Vitamin D in the Prevention and Treatment of Multiple Sclerosis

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS); it is the most common cause of neurological disability in young adults. The cause of MS is unknown but it is believed to be precipitated by both genetic and environmental risk factors. An association between vitamin D deficiency and increased risk of MS has been detected in several epidemiological and case-control studies and is further supported by immunological and genetic studies. It is still unclear whether there is any special age at which exposure to vitamin D deficiency increases the MS risk e.g. is in utero vitamin D deficiency particularly detrimental. Serum levels of vitamin D are associated with both clinical and magnetic resonance imaging (MRI)-assessed disease activity but there have been very few randomized placebo-controlled trials (RCTs) investigating the benefits of vitamin D supplementation in established MS patients. Aims of the study: This study initially investigated the association between vitamin D status during early pregnancy and the risk of MS in the offspring in the Finnish Maternity Cohort. Secondly, we performed the first RCT with vitamin D in MS, evaluating the safety and efficacy of 500 ug weekly dose of vitamin D supplementation or placebo in 68 MS patients receiving interferon beta-therapy. We also studied the mechanism of action of vitamin D supplementation in our study participants. Finally, we updated the MS prevalence and studied the fracture risk and the role of vitamin D in the risk of fractures in MS patients in Southwest Finland. Results: Maternal vitamin D deficiency during early pregnancy was associated with a nearly 2-fold increased risk of MS in their children in comparison with children born to mothers who were non-deficient for vitamin D. In the vitamin D supplementation study there was a statistically significant decrease in the total number of T1 Gadolinium (Gd) enhancing lesions in patients treated with vitamin D in comparison with placebo treated patients. Serum levels of transforming growth factor beta (TGF-β), an immunoregulating cytokine, indirectly measured by a latency-associated peptide (LAP) immunoassay, increased significantly in the vitamin D treated group but not in the placebo group. The prevalence of MS in southwest Finland was 212/105. The relative risk was 1.3 for all types of fractures and 1.5 for osteoporotic fractures in patients with MS compared with matched controls. Conclusions: Correcting vitamin D deficiency during pregnancy may exert a beneficial effect on the risk of the offspring developing MS. Vitamin D supplementation at 500 ug/week influenced the MRI-assessed activity in patients with MS. The immunoregulatory effects of TGF-β may play a role in the improved MRI outcomes observed in our vitamin D treated MS patients. At a mean serum level of 110 nmol/l of 25-hydroxyvitamin D (25(OH)D), its immunological effects can already be detected. We observed a statistically significantly elevated risk of osteoporotic fractures in patients with MS. Several conclusions emerge from our results. First, we recommend correcting vitamin D deficiency during pregnancy at the population level but especially in MS patients planning to become pregnant. Second, we recommend that vitamin D levels should be analyzed in all MS patients after the diagnosis of MS and vitamin D supplementation should be initiated at a dose of 50 to 100 ug/day, targeting serum levels above 100 nmol/l.D-vitamiini MS-taudin ehkäisyssä ja hoidossa Tausta: Multippeliskleroosi eli MS-tauti on keskushermoston krooninen autoimmuunisairaus ja yleisin liikunta- ja toimintakykyyn vaikuttava neurologinen sairaus nuorilla aikuisilla. MS-taudin aiheuttajaa ei tiedetä, mutta sen uskotaan syntyvän perintötekijöiden ja ympäristöriskitekijöiden yhteisvaikutuksesta. D-vitamiinin puute on noussut tärkeäksi MS-taudin ympäristöriskitekijäksi useissa epidemiologisissa ja tapaus-verrokkitutkimuksissa sekä immunologisissa ja geneettisissä tutkimuksissa. Vielä on epäselvää, missä iässä koettu D-vitamiinin puute lisää MS-taudin riskiä ja vaikuttaako esimerkiksi äidin raskaudenaikainen D-vitamiinin puute lapsen riskiin sairastua MS-tautiin. Seerumin D-vitamiinitasojen on todettu olevan yhteydessä MS-taudin kliiniseen ja magneettikuvauksella (MRI) todettavaan aktiivisuuteen, mutta D-vitamiinilisän tehoa jo puhjenneessa MS-taudissa on tutkittu vasta vähän satunnaistetussa lumekontrolloidussa asetelmassa. Tavoitteet: Tämän tutkimuksen tavoitteena oli tutkia äidin raskaudenaikaisen D-vitamiinitason yhteyttä lapsen MS-tautiriskiin Äitiysneuvolakohorttiin kuuluvilla naisilla. Tavoitteenamme oli myös tutkia 500 ug viikossa annosteltavan D-vitamiinilisän tai lumevalmisteen vaikutusta aivojen magneettikuvauksella todettavaan ja kliiniseen tautiaktiviteettiin MS-potilailla, jotka käyttävät interferoni beetaa, sekä selvittää D-vitamiinin immunologisen vaikutuksen mekanismeja näillä potilailla. Tavoitteenamme oli myös päivittää MS-taudin esiintyvyysluvut ja murtumariski MS-potilailla Varsinais-Suomen sairaanhoitopiirin alueella ja tutkia D-vitamiinin yhteyttä MS-potilaiden murtumariskiin. Tulokset: Äidin raskaudenaikainen D-vitamiinin puute oli yhteydessä lapsen lähes kaksinkertaiseen riskiin sairastua MS-tautiin verrattuna niihin lapsiin, joiden äidillä ei ollut D-vitamiinin puutetta. D-vitamiinilisän vaikutuksia selvittäneessä tutkimuksessa D-vitamiinilisää saaneilla potilailla aivojen MRI:ssä nähtävät T1-painotteiset gadoliniumilla (Gd) tehostuvat muutokset vähenivät tilastollisesti merkitsevästi verrattuna lumevalmistetta saaneisiin potilaisiin. Immunologisessa osatutkimuksessa todettiin immuunivastetta vaimentavan sytokiinin, transformoiva kasvutekijä beetan (TGF-β), pitoisuutta mittaavan latency-associated peptide LAP:n pitoisuuden nousevan tilastollisesti merkitsevästi enemmän D-vitamiini- kuin lumeryhmässä. MS-taudin esiintyvyys Varsinais-Suomessa oli 212/105 vuonna 2012. Murtumariski MS-potilailla oli 1.3-kertainen ja osteoporoottisten murtumien riski 1.5-kertainen verrokkeihin nähden. Johtopäätökset: Äidin raskaudenaikaisen D-vitamiinin puutoksen korjaamisesta saattaa olla hyötyä lasten MS-taudin ehkäisyssä. D-vitamiinilisä 500 ug viikossa vähensi aivojen magneettikuvauksella todettavaa MS-taudin aktiivisuutta. TGF-β:n immuunivastetta säätelevillä vaikutuksilla saattaa olla osuus MRI-tuloksiin, jotka havaittiin D-vitamiiniryhmässä. Immunologisia vaikutuksia voitiin todeta keskimäärin D-vitamiinitasolla 110 nmol/l. MS-potilaiden riski saada osteoporoottinen murtuma on merkitsevästi kohonnut. Tulostemme pohjalta suosittelemme D-vitamiinin puutoksen korjaamista raskausaikana sekä väestötasolla että erityisesti MS-potilailla, jotka suunnittelevat raskautta. Suosittelemme D-vitamiinitason määrittämistä kaikilta MS-potilailta ja D-vitamiinilisän aloittamista annoksella 50-100 ug päivässä tavoitteena seerumin D-vitamiinitaso yli 100 nmol/l

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 forMS 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 mother’s birth, and date of child’s birth. MAIN OUTCOMES AND MEASURES Maternal serum 25(OH)D levelswere 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 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 pregnancymay increase the risk of MS in offspring</p

Intensity of statin therapy after ischaemic stroke and long-term outcomes: a nationwide cohort study

Background Statins are essential for secondary prevention after ischaemic stroke (IS). However, statin intensity recommendations differ, and there is a concern about intracerebral haemorrhage (ICH). We studied the long-term impacts of initial statin intensity following IS.Methods Consecutive patients using high-intensity, moderate-intensity or low-intensity statin early after IS (n=45 512) were retrospectively studied using national registries in Finland. Differences were adjusted using multivariable regression. The primary outcome was all-cause death within 12-year follow-up (median 5.9 years). Secondary outcomes were recurrent IS, cardiovascular death and ICH studied using competing risk analyses.Results High-intensity therapy was initially used by 16.0%, moderate-intensity by 73.8% and low-intensity by 10.2%. Risk of death was lower with high-intensity versus moderate-intensity (adjusted HR (adj.HR) 0.92; 95% CI 0.87 to 0.97; number needed to treat (NNT) 32.0), with moderate-intensity versus low-intensity (adj.HR 0.91; 95% CI 0.87 to 0.95; NNT 27.5) and with high-intensity versus low-intensity (adj.HR 0.83; 95% CI 0.78 to 0.89; NNT 14.6) statin. There was a dose-dependent association of initial statin intensity with a lower probability of recurrent IS (p&lt;0.0001) and cardiovascular death (p&lt;0.0001). The occurrence of ICH was not associated with initial statin intensity (p=0.646).Conclusions Following IS, more intense initial statin treatment is associated with improved long-term outcomes but not with the risk of ICH. These findings emphasise the importance of high statin intensity shortly after IS

Epstein–Barr virus and multiple sclerosis risk in the Finnish Maternity Cohort

Abstract Objective: To determine whether maternal Epstein–Barr virus (EBV) IgG antibody levels are associated with risk of multiple sclerosis (MS) in the offspring. Methods: We conducted a prospective nested case–control study in the Finnish Maternity Cohort (FMC) with serum samples from &gt;800,000 women collected during pregnancy since 1983. Cases of MS among offspring born between 1983 and 1991 were identified via hospital and prescription registries; 176 cases were matched to up to 3 controls (n = 326) on region and dates of birth, sample collection, and mother‘s birth. We used conditional logistic regression to estimate relative risks (RRs) and adjusted models for sex of the child, gestational age at sample collection, and maternal serum 25‐hydroxyvitamin D and cotinine levels. Similar analyses were conducted among 1,049 women with MS and 1,867 matched controls in the FMC. Results: Maternal viral capsid antigen IgG levels during pregnancy were associated with an increased MS risk among offspring (RRtop vs bottom quintile = 2.44, 95% confidence interval [CI] = 1.20–5.00, p trend = 0.004); no associations were found between maternal EBV nuclear antigen 1 (EBNA‐1), diffuse early antigen, or cytomegalovirus IgG levels and offspring MS risk. Among women in the FMC, those in the highest versus lowest quintile of EBNA‐1 IgG levels had a 3‐fold higher risk of MS (RR = 3.21, 95% CI = 2.37–4.35, p trend &lt;1.11e‐16). These associations were not confounded or modified by 25‐hydroxyvitamin D. Interpretation: Offspring of mothers with high viral capsid antigen IgG during pregnancy appear to have an increased risk of MS. The increase in MS risk among women with elevated prediagnostic EBNA‐1 IgG levels is consistent with previous results