CI to -25.3 to -2.4, p = 0.02) respectively, compared to baseline level. Carriers of the HLA-DRB1*15:01 allele had higher EBNA1 IgG levels at baseline (p = 0.02). The VCA IgG levels significantly increased by 13.7 % (95 % CI 9.4 to 18.1, p < 0.001) after 3 months, compared to baseline, and persisted at this level throughout the follow-up. CMV IgG levels decreased, but to a lesser extent than the decrease of EBNA1 IgG, and total IgG levels decreased during therapy. Circulating EBV-DNA was found in only three of 156 samples from 64 patients. CONCLUSIONS: EBNA1 IgG levels decreased, while VCA IgG levels increased, during B cell depletion therapy. This supports the hypothesis that the mechanism of action for B cell depletion therapy might be mediated by effects on EBV infection, which, in turn, mitigate immune cross-reactivity and disease perpetuation.

Childbirth delivery mode and the risk of multiple sclerosis: a prospective population-based study.

BACKGROUND: Caesarean section (CS) may affect the risk of developing multiple sclerosis (MS) in the offspring, possibly through changes in gut microbiota composition, but findings from previous studies are inconsistent. We investigated whether birth by CS was associated with the risk of adult-onset MS. METHODS: We conducted a prospective population-based cohort study, including all individuals born in Norway between 1967 and 2003, using the Medical Birth Registry of Norway linked with the Norwegian Multiple Sclerosis Registry and Biobank. The follow-up was until 2021. We used multivariable Cox models to estimate HRs for MS risk with 95% CIs. RESULTS: Among 2 046 637 individuals in the cohort, 4954 MS cases were identified. Being born by CS was associated with a modest increase in MS risk (HR=1.18, 95% CI 1.05 to 1.32). In the sibling-matched analysis, we found no association between CS and MS risk. We found an interaction between CS and gestational age (p=0.03): CS was associated with an increased risk of MS in individuals born preterm (HR=1.62, 95% CI 1.18 to 2.24), whereas there was no association in individuals born at term (HR=1.13, 95% CI 0.99 to 1.27). In a subgroup analysis of individuals born in 1988 and onwards, emergency CS was related to an elevated MS risk (HR=1.40, 95% CI 1.07 to 1.83), whereas planned CS was not (HR: 1.10, 95% CI 0.77 to 1.58). CONCLUSIONS: CS was associated with a modestly higher risk of developing MS. However, the stronger associations seen in subgroups who likely experienced a more complicated pregnancy/delivery may point to confounding underlying these associations.

Microstructural changes precede depression in patients with relapsing-remitting Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis lesions in the brain and spinal cord can lead to different symptoms, including cognitive and mood changes. In this study we explore the temporal relationship between early microstructural changes in subcortical volumes and cognitive and emotional function in a longitudinal cohort study of patients with relapsing-remitting Multiple Sclerosis. METHODS: In vivo imaging in forty-six patients with relapsing-remitting Multiple Sclerosis was performed annually over 3 years magnetic resonance imaging. Microstructural changes were estimated in subcortical structures using the free water fraction, a diffusion-based MRI metric. In parallel, patients were assessed with the Hospital Anxiety and Depression Scale amongst other tests. Predictive structural equation modeling was set up to further explore the relationship between imaging and the assessment scores. In a general linear model analysis, the cohort was split into patients with higher and lower depression scores. RESULTS: Nearly all subcortical diffusion microstructure estimates at the baseline visit correlate with the depression score at the 2 years follow-up. The predictive nature of baseline free water estimates and depression subscores after 2 years are confirmed in the predictive structural equation modeling analysis with the thalamus showing the greatest effect size. The general linear model analysis shows patterns of MRI free water differences in the thalamus and amygdala/hippocampus area between participants with high and low depression score. CONCLUSIONS: Our data suggests a relationship between higher levels of free-water in the subcortical structures in an early stage of Multiple Sclerosis and depression symptoms at a later stage of the disease.

Signals between the brain and spinal cord are disrupted in people with Multiple Sclerosis. For those with relapsing-remitting Multiple Sclerosis (RRMS), symptoms get periodically better and worse over time. We looked at whether changes in the brain of people with RRMS were associated with changes in their mood over time. People who had more changes in certain areas of the brain at the start of the study were more likely to have symptoms of depression later. This work suggests that early changes in the brain may be linked to increased symptoms of depression over time in people with RRMS. We believe this could be an opportunity to provide care to those suffering from RRMS to lessen the impact of severe depression symptoms before they arise.

Predictors of hospitalization due to infection in rituximab-treated MS patients.

BACKGROUND: Rituximab is extensively used off-label to treat multiple sclerosis (MS), and long-term vigilance for adverse events is needed. This study was conducted to determine frequencies and predictors of hematological adverse events, including hypogammaglobulinemia, severe lymphopenia, neutropenia, and infections leading to hospitalization. METHODS: This retrospective cohort study included all patients with MS initiating rituximab treatment at Haukeland University Hospital between January 1st, 2017, and July 1st, 2021. Patients were followed by clinical monitoring and repeated blood sampling every six months. Clinical outcomes and laboratory results were retrieved from the Norwegian MS Registry and Biobank and the patient administrative system at Haukeland University Hospital. RESULTS: Five hundred and fifty-six patients were included, 515 with relapsing-remitting MS (RRMS) and 41 with progressive MS. Overall, 33 patients (5.9%) experienced 56 episodes of infections requiring hospital admission. Sixty patients (10.8%) had confirmed hypogammaglobulinemia, 17 (3.1%) had confirmed severe lymphopenia, and 10 (1.8%) had confirmed severe neutropenia. Predictors of infection requiring hospital admission were progressive MS (adjusted OR (aOR): 4.81; 95%CI: 1.25-18.48), duration of treatment with rituximab (aOR: 1.52; 95%CI: 1.11-2.09) and confirmed severe lymphopenia (aOR: 13.58; 95%CI: 3.41-54.06) and neutropenia (aOR: 13.40; 95%CI: 2.93-61.25). Of the hematological abnormalities, only hypogammaglobulinemia was associated with treatment duration (aOR: 1.35; 95%CI: 1.09-1.69). CONCLUSION: The risk of hospitalization due to infection is associated with time on rituximab treatment, in patients with lympho- or neutropenia, and in patients with primary progressive MS. We observed a time-dependent decline in IgG values, in contrast to neutrophil and lymphocyte count, suggesting a cumulative dose-dependent response. These predictors can assist clinicians in assessing and monitoring MS patients receiving rituximab.

Interferon ß1a treatment does not influence serum Epstein-Barr virus antibodies in patients with multiple sclerosis.

There is increasing evidence of Epstein-Barr virus (EBV) being conditional in multiple sclerosis (MS) pathogenesis and influential for disease activity. Interferon-beta (IFNß) is a cytokine with antiviral effects used to treat MS, in which a possible antiviral effect against EBV has been questioned. In this study, we investigated the effect of IFNß-1a treatment on serum EBV antibody levels in 84 patients with relapsing-remitting MS. In the 18 months following IFNß-1a treatment initiation, there were no significant associations between treatment and serum levels of Epstein-Barr nuclear antigen 1 (EBNA-1) immunoglobulin (Ig) G, early antigen (EA) IgG, viral capsid antigen (VCA) IgG or VCA IgM. The findings suggest that IFNß-1a treatment does not influence the humoral response to EBV in patients with MS.

Cancer related mortality in multiple sclerosis. A population based cohort study.

BACKGROUND: Cancer is a major cause of death, but how cancer influences mortality risk in Multiple Sclerosis (MS) is unclear. OBJECTIVES: Determine all-cause mortality and mortality following a cancer diagnosis among MS patients compared with matched population controls. METHODS: Norwegian MS patients born 1930 - 1979 (n= 6950) followed-up 1953 - 2016, were matched with 37 922 controls. We compared incident cancer diagnosis from the Cancer Registry of Norway, date of death from the Cause of Death Registry, education from the National Education Database, by multivariate Cox proportional hazard regression. RESULTS: Hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality among MS patients was 4.97 (4.64 - 5.33), and 2.61 (2.29 - 2.98) for mortality following a cancer diagnosis. Mortality in MS was highest following urinary- (2.53: 1.55 - 4.14), colorectal- (2.14: 1.47 - 3.11), hematological- (1.76: 1.08 - 2.88), ovarian - 2.30 (1.73-3.06) and breast cancer diagnosis (2.61: 1.85 - 3.68), compared to controls. High education was inversely associated with mortality among MS patients. CONCLUSIONS: All-cause mortality was five- fold and mortality following a cancer diagnosis was two- fold increased among MS patients. Mortality following specific cancers raises the possibility of diagnostic neglect.

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.

Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations.

INTRODUCTION: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic. OBJECTIVE: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS). METHODS: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects. RESULTS: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response. CONCLUSIONS: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations.

Breastfeeding and treatment for multiple sclerosis. / Amming og behandling av multippel sklerose.

Monoclonal antibody therapy is effective for multiple sclerosis, and only small amounts of antibodies are transferred to breast milk. Even though the approved product descriptions advise against breastfeeding during medicinal treatment, several of the most effective MS drugs are compatible with breastfeeding.

Mortality and cause of death in multiple sclerosis in western Norway 1950-2021: a registry-based linkage study.

BACKGROUND: Persons with multiple sclerosis (pwMS) have higher risk of mortality compared with the general population. Longitudinal studies are important for understanding the evolution of survival in pwMS. OBJECTIVE: Examine changes in mortality among pwMS during the past seven decades. METHODS: We followed pwMS from Hordaland and Møre and Romsdal in Western Norway, with disease onset from before 1950, identified from population-based epidemiological surveys and the Norwegian MS Registry and Biobank, until 1 January 2021. Data were linked to the Norwegian Cause of Death Registry to obtain underlying cause of death. We examined all-cause, and cause-specific mortality using standardised mortality ratios (SMR) and excess death rates (EDR). We calculated life expectancies and assessed survival stratified by sex, age and disease phenotype at onset. We compared hazard ratios (HRs) for mortality, in pwMS diagnosed before and after the era of disease-modifying treatment (DMT). RESULTS: Of 3624 pwMS, 964 (55.5% women) had died, predominantly of multiple sclerosis (49.0%). Median life expectancy for pwMS was 74.3 years (95% CI 73.3 to 75.3), compared with 83.1 years for the general population (p<0.001). From disease onset, pwMS survived 14.6 years shorter than the general population (p<0.001). Overall, SMR was 2.3 (95% CI 2.13 to 2.42) and EDR was 6.8 (95% CI 6.42 to 7.09) for pwMS. Treatment-eligible pwMS diagnosed in the DMT era had the lowest risk of mortality, HR 0.49 (95% CI 0.34 to 0.70,p<0.001). CONCLUSION: Excess mortality among pwMS declined during the past seven decades, possibly due to improved diagnostics, better symptomatic treatment and access to DMTs.

Ocrelizumab quantitation by liquid chromatography-tandem mass spectrometry.

Introduction: Ocrelizumab is a monoclonal anti-CD20 antibody approved for the treatment of multiple sclerosis (MS). The clinical value of therapeutic drug monitoring (TDM) for this antibody in treatment of MS is unknown, and an adequately specific and precise quantitation method for ocrelizumab in patient serum could facilitate investigation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based quantitation methods have been shown to have higher analytic specificity and precision than enzyme-linked immunosorbent assays. Objectives: To establish and validate an LC-MS/MS-based quantitation method for ocrelizumab. Methods: We present an LC-MS/MS-based quantitation method using immunocapture purification followed by trypsinization and analysis by a triple quadrupole mass analyzer obtaining results within the same day. Results: We found that the ocrelizumab peptide GLEWVGAIYPGNGDTSYNQK (Q1/Q3 Quantifier ion: 723.683+/590.77 y112+ Qualifier ion: 723.683+/672.30 y122+) can be used for quantitation and thereby developed a method for quantifying ocrelizumab in human serum with a quantitation range of 1.56 to 200 µg/mL. The method was validated in accordance with EMA requirements in terms of selectivity, carry-over, lower limit of quantitation, calibration curve, accuracy, precision and matrix effect. Ocrelizumab serum concentrations were measured in three MS patients treated with ocrelizumab, immediately before and after ocrelizumab infusion, with additional sampling after 2, 4, 8 and 12 weeks. Measured serum concentrations of ocrelizumab showed expected values for both Cmax and drug half-life over the sampled time period. Conclusion: We have established a reliable quantitation method for serum ocrelizumab that can be applied in clinical studies, facilitating the evaluation of ocrelizumab TDM in 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.

Abuse and revictimization in adulthood in multiple sclerosis: a cross-sectional study during pregnancy.

BACKGROUND: Knowledge concerning exposure to abuse in adulthood and in pregnancy in people with multiple sclerosis (MS) is sparse. OBJECTIVE: To determine the occurrence of adult abuse and abuse in relation to pregnancy in women with MS and their risk of revictimization (repeated abuse as adults after childhood abuse). METHODS: This cross-sectional study comprised pregnant women from the Norwegian Mother, Father and Child Cohort study. Information on abuse was acquired through self-completed questionnaires. We used logistic regression to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: We identified 106 women with MS at enrollment through linkage with national health registries. The reference group consisted of 77,278 women without MS. Twenty-seven women (26%) with MS reported any adult abuse compared to 15,491 women (20%) without MS, aOR 1.33 (0.85-2.09). Twenty-two (21%) women with MS reported systematic emotional abuse compared to 13% without MS, aOR 1.75 (1.08-2.83). Ten women (10%) with MS reported sexual abuse, compared to 6% without MS, aOR 1.72 (0.89-3.33). More women with MS reported rape as an adult, aOR 2.37 (1.02-5.49). Women with MS had higher risk of revictimization as adults, after childhood abuse, aOR 2.23 (1.22-4.10). The risk of abuse during pregnancy or 6 months preceding pregnancy was similar between the groups. CONCLUSIONS: Women with MS had increased occurrence of systematic emotional abuse, rape, and revictimization as adults, compared to women without MS.

Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study.

BACKGROUND: The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. OBJECTIVE: Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. METHODS: 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. RESULTS: Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (ß=-0.399, p=0.040) and deep (ß=-0.556, p=0.010) GM volume, lower mean cortical thickness (ß=-0.581, p=0.010) and higher T2 lesion count (ß=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (ß=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. CONCLUSION: Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.

The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS). METHODS: We included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status. RESULTS: After 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (ß = -21.74, p = 0.039) and higher logT2 lesion volume (ß = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (ß = -2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (ß = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (ß = -3.58, p = 0.029). DISCUSSION: Smoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression.

Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis.

BACKGROUND: A sudden onset of extensive disease activity, including severe clinical relapse and extensive brain or spinal magnetic resonance imaging (MRI) lesions, termed "rebound" disease activity has been reported after withdrawal of fingolimod in patients with multiple sclerosis (MS). OBJECTIVE: To compare the risk of rebound after switching from fingolimod to cladribine or rituximab in MS. METHODS: All patients switching from fingolimod to cladribine or rituximab were included in a retrospective cohort study utilizing prospectively collected data from two university hospitals with different treatment strategies. RESULTS: A total of 73 patients with at least 6 months follow-up after switching were identified, 33 patients had switched from fingolimod to cladribine and 40 patients to rituximab. No patients in the rituximab group and seven (21.1%) in the cladribine group qualified for rebound disease activity. Ten (30.3%) of the patients using cladribine and five (12.5%) of the patients using rituximab experienced a relapse. MRI disease activity was seen in 18 (54.5%) and eight (20.0%) of the patients using cladribine and rituximab, respectively. Younger age and previous high relapse rate were associated with increased risk of rebound in the cladribine group. CONCLUSIONS: We identify a lower risk of rebound during the first year after switching from fingolimod to rituximab compared to cladribine, indicating a better initial clinical outcome with the former treatment strategy.