Oral Contraceptives Interact with Adiposity-Associated Markers in Patients with Multiple Sclerosis.

Growing evidence suggests the involvement of adipose tissue in modulating the clinical course of relapsing-remitting multiple sclerosis (RRMS). This study aimed to investigate whether the intake of combined oral contraceptives (COCs) affects body weight and leptin and adiponectin (APN) blood levels in these patients. Clinical data from 62 women (M = 33.23 year) were recorded prior to the initiation of disease-modifying therapy. Patients who were taking COCs at the time of experiencing the first symptoms of disease (COC user) were compared with those who never used these formulations or stopped taking them before disease onset (COC non-user). Bivariate Pearson's correlations and hierarchical multiple linear regressions analysis were conducted. Normalized APN levels were lower in the COC-using patients (p = 0.013). Negative correlations between waist circumference and normalized APN (p = 0.001) were observed only in the COC non-user patients. A longer duration of COC intake was associated with increased body mass index and waist circumference (p = 0.003). Normalized APN predicted the MS Severity Score (MSSS) (p = 0.020), but this correlation was lost in the COC user patients. After adjusting for confounders, only age (p = 0.027) and, later, disease onset (p = 0.014) were correlated with the MSSS. Larger and prospective studies are needed to investigate the interactions of sex steroids with adipose metabolism in modulating disease progression.

Fingolimod treatment modulates PPARγ and CD36 gene expression in women with multiple sclerosis.

Fingolimod is an oral immunomodulatory drug used in the treatment of multiple sclerosis (MS) that may change lipid metabolism. Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate lipoprotein metabolism and immune functions and have been implicated in the pathophysiology of MS. CD36 is a scavenger receptor whose transcription is PPAR regulated. The objective of this study was to evaluate whether fingolimod treatment modifies PPAR and CD36 gene expression as part of its action mechanisms. Serum lipoprotein profiles and PPAR and CD36 gene expression levels in peripheral leukocytes were analysed in 17 female MS patients before and at 6 and 12 months after fingolimod treatment initiation. Clinical data during the follow-up period of treatment were obtained. We found that fingolimod treatment increased HDL-Cholesterol and Apolipoprotein E levels and leukocyte PPARγ and CD36 gene expression. No correlations were found between lipid levels and variations in PPARγ and CD36 gene expression. PPARγ and CD36 variations were significantly correlated during therapy and in patients free of relapse and stable disease. Our results suggest that PPARγ and CD36-mediated processes may contribute to the mechanisms of action of fingolimod in MS. Further studies are required to explore the relation of the PPARγ/CD36 pathway to the clinical efficacy of the drug and its involvement in the pathogenesis of the disease.

Serum Lipoprotein Profile Is Associated With Protective Effects of Oral Contraceptive Use on Multiple Sclerosis Severity: A Cross-Sectional Study.

Background: The mechanisms underlying the influence of sex hormones in multiple sclerosis (MS) are uncertain. Sex steroids interact with cholesterol metabolism and the serum lipid profile has been associated with the severity of the disease. We hypothesized that the putative associations between lipoprotein metabolism and MS could be modulated by sex steroids exposure. The aim of this study was to investigate whether oral contraceptives (OC) use changes the lipoprotein profile associated with disability in patients with multiple sclerosis. Methods: Clinical data was collected from 133 relapsing-remitting multiple sclerosis (RRMS) women with a mean of 6.5 years of disease duration and prior to the start of disease-modifying therapies. Patients who were using OC after disease onset (DO) (OC+, n = 57) were compared to those who never used OC or discontinued its intake before DO (OC-, n = 76). In both cohorts of subjects, the associations between the apolipoprotein E (ApoE) polymorphism, and plasma lipid levels, and the annualized relapse rate (RR), the Expanded Disability Status Score (EDSS), and the Multiple Sclerosis Severity Score (MSSS) were evaluated using a hierarchic multiple regression analysis after adjustment for confounders. Results: Low density lipoprotein (LDL) levels were associated with higher EDSS (p = 0.010) and MSSS (p = 0.024) in the whole studied cohort. In E3/E3 phenotype carriers (73.7%), EDSS and MSSS were lower in OC+ in comparison with OC- subgroup of patients (p < 0.01). LDL and total cholesterol were associated with EDSS (p = 0.005 and p = 0.043, respectively), and LDL and the triglyceride/high density lipoprotein ratio with MSSS (p = 0.011 and p = 0.048, respectively) in OC+ patients. In OC- subgroup of patients, ApoE levels were associated with EDSS (p = 0.012) and MSSS (p = 0.031). No significant interactions between the lipid variables or OC use and RR were observed. Conclusions: Serum lipid profile is associated with protective effects of OC use on disability of RRMS patients. Lipoprotein metabolism may be involved in the modulatory effects of sex steroids on the severity of the disease.

Metabolic Dysfunction and Peroxisome Proliferator-Activated Receptors (PPAR) in Multiple Sclerosis.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) probably caused, in most cases, by the interaction of genetic and environmental factors. This review first summarizes some clinical, epidemiological and pathological characteristics of MS. Then, the involvement of biochemical pathways is discussed in the development and repair of the CNS lesions and the immune dysfunction in the disease. Finally, the potential roles of peroxisome proliferator-activated receptors (PPAR) in MS are discussed. It is suggested that metabolic mechanisms modulated by PPAR provide a window to integrate the systemic and neurological events underlying the pathogenesis of the disease. In conclusion, the reviewed data highlight molecular avenues of understanding MS that may open new targets for improved therapies and preventive strategies for the disease.

Natalizumab Treatment Modulates Peroxisome Proliferator-Activated Receptors Expression in Women with Multiple Sclerosis.

Peroxisome Proliferator-Activated Receptors (PPAR) are transcription factors suggested to be involved in inflammatory lesions of autoimmune encephalomyelitis and multiple sclerosis (MS). Our objective was to assess whether Natalizumab (NTZ) therapy is associated with alterations of PPAR expression in MS patients. We analyzed gene expression of PPAR in peripheral blood mononuclear cells (PBMC) as well as blood inflammatory markers in women with MS previously medicated with first-line immunomodulators (baseline) and after NTZ therapy. No differences in PPARα, PPARß/δ, PPARγ, and CD36 mRNA expression were found in PBMC between patients under baseline and healthy controls. At three months, NTZ increased PPARß/δ mRNA (p = 0.009) in comparison to baseline, while mRNA expression of PPARγ and CD36 (a well-known PPAR target gene) was lower in comparison to healthy controls (p = 0.026 and p = 0.028, resp.). Although these trends of alterations remain after six months of therapy, the results were not statistically significant. Osteopontin levels were elevated in patients (p = 0.002) and did not change during the follow-up period of NTZ treatment. These results suggest that PPAR-mediated processes may contribute to the mechanisms of action of NTZ therapy.

Oral contraceptive use and clinical outcomes in patients with multiple sclerosis.

Experimental and clinical data suggest a role of sex steroids in the pathogenesis of multiple sclerosis (MS). Scant information is available about the potential effect of oral contraceptive (OC) use on the prognosis of the disease. We aimed to evaluate this. The study population consisted of 132 women with relapsing-remitting MS before receiving disease modifying treatment and a mean disease duration 6.2 (SD 5.1) years. Three groups of patients were distinguished according to their OC behavior: [1] never-users, patients who never used OC [2] past-users, patients who stopped OC use before disease onset, and [3] after-users, those who used these drugs after disease onset. Multiple linear and logistic regression models were used to analyze the association between oral contraceptive use and annualized relapse rates, disability accumulation and severity of the disease. After-user patients had lower Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) values than never users (p<0.001 and p=0.002, respectively) and past users (p=0.010 and p=0.002, respectively). These patients were also more likely to have a benign disease course (MSSS<2.5) than never and past users together (OR: 4.52, 95%CI: 2.13-9.56, p<0.001). This effect remained significant after adjustment for confounders, including smoking and childbirths (OR: 2.97, 95%CI: 1.24, 6.54, p=0.011 and for MSSS ß: -1.04; 95% C.I. -1.78, -0.30, p=0.006). These results suggest that OC use in women with relapsing-remitting MS is possible associated with a milder disabling disease course.

Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta.

Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated with the development of NAbs. Thirty-one female MS patients treated with subcutaneously administered IFN-beta were included. Demographic and clinical characteristics were compared between NAbs response groups using t tests for continuous and logistic regression analysis and Fisher's exact tests for categorical data, respectively. Multivariate logistic regression was used to evaluate the effect of potential confounders. Patients who developed NAbs had lower apoE levels before treatment, 67 (47-74) mg/L median (interquartile range), and at the moment of NAb analysis, 53 (50-84) mg/L, in comparison to those who remained NAb-negative, 83 (68-107) mg/L, P = 0.03, and 76 (66-87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a one-standard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04-0.77), P = 0.04. When adjusting for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta.