Epstein-barr virus and multiple sclerosis risk in the finnish maternity cohort.

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 >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 <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. ANN NEUROL 2019;86:436-442.

Risk of cancer among Finnish multiple sclerosis patients.

BACKGROUND: Most studies that have investigated the association between multiple sclerosis (MS) and cancer have suggested a reduced overall cancer risk and no effect of long-term exposure to the immunomodulatory disease modifying treatments (DMTs). Some studies have suggested an increased cancer risk among MS patients treated with immunosuppressive (IS) therapies. Cancer risk among Finnish MS patients has previously been studied from an incidence cohort from 1964 to 1993 followed until year 1999. The objective of this nested case-control study was to assess the cancer risk among Finnish MS patients in a hospital district cohort from southwest Finland during the DMT era. METHODS: Patients with MS and cancer comorbidity were identified from the hospital administrative data at the Hospital District of Southwest Finland during a period from 1.1.2004 to 31.12.2012. Case ascertainment for MS diagnosis by the McDonald criteria was performed by review of medical records. During the follow-up 1074 confirmed MS cases were treated in the hospital district, including the deceased cases after 1.1.2004 (5.9%, n = 70). 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) for each cancer diagnosis. Another separate control population from the same patient pool was used to verify the stability of the results. The Kaplan-Meier analysis and ANOVA test log rank test was applied to study cumulative index proportion and age (years) at breast cancer diagnosis in the MS and in the control group. RESULTS: A total of 61 (5,7%) of the MS patients and 757 (7,0%) of the controls were diagnosed with cancer during the study period. The overall risk of cancer in the MS cohort did not significantly differ form the controls (OR 0.80, 95% CI 0.6-1.0, p = 0.092). The age at breast cancer diagnosis in the MS cohort was statistically significantly higher in comparison to the control cohort (61,7 vs. 55.7 years, ANOVA test p-value 0.010). However, the risk for breast cancer did not statistically significantly differ between MS patients and controls (OR 0.9, 95% CI 0.5-1.4, p-value 0.566). In the MS cohort we observed an increased risk of oral cavity cancers (OR 10, CI 1.1-94.2, p-value 0.04), colon cancer (OR 2.3, 95% CI 1.1-5.2, p-value 0.037), lung cancer (OR 4.4, CI 1.5-13.0, p-value 0.007), renal cancer (OR 3.6, CI 1.2-10.6, p-value 0.018), brain cancer (OR 5, 95% CI 1.1-23.0, p-value 0.039) and thyroid cancer (OR 3.6, 95% CI 1.2-10.6, p-value 0.018), and a decreased risk for prostate cancer (OR 0.2, 95% CI 0.1-0.8, p-value 0.026), although for these cancer subtypes the patient numbers were small. CONCLUSIONS: Overall risk of cancer in our MS cohort did not significantly differ from the controls. However, the age at diagnosis of breast cancer was statistically significantly higher among the MS patients in comparison with a control population from the same patient pool. Further population-based larger studies spanning longer follow-up periods and longer exposure to emerging MS therapies are needed to evaluate cancer risk related to MS treatments and breast cancer risk in particular.

Efficacy and safety outcomes in vitamin D supplement users in the fingolimod phase 3 trials.

BACKGROUND: Low serum levels of 25-hydroxyvitamin D have been associated with worse outcomes in multiple sclerosis (MS) patients treated with interferon-beta. Association of vitamin D nutrition on the outcomes of other MS therapies has been studied less. OBJECTIVE: Whether patients in the phase 3 fingolimod trials using vitamin D supplements have better clinical, MRI and safety outcomes than non-users. MATERIALS AND METHODS: Pooled data from phase 3 FREEDOMS trials was analyzed post hoc. Vitamin D use was defined as 'non-users' (n = 562), 'casual users' (n = 157) and 'daily users' (usage 100% time in the study, n = 110). RESULTS: Expanded Disability Status Scale change from baseline to month 24, and annual relapse rate and proportion of patients with relapses were similar across the vitamin D user groups. Proportion of patients free of new/enlarging T2 lesions significantly favored vitamin D 'daily users' versus 'non-users'. Mean number of lesions were lower and proportion of patients free of gadolinium-enhanced T1-lesions were higher in the 'daily users'. At month 12, percent brain volume change was significantly lower in the 'daily users' versus 'non-users' and remained low at month 24 (non-significant). Incidence of depression was lower for vitamin D 'daily users' (non-significant). CONCLUSIONS: We observed improved MRI outcomes on percent brain volume change and proportion of patients free of new/enlarging T2 lesions, and a trend of less depression in the 'daily users' of vitamin D supplement in patients in the FREEDOMS trials.

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.

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 mother's birth, and date of child's 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.