Personalized Intervention to Improve Medication Adherence for Persons with Multiple Sclerosis.

Purpose: To evaluate the acceptability, retention, and efficacy of face-to-face intervention, incorporating education and Motivational Interviewing (MI) to support persons with relapsing-remitting multiple sclerosis (PwRRMS) and increase self-reported medication adherence. Patients and Methods: PwRRMS (N = 60) prescribed Disease Modifying Treatment (DMT), who were identified as non-adherent and consented to participate in an intervention, received verbal education and counseling from their treating physician, a tailored MI counseling and a booster session via telephone with a health psychologist, and a concluding MI counseling six months later. Each PwRRMS filled a battery of patient-reported outcomes (PROs) at baseline, six and 12 months later. The design was a quasi-experimental pre-test post-test across a year. Results: Of the sixty identified persons who consented to enroll, 52 completed the intervention and 46 completed the follow-up. At six months following the baseline, adherence scores increased (median = 12.0) and were significantly different than at baseline (median=10.0, p = 0.030). Still, at 12 months follow-up there was no significant difference from baseline in reported adherence (median = 11.0, p = 0.106). Conclusion: This study demonstrated reasonable retention and initial efficacy of a combined psycho-education and MI protocol for PwRRMS to enhance medication adherence to DMT. To maintain the change, a more sustained intervention is required.

The study focused on persons with relapsing-remitting multiple sclerosis (PwRRMS) who do not adhere to their prescribed medication. Following the identification of non-adherent persons, PwRRMS were offered an intervention to increase their adherence. The study examined how many of those identified consented to enroll in the intervention, how many remained in the intervention, and whether the intervention was efficacious in terms of self-reported adherence. The intervention included verbal education and counseling from the treating physician, immediately followed by tailored counseling by a psychologist. There was a booster session via telephone with the psychologist, and a concluding counseling meeting six months later. Participants were followed for a year after the initial counseling. Two-thirds of PWMS identified as non-adherent consented to enroll (n = 60), 52 completed the intervention and 46 completed the follow-up. At six months following counseling, self-reported adherence scores significantly increased, but at 12 months follow-up there was no significant difference from baseline in reported adherence. To maintain the change, a more sustained intervention is required.

Is infertility more common among patients with multiple sclerosis? Implications for utilization of assisted reproductive techniques.

RESEARCH QUESTION: Is fertility affected in women with multiple sclerosis (MS), and what is their usage of assisted reproductive technology (ART)? DESIGN: Data regarding multiple sclerosis and ART usage among patients with multiple sclerosis were extracted from the Israeli health maintenance organization Clalit Health Service database. Data regarding the diagnosis and treatment of multiple sclerosis, cause of infertility and use of fertility treatments were collected for all female multiple sclerosis patients aged 18-45 years between 2005 and 2021. Each patient was matched by age in a 1:10 ratio with reference women from the general population. The prevalence of infertility was compared between the two groups. Univariate and multivariate statistical tests were used to analyse the association between multiple sclerosis and fertility treatments including IVF and ovarian stimulation. RESULTS: During the study period, 1309 multiple sclerosis patients were compared with 13,090 controls from the general population matched for age. The mean age was 29 ± 7.8 years. The overall prevalence of infertility was 15.4% (202/1309) among the multiple sclerosis patients, similar to the general population (16.3%; 2129/13090) (P = 0.436). The prevalence of IVF and ovarian stimulation was similar among multiple sclerosis patients and matched controls from the general population (8.1% versus 7.2%, P = 0.240; 13.8% versus 14.3%; P = 0.624, respectively). CONCLUSIONS: The results show similar rates of infertility and fertility treatments among multiple sclerosis patients and the general population. This provides reassurance that fertility among women with multiple sclerosis does not differ from that of women in the general population, and indicates there is no excessive usage of ART.

Familial vs sporadic multiple sclerosis in the Israeli population: Differences in ethnicity distribution and disease progression, with anticipation in successive generations.

BACKGROUND: Multiple Sclerosis (MS) may cluster in families, an entity known as familial MS (FMS), possibly due to aggregation of genetic and environmental factors. Though previous studies have characterized FMS in different populations, no study to the best of our knowledge has yet characterized FMS in the unique Israeli population, which is comprised of relatively endogamous ethnicities. Our goal in this study was to compare demographic and clinical characteristics between FMS and sporadic MS (SMS), and to search for intra-familial patterns. METHODS: In a retrospective study of 101 FMS patients and 508 SMS patients, ethnicity and sex distribution was assessed. Clinical aspects were compared between 172 paired FMS and SMS patients, matched for sex, age and ethnicity, and between generations of the FMS cohort. RESULTS: Females comprised 75.3 % of FMS and 67.5 % of SMS patients (p = 0.1). Ethnic distribution was significantly different between FMS and SMS (p = 0.014), with the former comprising a higher proportion of Christian-Arabs (15.4% vs. 5.1 %, p = 0.004) and lower proportion of Jews (60% vs. 74.2 %, p = 0.016). Age at disease onset or diagnosis, frequency of positive Oligoclonal bands and comorbidity of other autoimmune/inflammatory disease or chronic diseases was comparable between FMS and SMS, yet motor symptoms at onset were more prevalent in FMS (34% vs. 20 %, p = 0.02). Annualized relapse rates throughout 10 years from onset were comparable. Among FMS, mean Expanded-Disability-Status-Scale (EDSS) and slope of deterioration in EDSS over 20 years from diagnosis were higher (p = 0.0004 and p = 0.023, respectively), time to EDSS ≥ 3 was shorter (7.1 vs. 12.1 years, HR 1.6, p = 0.036) and MS-Severity-Score (MSSS) was higher (3.84 vs. 2.95, p = 0.04), compared to SMS. Following adjustment for smoking, which tended to be higher among FMS patients (P = 0.06), mean EDSS and slope of deterioration in EDSS over 20 years remained significantly higher (p = 0.0006 and p = 0.025, respectively) in FMS, time to EDSS ≥ 3 tended to be higher (HR 1.5, p = 0.06), while MSSS was comparable. An inter-generational analysis of the total FMS cohort, as well as an intra-familial analysis, both adjusted for year of diagnosis, revealed significantly earlier age of onset (p < 0.0001 and p < 0.0001) and diagnosis (p = 0.001 and p < 0.0001) in the younger compared to the older generations, respectively. CONCLUSION: In this Israeli cohort, the proportions of specific ethnicities differ between FMS and SMS, indicating that FMS has a population-specific prevalence pattern, and that further investigation for susceptibility genes is warranted. Disease progression is faster in FMS patients and anticipation is observed in families with multiple cases of MS. Closer surveillance and application of a pro-active induction or early highly-effective therapeutic strategy for FMS patients should be considered, to reduce high disease activity and fast disability progression.

Multiple Sclerosis-Associated Gut Microbiome in the Israeli Diverse Populations: Associations with Ethnicity, Gender, Disability Status, Vitamin D Levels, and Mediterranean Diet.

Microbiome dysbiosis is increasingly being recognized as implicated in immune-mediated disorders including multiple sclerosis (MS). The microbiome is modulated by genetic and environmental factors including lifestyle, diet, and drug intake. This study aimed to characterize the MS-associated gut microbiome in the Israeli populations and to identify associations with demographic, dietary, and clinical features. The microbiota from 57 treatment-naive patients with MS (PwMS) and 43 age- and gender-matched healthy controls (HCs) was sequenced and abundance compared. Associations between differential microbes with demographic or clinical characteristics, as well as diet and nutrient intake, were assessed. While there was no difference in α- or ß-diversity of the microbiome, we identified 40 microbes from different taxonomic levels that differ in abundance between PwMS and HCs, including Barnesiella, Collinsella, Egerthella, Mitsuokella, Olsenella Romboutsia, and Succinivibrio, all enhanced in PwMS, while several members of Lacnospira were reduced. Additional MS-differential microbes specific to ethnicity were identified. Several MS-specific microbial patterns were associated with gender, vitamin D level, Mediterranean diet, nutrient intake, or disability status. Thus, PwMS have altered microbiota composition, with distinctive patterns related to geographic locations and population. Microbiome dysbiosis seem to be implicated in disease progression, gender-related differences, and vitamin D-mediated immunological effects recognized in MS. Dietary interventions may be beneficial in restoring a "healthy microbiota" as part of applying comprehensive personalized therapeutic strategies for PwMS.

Using an Intervention Mapping Approach to Improve Adherence to Disease-Modifying Treatment in Multiple Sclerosis.

BACKGROUND: Up to 50% of individuals with multiple sclerosis (MS) who are prescribed disease-modifying treatments (DMTs) do not take them as advised. Although many studies report on DMT adherence rate, few studies report on interventions involving individuals with MS. The current paper describes the development of an intervention aimed at improving adherence to DMTs among identified nonadherent individuals with MS. METHODS: An intervention was developed using an Intervention Mapping approach, recommendations from reviews on medication adherence, and input from individuals with MS. Its content was determined by theories of health behavior (specifically, a perceptions and practicalities approach), empirical evidence collected among the specific target population (an observational "needs assessment" stage [n = 186]), and other studies. RESULTS: A personalized intervention was tailored to the reasons for nonadherence, uncovered during the observational needs assessment stage, to be delivered sequentially by a neurologist and a psychologist. After the intervention objectives were identified, components of the intervention were set: psychoeducation and ways of coping with adverse effects; modification of unhelpful treatment beliefs (such modifications were found predictive of adherence in the observational phase of the study); improving confidence and self-efficacy; and developing strategies for remembering to take DMTs. These components were embedded within motivational interviewing. CONCLUSIONS: Intervention Mapping was useful in developing an intervention grounded both in the theoretical approach of perceptions and practicalities and in empirical evidence from the literature and the target sample; concurrently, identifying determinants that the intervention did not address. The effectiveness of the intervention-which could potentially improve adherence among individuals with MS-needs to be examined.

Medication habits among persons with multiple sclerosis.

BACKGROUND: Though habitual behavior is part of medication-taking behavior, studies of adherence to medication among persons with relapsing remitting multiple sclerosis (PwRRMS) have not prospectively examined habit in relation to disease-modifying treatments (DMTs). OBJECTIVES: 1. Examine habit dimensions - repetition, lack of awareness, and lack of control - across time and route of administration (oral vs. injectable). 2. Examine the association (prospective and cross sectional) of the dimension of repetition and the habit index with adherence and persistence in medication taking and to medication perceptions. METHODS: PwMS (n = 140), in their first year of treatment with a DMT, were prospectively assessed at three time points: at baseline, 6 months later (Time 1), and 12 months later (Time 2). Clinical and demographic information were obtained in-person, as were patient-reported medication habits and medication perceptions. Adherence and persistence were assessed with a combination of self-reporting and retrospective review of medication claims. RESULTS: Repeated measures analysis of variance (ANOVA), with dimension as the within-subject factor at each time point, indicated that the repetition dimensions at all points were significantly higher than lack of awareness and lack of control dimensions. Repeated measures ANOVA, with time as the within-subject factor and route of administration as between-subject factor, yielded a significant time effect in repetition and lack of awareness dimensions so that they increased across time but not in lack of control; administration route effects were found to be nonsignificant in all dimensions. Repetition at Time 1 was positively associated with patient-reported adherence at this time point (rs = 0.33, p = 0.002) but this was not consistently found at other time points . Likewise, reported repetition at Time 1 was higher among PwRMS who persisted with their medication a year later than among those who did not persist. Perceptions of medication (concern, harm, and overtreatment) were significantly negatively associated with reported repetition. CONCLUSIONS: Over time, PwRMS reported an increase in two habit dimensions, repetition and lack of awareness, in medication taking. No significant differences in habit by administration modality were found. The habit dimension of repetition was significantly associated with perceptions of medication, adherence, and prospectively predicted persistence. However, the low values obtained for lack of awareness and lack of control, compared with the higher levels of repetition, indicate that the habit is not well ingrained. Hence, intervention to target habit formation and maintenance, to be tailored to the individual, are a promising venue for enhancing medication adherence and improving disease outcomes.

Humoral and Cellular Immune Responses to SARS-CoV-2 mRNA Vaccination in Patients with Multiple Sclerosis: An Israeli Multi-Center Experience Following 3 Vaccine Doses.

Background: Immunomodulatory/immunosuppressive activity of multiple sclerosis (MS) disease modifying therapies (DMTs) might affect immune responses to SARS-CoV-2 exposure or vaccination in patients with MS (PwMS). We evaluated the effect of DMTs on humoral and cell-mediated immune responses to 2 and 3 vaccinations and the longevity of SARS-Cov-2 IgG levels in PwMS. Methods: 522 PwMS and 68 healthy controls vaccinated with BNT162b2-Pfizer mRNA vaccine against SARS-CoV-2, or recovering from COVID-19, were recruited in a nation-wide multi-center study. Blood was collected at 3 time-points: 2-16 weeks and ~6 months post 2nd vaccination and 1-16 weeks following 3rd vaccination. Serological responses were measured by quantifying IgG levels against the spike-receptor-binding-domain of SARS-CoV-2, and cellular responses (in a subgroup analysis) by quantifying IFNγ secretion in blood incubated with COVID-19 spike-antigen. Results: 75% PwMS were seropositive post 2nd or 3rd vaccination. IgG levels decreased by 82% within 6 months from vaccination (p<0.0001), but were boosted 10.3 fold by the 3rd vaccination (p<0.0001), and 1.8 fold compared to ≤3m post 2nd vaccination (p=0.025). Patients treated with most DMTs were seropositive post 2nd and 3rd vaccinations, however only 38% and 44% of ocrelizumab-treated patients and 54% and 46% of fingolimod-treated patients, respectively, were seropositive. Similarly, in COVID-19-recovered patients only 54% of ocrelizumab-treated, 75% of fingolimod-treated and 67% of cladribine-treated patients were seropositive. A time interval of ≥5 months between ocrelizumab infusion and vaccination was associated with higher IgG levels (p=0.039 post-2nd vaccination; p=0.036 post-3rd vaccination), and with higher proportions of seropositive patients. Most fingolimod- and ocrelizumab-treated patients responded similarly to 2nd and 3rd vaccination. IFNγ-T-cell responses were detected in 89% and 63% of PwMS post 2nd and 3rd vaccination, however in only 25% and 0% of fingolimod-treated patients, while in 100% and 86% of ocrelizumab-treated patients, respectively. Conclusion: PwMS treated with most DMTs developed humoral and T-cell responses following 2 and 3 mRNA SARS-CoV-2 vaccinations. Fingolimod- or ocrelizumab-treated patients had diminished humoral responses, and fingolimod compromised the cellular responses, with no improvement after a 3rd booster. Vaccination following >5 months since ocrelizumab infusion was associated with better sero-positivity. These findings may contribute to the development of treatment-stratified vaccination guidelines for PwMS.

Concordance Between Persons with Multiple Sclerosis and Treating Physician on Medication Effects and Health Status.

BACKGROUND: As the number of treatment options for multiple sclerosis (MS) has expanded, alignment between physician and patient on effects of medication has emerged as important for medication persistence/discontinuation. OBJECTIVE: To evaluate physician-patient agreement levels on medication effect and health status. METHODS: Persons with MS (PwMS) (n=71) participated in a cross-sectional study collecting their satisfaction (using the Treatment Satisfaction Questionnaire for Medication), intention to dis/continue treatment and global health perception; physicians assessed response to medication and global health status. RESULTS: Concordance between PwMS' assessment of medication effectiveness and physician's assessment on response to medication, health status and EDSS were r s= 0.50, r s= 0.57 and r s= -0.58, respectively. CONCLUSION: The significant concordance attests to physician-patient effective communication and may contribute to improved medication adherence.

Mobile-phone-based e-diary derived patient reported outcomes: Association with clinical disease activity, psychological status and quality of life of patients with multiple sclerosis.

BACKGROUND: The applicability of mobile digital technology to promote clinical care of people with multiple sclerosis (pwMS) is gaining increased interest as part of the implementation of patient-centered approaches. We aimed at assessing adherence to a smartphone-based e-diary, which was designed to collect patient-reported outcomes (PROs). Secondary objectives were to evaluate the construct and predictive validity of e-diary derived PROs and to explore the various factors that were associated with changes in PROs over time. MATERIALS AND METHODS: In this observational cohort study patients downloaded an MS tailored e-diary into their personal smartphones. Report of PROs was enquired once monthly for a period of one year through a smartphone-based application, using previously validated tools. An e-diary derived bodily function summary score (eBF) was defined as the sum of scores depicting vision, limbs function, pain, bowl/ bladder dysfunction, pseudobulbar affect and spasticity. Multiple linear regression and analysis of covariance were used to determine the association between PROs, clinician-reported outcomes (ClinROs) of disease activity and quality of life (QoL). Regression coefficient analysis was used to compare the slope of change in eBF before and after a relapse. RESULTS: 97 pwMS downloaded the e-diary [Female: 64 (66%), EDSS 3.4±2.1]. 76 patients (78%) completed the 12-month study period. 53 patients (55%) submitted ≥75% of requested surveys. Anxiety was negatively associated with adherence to periodic PROs assessments by the e-diary. E-diary derived PROs were significantly correlated with corresponding functional system scores (0.38< r <0.8, P<0.001). eBF score significantly predicted QoL (ß = -0.36, P = 0.001) while EDSS did not. Change in eBF score over time was independently associated with the occurrence of an MS relapse (F = 4.4, P = 0.04), anxiety (F = 6.4, P = 0.01) and depression (F = 5.1, P = 0.03). Individual regression slopes of eBF scores were significantly higher pre-relapse than post-relapse (3.0±3.3 vs. -0.8±2.0, P = 0.007). CONCLUSION: Adherence of pwMS to recording in an e-diary collecting PROs was high. Changes in e-diary derived PROs over time predict clinical MS relapses on the group level and thus carry the potential of usage in clinical research as well as for improved MS care in real world setting.

Beliefs about medication as predictors of medication adherence in a prospective cohort study among persons with multiple sclerosis.

BACKGROUND: Though adherence to disease-modifying therapies (DMTs) among persons with multiple sclerosis (PwMS) varies and is often below 80%, only few prospective studies on adherence examined predictors beyond demographic and clinical characteristics. OBJECTIVES: Identify antecedents to adherence and persistence to DMT in a prospective design among PwMS. METHODS: PwMS (n = 186) were prospectively assessed at three time points: baseline, 6 (Time 1) and 12 months later (Time 2). Clinical, demographic information and patient-reported medication beliefs, illness perceptions, medication habits, perceived health and affect were surveyed in-person. Adherence and persistence were assessed by a combination of self-reports and retrospective review of medication claims. FINDINGS: PwMS were 69.9% (Time 1) and 71% (Time 2) adherent to their DMTs and 64.5.9% were persistent. Beliefs about Medications were consistently predictive at both time points (baseline to Time 1 and Time 1 to Time 2) of medication adherence and persistence whereas other perceptions were predictive in some analyses; clinical and demographic characteristics were mostly not predictive of adherence nor persistence. The prospective association of beliefs about medication with adherence held also in multivariate analyses (OR = 0.88, 95% CI 0.78-0.99, p = 0.029). CONCLUSIONS: Adherence and persistence are predicted by medication beliefs of PwMS. As medication beliefs are modifiable, they should be assessed periodically and targeted as a focus of tailored interventions aimed to improve adherence and consequently health outcomes in PwMS. REGISTRATION: Clinical trials registry # NCT02488343 , date: 06/08/2015.

Mobile phone-based e-diary for assessment and enhancement of medications adherence among patients with multiple sclerosis.

BACKGROUND: Adherence to multiple sclerosis (MS) disease-modifying drugs (DMDs) is essential for realization of their optimal effectiveness and benefits. OBJECTIVE: To evaluate the usefulness and validity of a smartphone-based e-diary as a tool for adherence assessment as well as its effectiveness as a promoter of adherence to DMDs. METHODS: An MS tailored e-diary (MyMS&Me) reminded patients to take their DMDs on time. DMD intake was self-recorded in the e-diary by the participants. Three methods of adherence evaluation were compared: e-diary derived, retrospective self-reported, and the medication possession rate (MPR). The proportion of patients with poor adherence to DMDs (defined as MPR <80%) among e-diary users was compared with a control group without intervention. RESULTS: Sixty-two patients downloaded the e-diary (Female: 41 (66%), Expanded Disability Status Scale 3.2 ± 2.2) and 55 controls were enrolled. The median difference between e-diary-derived adherence and the MPR was -3% (95% limits of agreement: -53% to 12%). The median difference between retrospective self-reported adherence and the MPR was 0.3% (95% limits of agreement: -20% to 42%). The proportion of participants with poor adherence to DMDs was similar in the e-diary and control groups (10% vs. 13%, p = 0.6). CONCLUSIONS: Substantial and clinically important disagreement between methods of medication adherence evaluation was noted. Smartphone reminders did not significantly improve the MPR of DMDs.

Dimethyl fumarate promotes B cell-mediated anti-inflammatory cytokine profile in B and T cells, and inhibits immune cell migration in patients with MS.

Dimethyl Fumarate (DMF), known for its mechanism of action targeting Nrf2 and related redox homeostasis, is an approved immunotherapy for patients with Multiple Sclerosis (PwMS) in the relapsing form. We assessed how DMF modulates immune cell functions, namely the cytokine profile of co-cultured B and T cells, and the chemokine-mediated migration of immune cells. Following DMF therapy, LTα+, TNFα+ and IFNγ+ B cells were reduced while TGFß and IL10 expression elevated. B cells from DMF-treated patients increased TGFß and LTα expression on T cells, while DMF directly reduced TNFα+ and IFNγ+ T cells. CXCL12/CXCL13-mediated migration of B cells, Monocytes, CD4 and CD8 T cells was reduced, with altered CXCR5 and CXCR4 expression. Induction of regulatory B and T cells and reduced migration of immune cells may be part of the beneficial mechanism of DMF in PwMS.

Multiple modality approach to assess adherence to medications across time in Multiple Sclerosis.

BACKGROUND: Medication adherence is especially challenging in a chronic condition such as Relapsing Multiple Sclerosis (RMS). Medication adherence among persons with MS (PwMS) is usually assessed via a single measure, mostly electronic pharmacy records. OBJECTIVES: Assess medication adherence in multiple modes across time among PwMS; examine consistency across time and associations between measures. METHODS: PwMS (N = 194) were surveyed prospectively at three time points (baseline, 6 and 12 months later) and their health records and medication claims were retrospectively obtained. Adherence score was based on medication possession ratio (MPR) and two patient-reported outcome (PRO) measures. Electronic monitoring devices assessing medication adherence were also initiated. RESULTS: MPR of each nonadherent PwMS, once compared to medical records containing prescription changes, was found as underestimating adherence. MPR was between the two PROs in identifying nonadherence and associations between the measures and across time was moderate (Kappa ranged 0.37-0.42). The use of electronic monitoring devices was not adopted by patients. A score indicated adherence as 66% and 64.9% at Time1 and Time 2, respectively, with 21.1% of PwMS nonadherent at both time points. Adherence did not vary significantly by DMT type. CONCLUSIONS: Being a dynamic behavior, medication adherence should be repeatedly monitored by using multiple modalities and focused on in clinician-patient encounters, especially in chronic diseases such as MS, which requires long-term treatments. Applying PROs in monitoring medication adherence would facilitate implementation of Participatory Medicine and patient-centered strategies in MS care.

Caring for patients with venomous Crotalinae snakebites.

Venomous snakebites are surprisingly common in the US. This article provides an overview of what to do when a patient has been bitten by a North American pit viper, a venomous subset of indigenous snakes.

Fingolimod reduces CXCR4-mediated B cell migration and induces regulatory B cells-mediated anti-inflammatory immune repertoire.

BACKGROUND: Fingolimod, an oral therapy for patients with relapsing Multiple Sclerosis (MS), traps CC chemokine receptor type 7 (CCR7)-expresssing lymphocytes within lymphoid tissues in the periphery, thereby supposedly reducing the infiltration of pathogenic cells into the central nervous system. Additional immunomodulatory effects of Fingolimod, involving cell function, B and T cells interactions and cross-regulation, have scarcely been studied. The objective of this study was to assess how Fingolimod therapy affects B cells functions, namely cell migration, immunoglobullin production and T cell stimulation. METHODS: B cells from 36 patients with relapsing MS were obtained before and after 3 months Fingolimod therapy, while CD4 T cells were collected pre-treatment. Clinical follow-up was performed for 1 year. For in-vitro validation, Lymphoblastoid cell-lines from 16 patients were cultured with Fingolimod. B cell migration towards C-X-C Motif Chemokine Ligand 12 (CXCL12) was assessed using a transwell system. C-X-C chemokine receptor 4 (CXCR4) expression was assessed by flow cytometry and western blot. Plasma immunoglobullins and Brain-derived Neurotrophic Factor (BDNF) were assessed by ELISA or RT-PCR. Drug effect on interacting co-cultured B and T cells on cytokine profiles and T cell proliferation was explored by flow cytometry. RESULTS: Lymphocyte count reduction did not predict clinical response of patients. Fingolimod therapy reduced CXCR4 expression and B cell migration towards CXCL12. No effect was found on immunoglobulins and BDNF. B cells from Fingolimod-treated patients induced a reduction in pro-inflammatory cytokines in T cells, while increased transforming growth factor beta (TGFß)+ B and T cells, and downregulated IL2-secretion from proliferative T cells. CONCLUSIONS: Fingolimod promotes anti-inflammatory cytokine profiles of B and T cells, through induction of regulatory B cells. Reduced B cell migration capacity in Fingolimod-treated patients leading to decreased cerebral inflammatory infiltration, may be part of the mechanism by which Fingolimod reduces disease activity in MS.

Dimethyl fumarate as a first- vs second-line therapy in MS: Focus on B cells.

OBJECTIVE: To elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a "1st-line" vs "2nd-line" therapy. METHODS: B cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up. RESULTS: 1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10+ B-cell subsets and TGFß+ B cells were increased. Proinflammatory LTα+ and TNFα+ B cells were reduced, while IL4+ B cells elevated, whereas IFNγ+ B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86+ B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased. CONCLUSIONS: DMF is associated with increased transitional and IL10+ and TGFß+ regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.

Exhaled Breath Markers for Nonimaging and Noninvasive Measures for Detection of Multiple Sclerosis.

Multiple sclerosis (MS) is the most common chronic neurological disease affecting young adults. MS diagnosis is based on clinical characteristics and confirmed by examination of the cerebrospinal fluids (CSF) or by magnetic resonance imaging (MRI) of the brain or spinal cord or both. However, neither of the current diagnostic procedures are adequate as a routine tool to determine disease state. Thus, diagnostic biomarkers are needed. In the current study, a novel approach that could meet these expectations is presented. The approach is based on noninvasive analysis of volatile organic compounds (VOCs) in breath. Exhaled breath was collected from 204 participants, 146 MS and 58 healthy control individuals. Analysis was performed by gas-chromatography mass-spectrometry (GC-MS) and nanomaterial-based sensor array. Predictive models were derived from the sensors, using artificial neural networks (ANNs). GC-MS analysis revealed significant differences in VOC abundance between MS patients and controls. Sensor data analysis on training sets was able to discriminate in binary comparisons between MS patients and controls with accuracies up to 90%. Blinded sets showed 95% positive predictive value (PPV) between MS-remission and control, 100% sensitivity with 100% negative predictive value (NPV) between MS not-treated (NT) and control, and 86% NPV between relapse and control. Possible links between VOC biomarkers and the MS pathogenesis were established. Preliminary results suggest the applicability of a new nanotechnology-based method for MS diagnostics.

Effector and regulatory B cells in Multiple Sclerosis.

The role of B cells in the pathogenesis of Multiple Sclerosis (MS), an autoimmune neurodegenerative disease, is becoming eminent in recent years, but the specific contribution of the distinct B cell subsets remains to be elucidated. Several B cell subsets have shown regulatory, anti-inflammatory capacities in response to stimuli in vitro, as well as in the animal model of MS: Experimental Autoimmune Encephalomyelitis (EAE). However, the functional role of the B regulatory cells (Bregs) in vivo and specifically in the human disease is yet to be clarified. In the present review, we have summarized the updated information on the roles of effector and regulatory B cells in MS and the immune-modulatory effects of MS therapeutic agents on their phenotype and function.

Methylome and transcriptome profiling in Myasthenia Gravis monozygotic twins.

OBJECTIVE: To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design. METHODS: The transcriptome and methylome of peripheral monocytes were compared between monozygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples. RESULTS: >100 differentially expressed genes and ∼1800 differentially methylated CpGs were detected in peripheral monocytes between MG patients and controls. Several transcripts associated with immune homeostasis and inflammation resolution were reduced in MG patients. Only a relatively few genes differed between the discordant healthy and MG co-twins, and both their expression and methylation profiles demonstrated very high similarity. INTERPRETATION: This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression or methylation might together contribute to disease. Impaired monocyte function in MG and decreased expression of genes associated with inflammation resolution could contribute to the chronicity of the disease. Findings may serve as potential new predictive biomarkers for disease and disease activity, as well as potential future targets for therapy development. The high similarity between the healthy and the MG discordant twins, suggests that a molecular signature might precede a clinical phenotype, and that genetic predisposition may have a stronger contribution to disease than previously assumed.

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules.

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.