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

Results

We identified 3624 pwMS, of which 3088 were held by NorMSR. 964 (26.6%) were deceased by 1 January 2021, of whom 535 (55.5 %) were women, yielding a total of 79 897 person-years. Initial course of disease was unknown for 12 (1.2 %), and we could not obtain the UCoD for 31 (3.2 %), deceased pwMS. At the time of death, 109 pwMS were residing outside the geographic areas under investigation, but none was lost to follow-up. Among the deceased, 768 (79.7 %) died in a health institution or hospital. Autopsy was performed in 86 (8.9 %) cases. An overview of the study population, including demographics and clinical characteristics, is shown in table 1.

Table 1

Clinical and demographic data on deceased persons with multiple sclerosis by period of disease onset, in Hordaland and Møre and Romsdal counties, Western Norway

Categorical survival

The 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). For women with MS, the median life expectancy was 75.9 years (95% CI 74.6 to 77.6), and for men with MS, it was 72.0 years (95% CI 70.9 to 73.4), compared with 85.2 years for women (p<0.001) and 80.0 years for men (p<0.001) in the general population. The median life expectancy for pwROMS was 75.0 years (95% CI 73.8 to 76.3) and 69.7 years (95% CI 66.7 to 72.9) for pwPOMS (p<0.001). The survival curves are shown in figure 1A.

Figure 1Figure 1Figure 1

Survival for persons with multiple sclerosis, from birth (A) and disease onset (B), stratified by sex and initial course of disease, in Hordaland and Møre and Romsdal.

Calculated from MS onset (figure 1B), the median survival time for pwMS was 14.6 years shorter compared with the general population (p<0.001). Correspondingly, the median survival time for women and men with MS was reduced by 14.9 (p<0.001) and 13.4 (p<0.001) years. Similarly, survival from disease onset of pwROMS and pwPOMS was shortened by 12.0 (p<0.001) and 19.3 (p<0.001) years.

The median age at death, and the median time from MS onset to death, stratified by sex and initial disease course, is found in supplemental material (online supplemental table 1).

All-cause mortality

When assessing all-cause mortality, the overall EDR was 6.8 (95% CI 6.42 to 7.09) and SMR was 2.3 (95% CI 2.13 to 2.42, p<0.001) for pwMS compared with the general population. The all-cause EDR and SMR for women were 6.1 (95% CI 5.75 to 6.46) and 2.5 (95% CI 2.25 to 2.67, p<0.001), while the corresponding numbers for men were 7.9 (95% CI 7.22 to 8.60) and 2.1 (95% CI 1.90 to 2.30, p<0.001). For pwROMS, all-cause EDR and SMR were 5.6 (95% CI 5.28 to 5.98) and 2.2 (95% CI 2.03 to 2.35, p<0.001), whereas for pwPOMS, EDR was 14.5 (95% CI 13.24 to 15.60) and the SMR was 2.6 (95% CI 2.25 to 2.92, p<0.001). The all-cause EDRs and SMRs for the different age groups at onset and onset cohorts are shown in table 2.

Table 2

All-cause standardised mortality ratios (SMRs) and excess death rates (EDRs) among persons with multiple sclerosis in Hordaland and Møre and Romsdal counties, Western Norway

The all-cause EDRs for five decades after MS onset are shown in table 3 stratified by sex and disease course.

Table 3

Excess death rate (EDR) with 95% CIs by decade after disease onset in deceased persons with multiple sclerosis, in Hordaland and Møre and Romsdal counties, Western Norway

Cause-specific mortality

Overall, during the study period, the most frequent UCoD was MS (n=473, 49.0 %), followed by diseases of the circulatory system (n=148, 15.4 %) and neoplasms (n=144, 14.9 %).

We found a marked excess in mortality due to epilepsy, SMR 22.4 (95% CI 14.9 to 32.3, p<0.001). Similarly, we found increased cause-specific mortality from diseases of the respiratory system, SMR 1.6 (95% CI 1.17 to 2.09, p<0.01). For this main UCoD category, we found an excess in the number of deaths in men, SMR 1.8 (95% CI 1.12 to 2.61, p<0.05), in pwROMS, SMR 1.5 (95% CI 1.07 to 2.11, p<0.05), in pwMS with onset before 30 years of age, SMR 2.3 (95% CI 1.37 to 3.65, p<0.01) and those with disease onset before 1951, SMR 2.5 (95% CI 1.34 to 4.30, p<0.01). Overall, twenty-one participants died due to pneumonia, SMR 2.3 (95% CI 1.14 to 3.49, p<0.01). For this, UCoD subcategory we found excess mortality both among women with SMR 2.3 (95% CI 1.13 to 4.03, p<0.05) and men with SMR 2.3 (95% CI 1.11 to 4.25, p<0.05), for pwROMS with SMR 2.4 (95% CI 1.34 to 2.82, p<0.01) and among pwMS with disease onset before 1951 with SMR 2.8 (95% CI 1.45 to 6.03, p<0.01) and those experiencing their first MS symptom before 30 years of age with SMR 3.1 (95% CI 1.23 to 6.30, p<0.05).

We found excess mortality due to gastrointestinal cancers in the 1980–1989 onset cohort, SMR 2.2 (95% CI 1.02 to 4.24, p<0.05), but, overall, we could not observe excess mortality due to neoplasms, SMR 1.0 (95% CI 0.82 to 1.15). Although we could not find excess mortality due to diseases of the digestive system in total, there was an increase in SMR among pwMS with onset before age 30 in this main category, SMR 2.4 (95% CI 1.11 to 4.62, p<0.05).

Overall, there was no excess mortality due to diseases of the circulatory system, SMR 1.1 (95% CI 0.97 to 1.34). However, we found excess mortality from diseases of the circulatory system, among women with MS for the total study period, SMR 1.4 (95% CI 1.07 to 1.70, p<0.05), and for the 1970–1979 onset cohort, SMR 1.7 (95% CI 1.20 to 2.39, p<0.01). Death due to underlying acute myocardial infarction was increased in the same subgroups, SMR 1.6 (95% CI 1.02 to 2.33, p<0,05) in women and SMR 1.9 (95% CI 1.05 to 3.22, p<0.05) for the 1970–1979 onset cohort. For the latter subgroup mortality from cerebrovascular diseases was increased, SMR 2.5 (95% CI 1.27 to 4.55, p<0.05).

The cause-specific SMRs for all the reported UCoD categories and selected subcategories are shown in table 4.

Table 4

Overall cause-specific standardised mortality ratios (SMRs) in persons with multiple sclerosis for selected* underlying causes of death (UCoDs)

All-cause mortality risk before and after the introduction of immunomodulatory therapy

We identified 715 deceased pwROMS. Of these, 559 were diagnosed before 1990, including 190 between 1980 and 1989. Between 1990 and 1999, 112 pwROMS were diagnosed, and 44 in the subsequent years until 2019.

All-cause mortality risk was lower for pwROMS diagnosed between 2000 and 2019, HR 0.49 (95% CI 0.34 to 0.70, p<0.001) compared with the reference group, that is, those diagnosed between 1990 and 1999 (table 5). For pwROMS diagnosed before DMTs became available, those diagnosed between 1980 and 1989 had lower risk of mortality, HR 1.7 (95% CI 1.30 to 2.10, p<0.001), than those diagnosed before 1980, HR 2.4 (95% CI 1.94 to 3.05, p<0.001). These findings remained consistent in the sensitivity analysis in which follow-up time was restricted to 20 years (results not shown).

Table 5

All-cause mortality risk in relapsing-remitting multiple sclerosis by period of diagnosis, sex, age at onset and diagnostic delay

Discussion

In this longitudinal study, we found shortened lifespans and excess mortality in pwMS, corroborating the findings from a recent meta-analysis.6 Approximately, 8 out of 10 pwMS died while receiving care at a hospital or another health institution, which is similar to a study from Finland published recently.20

The life expectancy for pwMS was, on average, reduced by 8.8 years, which is similar to the findings in a Canadian population-based study.21 The observed 3.9-year difference in median life expectancy between women and men with MS is comparable to the sex difference observed in the general Norwegian population. On average, pwROMS survived, 5.3 years longer than pwPOMS.

When evaluating survivorship from disease onset, the survival of pwMS started to diverge from that of the general population after approximately 10 years of disease duration. Furthermore, this decrement appears to occur earlier in men and is most pronounced for pwPOMS (figure 1B).

When assessing the effect of age at onset on survival, a later onset appears favourable when attained age is considered. However, in terms of absolute survival time in years, those who experience onset of MS at younger ages survive the longest (online supplemental table 1). A similar phenomenon has been observed for clinical, neuropsychological and radiologic markers of disease progression when comparing adult-onset to paediatric-onset MS, where the paediatric group requires longer time to achieve specific disability and MRI milestones but does so at younger age.22

As shown in table 2, the all-cause SMR initially increased for pwMS with disease onset from before 1950 and up to 1979, whereas EDR remained stable in the same period. For the subsequent onset cohorts, we observed a decrease in comparative and absolute excess mortality as measured by all-cause SMR and EDR, corroborating previous findings from Hordaland.3 However, and as pointed out by the authors of a recent meta-analysis, which failed to demonstrate a reduction in all-cause SMR in pwMS during the past 65 years6, shorter follow-up time for participants enrolled towards the end of a study period, among other factors, offers a plausible explanation for the apparent improvement in survivorship observed in previously published reports from Scandinavia.2 4

When assessing all-cause mortality by age of MS onset, SMR was highest for the youngest onset group, and lowest for the oldest onset group, implying a higher relative mortality risk for pwMS that experience early onset compared with the general population (table 2). This observation is expected when acknowledging that competing mortality risks increase with age, and when considering that mortality in the younger background population is low.

In absolute terms, however, we found similar EDRs for all the different age at onset groups, apart from the oldest (≥50 years) group (table 2). Current age was recently shown, in a study modelling EDR trajectories in a large cohort of pwMS from France, to have a stronger effect on mortality in pwROMS compared with duration of disease.23 In the present study, we did not find an excess mortality during the first decade after disease onset, but after more than 10 years of disease duration, we found a time-dependent successive increase in EDR (table 3), which corroborates findings from previous reports.18 19

As expected, the cause-specific mortality due to MS was high (table 4). The SMR for epilepsy was also considerable and comorbid epilepsy has been associated with increased risk of mortality in pwMS.24 However, 26 out of 28 deaths in this subcategory occurred in patients experiencing onset before 1959. Thus, epilepsy appears to be a historical UCoD in this longitudinal study population.

Cancer mortality was not increased among patients with RRMS, nor among the latest onset cohorts, which constitute patients most likely exposed to DMTs. Excess mortality from gastrointestinal neoplasms was only observed for the 1980–1989 onset cohort, possibly due to fluctuations in cancer incidence.

Among pwMS with onset before age 30, we found excess mortality due to diseases of the digestive system, but not in total (table 4).

Overall, we found excess mortality due to disease of the circulatory system in women and for the 1970–1979 onset cohort. Indeed, pwMS, and females more than males, appear to have an increased cardiovascular disease mortality.25 The observed increase in comparative mortality for the 1970–1979 onset cohort is arguably a reflection of known cardiovascular risk factors, for example, smoking, and high dietary intake of saturated fats, which previously were more common.

We observed an excess in mortality from diseases of the respiratory system, particularly pneumonia, and most evident in pwMS with disease onset before 30 years of age. Progressive disability accumulation and immobility are known risk factors for developing respiratory infections, including aspiration pneumonia, which are common causes of death in pwMS.21

When comparing all-cause mortality risk for pwROMS before and after the start of the DMT era, and by using pwROMS diagnosed between 1990 and 1999 as the reference group, we found the risk to be highest among those diagnosed before 1980. Between 1980 and 1989, this risk decreased, and after DMTs were made readily available between 2000 and 2019, this risk was more than halved (table 5).

We suggest that several healthcare improvements, not only access to DMTs, are associated with the observed improvement in all-cause mortality risk for pwROMS, but also the implementation of MRI contributing to reduced diagnostic delay and better symptomatic therapies (table 1).

Strengths and limitations

The use of national health registries, a well-defined study population, and the long duration of follow-up are strengths of the present study.

However, our study has limitations. During the study period, different diagnostic criteria have been applied, including outdated revisions based primarily or exclusively on clinical assessment, and without the use of advanced ancillary examinations. The clinical application of different diagnostic criteria, in combination with early initiation of DMT, is associated with pwMS reaching disability milestones at a slower rate.26 Following a diagnosis of MS, early exposure to DMTs, or treatment of disease related symptoms and signs, could convey beneficial effects on survival and mortality. However, and since we did not have detailed data on symptomatic therapy or DMT use, we are unable to elaborate on these potential effects.

Due to the longitudinal study design, pwMS diagnosed during the earliest periods may have inherent differences in disease severity and interval from onset to diagnosis. The median diagnostic delay from MS onset varied noticeably for the different onset cohorts (table 1). Using survival measures based on time of disease onset negates this effect partially, but a person’s recollection of their first suggestive symptom of MS is subject to recall bias, particularly for pwMS brought to late diagnostic attention or who initially developed mild or unspecific transient symptoms. Furthermore, retrospective determination of disease onset based on suggestive symptomatology, as provided by pwMS themselves or through scrutinising medical records, is unlikely to be accurate, especially when considering the increasing amount of evidence of a protracted prodromal, preclinical and presymptomatic phase in MS.27–29

For the survival and mortality analyses, we were unable to evaluate objective measures of individual disease severity, for example, frequency of relapses and clinical signs of disability progression, and paraclinical evidence of disease activity, that is, formation of new lesions on MRI and accelerated brain atrophy. We did not have comprehensive data on smoking history for estimating the amount of tobacco exposure in the study population. Smoking in pwMS has been associated with disability progression, conversion to SPMS and premature mortality.30 31 Similarly, we did not have access to data on comorbid conditions to assess individual disease burden beyond MS. Comorbidities are common in pwMS and affect disability progression and survival negatively.32 33 This also pertains to certain types of malignancies, which appear to be more prevalent among pwMS,34 and the incidence of cancer was higher among pwMS in Norway after DMTs became available.10 However, in the present study, we did not find excess cancer mortality among persons considered eligible for treatment with DMTs, that is, pwROMS.

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