Marja-Liisa Sumelahti

A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis

Objectives To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB) in patients with multiple sclerosis (MS). Methods 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests. Results Median change in BOD was 287 mm3 in the placebo group and 83 mm3 in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19–82) nmol/l to 110 (range 67–163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate. Conclusion Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS. Trial registration number EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.

Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

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 Posers criteria. Results– In the western health‐care districts, Seinäjoki and Vaasa, prevalences in 1993 were 202/105 and 111/105. In the southern district Uusimaa the respective figure was 108/105. 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.

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.

Causes of death among patients with multiple sclerosis

Background: Several studies show a high mortality risk among patients with multiple sclerosis (MS). Objectives: In this study, mortality and underlying causes of death were analysed among patients with MS diagnosed between 1964—1993 in Finland (n = 1595). Methods: Standardized mortality ratios (SMRs) were calculated for both genders. The follow-up was based on linkage to the national computerized Cause-of-Death Register of Statistics Finland. Results: Altogether, 464 deaths were recorded by the end of 2006. The SMR as compared with the general population among females was 3.4 (95% confidence interval 3.0—3.9) and among males 2.2 (1.9—2.6). In total, 270 patients (58%) died from MS; only one of these deaths occurred during the first 2 years after the MS diagnosis. Mortality was also increased for other natural causes of death (n = 160) in patients followed for more than 10 years (SMR 1.4, 1.2—1.7), with a significant increase in deaths from influenza (29, 6.0—85), pneumonia (4.7, 2.5—8.0) and gastrointestinal causes (4.4, 2.3—7.7). The SMR for violent causes was 1.2 (0.7—1.9) and for alcohol-related deaths 0.2 (0.02—0.7). The SMR for suicides was 1.7 (0.9—2.7). Conclusions: The MS population has an increased disease mortality, while the increase in the risk of accidents and suicides is not significantly increased among patients with MS in Finland.

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 patients 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.

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 105 and decreased in Vaasa from 1.9 to 0.2 per 105; 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.

Cancer incidence in multiple sclerosis: a 35-year follow-up.

The risk of cancer among multiple sclerosis (MS) patients was evaluated emphasising cancers with a potentially infectious aetiology. Cancer incidence was estimated among incident MS patients in 1964–1993 (n = 1,597) in Finland. The cohort was followed up for cancer incidence through the Finnish Cancer Registry until 1999. A total of 85 cancer cases were diagnosed showing a standardised incidence ratio (SIR) of 1.0 (95% CI 0.8–1.2) for all cancers. The risk (SIR) of haematological tumours was 1.1 and that of central nervous system (CNS) tumours 1.3. The small excess risk of haematological malignancies is consistent with infectious aetiology, whereas the association between MS and CNS tumours may be due to misclassification.

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.