Norwegian Multiple Sclerosis Registry Research Articles

Hospitalisations and humoral COVID-19 vaccine response in vaccinated rituximab-treated multiple sclerosis patients

BackgroundPatients with multiple sclerosis (MS) treated with anti-CD20 therapies such as rituximab may have increased risk of severe COVID-19 disease. Vaccination induces protective immunity, but humoral vaccine response is known to be attenuated in rituximab-treated MS-patients-patients, which has indicated a need for real world data on severe morbidity and mortality from COVID-19 after vaccination. MethodsRituximab-treated patients treated at Haukeland University Hospital were identified through the National MS Registry and invited to participate in the study by giving a consent and providing a blood sample 3 weeks or later after ordinary COVID-19- vaccination, i.e. 2 doses given with a standard interval of 3 weeks. Blood samples were analysed with Enzyme-Linked Immunosorbent assay (ELISA) to evaluate humoral vaccine response with screening test against receptor-binding domain (RBD) and confirmatory Spike IgG-specific ELISA. A haemagglutination test (HAT) was performed as a marker of neutralizing antibodies. Patient serum concentration of rituximab were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Registry data from the Norwegian MS registry and information on hospitalization from patient records were collected and linked to laboratory results. Results111 patients were included in the study. A total of 7 (6.3%) were hospitalized due to COVID-19 disease during the observation period. No patient was admitted to ICU and there were no deaths. 34.2% did not have detectable titre of SARS CoV-2 Spike IgG antibodies, 72.1% did not have a detectable titre of SARS CoV-2 RBD antibodies, and 88.2% did not have a detectable HAT titre. There was a correlation between hospitalisation and the absence of SARS CoV-2 Spike IgG antibody titre, and between hospitalisation and MS disease duration, as well as between spike IgG antibody titre and CD19 B-cell count, time since last rituximab infusion, cumulative rituximab treatment time and total IgG level in the patients. ConclusionA substantial proportion of rituximab-treated MS-patients-patients did not have detectable humoral vaccine responses after 2 doses of COVID-19 vaccination. Despite this, the cumulative percentage of patients hospitalized with COVID-19 disease throughout the observation period of 22 months was low, and no patients required ICU treatment. The results support that vaccinated MS-patients treated with rituximab have a protective effect against serious Covid-19 infection.

BCG vaccination and multiple sclerosis risk: A Norwegian cohort study

Introduction: Bacillus Calmette–Guérin (BCG) vaccination induces long-lasting effects on the adaptive and innate immune systems and prevents development of experimental autoimmune encephalomyelitis and possibly also inflammatory disease activity in multiple sclerosis (MS). Objective: The objective is to examine if BCG given in early adulthood decreases MS risk. Methods: From 791,369 (52% females) Norwegians participating in a national tuberculosis screening program from 1963 to 1975, we collected information on BCG vaccination and tuberculosis disease status. Later, MS disease was ascertained through both the Norwegian MS Registry and Biobank and the Norwegian Death Registry. We used logistic regression models to assess the relationship between BCG vaccination and MS risk. Results: In those BCG vaccinated, mean age at vaccination was 15.6 (standard deviation (SD) = 5.5) years. A total of 2862 (65% females) MS cases were retrieved. Overall, we found no association between MS risk and BCG vaccination. Compared to non-BCG-vaccinated individuals with no signs of tuberculosis infection, odds ratio (OR) for MS was 1.00 (95% confidence interval (CI) = 0.80–1.25) in the BCG-vaccinated group. In those not BCG vaccinated because of latent tuberculosis infection, the corresponding OR was 0.86 (95% CI = 0.66–1.13). Conclusion: We found no evidence of BCG vaccination or latent tuberculosis infection in young adulthood being linked to MS risk.

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

BackgroundCaesarean 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...

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

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. 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. 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). 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.

Association of Body Mass Index in Adolescence and Young Adulthood and Long-term Risk of Multiple Sclerosis: A Population-Based Study.

To prospectively investigate the long-term relationship between body mass index (BMI) in adolescents and young adults and risk for multiple sclerosis (MS) at the population level. We used data from the population-based compulsory Norwegian tuberculosis screening program during 1963 to 1975, including objectively measured height and weight from ≈85% of all eligible citizens. This was combined with data from the Norwegian MS registry and biobank up to November 2020. BMI was standardized according to age and sex, and risk for MS was calculated with Cox proportional hazard models. During 30,829,506 years of follow-up, we found 1,409 cases of MS among 648,734 participants in eligible age groups (14-34 years). Overall, obesity was associated with increased MS risk (hazard ratio [HR] 1.53 [95% confidence interval (CI) 1.25-1.88]), and the risk was similar in men (HR 1.4 [95% CI 0.95-2.06] and women (HR 1.59 [95% CI 1.25-2.02]). Risk was highest for the youngest age groups (age 14-16: HR 1.73 [95% CI 1.19-2.53]; 17-19: HR 1.61 [95% CI 1.08-2.39]; 20-24: HR 1.56 [95% CI 1.04-2.36]) and was no longer present for those >30 years of age. High BMI in individuals 14 to 24 years of age was associated with increased MS risk later in life in both male and female individuals.

Exposure to breastfeeding and risk of developing multiple sclerosis.

Early-life factors are reported to modulate the risk of developing multiple sclerosis (MS) among adults. The association between exposure to breastfeeding and the risk of MS is debated. We aimed to disclose whether past exposure to breastfeeding and its duration are associated with the risk of developing MS. We used a cohort design linking prospectively collected information on breastfeeding from the Cohort of Norway community-based surveys on health status (CONOR) with the Norwegian MS Registry and the population-based Medical Birth Registry of Norway that includes information on all births in Norway since 1967. MS clinical onset was collected throughout 2016. A total of 95 891 offspring born between 1922 and 1986 to mothers participating in CONOR were included. We identified 215 offspring within this cohort who developed adult-onset MS. Associations between breastfeeding and MS risk were estimated as hazard ratios using Cox proportional hazard models adjusting for maternal factors including education. We found no association between having been breastfed for ≥4 months and MS risk, also after adjusting for various maternal factors (hazard ratio = 0.90; 95% confidence interval 0.68-1.19). The estimates did not change for different durations of breastfeeding. The results were similar when adjusting for other perinatal factors. Our study could not confirm previous findings of an association between breastfeeding and risk of MS. Breastfeeding information was less likely to be biased by knowledge of disease compared with case-control studies.

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

ObjectiveTo determine prevalence and longitudinal trends in incidence of MS in Møre and Romsdal County, Western Norway, from 1950 to 2018.MethodsRetrospective 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.ResultsOn 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.ConclusionMøre 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.

Risk of cancer among multiple sclerosis patients, siblings, and population controls: A prospective cohort study

Background: Risk of cancer in multiple sclerosis (MS) patients compared to their siblings is unknown. Objective: The objective was to prospectively investigate the risk of cancer among MS patients compared to siblings without MS and to population controls. Methods: We retrieved data on MS patients born between 1930 and 1979 from the Norwegian Multiple Sclerosis Registry and population studies and on cancer diagnosis from the Cancer Registry of Norway. We used adjusted Cox proportional hazard regression to estimate cancer risk among 6883 MS patients, 8918 siblings without MS, and 37,919 population controls. Results: During 65 years of follow-up, cancer risk among MS patients was higher than that among population controls (hazard ratio (HR) = 1.14, 95% confidence interval (CI): 1.05–1.23) in respiratory organs (HR = 1.66, 95% CI: 1.26–2.19), urinary organs (HR = 1.51, 95% CI: 1.12–2.04), and the central nervous system (HR = 1.52, 95% CI: 1.11–2. 09). Siblings had higher risk of hematological cancers compared with MS patients (HR = 1.82, 95% CI: 1.21–2.73) and population controls (HR = 1.72, 95% CI: 1.36–2.18). Conclusion: MS patients were associated with increased risk of cancer compared to population controls. Siblings had increased risk of hematological cancer. This indicates that MS and hematological cancer could share a common etiology.

Body size and physical exercise, and the risk of multiple sclerosis

Background: Whether large body size increases multiple sclerosis (MS) risk in men is not well understood. Concurrently, physical exercise could be an independent protective factor. Objective: To prospectively investigate the association between body mass index (BMI) and aerobic fitness, indicators of body size and exercise, and MS risk in men. Methods: We performed a population-based nested case-control study within the historical cohort of all Norwegian men, born in 1950–1975, undergoing mandatory conscription at the age of 19 years. 1016 cases were identified through linkage to the Norwegian MS registry, while 19,230 controls were randomly selected from the cohort. We estimated the effect of BMI and fitness at conscription on MS risk using Cox regression. Results: Higher BMI (≥25 vs 18.5–<25 kg/m2) was significantly associated with increased MS risk (adjusted relative risk (RRadj) = 1.36, 95% confidence interval (CI): 1.05–1.76). We also found a significant inverse association between aerobic fitness (high vs low) and MS risk independent of BMI (RRadj = 0.69, 95% CI: 0.55–0.88, p-trend = 0.003), remaining similar when men with MS onset within 10 years from conscription were excluded (p-trend = 0.03). Conclusion: These findings add weight to evidence linking being overweight to an increased MS risk in men. Furthermore, they suggest that exercise may be an additional modifiable protective factor for MS.

Preclinical disease activity in multiple sclerosis: A prospective study of cognitive performance prior to first symptom.

To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort. We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study, cognitive test scores were available for 924 male cases and 19,530 male controls. We estimated mean score differences among cases and controls (Student t test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset. Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ = 0.80, p = 0.0095), corresponding to a 6 intelligence quotient (IQ)-point difference. Those scoring lowest, that is, >1 standard deviation below the controls' mean, had an increased MS risk during the 2 following years (relative risk = 2.81, 95% confidence interval = 1.52-5.20). Whereas results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored a significant 4.6 to 6.9 IQ points lower than controls up to 20 years prior to first progressive symptoms. RRMS may start years prior to clinical presentation, and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. Ann Neurol 2016;80:616-624.

The Norwegian Multiple Sclerosis Registry and Biobank

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with unknown cause and various benefits from disease modifying therapies. Systematic recording of data into national MS registries is therefore needed to optimize treatment and define the pathogenesis of the disease. The Norwegian MS Registry and Biobank was established for systematic collection of clinical and epidemiological data, as well as biological samples. Data collection is based on informed consent from the individual patients and recordings by treating neurologists. All researchers have, by application, access to data and biological samples from the Norwegian Multiple Sclerosis Registry and Biobank. By this combined effort from both patients and healthcare personnel, the Registry and Biobank aims to facilitate research for improved understanding of disease mechanisms and improved health care in MS.

Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades.

Norway has been subjected to numerous epidemiological investigations on the prevalence and incidence of multiple sclerosis (MS), dating back to 1935. The objective of this study was to review the studies on the prevalence and incidence of MS in Norway, provide an update on the prevalence of MS in Norway, and describe the time trends in the prevalence and incidence of MS in relation to risk factors, case ascertainment, and data. We performed a systematic search on PubMed and MEDLINE up to November 2014 using the search string ‘multiple sclerosis prevalence in Norway’ or ‘multiple sclerosis incidence in Norway’. In addition, we scrutinized the reference lists of the publications identified for relevant citations. We retrieved data on the distribution of MS in Norway on December 31, 2013 from the Norwegian Multiple Sclerosis Registry and Biobank and the Norwegian Patient Registry. We identified 29 articles. From 1961 to 2014, the reported prevalence of MS increased from 20 to 203 per 100,000 inhabitants, and the incidence increased from 1.9 to 8.0 per 100,000. The nationwide crude prevalence in Norway, based on the Norwegian Patient Registry, was 208 per 100,000 on December 31, 2013. The reported prevalence of MS in Norway has increased 10-fold, with several possible causes. During eight decades, neurological health services have generally become more accessible to the population, and transforming diagnostic criteria has made the diagnosis of MS more precise and valid. There have also been changes in lifestyle behavior and known risk factors, such as vitamin D and smoking, that might have contributed to the increased incidence of MS. A possible role of increased survival in MS needs to be examined further.This article is commented on by Berg-Hansen et al, published in 132: 364–367 (DOI: 10.1111/ane.12489).

High prevalence and no latitude gradient of multiple sclerosis in Norway

The prevalence of multiple sclerosis (MS) is increasing, and the presence of a latitude gradient for MS risk is still discussed. We present the first nationwide prevalence estimates for Norway, spanning the latitudes from 58–71 degrees North, in order to identify a possible latitude gradient. Information from the Oslo MS Registry and the Norwegian MS Registry and Biobank was combined with data from the Norwegian Patient Registry, the Norwegian Prescription Database and Statistics Norway. We estimated a crude prevalence of 203/100,000 on 1 January 2012. The prevalence in the Northern and Southern regions were not significantly different. MS prevalence in Norway is among the highest reported worldwide. We found no evidence of a latitude gradient.

Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58-71 °N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway, and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970-1979, which is significantly higher than in those born 1930-1969 (p < 0.001). In patients with relapsing remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.

Month of birth as a latitude-dependent risk factor for multiple sclerosis in Norway

Objective: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient. Methods: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose. Results: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98 – 1.24), in Middle Norway 1.11 (0.97 – 1.27) and in Northern Norway 1.28 (1.0 – 1.63) compared with the other months. Conclusions: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.

The Norwegian Multiple Sclerosis Registry and Biobank

OBJEVTIVES: Multiple sclerosis is a chronic inflammatory disease of the central nervous system with unknown cause and without any curable treatment. Research aiming at defining the pathogenesis of the disease is therefore needed. The Norwegian Multiple Sclerosis Registry and Biobank has been established for systematic collection of clinical and epidemiological data as well as biological samples. Data collection is based on informed consent from the individual patients and recordings by the treating neurologists. All researchers have, by application, access to data and biological samples from the Norwegian Multiple Sclerosis Registry and Biobank. By this combined effort from both patients and health care personnel, the Registry and Biobank aims to facilitate research for improved understanding of disease mechanisms and improved health care in multiple sclerosis.

Risk of MS is not associated with exposure to crude oil, but increases with low level of education

Background: Offshore workers in the Norwegian upstream petroleum industry are exposed to a number of chemicals such as organic solvents, mineral oils and other hydrocarbons, possibly contributing to an increased risk of multiple sclerosis (MS). Objective: To estimate the risk of MS in this population compared with the general working population in Norway, adjusting for education. Methods: Using the Norwegian Registry of Employers and Employees we included all 27,900 offshore workers registered from 1981 to 2003 and 366,805 referents from the general working population matched by gender, age and community of residence. The cohort was linked to the Norwegian MS Registry and the Norwegian Education Registry. Results: There was no increased risk of MS among the offshore workers. We found a marked and linear inverse relationship between level of education and the risk of MS in the total study population, with a rate ratio of 0.48 (95% CI, 0.53 to 0.88) for workers with a graduate degree compared to workers with elementary school only. Conclusions: These findings do not support a major aetiological role of petroleum-based products, but rather point to smoking and other lifestyle factors related to the level of education as being important for the risk of MS.

National MS registries

This review gives an overview of national registries that are currently in use for patients with multiple sclerosis (MS). The large-scale registries described herein include the Danish MS Registry, the Norwegian MS Registry, the Swedish MS Registry, the Italian MS Database Network, the North-American NARCOMS Registry, and the German MS Registry. These MS registries are extremely helpful for studying disease characteristics in large populations and monitoring the long-term outcome of disease-modifying therapies. Furthermore, an almost complete ascertainment of cases provides information on the provision of treatments, services and supplies within a given area that may be used to compare different levels of health care within and between these regions. In the long-term, MS registries monitor the health care situation of MS patients over time including the implementation of guidelines relating to care and treatment, measure the improvements that have taken place, and reveal shortages and/or misalignment in health care services. The information gathered herein is not only useful for the long-term follow-up of the individual patient, but also for society as a whole by increasing understanding of and knowledge about MS and allowing national authorities and relevant parties to make informed and relevant decisions about MS.