Relapses in Patients Treated with High-Dose Biotin for Progressive Multiple Sclerosis

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Several reports have suggested that HDB treatment may be associated with an increased risk of relapse. We aimed to determine whether HDB increases the risk of clinical relapse in PMS and describe the characteristics of the patients who experience it. We conducted a French, multicenter, retrospective study, comparing a group of PMS patients treated with HDB to a matched control group. Poisson regression was applied to model the specific statistical distribution of the annualized relapse rate (ARR). A propensity score (PS), based on the inverse probability of treatment weighting (IPTW), was used to adjust for indication bias and included the following variables: gender, primary PMS or not, age, EDSS, time since the last relapse, and co-prescription of a DMT. Two thousand six hundred twenty-eight patients treated with HDB and 654 controls were analyzed with a follow-up of 17 ± 8 months. Among them, 148 validated relapses were observed in the group treated with biotin and 38 in the control group (p = 0.62). After adjustment based on the PS, the ARR was 0.044 ± 0.23 for the biotin-treated group and 0.028 ± 0.16 for the control group (p = 0.18). The more relapses there were before biotin, the higher the risk of relapse during treatment, independently from the use of HDB. While the number of relapses reported for patients with no previous inflammatory activity receiving biotin has gradually increased, the present retrospective study is adequately powered to exclude an elevated risk of relapse for patients with PMS treated with HDB.Observatoire Français de la Sclérose en Plaque

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

BACKGROUND: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. OBJECTIVE: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. METHODS: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. RESULTS: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. CONCLUSION: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.journal article2016 Nov2016 09 01importe

Cholesterol and Lipoprotein Dynamics in a Hibernating Mammal

Hibernating mammals cease feeding during the winter and rely primarily on stored lipids to fuel alternating periods of torpor and arousal. How hibernators manage large fluxes of lipids and sterols over the annual hibernation cycle is poorly understood. The aim of this study was to investigate lipid and cholesterol transport and storage in ground squirrels studied in spring, summer, and several hibernation states. Cholesterol levels in total plasma, HDL and LDL particles were elevated in hibernators compared with spring or summer squirrels. Hibernation increased plasma apolipoprotein A-I expression and HDL particle size. Expression of cholesterol 7 alpha-hydroxylase was 13-fold lower in hibernators than in active season squirrels. Plasma triglycerides were reduced by fasting in spring but not summer squirrels. In hibernators plasma β-hydroxybutyrate was elevated during torpor whereas triglycerides were low relative to normothermic states. We conclude that the switch to a lipid-based metabolism during winter, coupled with reduced capacity to excrete cholesterol creates a closed system in which efficient use of lipoproteins is essential for survival

Effects of dietary n-6 or n-3 polyunsaturated fatty acids protected or not against ruminal hydrogenation on plasma lipids and their susceptibility to peroxidation in fattening steers1

International audienceTwo experiments were conducted using crossbred Salers x Charolais fattening steers fed diets enriched with no supplemental oilseeds or oils rich in either n-6 PUFA (from sunflower seeds) or n-3 PUFA (from linseeds) provided either as seeds incorporated in the diet (i.e., not protected from ruminal bacterial hydrogenation) or by chronic infusion into the duodenum (protected form). In the Sunflower experiment, animals (initial age = 454 +/- 20 d; initial BW = 528 +/- 36 kg) received a control diet for 70 d (CS, n = six) consisting of hay and concentrate, or the same basal diet supplemented with sunflower oil (4% of dietary DM), either fed as seeds (SS, n = six) or infused into the duodenum (ISO, n = six). The same experimental design was applied to animals (initial age = 412 +/- 33 d; initial BW = 536 +/- 33 kg) used in the Linseed experiment (CL, LS, and ILO; n = 8 per group). For all animals, blood was sampled every 15 d during 70 d. In both trials, a significant diet x time interaction (P < 0.001) was detected for plasma concentrations of apolipoprotein A-I, phospholipids, and free and esterified cholesterol, with values increasing with time during administration of the PUFA-rich diets being more evident with ISO and ILO diets. Plasma fatty acids were altered with oil infusions, with increased concentrations of n-6 (1.6-fold; P < 0.05) and n-3 PUFA (4.5-fold; P < 0.05) and of their respective indicies of peroxidizability (1.2- and 1.5-fold with Diets ISO and ILO, respectively; P < 0.05). In vitro copper-induced peroxidation of lipids revealed a decreased length of the lag phase in the process of conjugated diene generation by 48% (P < 0.005) with the ILO diet, indicating less resistance against peroxidation than in control steers. Compared with CS, the ISO treatment increased plasma alpha-tocopherol (x2.5; P < 0.05) leading to similar resistance against peroxidation. After depletion of this vitamin, the rates of peroxidation and production of conjugated dienes were greater (twofold; P < 0.05) with the ISO and ILO diets than with the others. In conclusion, infusion of sunflower or linseed oil into the duodenum altered the composition and distribution of plasma lipids and increased the plasma concentration of PUFA. The sensitivity of plasma PUFA to peroxidation depends on the plasma level of antioxidants, especially vitamin E, a nutrient important both for the health of animals and for the stability of the blood lipids until their tissue deposit

Journées d’enseignement supérieur de neurologie – Nantes 2016

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Exploring T cell - B cell collaboration in multiple sclerosis through B cell differentiation analysis

International audienc

Activated Tfh1 cells infiltrate the cerebrospinal fluid in early multiple sclerosis

International audienceMeeting Abstract 02

Unique B cell differentiation profile in tolerant kidney transplant patients

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.International audienceOperationally tolerant patients (TOL) display a higher number of blood B cells and transcriptional B cell signature. As they rarely develop an allo-immune response, they could display an abnormal B cell differentiation. We used an in vitro culture system to explore T-dependent differentiation of B cells into plasma cells. B cell phenotype, apoptosis, proliferation, cytokine, immunoglobulin production and markers of differentiation were followed in blood of these patients. Tolerant recipients show a higher frequency of CD20(+) CD24(hi) CD38(hi) transitional and CD20(+) CD38(lo) CD24(lo) naïve B cells compared to patients with stable graft function, correlating with a decreased frequency of CD20(-) CD38(+) CD138(+) differentiated plasma cells, suggestive of abnormal B cell differentiation. B cells from TOL proliferate normally but produce more IL-10. In addition, B cells from tolerant recipients exhibit a defective expression of factors of the end step of differentiation into plasma cells and show a higher propensity for cell death apoptosis compared to patients with stable graft function. This in vitro profile is consistent with down-regulation of B cell differentiation genes and anti-apoptotic B cell genes in these patients in vivo. These data suggest that a balance between B cells producing IL-10 and a deficiency in plasma cells may encourage an environment favorable to the tolerance maintenance