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

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

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.publishedVersio

Deep Gray Matter Demyelination Detected by Magnetization Transfer Ratio in the Cuprizone Model

Abstract In multiple sclerosis (MS), the correlation between lesion load on conventional magnetic resonance imaging (MRI) and clinical disability is weak. This clinico-radiological paradox might partly be due to the low sensitivity of conventional MRI to detect gray matter demyelination. Magnetization transfer ratio (MTR) has previously been shown to detect white matter demyelination in mice. In this study, we investigated whether MTR can detect gray matter demyelination in cuprizone exposed mice. A total of 54 female C57BL/6 mice were split into one control group () and eight cuprizone exposed groups (Ns~6). The mice were exposed to 0:2% (w/w) cuprizone for up to six weeks. MTR images were obtained at a 7 Tesla Bruker MR-scanner before cuprizone exposure, weekly for six weeks during cuprizone exposure, and once two weeks after termination of cuprizone exposure. Immunohistochemistry staining for myelin (anti-Proteolopid Protein) and oligodendrocytes (anti-Neurite Outgrowth Inhibitor Protein A) was obtained after each weekly scanning. Rates of MTR change and correlations between MTR values and histological findings were calculated in five brain regions. In the corpus callosum and the deep gray matter a significant rate of MTR value decrease was found, 0:96% per week (pv:0001) and 0:39% per week (pv:0001) respectively. The MTR values correlated to myelin loss as evaluated by immunohistochemistry (Corpus callosum: R 2~: 43, pv:0001. Deep gray matter: R 2~: 21, pv:001), but did not correlate to oligodendrocyte density. Significant results were not found in the cerebellum, the olfactory bulb or the cerebral cortex. This study shows that MTR can be used to detect demyelination in the deep gray matter, which is of particular interest for imaging of patients with MS, as deep gray matter demyelination is common in MS, and is not easily detected on conventional clinical MRI

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.publishedVersio

Alpha-tocopherol and MRI outcomes in multiple sclerosis - association and prediction

Objective: Alpha-tocopherol is the main vitamin E compound in humans, and has important antioxidative and immunomodulatory properties. The aim of this study was to study alpha-tocopherol concentrations and their relationship to disease activity in Norwegian multiple sclerosis (MS) patients. Methods: Prospective cohort study in 88 relapsing-remitting MS (RRMS) patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids (the OFAMS study), before and during treatment with interferon beta. The patients were followed for two years with repeated 12 magnetic resonance imaging (MRI) scans and nine serum measurements of alpha-tocopherol. Results: During interferon beta (IFNB) treatment, each 10 µmol/L increase in alpha-tocopherol reduced the odds (CI 95%) for simultaneous new T2 lesions by 36.8 (0.5–59.8) %, p = 0.048, and for combined unique activity by 35.4 (1.6–57.7) %, p = 0.042, in a hierarchical regression model. These associations were not significant prior to IFNB treatment, and were not noticeably changed by gender, age, body mass index, HLA-DRB1*15, treatment group, compliance, or the concentrations of 25-hydroxyvitamin D, retinol, neutralising antibodies against IFNB, or the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. The corresponding odds for having new T1 gadolinium enhancing lesions two months later was reduced by 65.4 (16.5–85.7) %, p = 0.019, and for new T2 lesions by 61.0 (12.4–82.6) %, p = 0.023. Conclusion: During treatment with IFNB, increasing serum concentrations of alpha-tocopherol were associated with reduced odds for simultaneous and subsequent MRI disease activity in RRMS patients.publishedVersio

Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity

Background: Serum markers of inflammation are candidate biomarkers in multiple sclerosis (MS). ω-3 fatty acids are suggested to have anti-inflammatory properties that might be beneficial in MS. We aimed to explore the relationship between serum levels of inflammation markers and MRI activity in patients with relapsing remitting MS, as well as the effect of ω-3 fatty acids on these markers. Methods: We performed a prospective cohort study in 85 relapsing remitting MS patients who participated in a randomized clinical trial of ω-3 fatty acids versus placebo (the OFAMS study). During a period of 24 months 12 repeated magnetic resonance imaging (MRI) scans and nine serum samples were obtained. We measured 10 inflammation markers, including general down-stream markers of inflammation, specific markers of up-stream inflammatory pathways, endothelial action, and matrix regulation. Results: After Bonferroni correction, increasing serum levels of CXCL16 and osteoprotegerin were associated with low odds ratio for simultaneous MRI activity, whereas a positive association was observed for matrix metalloproteinase (MMP) 9. CXCL16 were also associated with low MRI activity the next month, but this was not significant after Bonferroni correction. In agreement with previously reported MRI and clinical results, ω-3 fatty acid treatment did not induce any change in the inflammation markers. Conclusions: Serum levels of CXCL16, MMP-9, and osteoprotegerin reflect disease activity in MS, but are not affected by ω-3 fatty acid treatment. CXCL16 could be a novel biomarker and potential predictor of disease activity in MS.© 2013 Holmøy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Association of adverse childhood experiences with the development of multiple sclerosis

Objective To study whether exposure to childhood emotional, sexual or physical abuse is associated with subsequent multiple sclerosis (MS) development. Methods A nationwide, prospective cohort study based on participants in the Norwegian Mother, Father and Child cohort study. Enrolment took place 1999–2008, with follow-up until 31 December 2018. Childhood abuse before age 18 years was obtained from self-completed questionnaires. We identified MS diagnoses through data-linkage with national health registries and hospital records. The Cox model was used to estimate HRs for MS with 95% CIs, adjusting for confounders and mediators. Results In this prospective cohort study, 14 477 women were exposed to childhood abuse and 63 520 were unexposed. 300 women developed MS during the follow-up period. 71 of these (24%) reported a history of childhood abuse, compared with 14 406 of 77 697 (19%) women that did not develop MS. Sexual abuse (HR 1.65, 95% CI 1.13 to 2.39) and emotional abuse (HR 1.40, 95% CI 1.03 to 1.90) in childhood were both associated with an increased risk of developing MS. The HR of MS after exposure to physical abuse was 1.31 (95% CI 0.83 to 2.06). The risk of MS was further increased if exposed to two (HR 1.66, 95% CI 1.04 to 2.67) or all three abuse categories (HR 1.93, 95% CI 1.02 to 3.67). Interpretation Childhood sexual and emotional abuse were associated with an increased risk of developing MS. The risk was higher when exposed to several abuse categories, indicating a dose–response relationship. Further studies are needed to identify underlying mechanisms.publishedVersio

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

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).publishedVersio

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. This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.publishedVersio