Stable excess mortality in a multiple sclerosis cohort diagnosed 1970-2010.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is associated with excess mortality. The use of disease-modifying treatments (DMTs) has recently been associated with survival benefits. METHODS: A regional MS database was linked with national registries. People with MS (pwMS) diagnosed in 1971-2010 were included and followed up until the end of the year 2019. Five matched controls were acquired for every person with MS. DMTs included in the analyses were interferon and glatiramer acetate. RESULTS: Median follow-up time of the 1795 pwMS was 20.0 years (range 0.1-48.7 years). Survival did not differ between decades of diagnosis (p = 0.20). Amongst pwMS, male sex (adjusted hazard ratio [aHR] 1.70; 95% confidence interval [CI] 1.41-2.06), higher age at diagnosis (aHR 1.83; 95% CI 1.65-2.03 per 10-year increment) and primary progressive disease course (aHR 1.29; 95% CI 1.04-1.60) were independently associated with poorer survival. DMT use was associated with better survival (p < 0.0001) and better survival during follow-up (aHR 0.56; 95% CI 0.38-0.81). Compared to matched controls, median life expectancy was 8-9 years shorter in pwMS with survival diverging from controls during the first decade after diagnosis, more clearly in men than women. CONCLUSION: Despite DMT use being associated with better survival, relative life expectancy of pwMS did not change over five decades in Western Finland. Male sex was an independent risk factor for death amongst pwMS, but excess mortality was higher in women. More work and methods are needed to improve survival in pwMS.

Evaluation of serum miR-191-5p, miR-24-3p, miR-128-3p, and miR-376c-3 in multiple sclerosis patients.

BACKGROUND: Biomarkers that could be used in early diagnosis of multiple sclerosis (MS), segregation of disease subtypes, and discrimination of the aggressive disease course from the benign one are urgently needed. OBJECTIVE: The aim of this study was to investigate the specificity of circulating microRNAs: miR-191-5p, miR-128-3p, miR-24-3p, and miR-376c-3p in MS and evaluate their association with disease activity and disability progression. METHODS: The expressions of circulating miRNAs were studied in serum of 100 subjects (53 relapsing-remitting (RRMS), 20 primary progressive (PPMS), and 27 controls), using miScript serum miRNA RT-PCR assay techniques. RESULTS: In comparison with controls, miR-191-5p and miR-24-3p were overexpressed in RRMS and PPMS, with no differences between the subtypes. miR-24-3p correlated positively with the disability progression index in the combined group of all patients with MS. miR-128-3p showed tendency toward the predominant expression in PPMS and correlated positively with the annual relapse rate in RRMS. miR-376c-3p expression levels did not differ between the groups, and no associations were found to clinical parameters. CONCLUSION: This study highlighted the connection of circulating miRNAs to MS. miR-24-3p and miR-128-3p showed a tendency of association with disability accumulation and disease activity, respectively. Further studies should evaluate their suitability for clinical use.

Painful musculosceletal disorders and depression among working aged migraineurs.

OBJECTIVE: Musculoskeletal disorders and depression are common among migraineurs. The aim of our study was to evaluate the occurrence of these disorders among working aged migraineurs. MATERIAL AND METHODS: The risk for fibromyalgia, rheumatoid arthritis (RA), osteoarthrosis (OA), sciatic syndrome, and the occurrence of depression was studied among cases who reported about these conditions and migraine in working aged Finnish population in The Health and Social Support Study (HeSSup) based on postal questionnaire in 2012. Group differences were tested by chi-square test. Odds ratios (ORs with 95% CI) adjusted for age, gender, education level and depression were calculated with logistic regression analysis. RESULTS: Total of 1505 migraineurs (13%) and 8092 controls were included among the 11 596 responders in 2012. Age and gender adjusted ORs, 2.37 (95% CI 1.81-3.09) for fibromyalgia, 1.46 (1.10-1.95) for RA, 1.58 (1.38-1.80) for OA, and 2.09 (1.84-2.37) for sciatic syndrome, were significant. At least moderate depression was more common among migraineurs (7.3%) than among controls (3.4%) (P < .001). CONCLUSION: Recognition of comorbid musculoskeletal disorders and mood disorders among migraineurs needs targeted outreach in working aged population. The acute and preventive treatments to control for neuronal sensitization in migraine and comorbid pain disorders may benefit of individual treatment plan and tailored use of antidepressants.

Common comorbidities and survival in MS: Risk for stroke, type 1 diabetes and infections.

BACKGROUND: Survival in MS has increased during the era of disease modifying therapies, but life expectancy in MS patients is still reduced by several years. Increased risk for common comorbidities related to brain health, such as risk for circulatory diseases have been reported in MS and could affect survival. In this paper, we studied age- and gender adjusted risks for circulatory diseases and related disorders, and their impact on overall MS survival in population of Southwest Finland. MATERIALS AND METHODS: The ICD-10 codes for hospital visits were searched from the administrative data pool from 1.1.2004 up to 31.12.2012 for the resident MS and control cases at the Hospital District of Southwest Finland. The MS population under study consisted of prevalent cases in 1.1.2004 and new cases from 1.1.2004 followed up to death or 31.12.2012. Patient documents were scrutinized to confirm the MS diagnosis (G 35) by the McDonald´s criteria and to confirm the diagnoses and causes of death for the cerebro- and cardiovascular diagnoses under study. The randomly chosen 10-fold control population was matched by birth year and gender to calculate the coincident risks (odds ratio, OR) with 95% confidence intervals (95% CI) and another separate control population from the same patient pool was used to verify the stability of the results. P-values were calculated using Pearson's χ2 test. The Kaplan- Meier analysis log rank test was applied to study survival. RESULTS: During the follow-up 1074 confirmed MS cases were treated in the hospital district, including the deceased cases after 1.1.2004 (5.9%). The probability of survival was 82.4 years among MS and 85.6 years among the control cases, log rank p < 0.001. The survival disadvantage within MS was associated with comorbidity for circulatory disease codes in ICD -10: I06-I71, log rank p < 0.001. The specific risk for ischemic and haemorrhagic stroke was significant with high OR of 1.49 (95% CI 1.03- 2.35) and 2.5 (1.24-5.06) respectively. The two-fold risk for type 1 diabetes in MS was significant, OR 2.1 (1.3-3.36). The main causes of death among the MS cases were infections and the coincident high risk for several infections was significant. There was no difference in the risk for acute myocardial infarct, transient ischemic attack, atrial fibrillation, hypertension, or obesity in comparison with the control cases. CONCLUSIONS: Given the high risk for stroke in this MS population and the observed complexity among the coincident common risk factors for circulatory diseases, the high risk for type 1 diabetes and common infections raise a need to recognize patients at risk with these conditions and with the other known risk factors such as metabolic syndrome and smoking. The survival disadvantage related to circulatory diseases observed in general population is true also in MS and should be recognized to reduce the burden of disease and premature mortality in MS.

Risk of osteoporotic fractures in multiple sclerosis patients in southwest Finland.

OBJECTIVES: Increased risk of osteoporotic fractures in multiple sclerosis (MS) patients compared with general population has been reported. The purpose of this study was to assess the risk of osteoporotic and other low-energy fractures in an MS cohort from a large hospital district in southwest Finland. Age-adjusted total and gender-specific prevalence for definite MS per 100 000 in a population of 472 139 was calculated as a point prevalence in December 31, 2012. MATERIALS AND METHODS: Patients with MS and comorbid fractures were identified by searching for ICD-9 and ICD-10 codes during a period from 2004 to 2012 from hospital administrative data in Turku University Hospital (TYKS) in southwest Finland Case ascertainment was performed by review of medical records. Osteoporotic fracture was defined as a low-energy fracture of the pelvis, hip, femur, tibia, humerus, collar bone, ulna/radius, vertebrae, or rib. The control population was a 10-fold age- and gender-matched population. RESULTS: The point prevalence (N 1004) of MS was 212.6/105 (CI 199.5-225.8) in December 31, 2012. A total of 100 (9.9%) of 1004 confirmed MS cases experienced at least one fracture during the study period. Relative risks (RRs) for all fractures (1.33, 95% CI 1.10-1.60) and osteoporotic fractures (1.50, 95% CI 1.18-1.90) were significantly increased in patients with MS compared with controls. In particular, RRs for hip fractures (5.00, 95% CI 2.96-8.43) and fractures of humerus (2.36, 95% CI 1.32-4.42) were elevated in patients with MS vs controls. CONCLUSIONS: We observed high prevalence of MS in southwest Finland and confirmed increased age-adjusted comorbid risk for osteoporotic fractures and other low-energy fractures compared with individually matched controls.

A visual migraine aura locus maps to 9q21-q22.

OBJECTIVE: To identify susceptibility loci for visual migraine aura in migraine families primarily affected with scintillating scotoma type of aura. METHODS: We included Finnish migraine families with at least 2 affected family members with scintillating scotoma as defined by the International Criteria for Headache Disorders-II. A total of 36 multigenerational families containing 351 individuals were included, 185 of whom have visual aura and 159 have scintillating scotoma. Parametric and nonparametric linkage analyses were performed with 378 microsatellite markers. The most promising linkage loci found were fine-mapped with additional microsatellite markers. RESULTS: A novel locus on chromosome 9q22-q31 for migraine aura was identified (HLOD = 4.7 at 104 cM). Fine-mapping identified a shared haplotype segment of 12 cM (9.8 Mb) on 9q21-q22 among the aura affected. Four other loci showed linkage to aura: a locus on 12p13 showed significant evidence of linkage, and suggestive evidence of linkage was detected to loci on chromosomes 5q13, 6q25, and 13q14. CONCLUSIONS: A novel visual migraine aura locus has been mapped to chromosome 9q21-q22. Interestingly, this region has previously been linked to occipitotemporal lobe epilepsy with prominent visual symptoms. Our finding further supports a shared genetic background in migraine and epilepsy and suggests that susceptibility variant(s) to visual aura for both of these traits are located in the 9q21-q22 locus.

Occurrence of multiple sclerosis in central Finland: a regional and temporal comparison during 30 years.

OBJECTIVE: We estimated the prevalence and incidence of multiple sclerosis (MS) in central Finland up to 2000. Rates were compared with those in other areas in Finland. MATERIAL AND METHOD: MS cases were identified in the hospital registry by ICD codes for demyelinating diseases from 1979 to 2000. Cases with definite MS were included. Incidence and prevalence were calculated with 95% CI and standardization was performed using direct method. RESULTS: In 1993 prevalence was 59/10(5) (n = 153). Incidence in 1979-93 was 3.8/10(5) person-years (n = 126). Rates are similar to average in areas with known rates of MS in Finland but substantially less than the over twofold MS risk in the neighbouring district Seinajoki. Extended follow-up to 2000 in central Finland showed increasing prevalence up to 105/10(5) (n = 277) and a significant increase in incidence 1994-98 up to 9.2/10(5) (n = 105). At the same time the diagnostic use of MRI increased up to 97%. CONCLUSION: Central Finland represents an average risk area of MS when compared with other areas of Finland but still a high risk in global comparison. The recent rapid increase in both prevalence and incidence is largely accounted for by increased use of MRI.

A two-stage study on multiple sclerosis susceptibility and chromosome 2q33.

We have performed a two-stage study to analyse the association of polymorphism on chromosome 2q33 with multiple sclerosis (MS). In all, 17 markers were analysed in stage-1 in 134 Finnish MS families and the observed associations were tested in stage-2 in 186 MS families. We did not find previously reported allelic or haplotype associations with CTLA4. We obtained a weak signal of two distinct predisposing genes, one proximal the other distal of CTLA4. The putative proximal gene was associated with the marker rs3977 in families lacking HLA-DR2 (P=0.02 and 0.02) and the other distal gene was associated with D2S1271 in families from a high-risk region in western Finland (P=0.02 and 0.01). Based on the >3 cM distance and the lack of linkage disequilibrium between these loci, we conclude that the two association signals are independent. Our results provide preliminary evidence for two distinct MS susceptibility genes on 2q33 outside of CTLA4.

Linkage disequilibrium between the MBP tetranucleotide repeat and multiple sclerosis is restricted to a geographically defined subpopulation in Finland.

We have previously found evidence for linkage as well as allelic and haplotype association between the myelin basic protein (MBP) gene and multiple sclerosis (MS). These findings have, however, not been reproduced in other populations. Here, we have analyzed association between MBP and MS in a new set of 349 Finnish triad families. Families with a parent born in the Southern Ostrobothnian region in western Finland (Bothnia families, n=98) were analyzed as a separate group since our previous studies included a high proportion of patients and families from this high-incidence region. Other families (n=251) were collected at five hospitals in southern, eastern, and northern Finland. The MBP short tandem repeat was genotyped, and haplotype patterns were verified by sequencing. In the Bothnia families, the previously detected associations with the 1.27 kb allele and haplotype 1.27-B10 were confirmed (P=0.01 and 0.02, respectively), whereas in the other families there was not even a trend toward association. These results demonstrate a geographic/genealogical restriction in the association between MS and the MBP short tandem repeat, highlight the importance of genealogical information in genetic studies of complex traits, and may provide an explanation why the association has not been found in many other populations.

Multiple sclerosis in Finland: incidence trends and differences in relapsing remitting and primary progressive disease courses.

OBJECTIVE: To compare the secular trends and geographical differences in the incidence of relapsing-remitting (RRMS) and primary progressive multiple sclerosis (PPMS) in Finland, and to draw inferences about aetiological differences between the two forms of the disease. METHODS: New multiple sclerosis cases in southern Uusimaa and the western districts Vaasa and Seinäjoki of Finland in 1979-1993 were verified from hospital records and classified into RRMS and PPMS. Patients met the Poser criteria for definite multiple sclerosis or otherwise satisfied the criteria for PPMS. Disease course was categorised by the same neurologist. Crude and age adjusted incidence in 1979-1993 was estimated. RESULTS: During 1979-1993 the age adjusted incidence was 5.1 per 100 000 person-years in Uusimaa, 5.2 in Vaasa, and 11.6 in Seinäjoki. The rates in Uusimaa remained stable, while a decrease occurred in Vaasa and an increase in Seinäjoki. Between 1979-86 and 1987-93 the incidence of PPMS increased in Seinäjoki from 2.6 to 3.7 per 10(5) and decreased in Vaasa from 1.9 to 0.2 per 10(5); the trends were similar for RRMS. CONCLUSIONS: There are significant differences in secular trends for multiple sclerosis incidence in Finland by geographical area, but these are similar for PPMS and RRMS. The recent changes point to locally acting environmental factors. The parallel incidence trends for RRMS and PPMS suggest similar environmental triggers for the two clinical presentations of multiple sclerosis.

Survival of multiple sclerosis in Finland between 1964 and 1993.

The long-term survival of multiple sclerosis (MS) was studied during 1964-1993 in a cohort of 1614 patents in Finland. Survival to death from the initial MS symptoms was analysed by the life-table method, separately for MS related and all causes of deaths. Survival at 40 years was 64% for MS deaths and 53% for all deaths. Higher proportions of violent deaths and neoplasms were observed among MS patients as compared to the general population, whereas the proportion of cardiovascular causes of death was low. MS-related causes accounted for 70% of the recorded 219 deaths. Favourable survival in MS was associated with relapsing-remitting disease course, age at onset below 30 years and optic neuritis or other sensory symptoms at presentation. We were unable to show any significant effect due to calendar time of diagnosis or gender, as the risk of men was similar (risk ratio [RR] = 1.1, confidence interval [CI] 0.8-1.6) as compared to women.

Chromosome 19q13 and multiple sclerosis susceptibility in Finland: a linkage and two-stage association study.

Several studies have previously provided some albeit weak evidence for linkage or association between chromosome 19q13 and multiple sclerosis (MS) susceptibility. We performed a two-stage association analysis with 19 markers spanning 7 Mb/5.5 cM of 19q13. In stage 1 analysis (135 MS families) allelic and haplotypic associations were found with markers within or close to the ApoE-ApoC subregion. These observations were taken as a hypothesis, which was tested in stage 2 in 125 families. However, none of the initial associations were replicated suggesting that they were most likely due to chance. Linkage analysis was performed in 27 Finnish multiplex families using 10 microsatellites spanning 23 Mb/24 cM of 19q13. DNA was available from 72 MS patients and 150 unaffected relatives. Parametric and non-parametric linkage analyses did not provide evidence for linkage when all families were tested. After stratifying the families according to HLA-DR15 there was weak evidence for linkage to the 19q13.1 subregion in DR15 negative families (LOD(max)=1.8). Taken together these results do not support a major role of chromosome 19q13.2-q13.3 in MS susceptibility among Finnish MS patients, whereas conclusions on the 19q13.1 subregion are less clear and this region requires further study.

Increasing prevalence of multiple sclerosis in Finland.

OBJECTIVES: To follow-up the prevalence trends of MS from 1983 to 1993 in western and southern Finland. MS epidemiology has been previously followed from 1964 to 1978 in these regions. The updated prevalences were correlated with incidence trends in the same period. METHODS: Age-adjusted and age-specific MS prevalence rates were calculated for cases classified by Poser's criteria. RESULTS: In the western health-care districts, Seinäjoki and Vaasa, prevalences in 1993 were 202/10(5) and 111/10(5). In the southern district Uusimaa the respective figure was 108/10(5). In Seinäjoki a significant 1.7-fold increase was found in 1993 as compared to 1983, mainly due to increased incidence. In Uusimaa a significant 1.2-fold increase in prevalence was found in the presence of stable incidence. In Vaasa prevalence was stable, although incidence was declining. CONCLUSION: The prevalence of MS is increasing in Seinäjoki and Uusimaa but not in Vaasa. Both the prevalence and incidence in Seinäjoki are now among the highest reported.

Regional and temporal variation in the incidence of multiple sclerosis in Finland 1979-1993.

Previous surveys in Finland from the 1960s have documented an uneven geographic distribution of multiple sclerosis (MS). In the present study, the incidence of MS was studied during 1979-1993 in the western Vaasa and Seinäjoki regions and in southern Uusimaa. The overall difference between the western and southern regions persisted; 8.7 per 100,000 in the western, and 5.1 per 100,000 in the southern region. The incidence of 11.6 per 100,000 in Seinäjoki was more than twofold greater than the 5.2 per 100,000 incidence found in neighboring Vaasa. An increasing incidence trend was observed for men in Seinäjoki, and a decrease for both sexes in Vaasa, while in Uusimaa the incidence remained stable for both sexes. The different incidence trends could not be readily explained by differences in case ascertainment but suggest the effect of environmental factors that have modulated the incidence of MS during the 15-year study period.