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

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

Month of birth and risk of multiple sclerosis: confounding and adjustments

A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population. © 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association

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

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

The cost of multiple sclerosis in Norway

Health economic aspects have been increasingly important during introduction of new treatments for multiple sclerosis. As a partial response for Norway, a costof- illness study was carried out to estimate the yearly cost of the illness to society and relate costs and patients’ quality of life to illness severity. Estimated cost to society was Euro 439 million in 2002 exclusive of the cost of reduced quality of life. The cost per patient was close to Euro 65,000. Account taken of methodological differences, the results compare to results for Sweden, Norway’s closest neighboring country. The illness reduced patients’ quality of life with 0.26. More patients were early retired because of their MS in Norway than in any of nine other European countries comprised by a recent European study, illustrating a liberal practice in Norway. The Norwegian cost of unpaid assistance was almost identical to the Swedish cost that was the lowest found across the countries in the European study. When related to illness severity, the cost per patient increased, and the patients’ experienced quality of life decreased with increasing EDSS levels in line with what has been found for other countries. Cost-of-MS studies have been carried out for a number of countries. Together they contribute to our understanding of the economic consequences of multiple sclerosis and, if their results are related to illness severity, also provide valuable information for further economic analyses of treatment and medication. Our study adds to this

The cost of multiple sclerosis in Norway – (and how certain can we be?)

The research question initially formulated for this study was to attempt to set a numerical target for the total yearly cost of MS to the Norwegian society, and relate the cost and patients´ experienced quality of life to illness severity. As work progressed, the question of how much confidence may be put in this kind of information in Norway as for today turned into another main issue. It turned out that much of the information that could be used for our study was so imprecise or unreliable that giving an impression that the information could be used to give an acceptably precise single estimate of the cost of MS to the Norwegian society would be seriously misleading. Therefore both “conservative” and “best” estimates are given. A conservative estimate of the yearly cost of MS to the Norwegian society around year 2002 is NOK 1 836 million. A best estimate is NOK 4 033 million, more than twice the conservative estimate. Mainly three factors account for the difference between the estimates: Uncertainty on what elements should be included in cost-of-illness studies, uncertainty on how some cost elements should be valued, and a combination of differences in information on the same phenomena in different sources of information and the researchers´ choices on how to handle them. For decision making purposes the combined effect of differences in information from different sources and the researchers´ choices on how to handle them is most grave since it will usually go unrecognized. When related to illness severity, the total cost per patient to society seem to increase, and the patients experienced quality of life to decrease, in a close to linear fashion with increasing EDSS-levels 1. However, a warning should be raised that because of the uncertainties as those mentioned, Norway probably has a long way to go before studies like ours in general might be regarded as providing acceptable information for decisions as important as those that have to be made in the health sector. 1 The EDSS, Kurtzke`s “Expanded Disability Status Scale”, is the most common tool used to express illness severity in MS. The scale ranges from 0 (no disability) to 10 (dead due to MS) and is divided in 20 half-point steps

A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway

Objective: Investigate the incidence of multiple sclerosis during 1953–2013 and estimate the prevalence rate of MS on 1 January 2003 and 2013 in Hordaland County, Western Norway. Methods: All patients with onset of disease in Hordaland 1953–2013 were identified in files from previous studies until 2003 and from patient records at the departments of Neurology, Haukeland University Hospital and Haugesund Hospital during 2003–2013. 1558 patients were assessed and 1402 of these were included, of whom 1035 were alive and living in Hordaland at prevalence day 1 January 2013. Annual incidence rates were calculated for 1953–2013. Results: On 1 January 2003, the crude prevalence rate was 191/100 000 population and on 1 January 2013, the crude prevalence rate was 211.4 (95% CI 198.3 to 224.2) per 100 000; 270.9 (95% CI 250.6 to 292.3) for women and 151.8 (95% CI 136.8 to 167.9) for men. Prevalence peaked at ages 55–59 years for women and 60–64 years for men. The annual incidence rate increased from 1.9 (95% CI 1.2 to 2.6) per 100 000 during 1953–1957 to 7.2 (95% CI 6.0 to 8.5) during 1978–1982 and to 8.5 (95% CI 7.3 to 9.7) during 2003–2007, thus indicating a stabilising incidence over the past 35 years. The female/ male ratio ranged from 1.2:1 to 1.8:1 (p=0.381) during the period. Conclusions: Stabilising rather than increasing incidence combined with the stable female/male ratio are indicative of non-fluctuating environmental factors in a geographical area otherwise characterised by lack of vitamin D effective sun exposure. The rising prevalence of MS could result from improved survival and follow-up methodology

Økonomisk analyse av behandling av MS-pasienter med Tysabri® i Norge

Økonomien i behandling av personer med multippel sklerose med Tysabri® er analysert. Hovedkonklusjonen er at behandling med Tysabri® mest sannsynlig vil gi reduserte kostnader for samfunnet og økte helsegevinster for pasientene. Noe av informasjonen som er benyttet for analysen er usikker og kostnadsdifferansene beskjedne. Moderate endringer i informasjonen vil kunne føre til analyseresultater som tilsier at kostnadene for samfunnet vil øke. Imidlertid, selv i disse tilfellene synes kostnadsøkningene i de aller fleste tilfellene å ville være så beskjedne at kostnaden per vunnet kvalitetsjustert leveår vil ligge godt under NOK 500 000 som normalt regnes som akseptabelt for slike helsegevinste

High incidence and prevalence of MS in Møre and Romsdal County, Norway, 1950–2018

Objective To determine prevalence and longitudinal trends in incidence of MS in Møre and Romsdal County, Western Norway, from 1950 to 2018. Methods Retrospective longitudinal population-based observational study. All patients diagnosed, or living, with MS in Møre and Romsdal were identified as incident or prevalent cases from local, regional, and national sources. We compiled the data in the Norwegian Multiple Sclerosis Registry and Biobank and used the aggregated data set to calculate incidence and prevalence rates using population measures obtained from Statistics Norway. Results On January 1, 2018, the estimated prevalence was 335.8 (95% CI, 314.1–358.5) per 100,000 inhabitants, with a female:male ratio of 2.3. From 1950 through 2017, we observed a considerable (p < 0.001) increase in average annual incidence rates from 2.1 (95% CI, 1.3–3.3) to 14.4 (95% CI, 11.9–17.3) per 100,000. From 2005 through 2017, the incidence among women increased from 17.1 (95% CI, 14.0–20.7) to 23.2 (95% CI, 18.7–28.5) per 100,000, whereas the incidence among men declined from 10.3 (95% CI, 7.9–13.2) to 5.9 (95% CI, 3.4–8.8) per 100,000. Conclusion Møre and Romsdal County in Western Norway has the highest prevalence of MS reported in Norway. The incidence has steadily increased since 1950, and during the latest 15 years, we observed opposing trends in sex-specific incidence rates