Jonatan Salzer

Vitamin D as a protective factor in multiple sclerosis

ABSTRACT Objective: To examine the association between 25-hydroxyvitamin D (25[OH]D) levels and the risk of multiple sclerosis (MS) in blood samples collected prospectively and during gestation. Methods: In this nested case-control study, 2 population-based biobanks with 291,500 samples from 164,000 persons collected since 1975 in the northern half of Sweden were used. We identified prospectively collected blood samples from MS cases (n = 192, controls matched 2:1) and gestational samples from pregnant mothers where the offspring had later developed MS (n = 37, control mothers matched 5:1). 25(OH)D levels were measured using an ELISA, and the risk of MS was analyzed using matched logistic regression. Results: Levels of 25(OH)D ≥75 (vs <75) nmol/L in prospectively collected blood samples were associated with a decreased risk of MS (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.16–0.98). No decrease in MS risk was found in the offspring exposed to gestational 25(OH)D levels ≥75 (vs <75) nmol/L (OR 1.8, 95% CI 0.53–5.8). The prevalence of 25(OH)D levels ≥75 nmol/L in female controls decreased gradually during 1976–2005 (p trend = 0.005). Conclusion: This study supports the presence of an association between high 25(OH)D levels during the years preceding disease onset and a decreased risk of MS. In the very limited material with samples drawn in early pregnancy, where month-of-birth effects were controlled for, we found no association between gestational 25(OH)D levels and MS risk in the offspring. Decreasing 25(OH)D levels in the population may contribute to explain the increasing MS incidence that is suggested from epidemiologic studies.

Neurofilament light as a prognostic marker in multiple sclerosis

Relapsing-remitting multiple sclerosis has a variable prognosis and lacks a reliable laboratory prognostic marker. Our aim in this study was to investigate the association between neurofilament light levels in cerebrospinal fluid in early multiple sclerosis and disease severity at long-term follow-up. Neurofilament light levels in cerebrospinal fluid collected at diagnostic lumbar puncture were measured in 99 multiple sclerosis cases. Clinical data were obtained from 95 out of those at follow-up visits made 14 years (range 8—20 years) after disease onset. Significant correlations between neurofilament light levels and the multiple sclerosis severity score were found for all cases (r = 0.30, p = 0.005), for relapsing-remitting multiple sclerosis cases (r = 0.47, p < 0.001) and for cases with a recent relapse (r = 0.60, p < 0.001). In the multivariate logistic regression analysis, neurofilament light levels >386 ng/L (median value of cases with detectable levels) increased the risk for severe multiple sclerosis fivefold (odds ratio 5.2, 95% confidence interval 1.8—15). Kaplan—Meier analysis showed that conversion to secondary-progressive multiple sclerosis was more likely in cases with neurofilament light levels >386 ng/L than in those with neurofilament light levels <60 ng/L (p = 0.01) or 60—386 ng/L (p = 0.03). We conclude that elevated levels of neurofilament light in cerebrospinal fluid collected at diagnostic lumbar puncture were associated with unfavourable prognosis. These data suggest that the neurofilament light level could be used as a prognostic marker in early relapsing-remitting multiple sclerosis.

Season of birth and multiple sclerosis in Sweden

Objective – To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. Materials and Methods – Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900– 2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. Results – More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February–July as compared with August– January. Conclusions – This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research. J. Salzer, A. Svenningsson, P. SundstrçmOBJECTIVE To estimate the risk of multiple sclerosis (MS) by month of birth in Sweden. MATERIALS AND METHODS Cases (n = 9361) were obtained from the Swedish MS Registry. All births in Sweden 1900-2007 served as controls (n = 12,116,853). The risk of MS was analyzed for each month of birth separately compared with birth during the other 11 months. RESULTS More (11%) cases with MS than expected were born in June. Fewer (8% and 10%) cases with MS than expected were born in December and January (non-significant after correction for multiple analyses). More (5%) cases with MS than expected were born in February-July as compared with August-January. CONCLUSIONS This study supports previous results suggesting an association between the risk of MS and the season of birth. Decreased exposure to sun in the winter leading to low vitamin D levels during pregnancy is a possible explanation that needs further research.

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients

Many JC virus antibody‐positive relapsing–remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy.

Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy

Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2–5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6–12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.

Smoking as a risk factor for multiple sclerosis

Background: Smoking has been associated with an increased risk for multiple sclerosis, but no studies have measured levels of the nicotine metabolite cotinine in prospectively collected samples to assess exposure. Objective: To investigate the effects of laboratory defined tobacco use on the risk for multiple sclerosis using prospectively collected biobank blood samples. Methods: Levels of cotinine were measured in n=192 cases, and n=384 matched controls, using an immunoassay. The risk for multiple sclerosis was estimated using matched logistic regression. Results: Elevated cotinine levels (≥10 ng/ml) were associated with a significantly increased risk for multiple sclerosis, (odds ratio, OR 1.5, 95% confidence interval, CI 1.0–2.1). This association was only present in young individuals (below median age at blood sampling, <26.4 years), (OR 2.2, 95% CI 1.3–3.8). Conclusions: This study confirms that smoking is a risk factor for multiple sclerosis. It has the advantage of using analyses of cotinine levels in samples that were collected several years before disease onset, thus excluding any risk for recall bias and minimising the risk for reversed causation. Our results also suggest that the smoking related immunological events that contribute to the development of multiple sclerosis occur early in life.

Epstein-Barr virus antibodies and vitamin D in prospective multiple sclerosis biobank samples.

Background: The antibody reactivity against Epstein-Barr nuclear antigen-1 (EBNA-1), and 25-hydroxyvitamin D (25(OH)D) status have been associated with multiple sclerosis (MS) risk. Interaction between these two factors has been proposed. Objectives: The objective of this paper is to examine the association between antibody reactivity against EBNA-1 and five EBNA-1 domains, and the risk of MS, and to examine if these antibodies and 25(OH)D status interact regarding MS risk in prospectively collected blood samples. Methods: Antibody reactivity and 25(OH)D levels were measured using ELISAs in n = 192 MS cases and n = 384 matched controls. The risk of MS was analysed using matched logistic regression. Interaction on the additive scale was assessed. Results: The risk of MS increased across tertiles of antibody reactivity against EBNA-1, domain EBNA-1402–502, and domain EBNA-1385–420; p trends < 0.001. In young individuals (below median age at sampling, < 26.4 years), these associations were stronger, and 25(OH)D levels correlated inversely to antibody reactivity against EBNA-1 and the EBNA-1 domains. No statistical interaction was found. Conclusions: We confirm that increased antibody reactivity against EBNA-1 is a risk factor of MS. 25(OH)D status might influence the immune response towards Epstein-Barr virus in young subjects, and thereby modulate MS risk.

Vitamin A and systemic inflammation as protective factors in multiple sclerosis

Background: Vitamin A is important for the immune system, and might suppress inflammatory activity in multiple sclerosis (MS). Objectives: We aimed to examine if vitamin A levels were associated with MS risk in samples collected prospectively and during gestation. Methods: We measured Retinol Binding Protein (RBP – a surrogate marker for vitamin A) and high-sensitivity C-reactive protein (hs-CRP) levels, in (1) prospectively collected biobank blood samples from MS cases and controls, and (2) gestational samples where the offspring had later developed MS, and gestational control samples. The risk of MS was calculated using matched multivariable logistic regression adjusted for confounders. Results: In prospective samples, RBP levels within the second quintile (vs. the first) were associated with a lower MS risk (OR = 0.38, 95% CI 0.19–0.74). No effect on MS risk in the offspring by gestational RBP levels was found. In young subjects hs-CRP levels ≥10 mg/l in prospective samples were associated with a lower MS risk (OR = 0.36, 95% CI 0.14–0.95). Conclusions: Our results suggest that sub-optimal vitamin A levels may be associated with MS risk. The association between hs-CRP levels and MS risk in young subjects may support the role of the hygiene hypothesis in MS aetiology.

Vitamin D and multiple sclerosis—from epidemiology to prevention

In the present review, we discuss observational and experimental data suggesting a protective effect from sun exposure and/or vitamin D in multiple sclerosis (MS). These data include geographic variations in MS occurrence, temporal trends, genetics, biobank, and questionnaire data. We look more closely at the differentiation between general effects from UV exposure, and those of vitamin D per se, including plausible mechanisms of action. Finally, primary prevention is touched upon, and we suggest actions to be taken while awaiting the results from ongoing randomized controlled trials with vitamin D in MS.

Vitamin D and multiple sclerosis: where do we go from here?

This article briefly introduces the basics of multiple sclerosis’ (MS) clinical hallmarks and pathophysiology. Vitamin D is presented, including its metabolism and effects on the immune system. The epidemiological observations linking vitamin D to MS range from a half century old findings of latitude gradients and migrational risk patterns to modern, nested, case–control biobank studies. These observations show an association without doubt although causation has yet to be proven. Vitamin D as a treatment for MS is an emerging concept and both current and anticipated data will be covered. Lastly, we discuss future challenges, ideas on how to move from association to causation, and the prospect of primary prevention of this disabling disease.