Relapsing-remitting Multiple Sclerosis Population Research Articles

SARS-CoV-2 pandemic as a model to assess the relationship between intercurrent viral infections and disease activity in Multiple Sclerosis: A propensity score matched case-control study.

An association between intercurrent viral respiratory infections and exacerbations of Multiple Sclerosis (MS) disease activity has been proposed by several studies. Considering the rapid spread of SARS-CoV2 worldwide and the systematic effort to immediately detect all incident cases with specific diagnostic tests, the pandemic can represent an interesting experimental model to assess the relationship between viral respiratory infections and MS disease activity. In this study, we have performed a propensity score matched case-control study with a prospective clinical/MRI follow-up, on a cohort of relapsing-remitting MS (RRMS) patients who tested positive for SARS-CoV2 in the period 2020-2022, with the aim to evaluate if the SARS-CoV2 infection influences the short-term risk of disease activity. Controls (RRMS patients not exposed to SARS-CoV-2, using 2019 as the reference period) were matched 1:1 with cases for age, EDSS, sex and disease-modifying treatment (DMT) (moderate efficacy vs high efficacy). Differences in relapses, MRI disease activity and confirmed disabilty worsening (CDW) between cases in the 6 months following the SARS-CoV-2 infection, and controls in a similar 6 months reference period in 2019 were compared. We identified 150 cases of SARS-CoV2 infection in the period March 2020 - March 2022, out of a total population of approximately 1500 MS patients, matched with 150 MS patients not exposed to SARS-CoV2 (controls). Mean age was 40.9±12.0 years in cases and 42.0±10.9 years in controls, mean EDSS was 2.54±1.36 in cases and 2.60±1.32 in controls. All patients were treated with a DMT, and a considerable proportion with a high efficacy DMT (65.3% in cases and 66% in controls), reflecting a typical real world RRMS population. 52.8% of patients in this cohort had been vaccinated with a mRNA Covid-19 vaccine. We did not observe a significant difference in relapses (4.0% cases, 5.3% controls; p=0.774), MRI disease activity (9.3% cases, 8.0% controls; p=0.838), CDW (5.3% cases, 6.7% controls; p=0.782) in the 6 months after SARS-CoV-2 infection between cases and controls. Using a propensity score matching design and including both clinical and MRI data, this study does not suggest an increased risk of MS disease activity following SARS-CoV-2 infection. All MS patients in this cohort were treated with a DMT, and a considerable number with a high efficacy DMT. These results therefore may not be applicable to untreated patients, for which the risk of increased MS disease activity after SARS-CoV-2 infection may not be excluded. A possible hypothesis explaining these results could be that SARS-CoV2 is less prone, compared to other viruses, to induce exacerbations of MS disease activity; another possible interpretation of these data might be that DMT is able to effectively suppress the increase of disease activity triggered by SARS-CoV2 infection.

COVID-19 and its implications on the clinico-radiological course of multiple sclerosis: A case–control study

BackgroundMultiple sclerosis (MS) is an immune-mediated disease that has been related to several risk factors such as various viral infections. We carried out this study in order to establish a relationship between COVID-19 infection and MS severity. MethodsIn a case–control study, we recruited patients with relapsing–remitting multiple sclerosis (RRMS). Patients were divided into two groups based on positive COVID-19 PCR at the end of the enrollment phase. Each patient was prospectively followed for 12 months. Demographical, clinical, and past medical history were collected during routine clinical practice. Assessments were performed every six months; MRI was performed at enrollment and 12 months later. ResultsThree hundred and sixty-two patients participated in this study. MS patients with COVID-19 infection had significantly higher increases in the number of MRI lesions (p: 0.019, OR(CI): 6.37(1.54–26.34)) and EDSS scores (p: 0.017), but no difference was found in total annual relapses or relapse rates. COVID-19 infections were positively correlated with EDSS progression (p: 0.02) and the number of new MRI lesions (p: 0.004) and predicted the likelihood of the number of new MRI lesions by an odds of 5.92 (p: 0.018). ConclusionCOVID-19 may lead to higher disability scores in the RRMS population and is associated with developing new Gd-enhancing lesions in MRI imaging. However, no difference was observed between the groups regarding the number of relapses during follow-up.

COVID-19 and its implications on the clinico-radiological course of multiple sclerosis: A case-control study.

Antecedentes: la esclerosis múltiple (EM) es una enfermedad inmunomediada que se ha relacionado con varios factores de riesgo, como diversas infecciones virales. Realizamos este estudio para establecer una relación entre la infección por COVID-19 y la gravedad de la EM.Métodos: En un estudio de casos y controles, reclutamos pacientes con esclerosis múltiple remitente-recurrente (EMRR). Los pacientes se dividieron en dos grupos según la PCR positiva para COVID-19 al final de la fase de inscripción. Cada paciente fue seguido prospectivamente durante 12 meses. Los antecedentes demográficos, clínicos y médicos anteriores se recogieron durante la práctica clínica habitual. Las evaluaciones se realizaron cada seis meses; La resonancia magnética se realizó en el momento de la inscripción y 12 meses después.Resultados: Trescientos sesenta y dos pacientes participaron en este estudio. Los pacientes con EM con infección por COVID-19 tuvieron aumentos significativamente más altos en el número de lesiones de resonancia magnética (p: 0.019, OR (IC): 6.37 (1.54-26.34)) y puntajes EDSS (p: 0.017), pero no se encontraron diferencias en total recaídas anuales o tasas de recaída. Las infecciones por COVID-19 se correlacionaron positivamente con la progresión de EDSS (p: 0,02) y la cantidad de nuevas lesiones en la resonancia magnética (p: 0,004) y predijeron la probabilidad de la cantidad de nuevas lesiones en la resonancia magnética con una probabilidad de 5,92 (p: 0,018).Conclusión: COVID-19 puede conducir a puntajes de discapacidad más altos en la población de RRMS y está asociado con el desarrollo de nuevas lesiones realzadas con Gd en imágenes de resonancia magnética. Sin embargo, no se observó diferencia entre los grupos en cuanto al número de recaídas durante el seguimiento.

Measuring productivity loss in early relapsing-remitting multiple sclerosis

BackgroundMultiple sclerosis is one of the most common causes of neurological disability in young adults with major consequences for their autonomy and capacity to maintain employment. ObjectiveThe aim of this study was to assess the impact on work productivity in early-stage relapsing-remitting multiple sclerosis (RRMS). MethodsA multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0–5.5 were included. Absenteeism, presenteeism, and unpaid work loss due to RRMS were measured using the Valuation of Lost Productivity (VOLP) questionnaire. The EDSS, SymptoMScreen, 5-item Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale, Symbol Digit Modalities Test, and Multiple Sclerosis Work Difficulties Questionnaire were used to gather information on disability, patients’ perception of symptom severity, fatigue, mood/anxiety, cognition, and problems in the workplace, respectively. Associations between the VOLP and clinical and work outcomes were analyzed using Spearman's rank correlations. ResultsA total of 189 patients were included. Mean age (SD) was 36.1 ± 9.4 years and 71.4% were female. Mean disease duration was 1.2 ± 0.8 years. Median EDSS score was 1.0 (IQR 0, 2.0). One hundred thirty patients (68.8%) were working for pay or self-employed. Fifty-three patients (40.8%) reported absence from work in the past 3 months with an average of 14.3 absent workdays. Their health problems resulted in the loss of 3.4% of their actual work time in the past 7 days. Thirty patients got help (11.8 h) with their unpaid work activities in the past 7 days. Absenteeism was significantly correlated with anxiety and depression (rho=0.298 and 0.291, p<0.001), fatigue (rho=0.214, p = 0.014), and symptom severity (rho=0.213, p = 0.015). Presenteeism was significantly correlated with fatigue (rho=0.375, p<0.001), symptom severity (rho=0.373, p<0.001), depression (rho=0.263, p = 0.008), and disability (rho=0.215, p = 0.031). ConclusionsProductivity loss even in a RRMS population with short disease duration stresses the need for more efficient treatment control of disease activity from earlier stages.

Latency of Multifocal Visual Evoked Potential in Multiple Sclerosis: A Visual Pathway Biomarker for Clinical Trials of Remyelinating Therapies.

Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing-remitting multiple sclerosis (RRMS) patients. The potential sample size required for a remyelination-based clinical trial using different treatment effect sizes and the mfVEP latency as an outcome measure was also estimated. A total of 50 RRMS consecutive patients with no previous history of optic neuritis in at least one eye and 15 normal controls of similar age and gender composition were prospectively enrolled. Fifteen patients had a history of unilateral ON more than 12 months earlier, whereas 41 patients demonstrated optic radiations lesions on MRI at baseline. Most patients were on disease modifying therapy. A mfVEP was recorded at baseline and 12 months later. At baseline, the mfVEP latency in RRMS patients was delayed compared with normal controls in both optic neuritis and nonoptic neuritis eyes. Latency delay was significantly correlated to optic radiation lesion volume (R2 = 0.38, P < 0.001). There was no significant latency change in multiple sclerosis patients' eyes or optic neuritis and nonoptic neuritis eyes over the follow-up period with latency remaining remarkably constant. This was despite the fact that 46 of 50 patients were on disease-modifying therapies, implying current treatments do not affect myelination in chronic RRMS cases. Sample size calculations to evaluate an additional or alternative remyelinating agent, based on a 40% treatment effect, revealed that a relatively small sample size (78 patients) would be required to demonstrate efficacy in future trials of remyelination therapies. Given its known sensitivity for latency changes and the stability found in this RRMS population, the mfVEP represents an ideal biomarker to assess the degree of latency recovery that may be achieved by remyelination in multiple sclerosis.

Epidemiology, characteristics and treatment of patients with relapsing remitting multiple sclerosis and incidence of high disease activity: Real world evidence based on German claims data.

BackgroundMultiple Sclerosis (MS) is a chronic inflammatory, immune mediated disease of the central nervous system, with Relapsing Remitting MS (RRMS) being the most common type. Within the last years, the status of high disease activity (HDA) has become increasingly important for clinical decisions. Nevertheless, little is known about the incidence, the characteristics, and the current treatment of patients with RRMS and HDA in Germany. Therefore, this study aims to estimate the incidence of HDA in a German RRMS patient population, to characterize this population and to describe current drug treatment routines and further healthcare utilization of these patients.MethodsA claims data analyses has been conducted, using a sample of the InGef Research Database that comprises data of approximately four million insured persons from around 70 German statutory health insurances (SHI). The study was conducted in a retrospective cohort design, including the years 2012–2016. Identification of RRMS population based on ICD-10 code (ICD-10-GM: G35.1). For identification of HDA, criteria from other studies as well as expert opinions have been used. Information on incidence, characteristics and current treatment of patients with RRMS and HDA was considered.ResultsThe overall HDA incidence within the RRMS population was 8.5% for 2016. It was highest for the age group of 0–19 years (29.4% women, 33.3% men) and lowest for the age group of ≥ 50 years (4.3% women, 5.6% men). Mean age of patients with RRMS and incident HDA was 38.4 years (SD: 11.8) and women accounted for 67.8%.Analyses of drug utilization showed that 82.4% received at least one disease-modifying drug (DMD) in 2016. A percentage of 49.8% of patients received drugs for relapse therapy. A share of 55% of RRMS patients with HDA had at least one hospitalization with a mean length of stay of 13.9 days (SD: 18.3 days) in 2016. The average number of outpatient physician contacts was 28.1 (SD: 14.0).ConclusionsThis study based on representative Germany-wide claims data from the SHI showed a high incidence of HDA especially within the young RRMS population. Future research should consider HDA as an important criterion for the quality of care for MS patients.

Modeling the impact of patient treatment preference on health outcomes in relapsing-remitting multiple sclerosis

Aims: Model how moving from current disease-modifying drug (DMD) prescribing patterns for relapsing-remitting multiple sclerosis (RRMS) observed in the United Kingdom (UK) to prescribing patterns based on patient preferences would impact health outcomes over time.Materials and methods: A cohort-based Markov model was used to measure the effect of DMDs on long-term health outcomes for individuals with RRMS. Data from a discrete choice experiment were used to estimate the market shares of DMDs based on patient preferences (i.e. preference shares). These preference shares and real-world UK market shares were used to calculate the effect of prescribing behavior on relapses, disability progression, and quality-adjusted life-years (QALYs). The incremental benefit of patient-centered prescribing over current practices for the UK RRMS population was then estimated; scenario and sensitivity analyses were also conducted.Results: Compared to current prescribing practices, when UK patients with RRMS were treated following patient preferences, health outcomes were improved. This population was expected to experience 501,690 relapses and gain 1,003,263 discounted QALYs over 50 years under patient-centered prescribing practices compared to 538,417 relapses and 958,792 discounted QALYs under current practices (−6.8% and +4.6%, respectively). Additionally, less disability progression was observed when prescribed treatment was based on patient preferences. In a scenario analysis where only oral treatments were considered, the results were similar, although the magnitude of benefit was smaller. Number of relapses was most sensitive to how the annualized relapse rate was modeled; disability progression was most sensitive to mortality rate assumptions.Limitations: Treatment efficacy estimates applied to various models in this study were based on data derived from clinical trials, rather than real-world data; the impact of patient-centered prescribing on treatment adherence and/or switching was not modeled.Conclusions: The population of UK RRMS patients may experience overall health gains if patient preferences are better incorporated into prescribing practices.

Burden of relapsing-remitting multiple sclerosis on workers in the US: a cross-sectional analysis of survey data

BackgroundMultiple sclerosis (MS) is prevalent among working age individuals (20–60 years), leading to high burden on work productivity. Few data are available about the absenteeism and presenteeism in employed individuals with MS in comparison to non-MS personnel. This study aimed to quantify the burden of illness of employed US adults with relapsing-remitting multiple sclerosis (RRMS) and examine burden by levels of work impairment.MethodsA retrospective cross-sectional analysis was conducted using patient-reported responses from the US National Health and Wellness Survey (NHWS). Data from NHWS 2015–2016 were analyzed from 196 employed RRMS respondents who were matched 1:4 to employed respondents without MS based on demographic and general health characteristics. Demographic and general health characteristics for employed RRMS individuals were analyzed by levels of work impairment (none, 1–30%; 31–68%; 69–100%). Work productivity (absenteeism, presenteeism, and work impairment), decrements in health-related quality of life (HRQoL) (short form-36, EQ-5D), and healthcare resource utilization (HCRU) were compared to determine the burden of RRMS.ResultsAfter propensity score matching, the levels of absenteeism and presenteeism were 2 and 1.8 times higher in the employed RRMS population than the employed non-MS population, respectively (P < 0.001 for both). HRQoL was significantly lower in employed respondents with RRMS than those without MS (P < 0.001 for all). Employed respondents with RRMS had significantly more HCRU over 6 months compared to those without MS (P < 0.001). Furthermore, among employed RRMS respondents, greater levels of impairment were associated with increasing disease severity, greater healthcare resource use, fatigue, and cognitive impairment and inversely associated with mental and physical HRQoL (P < 0.0001 for all).ConclusionsAmong employed individuals, respondents with RRMS had lower, work productivity, HRQoL, and higher HCRU as compared with those without MS. Given the large impact RRMS has on work impairment, a need exists to manage individuals on therapies that improve HRQoL, reduce symptoms, and improve their ability to perform in the workforce.

Costs of illness progression for different multiple sclerosis phenotypes: a population-based study in Sweden.

BackgroundLittle is known of how the cost of illness and health-related quality of life changes over time after a diagnosis of multiple sclerosis.ObjectivesThe aim was thus to explore the progression of annual direct and indirect costs and health-related quality of life among people with multiple sclerosis of working ages, following diagnosis with relapsing–remitting multiple sclerosis (RRMS), primary progressive multiple sclerosis (PPMS) or conversion to secondary progressive multiple sclerosis (SPMS) after RRMS.MethodsSwedish nationwide registers were linked to estimate the annual cost of illness in 2006–2013 among people with a registered new multiple sclerosis phenotype, including: direct costs, indirect costs, and health-related quality of life.ResultsDrugs and indirect costs for sick leave were the main cost drivers after diagnosis with RRMS. After conversion to SPMS, the RRMS cost drivers were replaced by indirect costs for disability pension. The main cost driver in newly diagnosed PPMS was indirect costs for sick leave, later replaced by disability pension. Health-related quality of life scores were similar after RRMS and SPMS.ConclusionsAfter initial high indirect costs for sick leave, people with RRMS had higher drug costs compared to people with PPMS. Cost drivers during SPMS initially followed the pattern in the RRMS population, but were replaced by indirect costs for disability pension.

Budget impact analysis for peginterferon beta-1a in relapsing remitting multiple sclerosis in Italy

BACKGROUND: Peginterferon beta-1a, injected every two weeks, is the first approved pegylated interferon beta-1a for the treatment of relapsing remitting multiple sclerosis (RRMS). The objective of this analysis was to estimate the economic impact due to the introduction of peginterferon beta-1a in Italy.METHODS: This analysis was conducted with a three-year time horizon with the support of a simple decision-analytic model adopting the perspective of the Italian National Healthcare Service (NHS). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, monitoring, relapse management, adverse events management) were calculated over 3 years and compared in two scenarios: the base scenario where interferons-beta and glatiramer acetate (GA) are used to treat RRMS patients, and an alternative scenario where peginterferon beta-1a can also be used to treat RRMS patients. The target population was approximately 35,500, 37,500 and 39,500 patients at year 1, 2 and 3 respectively, based on the published literature and market data. The efficacy of treatments was simulated as a reduction of relapse rates and was derived from a Network Meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A one-way sensitivity analysis was developed.RESULTS: According to current price and described assumptions, it was estimated that the introduction of peginterferon beta-1a would result in a decrease of total costs when compared with the base scenario. The cost in the base scenario was estimated to be € 321.5, € 339.7 and € 357.8 million in years 1, 2, and 3, respectively. In the alternative scenario, the same costs resulted in about € 321.1, € 338.6 and € 356.2 million, respectively. The cumulative budget impact over three years period was approximately a cost saving of € 3.1 million (about 0.3% saving).CONCLUSION: The adoption of peginterferon beta-1a for the treatment of RRMS would be viewed as economically sustainable by the Italian NHS.[Article in Italian]

Budget impact analysis of delayed-release dimethyl-fumarate in the treatment of relapsing-remitting multiple sclerosis in Italy

INTRODUCTION: Multiple Sclerosis (MS) is a condition with a significant economic and social burden that affects young adults, in their active working phase. The most recent evaluations show an annual average social cost of € 38-39 thousand per patient. Today the approval of the new oral therapies allows physicians to select further options that can meet patients’ clinical unmet needs.OBJECTIVES: To evaluate the economic impact of a recently approved therapy, delayed-release dimethyl-fumarate (DMF; also known as gastro-resistant DMF), on the overall management costs of relapsing-remitting multiple sclerosis (RRMS) in Italy.METHODS: A budget impact model, adopting the perspective of the Italian National Healthcare Service (NHS), was used to compare healthcare costs of two different treatment scenarios: a) base-case, where DMF is not available for RRMS patients (Scenario A), vs. b) alternative-case, where DMF is available for RRMS patients (Scenario B). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, administration, therapy and disease monitoring, relapse management, treatment-related adverse events) have been calculated over 3 years and compared for the two scenarios. Impact of relapses for the disease modifying therapies (DMTs) included in the analysis was estimated using an elaboration of the results from published mixed treatment comparison. RRMS population treated with DMTs was estimated using Italian prevalence and incidence data. According to these estimates, the number of treated patients amounted to 36,078 at Year 1, 38,832 at Year 2, and 40,673 at Year 3.RESULTS: According to the current price and to the assumptions reported in the methodology section, it was estimated that the introduction of DMF (Scenario B) determines a decrease of the budget impact, if compared with the base case (Scenario A) in the perspective of Italian NHS. Over three years, the budget impact would be € 1,376 mln in the Scenario A and € 1,354 mln in the Scenario B (-22.18 mln €; -1.61% relative budget variation). The main drivers for cost-saving were pharmacological treatment costs and reduced burden of relapses (corresponding to more than 1,800 avoided relapses).CONCLUSIONS: At the current cost conditions applied in Italy and according to the described assumptions, the use of DMF is economically sustainable for the Italian NHS. Plausibly, the introduction and usage of this new therapy in RRMS patients will ensure clinical benefits for patients without resulting in additional costs for the Italian NHS.[In Italian]

Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients.

Objective:To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)–β treatment in patients with multiple sclerosis (MS).Methods:Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays. Baseline cytokine profiles were grouped by hierarchical clustering analysis. Demographic features, changes in cytokines, and clinical outcome were then assessed in the clustered patient groups.Results:A total of 157 patients were included in the study and clustered into 6 distinct subsets by baseline cytokine profiles. These subsets differed significantly in their clinical and biological response to IFN-β therapy. Two subsets were associated with patients who responded poorly to therapy. Two other subsets, associated with a good response to therapy, showed a significant reduction in relapse rates and no worsening of disability. Each subset also had differential changes in cytokine levels after 3 months of IFN-β treatment.Conclusions:There is heterogeneity in the immunologic pathways of the RRMS population, which correlates with IFN-β response.

Anxiety and Depressive Symptoms Are Associated With Worse Performance on Objective Cognitive Tests in MS.

Cognitive impairment, anxiety, and depressive symptoms are common in multiple sclerosis (MS) and are known to interact in non-MS populations. This retrospective chart review examined this relationship in a relapsing-remitting MS population. A significant difference on measures of processing speed/working memory and visual-spatial memory was found in MS patients with anxiety compared with nonanxious MS patients, while a significant difference was found on measures of processing speed, visual-spatial memory and executive function in MS patients with depressive symptoms compared with those without. Further research is needed to determine the causal relationship between anxiety and depressive symptoms and cognitive impairment.

The Australian Multiple Sclerosis (MS) Immunotherapy Study: A Prospective, Multicentre Study of Drug Utilisation Using the MSBase Platform

ObjectiveTo prospectively characterise treatment persistence and predictors of treatment discontinuation in an Australian relapsing-remitting multiple sclerosis (RRMS) population.MethodsTertiary MS treatment centres participating in the MSBase registry prospectively assessed treatment utilisation, persistence, predictors of treatment discontinuation and switch rates. Multivariable survival analyses were used to compare treatment persistence between drugs and to identify predictors of treatment discontinuation.Results1113 RRMS patients were studied. Patients persisted on their first disease-modifying therapy (DMT) for a median of 2.5 years. Treatment persistence on GA was shorter than on all IFNβ products (p<0.03). Younger age at treatment initiation and higher EDSS were predictive of DMT discontinuation. Patients persisted on subsequent DMTs, for 2.3 years. Patients receiving natalizumab (NAT) as a subsequent DMT persisted longer on treatment than those on IFNβ or GA (p<0.000). The primary reason for treatment discontinuation for any drug class was poor tolerability. Annualised switch or cessation rates were 9.5–12.5% for individual IFNβ products, 11.6% for GA and 4.4% for NAT.ConclusionThis multicentre MS cohort study is the first to directly compare treatment persistence on IFNβ and GA to NAT. We report that treatment persistence in our Australian RRMS population is short, although patients receiving IFNβ as a first DMT persisted longer on treatment than those on GA. Additionally, patients receiving NAT as a subsequent DMT were more likely to persist on treatment than those switched to IFNβ or GA. EDSS and age at DMT initiation were predictive of DMT discontinuation. Treatment intolerance was the principal reason for treatment cessation.

Intramuscular interferon beta-1a is effective in Japanese patients with relapsing–remitting multiple sclerosis: a pre-treatment versus treatment comparison study of gadolinium-enhanced MRI brain lesions

Background and objective: Interferon beta (IFNβ) is standard therapy for multiple sclerosis (MS). The efficacy of intramuscular (IM) IFNβ-1a (AVONEX®) was assessed in 25 Japanese patients with relapsing–remitting MS (RRMS). Methods: Patients with RRMS not previously treated with IFNβ or other disease-modifying therapies were included in this 36-week study. The primary outcome was the average total number of gadolinium-enhanced lesions detected on four brain MRI scans during the last 12 weeks of 24 weeks’ treatment with IM IFNβ-1a 30 μg once weekly compared with the number during the 12-week pre-treatment period. Lesions were counted by blinded investigators. Results: IM IFNβ-1a significantly decreased the median number of gadolinium-enhanced lesions from 2.5 to 0.3 (p < 0.0001) compared with pre-treatment values. The median number of new gadolinium-enhanced lesions also decreased significantly from 2.0 to 0.3 (p = 0.0002). Serum neopterin was induced in a manner similar to that observed previously in a Caucasian RRMS population. No new adverse events occurred during the study. Conclusion: This first study of IM IFNβ-1a in Japanese patients with RRMS demonstrated a level of efficacy similar to that reported in Caucasian patients based on an assessment of pre-treatment and post-treatment gadolinium-enhanced lesions.

Type I Interferons: Beneficial in Th1 and Detrimental in Th17 Autoimmunity

In relapsing remitting multiple sclerosis (RRMS), type I interferon (IFN) is considered immuno-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. However, within the RRMS population, 30-50% of MS patients are nonresponsive to this treatment, and it consistently worsens neuromyelitis optica (NMO), a disease once considered to be a form of RRMS. In contrast to RRMS, type I IFNs have been shown to have properties that drive the inflammatory pathologies in many other autoimmune diseases. These diseases include Sjögren's syndrome, system lupus erythematosus (SLE), neuromyelitis optica (NMO), rheumatoid arthritis (RA) and psoriasis. Historically, autoimmune diseases were thought to be driven by a TH1 response to auto-antigens. However, since the discovery of the TH17 in experimental autoimmune encephalomyelitis (EAE), it is now generally thought that TH17 plays an important role in MS and all other autoimmune diseases. In this article, we will discuss recent clinical and basic research advances in the field of autoimmunity and argue that IFN-β and other type I IFNs are immuno-modulatory in diseases driven predominantly by TH1 but in contrast are inflammatory in diseases that have a predominant Th17 response.

Health perceptions and clinical characteristics of relapsing-remitting multiple sclerosis patients: baseline data from an international clinical trial

ABSTRACTObjective: Baseline clinical and health-related quality of life (HRQoL) data from a phase 2, multi-site, international, randomized, controlled trial were analyzed to: (1) characterize the health status of patients with relapsing-remitting multiple sclerosis (RRMS), (2) explore cross-sectional relationships between HRQoL and clinical measures, and (3) evaluate differences in HRQoL scores for subsequent validation as minimally important differences (MID). Clinical Trial Registration: www.clinicaltrials.gov, NCT00207727.Research design and methods: Baseline clinical and HRQoL data were selected and analyzed. HRQoL questionnaires included the Short Form-36 (SF-36), Fatigue Severity Scale (FSS), a Patient Assessment of multiple sclerosis (MS) Impact (PAMSI), and MS-specific symptom scales for Bladder and Bowel Control, Cognition, and Sexual Satisfaction. Standard summary statistics described the population while Pearson and Spearman correlations evaluated the baseline association between HRQoL and clinical measures. Cross-sectional estimates of MID in HRQoL scores were derived using several clinical anchors, the PAMSI, and two tests: Tukey multiple comparisons and adjacent mean difference.Results: Patients (n = 249) had a mean age of 39.0 (Standard deviation, SD = 10.5), 70% were female, 63% resided in Europe, and 96% were Caucasian. Baseline median Expanded Disability Severity Scale (EDSS) was 2.5 (range = 0.0–6.5); median disease duration was 1.9 years (range = 0.1–33.6). The worst baseline mean (normalized) SF-36 scores were for General Health (39.9), Role Physical (40.4), Physical Functioning (41.0), and Vitality (42.7). The worst MS symptom mean scores were for Cognition (6.3) and FSS (4.4). Fatigue scores indicated substantial burden and were consistent with SF-36 Vitality results. Baseline HRQoL scores (SF-36, FSS, MS symptom scales) correlated most with EDSS, Multiple Sclerosis Functional Composite (MSFC), age and disease duration. Lesion count and pre-baseline relapse rate had no meaningful association with HRQoL or other clinical measures. The MID for several HRQoL measures are proposed for confirmation in longitudinal patient datasets.Conclusion: Clinical and HRQoL assessments documented health impairments in physical functioning, fatigue, and cognition among these RRMS patients with relatively short disease duration. HRQoL data varied with clinical measures and contributed new information regarding disease burden. The association between clinical and HRQoL measures was limited to cross-sectional analysis and requires confirmation in longitudinal datasets. These findings reflect an ambulatory, early-stage RRMS population that was mostly European in location or descent. The PAMSI also requires further validation as a measure of patient health status.

Cost-Effectiveness Analyses of Natalizumab (Tysabri®) Compared with Other Disease-Modifying Therapies for People with Highly Active Relapsing-Remitting Multiple Sclerosis in the UK

Natalizumab (Tysabri) is a new disease-modifying therapy that has been shown to be clinically effective in patients with relapsing-remitting multiple sclerosis (RRMS) and has been licensed for use in patients with highly active RRMS (HARRMS). These patients are those who experience higher relapse rates and faster disability progression than the general RRMS population. To estimate the cost effectiveness of natalizumab compared with interferon-beta, glatiramer acetate and best supportive care from various UK cost perspectives. A 30-year Markov model was developed, based on previously published models for multiple sclerosis, to estimate transition between disability states and the probability of relapse within disability states. The model was parameterized with data from the UK Multiple Sclerosis (MS) Survey 2005 and data from the AFFIRM study, a 2-year multicentre, randomized, double-blind, placebo-controlled trial of natalizumab in RRMS patients. Additional data were sourced from the literature. A UK societal cost perspective was used in the base case, with additional cost perspectives considered in the sensitivity analysis. The baseline characteristics for the patient group were taken from the patient population in the AFFIRM study (mean age 36 years, mean time since diagnosis 5 years and a mean Kurtzke Extended Disability Status Scale [EDSS] score of 2.5). The model and its parameterization were designed and developed to support a reimbursement application for natalizumab submitted to the UK National Institute for Health and Clinical Excellence (NICE). Efficacies for natalizumab and glatiramer acetate were taken from clinical trial data, and for interferon-beta from a meta-analysis of clinical trial data. Disutilities from adverse events for each comparator were also included in the model. Outcomes and costs were discounted at 3.5% per anum. Costs for interferon-beta and glatiramer acetate were based on published prices (year 2006 values) under the UK Risk Sharing Scheme, and for natalizumab the UK NHS list price was used. Diagnostic, administration and adverse event costs were also included. The incremental cost-effectiveness ratios (ICERs) were calculated for the base case, and a probabilistic sensitivity analysis was performed to assess the probability of cost effectiveness at different willingness-to-pay thresholds. The ICER for natalizumab compared with interferon-beta was 2300 pound per QALY. Compared with glatiramer acetate, it was 2000 pound per QALY, and compared with best supportive care it was 8200 pound per QALY. From a health and social care cost perspective, the ICERs were 18,700 pound, 20,400 pound and 25,500 per QALY, respectively. At a willingness-to-pay threshold of 30,000 pound per QALY, the probability of natalizumab being cost effective against any comparator from a societal perspective was >89%. If UK society is willing to pay more than 8200 pound per QALY, or Health and Social Services are willing to pay more than 26,000 pound per QALY, this analysis suggests that natalizumab is likely to be a cost-effective treatment for all patients with HARRMS.