Cholecalciferol Supplementation Induced Up-Regulation of SARAF Gene and Down-Regulated miR-155-5p Expression in Slovenian Patients with Multiple Sclerosis.

Multiple sclerosis is a common immune-mediated inflammatory and demyelinating disease. Lower cholecalciferol levels are an established environmental risk factor in multiple sclerosis. Although cholecalciferol supplementation in multiple sclerosis is widely accepted, optimal serum levels are still debated. Moreover, how cholecalciferol affects pathogenic disease mechanisms is still unclear. In the present study, we enrolled 65 relapsing-remitting multiple sclerosis patients who were double-blindly divided into two groups with low and high cholecalciferol supplementation, respectively. In addition to clinical and environmental parameters, we obtained peripheral blood mononuclear cells to analyze DNA, RNA, and miRNA molecules. Importantly, we investigated miRNA-155-5p, a previously published pro-inflammatory miRNA in multiple sclerosis known to be correlated to cholecalciferol levels. Our results show a decrease in miR-155-5p expression after cholecalciferol supplementation in both dosage groups, consistent with previous observations. Subsequent genotyping, gene expression, and eQTL analyses reveal correlations between miR-155-5p and the SARAF gene, which plays a role in the regulation of calcium release-activated channels. As such, the present study is the first to explore and suggest that the SARAF miR-155-5p axis hypothesis might be another mechanism by which cholecalciferol supplementation might decrease miR-155 expression. This association highlights the importance of cholecalciferol supplementation in multiple sclerosis and encourages further investigation and functional cell studies.

Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group.

Fingolimod is the first oral treatment of multiple sclerosis. It is the first-in-class sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phophate receptors on lymphocytes and via downregulation of the receptor prevents lymphocyte egress from lymphoid tissues into the circulation. This mechanism reduces the infiltration of potentially auto-aggressive lymphocytes into the central nervous system. Two large phase III studies with fingolimod have shown superior efficacy of the drug in two dosages compared to placebo and to weekly intramuscular injections of Interferon beta-1a. Among possible side effects of the drug is a transient bradycardia after the first dose of fingolimod including possible AV blockade and therefore monitoring of pulse rate and blood pressure for 6 h following the first application is needed. During treatment, attention has to be given to specific infections, elevated liver enzymes, and ophthalmologic changes. Recommendations on the use of fingolimod including safety aspects are given in this article.

Subclinical atherosclerosis in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis is an inflammatory disorder of the central nervous system. Inflammation may create high susceptibility to subclinical atherosclerosis. The purpose of this study was to compare subclinical atherosclerosis and the role of inflammatory cytokines between the group of patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls matched for age and sex. METHODS: The study group consisted of 112 non-diabetic and non-hypertensive RRMS patients treated with disease modifying drugs (DMD) and the control group was composed of 51 healthy subjects. The common carotid artery (CCA) intima media thickness (IMT) was investigated. Serum levels of risk factors for atherosclerosis and inflammatory cytokines were also determined. RESULTS: The mean CCA IMT (0.572 ± 0.131 mm vs. 0.571 ± 0.114 mm) did not differ (p > 0.05) between patients and controls. The RRMS patients' CCA IMT was significantly correlated with serum interleukin 6 (IL-6) (p = 0.027), high-sensitivity C-reactive protein (hs-CRP) (p = 0.027), cystatin C (p < 0.0005), glucose (p = 0.031), cholesterol (p = 0.008), LDL (p = 0.021), erythrocyte sedimentation rate (p = 0.001) and triglyceride (p = 0.018) level. We fitted generalized linear models in order to assess the relationship between CCA IMT and IL­6 with adjustment for sex and age. The obtained results showed that adjusted for age (p < 0.001) and sex (p = 0.048) IL­6 serum levels statistically significantly (p = 0.009) predict CCA IMT only in the RRMS group. CONCLUSION: The findings of the present study suggest that when treated with DMD RRMS might not be an independent risk factor for early atherosclerosis presenting with arterial wall thickening; however, the results suggest a significant association of IL­6 serum levels with CCA IMT only in the RRMS group.

Factors influencing daily treatment choices in multiple sclerosis: practice guidelines, biomarkers and burden of disease.

At two meetings of a Central European board of multiple sclerosis (MS) experts in 2018 and 2019 factors influencing daily treatment choices in MS, especially practice guidelines, biomarkers and burden of disease, were discussed. The heterogeneity of MS and the complexity of the available treatment options call for informed treatment choices. However, evidence from clinical trials is generally lacking, particularly regarding sequencing, switches and escalation of drugs. Also, there is a need to identify patients who require highly efficacious treatment from the onset of their disease to prevent deterioration. The recently published European Committee for the Treatment and Research in Multiple Sclerosis/European Academy of Neurology clinical practice guidelines on pharmacological management of MS cover aspects such as treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and are based on expert consensus statements. However, the recommendations constitute an excellent framework that should be adapted to local regulations, MS center capacities and infrastructure. Further, available and emerging biomarkers for treatment guidance were discussed. Magnetic resonance imaging parameters are deemed most reliable at present, even though complex assessment including clinical evaluation and laboratory parameters besides imaging is necessary in clinical routine. Neurofilament-light chain levels appear to represent the current most promising non-imaging biomarker. Other immunological data, including issues of immunosenescence, will play an increasingly important role for future treatment algorithms. Cognitive impairment has been recognized as a major contribution to MS disease burden. Regular evaluation of cognitive function is recommended in MS patients, although no specific disease-modifying treatment has been defined to date. Finally, systematic documentation of real-life data is recognized as a great opportunity to tackle unresolved daily routine challenges, such as use of sequential therapies, but requires joint efforts across clinics, governments and pharmaceutical companies.

Anemia on admission and long-term mortality risk in patients with acute ischemic stroke.

BACKGROUND: Anemia is associated with adverse outcomes in patients with acute myocardial infarction and congestive heart failure. Additionally, it has been shown that anemia increases the short-term mortality risk in patients with acute stroke. OBJECTIVES: The aim of our study was to determine the importance of anemia as a long-term mortality risk factor by itself or in combination with other risk factors. MATERIAL AND METHODS: We included 390 Caucasian patients with acute ischemic stroke in our study. Their progress was followed from the day of their admission until their death or a max. of 1,669 days. Stroke and anemia were defined according to the World Health Organization (WHO) criteria. RESULTS: Anemia was present in 57 (14.6%) patients. The patients with anemia were older (p < 0.01) and more likely to be female (p < 0.001). They had higher NIHSS scores on admission (p < 0.001) and discharge (p < 0.001), lower estimated glomerular filtration rates (eGFRs) (p < 0.001), lower serum LDL cholesterol (p < 0.01) and lower serum albumin levels (p < 0.001), while their serum C-reactive protein (CRP) levels were higher (p < 0.001). The Kaplan-Meier curves showed that patients with anemia had higher mortality (p < 0.001). Cox's regression analysis revealed that anemia at admission was a predictor of long-term mortality in these patients (hazard ratio (HR) = 2.448, 95% confidence interval (95% CI) = 1.773-3.490; p < 0.001). Anemia remained a strong predictor of mortality after adjusting for other risk factors as well. CONCLUSIONS: Anemia was frequent among our patients and was an independent predictor of long-term mortality even after adjusting for other risk factors.

Ischemic stroke: the impact of renal dysfunction on 1-year mortality.

BACKGROUND: Atherosclerosis is accelerated in patients with different stages of chronic renal failure. Renal dysfunction predicts mortality in patients with myocardial infarction and congestive heart failure. Less is known about the impact of renal dysfunction on mortality after ischemic stroke. The aim of the study was to investigate the impact of renal dysfunction on 1-year mortality. PATIENTS AND METHODS: All 390 patients (207 men and 183 women) suffered from ischemic stroke in 1-year period were included in our study. Telephonic follow-up after 1 year was performed. The mean age of our patients was 71.0 ± 11.6 years, ranged from 36 to 96 years. Glomerular filtration rate (GFR) was calculated according to abbreviated Modification of Diet in Renal Disease formula. At admission and at discharge National Institutes of Health Stroke Scale (NIHSS) were performed. RESULTS: The mean GFR in our patients was 66.0 ± 20.68 ml/min/1.73 m(2). There were 123 (31.5 %) deaths in 1-year period. Patients who died were older (P < 0.001), had higher NIHSS at admission and at discharge (both P < 0.001), higher high-sensitive C-reactive protein (P = 0.002), lower albumin (P < 0.001), lower GFR (P = 0.044), had more frequent atrial fibrillation (P < 0.001), and were less frequent actual smokers (P = 0.003). No differences in presence of diabetes and hypertension, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides between patients who died or survived were found. With Cox multivariable regression analysis age (P = 0.037), gender (P = 0.005), NIHSS at admission (P = 0.005) and discharge (P < 0.001), albumin (P = 0.005) and also GFR (P = 0.025) were predictors of 1-year mortality. CONCLUSIONS: In patients with ischemic stroke, renal dysfunction (decreased GFR) was associated with 1-year mortality. GFR was independent predictor of mortality.

How does fingolimod (gilenya(®)) fit in the treatment algorithm for highly active relapsing-remitting multiple sclerosis?

Multiple sclerosis (MS) is a neurological disorder characterized by inflammatory demyelination and neurodegeneration in the central nervous system. Until recently, disease-modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta-interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya(®)) is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS) for adult patients with high disease activity despite basic treatment (beta-interferon) and for treatment-naïve patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from ten Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients.