Can vitamin D3 supplementation prevent bone loss in persons with MS? A placebo-controlled trial

Multiple sclerosis (MS) is a possible cause of secondary osteoporosis. In this phase II trial we assessed whether a weekly dose of 20,000 IU vitamin D3 prevents bone loss in ambulatory persons with MS age 18–50 years. ClinicalTrials.gov ID NCT00785473. All patients managed at the University Hospital of North Norway who fulfilled the main inclusion criteria were invited to participate in this double-blinded trial. Participants were randomised to receive 20,000 IU vitamin D3 or placebo once a week and 500 mg calcium daily for 96 weeks. The primary outcome was the effect of the intervention on percentage change in bone mineral density (BMD) at the hip, the spine, and the ultradistal radius over the study period. Of 71 participants randomised, 68 completed. Mean serum 25-hydroxyvitamin D [25(OH)D] levels in the intervention group increased from 55 nmol/L at baseline to 123 nmol/L at week 96. After 96 weeks, percentage change in BMD did not differ between groups at any site. BMD decreased at the hip, by 1.4% in the placebo group (95% CI −2.3 to −0.4, SD 2.7, p = 0.006) and by 0.7% in the treatment group (−1.6 to 0.2, 2.7, p = 0.118), difference 0.7% (−1.9 to 0.7, p = 0.332). Findings were not altered by adjustment for sex or serum 25(OH)D. Supplementation with 20,000 IU vitamin D3 a week did not prevent bone loss in this small population. Larger studies are warranted to assess the effect of vitamin D on bone health in persons with MS

Genetic epidemiology of amyotrophic lateral sclerosis in Norway - a 2-year population based study

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. In Europe, disease-causing genetic variants have been identified in 40-70% of familial ALS patients and approximately in 5% of sporadic ALS patients. In Norway, the contribution of genetic variants to ALS has not yet been studied. In light of the potential development of personalized medicine, knowledge of genetic causes of ALS in a population is becoming increasingly important. The present study provides clinical and genetic data on familial and sporadic ALS patients in a Norwegian population-based cohort. Methods: Blood samples and clinical information from ALS patients were obtained at all 17 neurological departments throughout Norway during a 2-year period. Genetic analysis of the samples involved expansion analysis of C9orf72 and exome sequencing targeting 30 known ALS-linked genes. The variants were classified using genotype-phenotype correlations and bioinformatics tools. Results: A total of 279 ALS patients were included in the study. Of these, 11.5% had one or several family members affected with ALS, whereas 88.5% had no known family history of ALS. A genetic cause of ALS was identified in 31 individuals (11.1%), among which 18 (58.1%) were familial and 13 (41.9%) were sporadic. The most common genetic cause was the C9orf72 expansion (6.8%), which was identified in 8 familial and 11 sporadic ALS patients. Pathogenic or likely pathogenic variants of SOD1 and TBK1 were identified in 10 familial and 2 sporadic cases. C9orf72 expansions dominated in patients from the Northern and Central regions, whereas SOD1 variants dominated in patients from the South-Eastern region. Conclusion: In the present study, we identified several pathogenic gene variants in both familial and sporadic ALS patients. Restricting genetic analysis to only familial cases would miss more than 40 percent of those with a disease-causing genetic variant, indicating the need for genetic analysis in sporadic cases as well.publishedVersio

Late Onset Myasthenia Gravis Is Associated with HLA DRB1*15:01 in the Norwegian Population

BACKGROUND: Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG. METHODOLOGY/PRINCIPAL FINDINGS: This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies. CONCLUSION: The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG

High dose vitamin D supplementation does not affect biochemical bone markers in multiple sclerosis – a randomized controlled trial

Background People with multiple sclerosis have high risk of osteoporosis and fractures. A poor vitamin D status is a risk factor for MS, and vitamin D supplementation has been recommended both to prevent MS progression and to maintain bone health. Methods We assessed the effect of 20,000 IU vitamin D3 weekly compared to placebo on biochemical markers of bone metabolism in 68 persons with relapsing remitting multiple sclerosis. Results Serum levels of 25-hydroxyvitamin D more than doubled in the vitamin D group, and parathyroid hormone decreased in the vitamin D group compared to the placebo group at week 48 and week 96. There was however no effect on bone formation as measured by procollagen type I N propeptide (PINP), or on bone resorption as measured by C-terminal cross-linking telopeptide of type I collagen (CTX1). Neither PINP nor CTX1 predicted bone loss from baseline to week 96. Conclusions These findings corroborate the previously reported lack of effect of weekly high dose vitamin D supplementation on bone mass density in the same patients, and suggest that such vitamin D supplementation does not prevent bone loss in persons with MS who are not vitamin D deficient. Trial registration The trial was registered at ClinicalTrials.gov on April 4 2008, registration number NCT00785473

Environmental risk factors in multiple sclerosis

Objectives – Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation. Results – Findings from studies on seasonality in MS patients' birth, disease onset and exacerbations, as well as apparent temporal trends in incidence and gender ratio support an influential effect of viruses, metabolic and lifestyle factors on MS risk. Epstein–Barr virus, vitamin D status, and smoking are factors that may explain such epidemiological patterns. Conclusions – Further epidemiological investigations are encouraged and opportunities to use data from existing cohort studies as well as the design of new studies should be pursued. In particular, the development of new large multicentre population-based case-control studies which incorporate the study of the role of environment and genetics, including epigenetic mechanisms, in determining MS risk is proposed

Incidence of cancer in multiple sclerosis before and after the treatment era– a registry- based cohort study

Background: Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain. Objectives: Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs. Methods: We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer. Results: During 1953–1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90–1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27–4.93). During 1996–2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28–1.52): in brain (IRR: 1.97 (1.41–2.78)), meninges (IRR: 2.44 (1.54–3.77)), respiratory organs (IRR: 1.96 (1.49–2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15–1.47)). Conclusion: Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age