Merja Soilu-Hänninen

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.

Vitamin D Status During Pregnancy and Risk of Multiple Sclerosis in Offspring of Women in the Finnish Maternity Cohort

IMPORTANCE Vitamin D has been associated with a decreased risk of multiple sclerosis (MS) in adulthood; however, some, but not all, previous studies have suggested that in utero vitamin D exposure may be a risk factor for MS later in life. OBJECTIVE To examine whether serum 25-hydroxyvitamin D (25[OH]D) levels in early pregnancy are associated with risk of MS in offspring. DESIGN, SETTING, AND PARTICIPANTS Prospective, nested case-control study in the Finnish Maternity Cohort conducted in May 2011. We identified 193 individuals with a diagnosis of MS before December 31, 2009, whose mothers are in the Finnish Maternity Cohort and had an available serum sample from the pregnancy with the affected child. We matched 176 cases with 326 controls on region of birth in Finland, date of maternal serum sample collection, date of mothers birth, and date of childs birth. MAIN OUTCOMES AND MEASURES Maternal serum 25(OH)D levels were measured using a chemiluminescence assay. The risk of MS among offspring and association with maternal 25(OH)D levels were the main outcomes. Conditional logistic regression was used and further adjusted for sex of the child, gestational age at the time of sample collection, and season of sample collection to estimate the relative risks and 95% CIs. RESULTS Of the 193 cases in the study, 163 were female. Of the 331 controls in the study, 218 were female. Seventy percent of serum samples were collected during the first trimester of pregnancy. The mean (SD) maternal vitamin D levels were in the insufficient vitamin D range, but higher in maternal control than case samples (15.02 [6.41] ng/mL vs 13.86 [5.49] ng/mL [to convert to nanomoles per liter, multiply by 2.496]). Maternal vitamin D deficiency (25[OH]D levels <12.02 ng/mL) during early pregnancy was associated with a nearly 2-fold increased risk of MS in the offspring (relative risk, 1.90; 95% CI, 1.20-3.01; P = .006) compared with women who did not have deficient 25(OH)D levels. There was no statistically significant association between the risk of MS and increasing serum 25(OH)D levels (P = .12). CONCLUSIONS AND RELEVANCE Insufficient maternal 25(OH)D during pregnancy may increase the risk of MS in offspring.

Vitamin D3 administration to MS patients leads to increased serum levels of latency activated peptide (LAP) of TGF-beta

BACKGROUND Deficiency of vitamin D is an environmental risk factor for MS. Vitamin D has immunomodulatory effects, including promotion of T-cell differentiation into T-regulatory cells, which produces regulatory cytokines including TGF-β. Increasing serum vitamin D levels have been associated with decreased disease activity in MS patients, but there are only few studies concerning the immunological effects of vitamin D supplementation in MS. In this study we investigated the effect of weekly supplementation of vitamin D3 or placebo on serum levels of multiple cytokines in patients with relapsing remitting MS. METHODS The study was conducted on the patient cohort of the Finnish Vitamin D study. All patients were using IFN-beta-1b and were randomized to add-on treatment with either cholecalciferol 20,000 IU/week or placebo. Concentrations of LAP (TGF-β), INF-γ, IL-17A, IL-2, IL-10, IL-9, IL-22, IL-6, IL-13, IL-4, IL-5, IL-1β and TNF-α were determined at screening and at 12 months using commercial fluorescent bead immunoassay kits. RESULTS LAP (TGF-β) levels increased significantly in the vitamin D treated group from a mean of 47 (SE 11) pg/ml to 55 (SE 14) pg/ml in 12 months (p-value=0.0249). Placebo treatment had no significant effect on LAP levels. The levels of the other cytokines did not change significantly in either group. CONCLUSIONS We showed increased serum latency activated peptide (LAP) of TGF-β levels in MS patients treated with vitamin D3. The immune regulatory effects of TGF-beta may play a role in the improved MRI outcomes that we observed earlier in the vitamin D treated group of patients.

25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort

Objective: To determine whether and to what extent vitamin D deficiency is associated with multiple sclerosis (MS) risk. Methods: We conducted a prospective nested case-control study among women in the Finnish Maternity Cohort (FMC). The FMC had 1.8 million stored serum samples taken during the pregnancies of over 800,000 women at the time of this study. Through linkages with hospital and prescription registries, we identified 1,092 women with MS diagnosed between 1983 and 2009 with at least 1 serum sample collected prior to date of MS diagnosis; ≥2 serum samples were available for 511 cases. Cases were matched to up to 3 controls (n = 2,123) on date of birth (±2 years) and area of residence. 25-Hydroxyvitamin D (25[OH]D) levels were measured using a chemiluminescence assay. We used conditional logistic regression adjusted for year of sample collection, gravidity, and parity to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: A 50 nmol/L increase in 25(OH)D was associated with a 39% reduced risk of MS (RR 0.61, 95% CI 0.44–0.85), p = 0.003. Women with 25(OH)D levels <30 nmol/L had a 43% higher MS risk (RR 1.43, 95% CI 1.02–1.99, p = 0.04) as compared to women with levels ≥50 nmol/L. In women with ≥2 samples, MS risk was 2-fold higher in women with 25(OH)D <30 nmol/L as compared to women with 25(OH)D ≥50 nmol/L (RR 2.02, 95% CI 1.18–3.45, p = 0.01). Conclusions: These results directly support vitamin D deficiency as a risk factor for MS and strengthen the rationale for broad public health interventions to improve vitamin D levels.

Hemophagocytic lymphohistiocytosis in 2 patients with multiple sclerosis treated with alemtuzumab

Alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS) with a complex safety profile, including secondary autoimmunity in 40% of patients.1 We report 2 cases of hemophagocytic lymphohistiocytosis (HLH) in patients after alemtuzumab treatment of RRMS. This hyperinflammatory syndrome consists of fever, lymphadenopathy, pancytopenia, liver abnormalities, hyperferritinemia, raised soluble interleukin 2 (IL-2) receptor, and hemophagocytosis; it may be secondary to malignancies, autoimmune diseases, or infections.2 The table summarizes the diagnostic criteria for secondary HLH.

T2-weighted high-intensity signals in the basal ganglia as an interesting image finding in Unverricht-Lundborg disease

We conducted a search for white matter changes (WMCs) in 13 Unverricht-Lundborg disease patients and compared the prevalence of WMCs in these patients to age-matched long-term epileptics and healthy controls. ULD patients had significantly more T2-weighted high-intensity signals on MRI than control subjects, due to the increased prevalence of these signals in the basal ganglia. Interestingly, ULD patients with the basal ganglia changes were overweight. Basal ganglia T2-weighted high-intensity signals are novel findings in ULD.

Admission sodium level and prognosis in adult Guillain–Barré syndrome

Purpose: Guillain–Barré syndrome (GBS) varies in severity and outcome. Hyponatremia predicts poor outcome but previous studies have used divergent methodology and (pseudo)hyponatremia caused by intravenous immunoglobulin administration may confound analysis. We studied if the plasma sodium level at admission was associated with GBS outcome. Methods: All 69 patients at least 16 years of age treated for GBS in Turku University Hospital in 2004–2013 were included in the study. Clinical information was obtained from patient charts. Results: Women had lower sodium levels at admission (138; IQR 135, 140) compared to men (140; IQR 138, 142; p = 0.0116) but no association of sodium levels with demographics, pre-hospital variables or basic GBS characteristics was found. Multivariate analyses showed lower admission sodium levels to be associated with worse functional status at one year from disease onset (OR 1.37; 95% CI 1.07–1.76; p = 0.0136) and probability of being discharged to another care facility from the hospital (OR 1.31; 95% CI 1.05–1.64; p = 0.0180) but not associated with need of intensive care unit care (p = 0.09) or mechanical ventilation (p = 0.45), length of hospital stay (p =0.48) or functional status at six months (p = 0.07). Conclusions: Low plasma sodium level at admission is associated with a more severe disease course and a worse outcome in GBS independently of previously identified prognostic factors. Hyponatremia does not, however, appear to be caused by disease-specific factors.

Risk of osteoporotic fractures in multiple sclerosis patients in southwest Finland

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.

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 Pearsons 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.

Adult hospital admissions associated with multiple sclerosis in Finland in 2004–2014

Abstract Introduction: Treatment of multiple sclerosis (MS) has developed significantly and several new immunotherapeutic drugs have become available in Finland since 2004. We studied whether this is associated with changes in hospital admission frequencies and healthcare costs and whether admission rates due to infection have increased. Methods: The national Care Register for Health Care was searched for all discharges from neurological, medical, surgical, neurosurgical and intensive care units with MS as a primary diagnosis or an auxiliary diagnosis for primary infection diagnosis in 2004–2014. Only patients ≥16 years of age were included. Results: We identified 12,276 hospital admissions for 4296 individuals. The number of admissions declined by 4.6% annually (p = .0024) in both genders. Proportion of admissions with an infection as the primary diagnosis increased but no change in their frequency was found. They were longer than admissions with MS as the primary diagnosis and were associated with increased in-hospital mortality. The annual aggregate cost of hospital admissions declined by 51% during the study period. Conclusions: This study shows that hospital admission rates and costs related to MS hospital admissions have markedly declined from 2004 to 2014 in Finland, which coincides with an increase in the use of disease-modifying therapies. Key message Hospital admission rates and costs related to MS hospital admissions have markedly declined from 2004 to 2014 in Finland. Proportion of admission related to infection has increased and they are associated with longer hospitalizations and increased in-hospital mortality pointing out the importance of infection prevention.