Kristin Ingeleiv Løken-Amsrud

Vitamin D and disease activity in multiple sclerosis before and during interferon-β treatment

Objective: Studies based on deseasonalized vitamin D levels suggest that vitamin D may influence the disease activity in multiple sclerosis (MS), and high doses are suggested as add-on treatment to interferon-β (IFN-β). Seasonal fluctuation of vitamin D varies between individuals, thus the relationship to disease activity should preferentially be studied by repeated and simultaneous vitamin D and MRI measurements from each patient. Methods: This was a cohort study comprising 88 patients with relapsing-remitting MS who were followed for 6 months with 7 MRI and 4 25-hydroxyvitamin D measurements before initiation of IFN-β, and for 18 months with 5 MRI and 5 25-hydroxyvitamin D measurements during IFN-β treatment. Results: Prior to IFN-β treatment, each 10 nmol/L increase in 25-hydroxyvitamin D was associated with 12.7% (p = 0.037) reduced odds for new T1 gadolinium-enhancing lesions, 11.7% (p = 0.044) for new T2 lesions, and 14.1% (p = 0.024) for combined unique activity. Patients with the most pronounced fluctuation in 25-hydroxyvitamin D displayed larger proportion of MRI scans with new T1 gadolinium-enhancing lesions (51% vs 23%, p = 0.004), combined unique activity (60% vs 32%, p = 0.003), and a trend for new T2 lesions (49% vs 28%, p = 0.052) at the lowest compared to the highest 25-hydroxyvitamin D level. No association between 25-hydroxyvitamin D and disease activity was detected after initiation of IFN-β. HLA-DRB1*15 status did not affect the results. Conclusion: In untreated patients with MS, increasing levels of 25-hydroxyvitamin D are inversely associated with radiologic disease activity irrespective of their HLA-DRB1*15 status.

Month of birth as a latitude-dependent risk factor for multiple sclerosis in Norway.

Objective: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient. Methods: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose. Results: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98 – 1.24), in Middle Norway 1.11 (0.97 – 1.27) and in Northern Norway 1.28 (1.0 – 1.63) compared with the other months. Conclusions: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.

Retinol levels are associated with magnetic resonance imaging outcomes in multiple sclerosis.

Background: Vitamin A has immunomodulatory properties and may regulate the transcription of genes involved in remyelination. Objective: To investigate the association between retinol and disease activity in multiple sclerosis (MS). Methods: Cohort study of 88 relapsing–remitting MS patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids in MS (the OFAMS study), followed prospectively for 24 months with repeated assessments of serum-retinol and magnetic resonance imaging (MRI). All patients were initiated on interferon β-1a after month 6. Results: Each 1 µmol/L increase in serum-retinol reduced the odds (95% confidence interval) for new T1 gadolinium enhanced (Gd+) lesions by 49 (8–70)%, new T2 lesions by 42 (2–66)%, and combined unique activity (CUA) by 46 (3–68)% in simultaneous MRI scans, and 63 (25–82)% for new T1Gd+ lesions, 49 (3–73)% for new T2 lesions and 43 (12–71)% for CUA the subsequent month. Serum-retinol also predicted new T1Gd+ and T2 lesions six months ahead. The associations were not affected by HLA-DRB1*15, or serum levels of 25-hydroxyvitamin D, eicosapentaenoic acid or docosahexaenoic acid. Conclusion: Serum retinol is inversely associated with simultaneous and subsequent MRI outcomes in RRMS.

Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis:

Background: Previous reports indicate an association between Epstein-Barr virus (EBV) antibody levels and multiple sclerosis (MS) disease activity, but the results have been conflicting. Objectives: The objective of this paper is to study if EBV antibody levels reflect MRI disease activity in MS and examine the potential for EBV antibody levels as biomarkers for treatment response. Methods: A total of 87 MS patients were followed for two years prior to and during interferon beta (IFNB) treatment, with MRI examinations and serum measurement of IgM and IgG antibodies to viral capsid antigen (VCA), EBV nuclear antigen 1 (EBNA-1) and early antigen (EA). Associations between EBV antibody levels and MRI activity were assessed by a logistic regression model. Results: Higher anti-EBNA-1 IgG levels were associated with increased MRI activity, OR = 2.95 (95% CI 1.07–8.10; p = 0.036) for combined unique activity (CUA; the sum of T1Gd+ lesions and new or enlarging T2 lesions). Although most patients were anti-VCA IgM negative, there was an inverse association, OR = 0.32 (95% CI 0.12–0.84; p = 0.021) with CUA during IFNB treatment. Conclusions: This study supports an association between anti-EBNA-1 IgG levels and MS disease activity. We also found an inverse association with anti-VCA IgM levels during IFNB treatment not previously described, indicating anti-VCA IgM as a possible biomarker for IFNB treatment response.

Month of birth and risk of multiple sclerosis: confounding and adjustments

A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher‐exact test; P = 0.011), mothers (Fisher‐exact test; P = 0.004), and fathers (Fisher‐exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population.

Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis

To explore the relationships between vitamin A, D and E and inflammation in relapsing remitting multiple sclerosis, we assessed their associations with 11 inflammation markers in 9 serial serum samples from 85 patients, before and during interferon-β1a treatment. A negative association was found between vitamin A and pentraxin 3 independent of interferon-β1a use, whereas positive associations between vitamin D and interleukin-1 receptor antagonist and secreted frizzled-related protein 3 were seen before, and between vitamin E and chemokine (C-X-C motif) ligand 16 during interferon-β1a treatment. These findings suggest associations with diverse inflammatory pathways, which may be differentially influenced by interferon-β1a treatment.

Fat-soluble vitamins as disease modulators in multiple sclerosis

Fat‐soluble vitamins (A, D, E and K) have properties that could be relevant as modulators of disease activity in multiple sclerosis (MS).

Vitamin D supplementation and monitoring in multiple sclerosis: who, when and wherefore

Observational studies suggest that increasing the serum concentration of 25‐hydroxyvitamin D with 50 nm could halve the relapse risk in relapsing–remitting multiple sclerosis (MS). Assuming that the association between disease activity and vitamin D status is entirely causal may however exaggerate the potential benefit. The aim of this paper is to address whether and how vitamin D should be monitored in patients with MS.

Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity

Background Serum markers of inflammation are candidate biomarkers in multiple sclerosis (MS). ω-3 fatty acids are suggested to have anti-inflammatory properties that might be beneficial in MS. We aimed to explore the relationship between serum levels of inflammation markers and MRI activity in patients with relapsing remitting MS, as well as the effect of ω-3 fatty acids on these markers. Methods We performed a prospective cohort study in 85 relapsing remitting MS patients who participated in a randomized clinical trial of ω-3 fatty acids versus placebo (the OFAMS study). During a period of 24 months 12 repeated magnetic resonance imaging (MRI) scans and nine serum samples were obtained. We measured 10 inflammation markers, including general down-stream markers of inflammation, specific markers of up-stream inflammatory pathways, endothelial action, and matrix regulation. Results After Bonferroni correction, increasing serum levels of CXCL16 and osteoprotegerin were associated with low odds ratio for simultaneous MRI activity, whereas a positive association was observed for matrix metalloproteinase (MMP) 9. CXCL16 were also associated with low MRI activity the next month, but this was not significant after Bonferroni correction. In agreement with previously reported MRI and clinical results, ω-3 fatty acid treatment did not induce any change in the inflammation markers. Conclusions Serum levels of CXCL16, MMP-9, and osteoprotegerin reflect disease activity in MS, but are not affected by ω-3 fatty acid treatment. CXCL16 could be a novel biomarker and potential predictor of disease activity in MS.

Alpha-tocopherol and MRI Outcomes in Multiple Sclerosis – Association and Prediction

Objective Alpha-tocopherol is the main vitamin E compound in humans, and has important antioxidative and immunomodulatory properties. The aim of this study was to study alpha-tocopherol concentrations and their relationship to disease activity in Norwegian multiple sclerosis (MS) patients. Methods Prospective cohort study in 88 relapsing-remitting MS (RRMS) patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids (the OFAMS study), before and during treatment with interferon beta. The patients were followed for two years with repeated 12 magnetic resonance imaging (MRI) scans and nine serum measurements of alpha-tocopherol. Results During interferon beta (IFNB) treatment, each 10 µmol/L increase in alpha-tocopherol reduced the odds (CI 95%) for simultaneous new T2 lesions by 36.8 (0.5–59.8) %, p = 0.048, and for combined unique activity by 35.4 (1.6–57.7) %, p = 0.042, in a hierarchical regression model. These associations were not significant prior to IFNB treatment, and were not noticeably changed by gender, age, body mass index, HLA-DRB1*15, treatment group, compliance, or the concentrations of 25-hydroxyvitamin D, retinol, neutralising antibodies against IFNB, or the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. The corresponding odds for having new T1 gadolinium enhancing lesions two months later was reduced by 65.4 (16.5–85.7) %, p = 0.019, and for new T2 lesions by 61.0 (12.4–82.6) %, p = 0.023. Conclusion During treatment with IFNB, increasing serum concentrations of alpha-tocopherol were associated with reduced odds for simultaneous and subsequent MRI disease activity in RRMS patients.