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's 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's 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.

Timely intervention, monitoring and education MATTERS in MS (TIME MATTERS in MS): Development of a globally applicable quality improvement tool.

Background: Previously, consensus MS care standards were defined by MS specialist neurologists from 19 countries. We developed, piloted and refined an Excel-based quality improvement tool to enable MS services to benchmark against these standards. Here, we examine the refined tool. Objective: To determine the applicability of the quality improvement tool in different healthcare settings. Methods: MS centres across the globe were invited to pilot the quality improvement tool by coding the medical records of 36 adults with MS. We invited feedback on user friendliness, quality improvement tool usefulness and relevance of data collected. Results: Seventeen centres from 14 countries participated; 14 completed the post-service evaluation survey. Over 50% of responders rated the tool 'very easy' or 'easy' to use and 'very relevant' to their service. Almost 85% of responders (11/13) planned to introduce changes to their service, including improvements in documentation, communication, interactions with colleagues and referrals; 85% would use a future shorter version of the tool. Conclusions: The quality improvement tool can enable MS centres globally to benchmark their services. Widespread uptake of a shorter tool may help MS centres to work towards achieving consensus standards for brain health-focused care. Incorporation into routine clinical practice would drive adoption.

High rates of JCV seroconversion in a large international cohort of natalizumab-treated patients.

AIMS: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. BACKGROUND: Natalizumab is highly effective for the treatment of relapsing-remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment. METHODS: Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia (n = 865) and 11 MS treatment centres in Brazil (n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion. RESULTS: From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1%; 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7%; 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk [adjusted hazard ratio 2.09 (95% confidence interval 1.17-3.71) p = 0.012]. CONCLUSION: In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.

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.

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 × 109/L was 2-4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC ≥0.91 × 109/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 × 109/L was 12-18 months vs 2-3 months in patients with lymphopenia persisting <6 months. 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.

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 "sphingosine-1-phosphate"(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 S1P1 receptors. 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/mm3 during treatment while the comparison group two included 101 patients who never reached less than 1000 lymphocytes/mm3 in 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.

Association of plasma levels of Protein S with disease severity in multiple sclerosis.

BACKGROUND: The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) play important roles in modulating innate immune responses and central demyelination. The TAM receptor ligand Protein S (PROS) has also been shown to modulate innate immune cell responses. OBJECTIVES: We assessed whether plasma levels of PROS are changed in multiple sclerosis (MS) patients and whether changes are associated with disease severity. METHODS: Plasma levels of total and free PROS were measured using enzyme-linked immunosorbent assay in a discovery cohort (MS: 65, control: 14) and an independent replication cohort (MS: 29, control: 29). The Multiple Sclerosis Severity Score (MSSS) was used to evaluate associations between plasma PROS levels and disease severity. RESULTS: We found plasma levels of total, but not free PROS, were decreased in MS patients compared with controls. In female MS patients, we observed decreases in total and free PROS levels compared with controls. In addition, we also observed higher MSSS in patients with very low levels of plasma free PROS. CONCLUSIONS: These data suggest PROS may represent a potential marker of disease severity in MS.

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-ß/glatiramer acetate (IFN-ß/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-ß/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.