Torben Fog - A Danish pioneer in a multi-faceted spectrum of multiple sclerosis research.

Torben Fog was committed to multiple sclerosis (MS) research for more than four decades, starting before the defence of his thesis in 1948 and lasting until his death in 1987. His research was multi-facetted, making him one of the great pioneers in the study of essential parts of the pathology, immunology and treatment of MS. He has contributed with meticulous studies of the MS plaques, documenting the perivenous distribution of plaques in the spinal cord. He constructed a scoring system for the disability in MS and used a computer programme to calculate a total neurological deficit. Together with his co-workers, Fog in 1972 was the first to report the association between MS and the human leukocyte antigen system. Fog can be considered as the father of immunomodulatory therapy in MS, treating MS patients with the first transfer factor, and as early as 1980, he was the first to treat MS with intramuscular natural interferon.

Using instrumental variables to correct for bias in real-world cohort studies of the effects of disease-modifying treatment in MS.

BACKGROUND: Estimating the effect of disease-modifying treatment of MS in observational studies is impaired by bias from unmeasured confounders, in particular indication bias. OBJECTIVE: To show how instrumental variables (IVs) reduce bias. METHODS: All patients with relapsing onset of MS 1996-2010, identified by the nationwide Danish Multiple Sclerosis Registry, were followed from onset. Exposure was treatment index throughout the first 12 years from onset, defined as a cumulative function of months without and with medium- or high-efficacy treatment, and outcomes were hazard ratios (HRs) per unit treatment index for sustained Expanded Disability Scale Score (EDSS) 4 and 6 adjusted for age at onset and sex, without and with an IV. We used the onset cohort (1996-2000; 2001-2005; 2006-2010) as an IV because treatment index increased across the cohorts. RESULTS: We included 6014 patients. With conventional Cox regression, HRs for EDSS 4 and 6 were 1.15 [95% CI: 1.13-1.18] and 1.17 [1.13-1.20] per unit treatment index. Only with IVs, we confirmed a beneficial effect of treatment with HRs of 0.86 [0.81-0.91] and 0.82 [0.74-0.90]. CONCLUSION: The use of IVs eliminates indication bias and confirms that treatment is effective in delaying disability. IVs could, under some circumstances, be an alternative to marginal structural models.

Heterogeneity on long-term disability trajectories in patients with secondary progressive MS: a latent class analysis from Big MS Data network.

BACKGROUND: Over the decades, several natural history studies on patients with primary (PPMS) or secondary progressive multiple sclerosis (SPMS) were reported from international registries. In PPMS, a consistent heterogeneity on long-term disability trajectories was demonstrated. The aim of this study was to identify subgroups of patients with SPMS with similar longitudinal trajectories of disability over time. METHODS: All patients with MS collected within Big MS registries who received an SPMS diagnosis from physicians (cohort 1) or satisfied the Lorscheider criteria (cohort 2) were considered. Longitudinal Expanded Disability Status Scale (EDSS) scores were modelled by a latent class growth analysis (LCGA), using a non-linear function of time from the first EDSS visit in the range 3-4. RESULTS: A total of 3613 patients with SPMS were included in the cohort 1. LCGA detected three different subgroups of patients with a mild (n=1297; 35.9%), a moderate (n=1936; 53.6%) and a severe (n=380; 10.5%) disability trajectory. Median time to EDSS 6 was 12.1, 5.0 and 1.7 years, for the three groups, respectively; the probability to reach EDSS 6 at 8 years was 14.4%, 78.4% and 98.3%, respectively. Similar results were found among 7613 patients satisfying the Lorscheider criteria. CONCLUSIONS: Contrary to previous interpretations, patients with SPMS progress at greatly different rates. Our identification of distinct trajectories can guide better patient selection in future phase 3 SPMS clinical trials. Additionally, distinct trajectories could reflect heterogeneous pathological mechanisms of progression.

Changes in prognosis of the Danish multiple sclerosis population over time.

BACKGROUND: The course of multiple sclerosis (MS) appears to be milder in recent decades. OBJECTIVE: To investigate how time from onset to disability milestones and how demographic and clinical characteristics have changed through subsequent onset cohorts of patients with MS. METHODS: In the nationwide Danish Multiple Sclerosis Registry, we have registered all 13,562 Danish patients with onset of MS or clinically isolated syndrome from 1996 through 2020. For the analyses of prognosis, we used all cases with relapsing onset (N = 11,669). After stratification into 5-year onset cohorts, we computed the hazard ratios for disability endpoints for all cohorts having at least 10 years of follow-up and the oldest 1996-2000 onset cohort as reference. RESULTS: Patients in more recent MS onset cohorts have a shorter diagnostic delay and more of them start disease-modifying treatment within 1 year since diagnosis. The prognosis was better for later onset cohorts. For the 2001-2005 cohort, the hazard ratio for confirmed Expanded Disability Status Scale (EDSS) 4 was 0.85 (95% confidence interval (CI), 0.76-0.95) and for confirmed EDSS 6: 0.76 (95% CI, 0.65-0.88). For the more recent 2006-2010 cohort, the corresponding hazard ratios were 0.70 (95% CI, 0.62-0.79) and 0.60 (95% CI, 0.50-0.71). CONCLUSION: We observed a considerable improvement of the prognosis in recent onset cohorts of relapsing-onset MS.

Quantitative effect of sex on disease activity and disability accumulation in multiple sclerosis.

OBJECTIVE: To quantify sex differences in activity and severity of multiple sclerosis (MS) and how it depends on disease duration and time since clinical onset. METHODS: All Danish citizens with onset of relapsing MS since 1996 who have received disease-modifying therapy have been followed with annual or biannual control visits with mandatory notification of the Danish Multiple Sclerosis Registry. Men and women were compared by the inverse probability of being female. Relapse rates and changes in the Expanded Disability Status Scale (EDSS) scores were analysed with weighted general linear models, and we used weighted Cox regression for HRs between men and women for different EDSS endpoints. RESULTS: We included 3028 men and 6619 women. The weighted female:male relapse rate ratio was 1.16 (95% CI: 1.10 to 1.22) but after age 50 years, the difference disappeared. The annualised increase in EDSS was 0.07 in men (95% CI: 0.05 to 0.08) and 0.05 in women (95% CI: 0.04 to 0.06); p=0.017. With women as reference, the HR for reaching EDSS 4 was 1.34 (95% CI: 1.23 to 1.45; p<0.001), and for reaching EDSS 6 it was 1.43 (95% CI: 1.28 to 1.61; p<0.001). The diagnostic delay did not differ significantly between the sexes. CONCLUSION: Women have more inflammatory disease activity in terms of relapses than men up to the age of menopause indicating that sex hormones may play a role. Men are more subject to the neurodegenerative component of MS than women, particularly after the age of 45 years.

Apparent changes in the epidemiology and severity of multiple sclerosis.

Multiple sclerosis (MS) is an immunological disease that causes acute inflammatory lesions and chronic inflammation in the CNS, leading to tissue damage and disability. As awareness of MS has increased and options for therapy have come into use, a large amount of epidemiological data have been collected, enabling studies of changes in incidence and disease course over time. Overall, these data seem to indicate that the incidence of MS has increased, but the course of the disease has become milder, particularly in the 25 years since the first disease-modifying therapies (DMTs) became available. A clear understanding of these trends and the reasons for them is important for understanding the factors that influence the development and progression of MS, and for clinical management with respect to prevention and treatment decisions. In this Review, we consider the evidence for changes in the epidemiology of MS, focusing on trends in the incidence of the disease over time and trends in the disease severity. In addition, we discuss the factors influencing these trends, including refinement of diagnostic criteria and improvements in health-care systems that have increased diagnosis in people with mild disease, and the introduction and improvement of DMT.

The value of general health perception in health equity research: A community-based cohort study of long-term mortality risk (Finnmark cohort study 1987-2017).

BACKGROUND: General health perception as measured by self-rated health (SRH) is an individual's synthesis of personal overall health and has value in its own right. In addition, this subjective perspective has a unique predictive power of subsequent mortality and adds valuable information not captured by objective measures. We studied the relationship between SRH and subsequent mortality to demonstrate how simple self-ratings can enhance our understanding of health inequities. METHODS: Data from a population-based survey conducted in Finnmark 1987/1988 were linked to the Norwegian Cause of Death Registry for information on all deaths by the end of 2017. We used Cox proportional hazard regression modelling to estimate the relative effects of all-cause mortality separately for sex and age (30-49 and 50-62 years) with stepwise adjustment for socio-demographics and various other health status and behavioural measures. RESULTS: The age-adjusted power of mortality prediction of SRH was strong (most pronounced in the youngest age-group) but markedly attenuated by other factors. Education inequality in mortality was most substantial in the youngest age-group, which might partly be due to a combination of selective mortality and historical changes in health inequality. In comparison, educational inequality in SRH was clearly pronounced regardless of age. Work disability pension appeared as the common key factor affecting the mortality prediction of SRH and educational inequity for both subsequent mortality and SRH. CONCLUSION: SRH adds unique information to our understanding of health inequities. The consistency in shared predictors of educational inequity concerning both mortality and SRH underscores the correspondence of these measures. In addition to predicting the fatal effects of social selection mechanisms, SRH adds non-fatal effects and seems less prone to selective mortality. The results are relevant to approaches in health equity research and have important policy implications.

The effectiveness of natalizumab vs fingolimod-A comparison of international registry studies.

BACKGROUND: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. METHODS: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. RESULTS: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. CONCLUSION: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.

Relapses add to permanent disability in relapsing multiple sclerosis patients.

OBJECTIVE: Whether relapses have direct effects on permanent disability in multiple sclerosis is still an unsettled issue. We aimed at investigating the cumulative effect of breakthrough relapses on the Expanded Disability Status Scale (EDSS) in relapsing-onset MS patients under disease modifying therapy (DMT). METHODS: From the Danish Multiple Sclerosis Registry we identified all patients in Denmark with relapsing-onset MS who had started DMT and followed them from the first day of treatment. We included patients aged 18-59 with Kurtzke's EDSS score < 6.0 at entry, and we compared patients with and without relapses during follow-up. Endpoints were 1) annualized increase in EDSS; 2) time to 6-month sustained EDSS-worsening; 3) time to EDSS 6.0; and 4) time to increase in pyramidal- and cerebellar functional systems. Patients with and without relapses after entry were 1:1 matched by sex, EDSS, and age at entry. We analysed EDSS-worsening with adjusted Generalized Linear Models and time to the endpoints with adjusted Cox regression. RESULTS: We included 1,428 patients with breakthrough relapses and 1,428 without. The adjusted annualized increase in EDSS was 0.179 in patients with relapses (95% CI 0.164 - 9.194) and 0.086 in patients without relapses (95% CI 0.074 - 0.097), but in patients with EDSS ≥ 4.0 at entry there was no difference. The hazard ratio for irreversible worsening of EDSS was 1.83 (95% CI 1.58 - 2.12) and for irreversible increase to EDSS 6.0 or more 1.62 (95% CI 1.25 - 2.10). Irreversible increase in pyramidal and cerebellar functional system scores also happened significantly earlier in patients with breakthrough relapses. CONCLUSIONS: Our results indicate that breakthrough relapses under DMT is associated with increasing permanent disability in patients with EDSS < 4.0 at treatment start which calls for effective prevention of relapses.

Early treatment delays long-term disability accrual in RRMS: Results from the BMSD network.

BACKGROUND: The optimal timing of treatment starts for achieving the best control on the long-term disability accumulation in multiple sclerosis (MS) is still to be defined. OBJECTIVE: The aim of this study was to estimate the optimal time to start disease-modifying therapies (DMTs) to prevent the long-term disability accumulation in MS, using a pooled dataset from the Big Multiple Sclerosis Data (BMSD) network. METHODS: Multivariable Cox regression models adjusted for the time to first treatment start from disease onset (in quintiles) were used. To mitigate the impact of potential biases, a set of pairwise propensity score (PS)-matched analyses were performed. The first quintile, including patients treated within 1.2 years from onset, was used as reference. RESULTS: A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively. The risk of reaching all the disability outcomes was significantly lower (p < 0.0004) for the first quintile patients' group. CONCLUSION: Real-world data from the BMSD demonstrate that DMTs should be commenced within 1.2 years from the disease onset to reduce the risk of disability accumulation over the long term.

Population-based head-to-head comparison of the clinical characteristics and epidemiology of AQP4 antibody-positive NMOSD between two European countries.

BACKGROUND: Population-based clinical studies in neuromyelitis optica spectrum disorder (NMOSD) and epidemiological and clinical comparisons of White ethnicities are missing. In a large population-based international cohort, we extensively characterized aquaporin-4 antibody seropositive (AQP4-Ab+) NMOSD, and also compared the clinical, radiological and epidemiological features between two European populations residing in different areas. METHODS: Between self-reported Danish and Hungarian ethnicities, we compared the population-based clinical features, disability outcomes, and death of 134 AQP4-Ab+ NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis (IPND) criteria. For precise comparison of epidemiology, we conducted a population-based head-to-head comparative study of the age-standardized prevalence (January 1, 2014) and incidence (2007-2013) of AQP4-Ab+ NMO/NMOSD among adults (≥16 years) in Denmark (4.6 million) and Hungary (6.4 million) by applying 2015 IPND (NMOSD) criteria and 2006 Wingerchuk (NMO). RESULTS: Danes were more likely to present with transverse myelitis and were more affected by spinal cord damage on long-term disability. Hungarians presented most often with optic neuritis, although visual outcome was similar in the groups. No differences were observed in sex, disease course, relapse rate, autoimmune comorbidity, mortality, brain MRI, and treatment strategies. The age-standardized prevalence estimates of AQP4-Ab+ NMOSD (2015 IPND criteria) in Denmark vs. Hungary were 0.66 vs. 1.43 (/100,000) while incidence rates were 0.04 vs. 0.11 (/100,000 person-years); similar differences were found based on the 2006 NMO criteria. CONCLUSIONS: This head-to-head comparative study indicates different disease characteristics and epidemiology among White populations in Europe, and substantiates the need for population-based genetic and environmental studies in NMOSD.

Seasonal patterns of relapse and disability in Danish MS patients: A population-based cohort study.

BACKGROUND: The importance of environmental risk factors in the onset of multiple sclerosis (MS) has been studied extensively. Similarly, a growing number of studies address the importance of environmental factors, including seasonality, for ongoing activity of established disease. Specifically, past research demonstrates higher rates of relapse activity in summer months among individuals with MS. Our study adds to the existing literature on seasonality of disease relapse by analysing a large population-based and virtually complete cohort of patient with relapsing and remitting MS (RRMS) in an area of temperate climate. METHODS: The Danish Multiple Sclerosis Registry includes follow-up for all patients receiving disease modifying treatment from 1996-2020, with near-complete registration of all relapses and their dates. We compared the observed and expected numbers of relapses for each calendar month and calculated month-specific annualized relapse rates (ARR) using Poisson regression. In addition, we analysed seasonal variation in disability as measured by the Expanded Disability Status Scale (EDSS). RESULTS: From 1996 to 2020 we followed 13,575 MS patients treated with disease modifying therapy (4165 men and 9410 women) for a total of 82,187 person years and 134,593 control visits. The mean age at entry was 41.1 years with standard deviation 10.9 years. We recorded 16,083 relapses throughout the observation period, and for 15,728 of the relapses the date of onset was known. Relapses were unevenly distributed by calendar month (p < 0.00001). The most prominent deviation was a paucity of relapses in July in which the ARR was 0.166 compared with mean of 0.191 for the whole year. Otherwise, the ARR formed a plateau slightly above mean during the spring months. Mean EDSS was slightly higher in autumn (2.78) than in spring (2.74), but there was no difference between winter and summer; p < 0.0001. CONCLUSION: In contrast with previous studies, we observed a nadir of relapses in July among Danish patients with RRMS. This finding may be related to increased exposure to sunlight in the summer, particularly during vacation when outdoor recreational activities are more frequent and potential exposure to infections is decreased. Confirmation of this in future studies is warranted.

The Danish Multiple Sclerosis Registry.

OBJECTIVES: The Danish Multiple Sclerosis Registry is the oldest operative and nationwide MS registry. We present The Danish Multiple Sclerosis Registry with its history, data collection, scientific contribution, and national and international research collaboration. MATERIALS AND METHODS: Detailed description of data collection, completeness, quality optimizing procedures, funding, and legal, ethical and data protection issues are provided. RESULTS: The total number of registered cases with clinical isolated syndrome and multiple sclerosis since 1956 was by start of May 2020 30,023 of whom 16,515 cases were alive and residing in Denmark, giving a prevalence rate of about 284 per 100,000 population. The mean annual number of new cases receiving an MS diagnosis was 649 per year in the period 2010 to 2019. In total, 7,945 patients (48.1%) are receiving disease modifying therapy at the start of May 2020. CONCLUSIONS: Multiple Sclerosis registers are becoming increasingly important, not only for epidemiological research but also by quantifying the burden of the disease for the patients and society and helping health care providers and regulators in their decisions. The Danish Multiple Sclerosis Registry has served as data source for a number of scientific publications including epidemiological studies on changes in incidence and mortality, cohort studies investigating risk factors for developing MS, comorbidities and socioeconomic outcomes in the MS population, and observational studies on effectiveness of disease modifying treatments outside the narrow realms of randomized clinical trials.

Exposure to passive smoking during adolescence is associated with an increased risk of developing multiple sclerosis.

BACKGROUND: Environmental factors are associated with acquiring multiple sclerosis (MS) particularly in adolescence. OBJECTIVE: To test for association between MS and exposure to passive smoking at the age of 10-19. METHODS: A total of 919 patients from the Danish MS Registry and Biobank and 3419 healthy blood donors who had not smoked before the age of 19 were targeted. We analyzed separately for each sex and for those never-smokers (cohort 1) and active smokers above the age of 19 (cohort 2). All participants completed standardized questionnaires about smoking and lifestyle. We matched cases and controls in the ratio of 1:2 by propensity scores discarding unmatchable individuals and used logistic regression adjusted for all covariates and interactions. RESULTS: After matching, we included 110/213 male cases/controls and 232/377 female case/controls in cohort 1. In cohort 2, the numbers were 160/320 and 417/760, respectively. Among women in cohort 1, the odds ratio (OR) for MS by passive smoking at the age of 10-19 was 1.432 (p = 0.037) but in men it was 1.232 (p = 0.39). Among men in cohort 2, OR was 1.593 (p = 0.022) but among women it was only 1.102 (p = 0.44). CONCLUSION: Among never smokers, female MS cases were more often than female controls reported with passive smoking between the age of 10 and 19, and among smokers above the age of 19, male MS patients were more often than male controls reported with passive smoking.

Perceptions of Family Caregivers of Home-Dwelling Persons with Dementia regarding Access to Information and Involvement in Decisions.

This cross-sectional study explored factors affecting information about available health services, content of services provided, and involvement in decisions regarding services as perceived by the family caregivers of home-dwelling persons with dementia in Northern Norway. Altogether, 788 family caregivers were invited to participate in a survey, with a response rate of 54.6% (n = 430). The respondents reported modest levels of perceived information and involvement. Few of the expected predictors were associated with the outcomes. Ordinal logistic regression analyses revealed that primary school as the highest level of education and perception of caregiving as moderately or very demanding predicted lower scores on family caregivers' perceived level of information about available services, information on service content, and involvement in decisions. In addition, medium household income predicted lower scores on information about service content. The results may point to mechanisms that create inequalities in the processing of information and involvement in care decisions regarding care arrangements among different caregiver groups. Health authorities should investigate potential social inequalities in complementary health care for home-dwelling persons with dementia.

Factors affecting the use of home-based services and out-of-home respite care services: A survey of family caregivers for older persons with dementia in Northern Norway.

BACKGROUND: Family caregivers contribute substantially to the care for older home-dwelling people with dementia, although community healthcare services tend to be underutilized. In this study, we aimed to explore the use and predictors of use of home-based and out-of-home respite care services available to older home-dwelling persons with dementia, as reported by the family caregivers. METHOD: A cross-sectional survey was administered to family caregivers (n = 430) in Northern Norway during April to November 2016. The use of healthcare services was categorized into two types according to principal component analysis: home-based services and out-of-home respite care services (R2 = 44.1%). Predictors of service use were examined with bivariate correlation, multiple linear regression, and Poisson regression analyses. RESULTS: The use of home-based services among persons with dementia was significantly higher for persons with advanced age, persons living in urban areas, persons living in an assisted living facility, persons living alone, and persons able to manage being alone for a short period of time. Among the family caregiver variables, higher age, status as a daughter, son, or other family member, higher educational level, and full-time employment also predicted greater use of home-based services. Same ethnicity was associated with use of fewer home-based services. The use of out-of-home respite care services was significantly higher among male persons with dementia and among those living in urban areas. In addition, fewer out-of-home respite care services were used by male caregivers or daughters of the care recipient, while the use was higher when the caregivers experienced more caregiving demands or had provided care for longer periods of time. CONCLUSIONS: These results indicate areas that policymakers and healthcare providers should consider to identify families who underutilize healthcare services and to achieve a more equal and efficient allocation of services in accordance with families' needs.

Variations in physiotherapy practice in neurological rehabilitation trajectories -an explorative interview and observational study.

Rehabilitation following acquired brain injury requires multidisciplinary efforts, including physiotherapy, across health care levels. Recent changes in the organization of health care services in western societies have led to earlier hospital discharge and increased responsibility for rehabilitation in primary care. The aim of this study was to describe and increase knowledge on the variations in physiotherapy practice for people with acquired brain injury across health care levels in Norway. We performed qualitative interviews with physiotherapists and field observations of physiotherapy treatments for 10 rehabilitation trajectories. We also performed systematic analyses using data from field observations, interviews, and hospital discharge records related to perspectives on social practices. The institutionalized rehabilitation context in hospitals promoted a more uniform approach by physiotherapists, emphasizing quality of movement and reacquisition of function. Physiotherapists in primary health care had to balance between interventions aiming to improve quality of movement versus interventions enabling patients to identify coping strategies. The informants highlighted the relevance of contextual surroundings when patients were discharged earlier from the hospital, as these patients' level of function was perceived to be lower. Moreover, the preconditions for providing rehabilitation in primary care challenged physiotherapists to practice and use their knowledge base in novel ways.