The comparative effects of bone marrow mesenchymal stem cells and supernatant transplantation on demyelination and inflammation in cuprizone model.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction. OBJECTIVES: We compared the remyelination and immunomodulation properties of mesenchymal stem cells (MSCs) with their conditioned medium (CM) in the cuprizone model. METHODS: Twenty-four C57BL/ 6 mice were divided into four groups. After cuprizone demyelination, MSCs and their CM were injected into the right lateral ventricle of mice. The expression level of IL-1ß, TNF-α, and BDNF genes was evaluated using the qRT-PCR. APC antibody was used to assess the oligodendrocyte population using the immunofluorescent method. The remyelination and axonal repair were studied by specific staining of the LFB and electron microscopy techniques. RESULTS: Transplantation of MSCs and CM increased the expression of the BDNF gene and decreased the expression of IL-1ß and TNF-α genes compared to the cuprizone group, and these effects in the cell group were more than CM. Furthermore, cell transplantation resulted in a significant improvement in myelination and axonal repair, which was measured by luxol fast blue and transmission electron microscope images. The cell group had a higher number of oligodendrocytes than other groups. CONCLUSIONS: According to the findings, injecting MSCs intraventricularly versus cell-conditioned medium can be a more effective approach to improving chronic demyelination in degenerative diseases like MS.

Neuroprotective effects of Embelin in an ethidium bromide-induced multiple sclerosis in rats: Modulation of p38 MAPK signaling pathway.

BACKGROUND: Multiple sclerosis (MS) is a debilitating inflammatory disease characterized by demyelination, varied remyelination conservation, and partial axonal retention in central nervous system (CNS) lesions. The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of MS. Embelin (EMB), derived from the Embelia ribes plant, possesses diverse biological activities, including anti-inflammatory properties. OBJECTIVE: This study aimed to investigate the neuroprotective effects of EMB in an ethidium bromide (EB)-induced model of MS in Wistar rats. METHODS: Wistar rats were randomly divided into five groups (n = 8). MS-like manifestations were induced by injecting EB (0.1 %/10 µl) into the intracerebropeduncle (ICP) region of the rat brain for seven consecutive days. EMB was administered at doses of 1.25, 2.5, and 5 mg/kg. Behavioral assessments, neuroinflammatory cytokine analysis like tumor necrosis factor-α, interleukin-1-ß, interleukin-6 (TNF-α, IL-1ß, IL-6), oxidative stress marker measurements malondialdehyde, reduced glutathione, superoxide dismutase (MDA, GSH, SOD), and nitrite (NO), Acetylcholinesterase enzyme (AchE), and neurotransmitter level analysis, dopamine, serotonin, and norepinephrine (DA, 5-HT, and NE) were conducted. RESULTS: The study assessed behavioral, neurochemical, biochemical, and neuroinflammatory parameters, along with the modulation of p38 MAPK signaling. EMB administration significantly ameliorated neurological consequences induced by EB, improving motor coordination and gait abnormalities in rats. Furthermore, EMB effectively reduced neuroinflammatory cytokines (TNF-α, IL-1ß, IL-6) and oxidative stress markers (AchE, SOD, MDA, GSH, nitrite). Notably, EMB exhibited a modulatory effect on neurotransmitter levels, increasing GABA, DA, and 5-HT, while reducing glutamate in EB-treated groups. CONCLUSION: This study demonstrates the neuroprotective potential of EMB against the EB-induced model of MS in rats. EMB administration mitigated neurological impairments, attenuated neuroinflammation, alleviated oxidative stress, and restored neurotransmitter balance. These findings highlight the promise of EMB as a therapeutic candidate for MS treatment, providing insights into its potential mechanism of action involving the modulation of p38 MAPK signaling.

Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis.

BACKGROUND: Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. OBJECTIVES: This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. METHODS: Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. RESULTS: We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. CONCLUSION: We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.

Concurrent administration of serotonergic antidepressants and ozanimod in participants with relapsing multiple sclerosis from the open-label extension DAYBREAK trial.

BACKGROUND: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro. OBJECTIVE: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717). METHODS: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use. RESULTS: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630). CONCLUSION: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use.

Safety of anti-varicella zoster virus vaccination in patients with multiple sclerosis treated with natalizumab: A case series.

The vaccination with live attenuated vaccines is generally not recommended during natalizumab (NTZ), as it is included among immunosuppressive/immunomodulating therapies. Nevertheless, considering the lack of evidence of a non-Central Nervous System (CNS) immunosuppressive effect of NTZ, after a risk/benefit evaluation, we decided to vaccinate four multiple sclerosis (MS) patients (three with an indication to switch to ocrelizumab for high-risk Progressive Multifocal Leukoencephalopathy (PML) and one for pregnancy planning). No vaccine-related adverse events of any type nor varicella zoster virus (VZV) infections were observed. To the best of our knowledge, these case series represent the first description of the good safety profile of anti-VZV vaccination in MS patients during NTZ treatment.

Lessons learned after 20 years of real-world experience with natalizumab.

BACKGROUND: While natalizumab (NTZ) is an effective therapy for multiple sclerosis (MS), it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). After 20 years (2002-2022) of experience with NTZ at our center, we observed no cases of PML. OBJECTIVES: We evaluated the likelihood of experiencing PML in a subset of our treatment cohort, as well as reviewed treatment practices at our center that may mitigate PML risk. METHODS: For this retrospective study, we reviewed patient characteristics, treatment practices, and clinical and MRI findings in patients receiving NTZ from 2006 to 2020. Observation of no PML cases was compared to the global and US PML incidences, and to the expected incidence based on published risk estimates. RESULTS: 766 patients were evaluated. The number of NTZ infusions received ranged from 1 to 126, with a mean of 28. Patients received neurological examination prior to each infusion, which sometimes resulted in a pause in therapy to rule out PML if clinical worsening occurred. Extended interval dosing (EID) was the overall dosing schedule for 31% of patients. EID did not result in higher rates of radiological disease worsening than standard interval dosing (SID) patients. Depending on the analysis conducted, the finding of 0 PML cases in our cohort ranged from slightly unexpected to slightly expected. CONCLUSIONS: The utilization of EID as well as regular clinical monitoring of patients may have lowered PML risk while still maintaining NTZ efficacy.

Risk of cancer with immunosuppressants compared to immunomodulators in multiple sclerosis: A nested case-control study within the French nationwide claims database.

PURPOSE: The objective was to compare the risk of malignancies in real-world settings between exclusive immunosuppressant (IS) and immunomodulator (IM) use in multiple sclerosis (MS). METHODS: A nested case-control study was designed within a new-user cohort of all patients with MS who initiated a first IM or IS between 2008 and 2014, and without cancer history, using the information of the SNDS nationwide French claims database. Incident cancer cases were matched with up to six controls on year of birth, sex, initiation date, and disease risk score of cancer. A conditional logistic regression (odds ratio [95% confidence interval]) was used to compare exclusive IS versus IM use during follow-up and according to three use durations. RESULTS: From 28 720 newly treated patients with MS, 407 incident cancers were observed during the follow-up with 2324 matched controls. A significant increase in cancer risk was observed for IS compared with IM (1.36 [1.05, 1.77]), with similar increases for the first 2 years of use but not for ≥2 years (1.06 [0.65, 1.75]). Similar increase was also observed for IS with indications other than MS (1.37 [1.04, 1.81]) but not for IS indicated only in MS (1.03 [0.45, 2.34]). CONCLUSIONS: Compared with IM, a 37% increase in cancer risk was observed for IS with indications other than MS and used for a short duration (≤2 years) but not for IS indicated only in MS. The absence of risk for prolonged exposure of IS with indications other than MS is not in favor of a causal relation with these drugs.

Cladribine tablets in people with relapsing multiple sclerosis: A real-world multicentric study from southeast European MS centers.

BACKGROUND: Cladribine is an oral disease-modifying drug authorized by the European Medicine Agency for the treatment of highly active relapsing multiple sclerosis (MS). OBJECTIVES: To provide real-world evidence of cladribine's effectiveness and safety in people with MS (pwMS). METHODS: A retrospective observational multi-center, multi-national study of pwMS who were started on cladribine tablets in ten centers from five European countries. RESULTS: We identified 320 pwMS treated with cladribine tablets. The most common comorbidities were arterial hypertension and depression. Three patients had resolved hepatitis B infection, while eight had positive Quantiferon test prior to cladribine commencement. There were six pwMS who had malignant diseases, but all were non-active. During year 1, 91.6% pwMS did not have EDSS worsening, 86.9% were relapse-free and 72.9% did not have MRI activity. During the second year, 90.2% did not experience EDSS worsening, 86.5% were relapse-free and 75.5% did not have MRI activity. NEDA-3 was present in 58.0% pwMS in year 1 and in 54.2% in year 2. In a multivariable logistic regression model age positively predicted NEDA-3 in year 1. The most common adverse events were infections and skin-related adverse events. Lymphopenia was noted in 54.7% of pwMS at month 2 and in 35.0% at month 6. Two pwMS had a newly discovered malignant disease, one breast cancer, and one melanoma, during the first year of treatment. CONCLUSION: Our real-world data on the effectiveness and safety of cladribine tablets are comparable to the pivotal study and other real-world data with no new safety signals.

[Translated Article] Disease-modifying treatments for patients with multiple sclerosis in Spain.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability. OBJECTIVE PRIMARY: To determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments. SECONDARY OBJECTIVES: to determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyze pharmacotherapeutic complexity. METHOD: Observational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions. RESULTS: 1407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had 1 comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3-15.0). CONCLUSIONS: We have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterized concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.

Soft Palate Malignant Melanoma as an Adverse Effect of Fingolimod in Multiple Sclerosis: A Case Report and Literature Review.

Fingolimod has been approved as a disease-modifying drug in multiple sclerosis since 2010. There are a few reports of melanoma as a side effect of Fingolimod in the literature. Herein we aim to report a known case of multiple sclerosis under Fingolimod presenting with persistent nasal congestion who was eventually diagnosed with soft palate malignant melanoma.

Index of cardiac-electrophysiological balance in relapsing-remitting multiple sclerosis patients treated with fingolimod.

BACKGROUND: Fingolimod is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS) and also targets cardiovascular system due to receptors on cardiomyocytes. Results of previous studies are controversial for the effect of fingolimod in terms of ventricular arrhythmias. Index of cardio-electrophysiological balance (iCEB) is a risk marker for predicting malignant ventricular arrhythmia. There is no evidence on the effect of fingolimod on iCEB in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to evaluate iCEB in patients with RRMS treated with fingolimod . METHODS: A total of 86 patients with RRMS treated with fingolimod were included in the study. All patients underwent a standard 12-lead surface electrocardiogram at initiation of treatment and 6 h after treatment. Heart rate, RR interval, QRS duration, QT, QTc (heart rate corrected QT), T wave peak-to-end (Tp-e) interval, Tp-e/QT, Tp-e/QTc, iCEB (QT/QRS) and iCEBc (QTc/QRS) ratios were calculated from the electrocardiogram. QT correction for heart rate was performed using both the Bazett and Fridericia formulas. Pre-treatment and post-treatment values were compared. RESULTS: Heart rate was significantly lower after fingolimod treatment (p< 0.001). While the post-treatment values of RR and QT intervals were significantly longer (p< 0.001) and post-treatment iCEB was higher (median [Q1-Q3], 4.23 [3.95-4.50] vs 4.53 [4.18-5.14]; p< 0.001), it was found that there was no statistically significant change in iCEB and other study parameters derived using QT after correcting for heart rate using both of two formulas. CONCLUSIONS: In this study, it was found that fingolimod did not statistically significantly change any of the heart rate-corrected ventricular repolarization parameters, including iCEBc, and it is safe in terms of ventricular arrhythmia.

Progressive multifocal leukoencephalopathy with natalizumab extended or standard interval dosing in the United States and the rest of the world.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited. RESEARCH DESIGN AND METHODS: A retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems. RESULTS: Of 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis. CONCLUSIONS: This analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.

Evaluating the efficacy and safety of transitioning patients with multiple sclerosis from natalizumab to ocrelizumab (OCTAVE).

INTRODUCTION: Natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients infected with John Cunningham virus (JCV). Ocrelizumab has demonstrated efficacy to treat MS; however, its safety in patients previously treated with natalizumab is unclear. OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab in patients with relapsing MS (RMS) previously treated with natalizumab. METHODS: Clinically and radiographically stable RMS patients, ages 18-65 treated with natalizumab for ⩾ 12 months, were enrolled in the study and initiated ocrelizumab 4-6 weeks after their final dose of natalizumab. Relapse assessment, expanded disability status scale, and brain magnetic resonance imaging (MRI) were performed prior to starting ocrelizumab and at months 3, 6, 9, and 12. RESULTS: Forty-three patients were enrolled, and 41 (95%) completed the study. Two patients had a relapse while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. Thirteen serious adverse events (SAEs) were recorded, four of which were considered possibly related to ocrelizumab. CONCLUSION: Overall, our study indicates clinical and MRI stability for most patients transitioning from natalizumab to ocrelizumab. CLINICALTRIALS.GOV IDENTIFIER: NCT03157830.

Disease-modifying treatments for patients with multiple sclerosis in Spain. / Tratamientos modificadores de la enfermedad en pacientes con esclerosis múltiple en España.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability. OBJECTIVE PRIMARY: To determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments. SECONDARY OBJECTIVES: To determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyse pharmacotherapeutic complexity. METHOD: Observational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions. RESULTS: 1,407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had one comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3 -- 15.0). CONCLUSIONS: We have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterised concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.

Real-world use of natalizumab in Austria: data from the Austrian Multiple Sclerosis Treatment Registry (AMSTR).

INTRODUCTION: With the approval of natalizumab in Europe in 2006, the Austrian Multiple Sclerosis Therapy Registry (AMSTR) was established. Here, we present data from this registry about effectiveness and safety of natalizumab in patients treated up to 14 years. PATIENTS/METHODS: Data retrieved from the AMSTR contained baseline characteristics and biannual documentation of annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score as well as adverse events and reasons for discontinuation on follow-up visits. RESULTS: A total of 1596 natalizumab patients (71% women, n = 1133) were included in the analysis and the observed treatment duration ranged from 0 to 164 months (13.6 years). The mean ARR was 2.0 (SD = 1.13) at baseline, decreasing to 0.16 after 1 year and 0.01 after 10 years. A total of 325 patients (21.6%) converted to secondary progressive multiple sclerosis (SPMS) during the observational period. Of 1502 patients, 1297 (86.4%) reported no adverse events (AE) during follow-up visits. The most common reported AEs were infections and infusion-related reactions. John Cunningham virus (JCV) seropositivity was the most common specified reason for treatment discontinuation (53.7%, n = 607). There were five confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) with 1 death. CONCLUSION: The effectiveness of natalizumab in patients with active relapsing-remitting multiple sclerosis (RRMS) could be confirmed in our real-world cohort even after follow-up of up to 14 years, though after year 10, there were less than 100 remaining patients. A low number of AE were reported in this nationwide registry study, establishing Natalizumab's favourable safety profile during long-term use.

An unforeseen reality: Hemophagocytic lymphohistiocytosis following alemtuzumab treatment for a multiple sclerosis.

Alemtuzumab is a humanized monoclonal antibody indicated for treatment of highly active relapsing-remitting multiple sclerosis (HA-RRMS). It binds to CD52 antigen and produces a rapid and prolonged lymphocyte depletion followed by a different pattern of T and B cell repopulation. Among others, its adverse events are autoimmune diseases.In this article, we present a patient with HA-RRMS, who was subsequently treated with alemtuzumab and afterwards developed hemophagocytic lymphohistiocytosis (HLH). Albeit rarely, HLH can be triggered by alemtuzumab treatment.HLH can favourably respond to prompt immunosuppressant therapy.Multidisciplinary approach by a team consisting of a neurology, hematology and rheumatology specialist is needed to treat this potentially lethal condition.

Gene-environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures.

BACKGROUND: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis. METHODS: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090). RESULTS: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes. CONCLUSIONS: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

Thyroid autoimmunity following alemtuzumab treatment in multiple sclerosis patients: a prospective study.

Autoimmune thyroid disease (AITD) is the most common adverse effect in alemtuzumab (ALZ) treated relapsing-remitting (RR) multiple sclerosis (MS) patients. The objective of this prospective study was to analyze the occurrence, timing of onset, clinical course, and laboratory characteristics of AITD post-ALZ. We evaluated 35 RRMS patients treated with ALZ at a single academic MS center; clinical and laboratory data were collected before ALZ initiation and thereafter quarterly on follow-up with a median of 43.5 months. Seventeen out of 31 patients (54.8%) with no prior history of thyroid dysfunction developed AITD with a mean onset of 19.4 months ± 10.2 (SD) after the first ALZ cycle; Graves' disease (GD) (n = 9); hypothyroidism with positive stimulating thyrotropin receptor antibodies (TRAb) (n = 1); Hashimoto thyroiditis (HT) (n = 6); HT with hypothyroidism (n = 1). Interestingly, seven of nine (77.7%) GD patients showed a fluctuating course. Three out of four patients with preexisting thyroid disease remained stable, whereas one with prior HT and hypothyroidism developed fluctuating GD. All patients with GD commenced antithyroid drugs (ATDs); five continued on "block and replace" treatment; one required radioactive iodine, and one total thyroidectomy. Our analysis showed earlier onset of ALZ-induced AITD in comparison to most other ALZ cohorts; overall, these patients required complex therapeutic approaches of the AITD. We observed a higher rate of fluctuating GD, with earlier onset and lower remission rate than previously reported, which in the majority of patients required prolonged "block and replace" therapy in the minimum dose of each therapeutic agent or more definitive interventions.

The effects of bupropion on sexual dysfunction in female patients with multiple sclerosis: A double-blind randomized clinical trial.

BACKGROUND: Sexual dysfunction (SD) is one of the most common complications of multiple sclerosis (MS). The aim of this study was to evaluate the effects of bupropion on SD among female patients with MS. METHODS: This double-blind placebo-control randomized clinical trial was conducted on MS patients with SD complaint. Diagnosis was based on the secondary SD subscale scores of the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19). Accordingly, individuals scoring above 27 based on this scale were diagnosed with SD. The subjects were randomly assigned to the bupropion and placebo groups. Bupropion was administered 75 mg twice daily for twelve weeks. As for the study outcomes, besides MSISQ-19, quality of life (Multiple Sclerosis Quality Of Life-54 (MSQOL-54)), fatigue (Multidimensional Fatigue Inventory (MFI)), depression and anxiety (Hospital Anxiety and Depression Scale), and bupropion tolerability were assessed at baseline as well as at weeks 6 and 12. RESULTS: From 84 patients who met the inclusion criteria, 64 patients completed the trial and were analyzed. Demographics and baseline clinical characteristics were not significantly differed between the two groups. The results showed the mean score of MSISQ-19 from baseline to the end of the study period significantly improved in the bupropion group compared with the placebo (week 6: P: 0.03; week 12: P: 0.03). Similarly, MFI scores showed significant improvement in the bupropion group compared with the placebo group (P: 0.001). Both anxiety and depression scores showed significant alterations at study interval between the two groups (Anxiety: weeks 6 and 12: P:0.04; depression: week 6: 0.01, week 12: 0.02). However, there was no significant change in the MSQOL-54 score between the two groups. CONCLUSION: The results of the study substantiated that bupropion can be an effective agent for SD improvement in female patients with MS. Further clinical trials with larger sample sizes can more accurately evaluate the observed findings.

Combination effects of mesenchymal stem cells transplantation and anodal transcranial direct current stimulation on a cuprizone-induced mouse model of multiple sclerosis.

Multiple sclerosis (MS) has no absolute treatment, and researchers are still exploring to introduce promising therapy for MS. Transcranial direct current stimulation (tDCS), is a safe, non-invasive procedure for brain stimulating which can enhance working memory, cognitive neurohabitation and motor recovery. Here, we evaluated the effects of tDCS treatment and Mesenchymal stem cells (MSCs) transplantation on remyelination ability of a Cuprizone (CPZ)-induced demyelination mouse model. tDCS significantly increased the motor coordination and balance abilities in CPZ + tDCS and CPZ + tDCS + MSCs mice in comparison to the CPZ mice. Luxol fast blue (LFB) staining showed that tDCS and MSCs transplantation could increase remyelination capacity in CPZ + tDCS and CPZ + MSCs mice compared to the CPZ mice. But, the effect of tDCS with MSCs transplantation on remyelination process was larger than each of treatment alone. Immunofluorescence technique indicated that the numbers of Olig2+ cells were increased by tDCS and MSCs transplantation in CPZ + tDCS and CPZ + MSCs mice compared to the CPZ mice. Interestingly, the combination effect of tDCS and MSCs was larger than each of treatment alone on Oligodendrocytes population. MSCs transplantation significantly decreased the TUNEL+ cells in CPZ + MSCs and CPZ + tDCS + MSCs mice in comparison to the CPZ mice. Also, the combination effects of tDCS and MSCs transplantation was much larger than each of treatment alone on increasing the mRNA expression of BDNF and Sox2, while decreasing P53 as compared to CPZ mice. It can be concluded that the combination usage of tDCS and MSCs transplantation enhance remyelination process in CPZ-treated mice by increasing transplanted stem cell homing, oligodendrocyte generation and decreasing apoptosis.