Multiple Sclerosis risk variants regulate gene expression in innate and adaptive immune cells

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS

The role of multidisciplinary MS care teams in supporting lifestyle behaviour changes to optimise brain health among people living with MS: A qualitative exploration of clinician perspectives

Introduction: Healthcare professionals have an important role in advocating for the adoption of a brain-healthy lifestyle for optimal multiple sclerosis (MS) care. Nonetheless, studies to date have mainly focussed on the consumer perspective. Herein, we aimed to explore the current practices of how healthcare professionals support protective, lifestyle-related behaviour changes to optimise brain health among people living with MS (plwMS), and their perspectives of professional roles. Methods: Australian healthcare professionals were recruited via study advertisements, purposive and snowball sampling, to participate in an online, semi-structured and audio-recorded interview. Clinicians were eligible if they had a minimum of a tertiary Bachelor\u27s degree and 12-months experience working with plwMS, access to the Internet and sufficient time to participant. An inductive, data-driven form of reflexive thematic analysis was undertaken before thematic categorisation of the quotes from transcripts. Data analysis was guided by the methods of Braun and Clark and the study\u27s underpinnings drew on the constructs of the Social Cognitive Theory (SCT). Results: Six physicians, 10 MS nurses, 18 allied health professionals, one exercise therapist and one alternative therapist were interviewed. Three primary themes encompassing the perceived role of healthcare professionals in supporting a brain-healthy lifestyle were identified: (1) the empowering role, (2) collaborative role and (3) communicative role. External factors/forces including time constraints, professional expertise, training and skill set, power dynamics, consumer readiness, health literacy, self-efficacy and motivation are at play, and affect how/when healthcare professionals may support behaviour change to optimise lifelong brain health for plwMS. Conclusion: Healthcare professionals recognise their critical role in encouraging and supporting the adoption of a brain-healthy lifestyle to optimise lifelong brain health for plwMS. However, discord is evident when they underestimate the complexity of translating knowledge of lifestyle-related behaviour change(s) into action. Greater awareness must be made in recognising and addressing the bidirectionality of external factors such as those in the SCT, that may influence how behaviour change occurs. Public Contribution: Healthcare professionals volunteered to be interviewed as part of the data collection phase of this study

Lymphocyte count in peripheral blood is not associated with the level of clinical response to treatment with fingolimod

Background Fingolimod is an efficient and safe drug for treating relapsing-remitting multiple sclerosis (RRMS). In vivo, fingolimod is phosphorylated and binds to â\u80\u9csphingosine-1-phosphateâ\u80\u9d(S1P) receptors that are expressed in a wide range of cells, including lymphocytes. Under the effect of fingolimod, lymphocytes are retained in lymphoid tissues through the regulation of S1P1receptors. The aim of the present study was to assess whether the degree of lymphopenia was correlated to the positive treatment response of RRMS patients with fingolimod. Methods Data was sourced from the MSBase Registry. Patients were divided into two groups, according to the lymphocyte count on peripheral blood examination. Annualized Relapse Rate (ARR), time to first relapse and time to six-month confirmed disability progression were compared between groups. Results Group one consisted of 202 patients who reached 750 lymphocytes/mm3during treatment while the comparison group two included 101 patients who never reached less than 1000 lymphocytes/mm3in peripheral blood during the observation period. There were no differences between groups in ARR, time to first relapse or time to six-month confirmed disability progression. Conclusion The degree of lymphopenia in peripheral blood was not associated to the positive treatment response of fingolimod in RRMS patients

Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS

Background Delayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF. Methods Data sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation. Results The majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC >= 0.8 x 10(9)/L was 2-4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC >= 0.91 x 10(9)/L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation; rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for >= 3 years, lymphocyte reconstitution to >= 0.91 x 10(9)/L was 12-18 months vs 2-3 months in patients with lymphopenia persisting Conclusions The majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2-4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation

Fingolimod after natalizumab and the risk of short-term relapse

OBJECTIVE: To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-β/glatiramer acetate (IFN-β/GA) and those previously treatment naive; and to determine predictors of time to first relapse on fingolimod. METHODS: Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod. RESULTS: A total of 536 patients (natalizumab-fingolimod [n = 89]; IFN-β/GA-fingolimod [n = 350]; naive-fingolimod [n = 97]) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR [ARR] 0.38) relative to natalizumab (ARR 0.26; p = 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001–0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio [HR] 1.59 per relapse; p = 0.002) and a gap in treatment of 2–4 months compared to no gap (HR 2.10; p = 0.041). CONCLUSIONS: RRs after switch to fingolimod were low in all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies