Karen O’Connell

Economic costs associated with an MS relapse

BACKGROUND Multiple sclerosis (MS) commonly affects young adults and can be associated with significant disability resulting in considerable socioeconomic burden for both patient and society. AIMS The aim was to determine the direct and indirect cost of an MS relapse. METHODS This was a prospective audit composed of medical chart review and patient questionnaire. Relapses were stratified into 3 groups: low, moderate and high intensity. Age, gender, MS subtype, disease duration, expanded disability status scale (EDSS) score, disease modifying therapy (DMT) use and employment status were recorded. Direct costs included GP visits, investigations, clinic visit, consultations with medical staff, medication and admission costs. Indirect costs assessed loss of earnings, partner׳s loss of earnings, childcare, meals and travel costs. RESULTS Fifty-three patients had a clinically confirmed relapse. Thirteen were of low intensity; 23 moderate intensity and 17 high intensity with mean costs of €503, €1395 and €8862, respectively. Those with high intensity episodes tended to be older with higher baseline EDSS (p<0.003) and change in EDSS (p<0.002). Direct costs were consistent in both low and moderate intensity groups but varied with length of hospital stay in the high intensity group. Loss of earnings was the biggest contributor to indirect costs. A decision to change therapy as a result of the relapse was made in 23% of cases, further adding to annual MS related costs. CONCLUSIONS The cost of an MS relapse is dependent on severity of the episode but even low intensity episodes can have a significant financial impact for the patient in terms of loss of earnings and for society with higher annual MS related costs.

Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial

BackgroundThere is increasing evidence linking vitamin D deficiency to both susceptibility to, and severity of, multiple sclerosis (MS). Patients with the clinically isolated syndrome represent the initial presentation of a demyelinating disorder, and those with asymptomatic lesions on magnetic resonance imaging (MRI) are at risk of progression to clinically definite MS. The aims of this study are to examine the immunologic effects of vitamin D in both healthy individuals and in patients with clinically isolated syndrome, and in the latter group the effects on disease progression assessed by MRI and clinical measures.Methods/DesignThis is a single-center double-blind randomized placebo-controlled clinical trial. The primary endpoint is the immunologic effects of two doses of vitamin D compared with placebo over 24 weeks in both healthy control participants and patients presenting with the clinically isolated syndrome. Healthy control participants (n = 39) and patients with clinically isolated syndrome (n = 45) will be randomized to one of three arms, namely 1) vitamin D 5,000 IU daily, 2) vitamin D 10,000 IU daily, or 3) placebo, and followed up for 24 weeks. In both patients and healthy control participants, the primary outcome will be immunologic measures of the frequency of CD4 T-cell subsets and cytokine responses in peripheral blood mononuclear cells, assessed at baseline, and after 16 and 24 weeks of treatment. Secondary endpoints, in the patients with clinically isolated syndrome, will be relapse activity, and the number of new T2 lesions and gadolinium-enhancing lesions assessed by MRI in the two vitamin D-treated groups compared with the placebo-treated group over the 24 weeks of the study.Trial registrationEU Clinical Trials Register: EudraCT: 2012-000635-68. ClinicalTrials.gov identifier: NCT01728922

Incidence of multiple sclerosis in the Republic of Ireland: A prospective population-based study

BACKGROUND Multiple sclerosis (MS) incidence and prevalence is increasing worldwide, with a disproportionally higher rate in women. Recent studies have questioned the presence of a latitudinal gradient in Europe. Ireland is a high prevalence country for MS with a previously reported North-South gradient making it ideal to further explore this concept. OBJECTIVES In this study we prospectively determined the incidence rate of newly diagnosed MS in Ireland over a 12-month period and demonstrated the presence of a North-South gradient. METHODS A national prospective population-based observational study was performed to ascertain all new cases of MS diagnosed from 1st March 2014 - 28th February 2015 in the Ireland. Within the main study there was a smaller nested cohort study to explore clinical outcomes with a view to future prospective follow-up of this cohort. Sources of case ascertainment included neurologists, MS nurse specialists and MS support services. The Irish census 2011 was used to obtain population statistics and the incidence rate was age-standardized to a European Standardised Population (ESP 2011). The North-South gradient was assessed, by comparing incidence rates between northern and southern counties. RESULTS 292 patients fulfilled the inclusion criteria equating to an age-standardised incidence rate (A-SIR) of 6/100,000 (95% CI: 5.3-6.6); for women the rate was 8.7/100,000 (95% CI: 7.7-9.6) and for men 3.3/100,000 (95% CI: 3.0-3.7). The female to male sex ratio was 2.7:1. Mean age at diagnosis amongst the RRMS group was 37 years (SD: 9.6) and 55 years (SD: 7.7) in the PPMS group; there were no gender differences associated with age of diagnosis. Onset was progressive in 10% of cases. A significant difference was seen in incidence rates between the northern region (A-SIR: 9.6×105, CI: 6.9-12.3) and the southern region (A-SIR: 5.1×105, CI: 3.8-6.3) (Z-score =3.34, p<0.05). Amongst the nested cohort (n=113) mean age at symptom onset in the RRMS group (n=106) was 34 years (SD: 8.7) and 50 years (SD: 11.8) in the PPMS group (n=7). The female to male sex ratio was 3.5:1. Eighty percent had started or were due to start disease modifying therapy at time of review and 77% were taking supplemental vitamin D. Using the hospital depression and anxiety scale (HADS) mild to severe depressive symptoms were reported in 34% with no prior history of depression. Seventy-five percent were in full or part-time employment with 8% not working due to disability arising from their MS. CONCLUSIONS This is the first study to prospectively assess the incidence rate of MS in Ireland and shows that Ireland has a high incidence rate, comparable with the rest of the British Isles, with a persistent North-South gradient. The age of onset of relapsing remitting multiple sclerosis appears to be increasing over the last 20 years. It will be of interest to re-assess this population over time to see if increasing incidence rates, as well as improved survival, are driving the reported increases in MS prevalence.

Effects of vitamin D3 in clinically isolated syndrome and healthy control participants: A double-blind randomised controlled trial:

Background Lowserum vitamin D levels are associated with susceptibility to, and severity of, multiple sclerosis. High dose vitamin D has been proposed as a potential immunomodulator in multiple sclerosis. Objectives We performed a single centre, investigator-led, exploratory, double-blind, randomised, placebo controlled, trial of vitamin D3 in clinically isolated syndrome and healthy control participants to assess its immunological effects. Secondary end-points included clinical and magnetic resonance imaging outcomes and safety. Methods Clinically isolated syndrome patients and healthy control participants were randomised to: placebo, 5000 IU or 10,000 IU vitamin D3/day (Vigantol oil). Study duration was 24 weeks. Results The trial did not meet its primary end point, with no difference in the frequency of pro-inflammatory CD4+ T cells (interleukin (IL)-17+/interferon (IFN)-γ+) seen. A higher level of disease freedom (67% versus 50%) was seen in those with serum 1,25 (OH) vitamin D levels>100 nmol/l but this did not reach significance. High dose vitamin D3 was well tolerated with no safety signal. Conclusions High dose vitamin D3 over 24 weeks was well tolerated but without immunological, magnetic resonance imaging or clinical evidence of benefit. The hypothesised therapeutic effects in clinically isolated syndrome or multiple sclerosis patients may require longer periods of administration or may only be seen in patients treated with vitamin D3 as an adjunct to established disease modifying therapies.

A Protocol for Improved Precision and Increased Confidence in Nanoparticle Tracking Analysis Concentration Measurements between 50 and 120 nm in Biological Fluids

Nanoparticle tracking analysis (NTA) can be used to quantitate extracellular vesicles (EVs) in biological samples and is widely considered a useful diagnostic tool to detect disease. However, accurately profiling EVs can be challenging due to their small size and heterogeneity. Here, we aimed to provide a protocol to facilitate high-precision particle quantitation by NTA in plasma, the supernatant of activated purified platelets [the platelet releasate (PR)] and in serum, to increase confidence in NTA particle enumeration. The overall variance and the precision of NTA measurements were quantified by root mean square error and relative standard error. Using a bootstrapping approach, we found that increasing video replicates from 5 s × 60 s to 25 s × 60 s captures led to a reduction in overall variance and a reproducible increase in the precision of NTA particle-concentration quantitation for all three biofluids. We then validated our approach in an extended cohort of 32 healthy donors. Our results indicate that for vesicles sized between 50 and 120 nm, the precision of routine NTA measurements in serum, plasma, and PR can be significantly improved by increasing the number of video replicates captured. Our protocol provides a common platform to statistical compare particle size distribution profiles in the exosomal-vesicle size range across a variety of biofluids and in both healthy donor and patient groups.

Thrombin generation correlates with disease duration in multiple sclerosis (MS): Novel insights into the MS-associated prothrombotic state:

Background Thrombin is well recognised for its role in the coagulation cascade but it also plays a role in inflammation, with enhanced thrombin generation observed in several inflammatory disorders. Although patients with multiple sclerosis (MS) have a higher incidence of thrombotic disease, thrombin generation has not been studied to date. Objectives The aim of this study was to characterise calibrated automated thrombography parameters in patients with relapsing–remitting MS (RRMS) and primary progressive MS (PPMS) in comparison to healthy controls (HCs). Methods Calibrated automated thrombography was performed on platelet poor plasma from 15 patients with RRMS, 15 with PPMS and 19 HCs. Results We found that patients with RRMS generate thrombin at a significantly faster rate than the less inflammatory subtype, PPMS or HCs. In addition, the speed of thrombin generation was significantly correlated with time from clinical diagnosis in both subtypes. However, in RRMS the rate of thrombin generation was increased with increased time from clinical diagnosis, while in PPMS the rate of thrombin generation decreased with increased time from clinical diagnosis. Conclusions These data likely reflect the differential active proinflammatory states in each MS subtype and provide novel mechanistic insights into the clinically relevant prothrombotic state observed in these patients.

IRAK1 Limits TLR3/4- and IFNAR-Driven IL-27 Production through a STAT1-Dependent Mechanism

IL-27 is a cytokine exerting pleiotropic immunomodulatory effects on a broad spectrum of immune cells. Optimal IL-27 production downstream of TLR3/4 ligand stimulation relies on autocrine type I IFN signaling, defining a first and second phase in IL-27 production. This work shows that IL-1 receptor-associated kinase 1 (IRAK1) limits TLR3/4- and IFNAR-induced IL-27 production. At the mechanistic level, we identified IRAK1 as a novel regulator of STAT1, IRF1, and IRF9. We found hyperactivation of STAT1 together with increased nuclear levels of IRF1 and IRF9 in IRAK1-deficient murine macrophages compared with control cells following stimulation with LPS and poly(I:C). IRAK1-deficient human microglial cells showed higher basal levels of STAT1 and STAT2 compared with control cells. Blocking the kinase activity of TBK1/IKKε in IRAK1 knockdown human microglial cells reduced the high basal levels of STAT1/2, uncovering a TBK1/IKKε kinase–dependent mechanism controlling basal levels of STAT1/2. Stimulating IRAK1 knockdown human microglial cells with IFN-β led to increased IL-27p28 expression compared with control cells. In IRAK1-deficient murine macrophages, increased IL-27 levels were detected by ELISA following IFN-β stimulation compared with control macrophages together with increased nuclear levels of p-STAT1, IRF1, and IRF9. Treatment of wild-type and IRAK1-deficient murine macrophages with fludarabine similarly reduced TLR3/4-induced IL-27 cytokine levels. To our knowledge, this work represents the first report placing IRAK1 in the IFNAR pathway and identifies IRAK1 as an important regulator of STAT1, controlling IL-27 production downstream of TLR3/4 and IFNAR signaling pathways.