Use Of Disease-modifying Treatments Research Articles

Primary myelofibrosis in untreated sickle cell disease: Are adult patients at higher risk for developing hematological myeloid neoplasms?

Primary myelofibrosis in untreated sickle cell disease: Are adult patients at higher risk for developing hematological myeloid neoplasms?

Clinical effects associated with five-year retinal nerve fiber layer thinning in multiple sclerosis

BackgroundNeurodegenerative changes in multiple sclerosis (MS) are associated with long-term disability progression (DP). Optical coherence tomography (OCT) measures may be used to monitor DP. ObjectiveTo determine significant effects driving the changes in OCT-based peripapillary retinal nerve fiber layer (pRNFL) in heterogeneous group of MS patients. MethodsTotal of 144 MS patients (109 relapsing-remitting MS and 35 progressive MS (PMS) with mean age at baseline of 47.6 and 56.5 years old, respectively) underwent clinical and OCT examination over 5-year follow-up. All OCT exams were reviewed using the OSCAR-IB criteria. The 5-year DP was determined based on Expanded Disability Status Scale (EDSS) changes and MS clinical trial criteria. Data regarding previous history of MS optic neuritis (MSON) and use of disease modifying treatment (DMT) was derived by in-person interview and review of electronic medical records. Mixed model-type of repeated measure analysis determined effects driving pRNFL change for analysis which utilized all eyes separately. ResultsOver an average of 5.3-years follow-up, the MS population demonstrated significant pRNFL thinning (F = 16.108, p < 0.001). The pRNFL thinning was greater due to progressive MS subtype (F = 5.102, p = 0.025), greater age at baseline (F = 4.554, p = 0.034), occurrence of DP (F = 6.583, p = 0.011), and previous history of MSON (F = 7.053, p = 0.008). Use of any or highly potent DMT (natalizumab versus first-line injectable treatments versus no DMT) significantly reduced the pRNFL thinning (F = 8.367, p = 0.004) over the follow-up. Lastly, occurrence of DP in PMS patients older than 50 years old was associated with greater pRNFL thinning (F = 6.667, p = 0.013). ConclusionLongitudinal pRNFL changes are modified by age, disease subtype, disabiltiy progression, history of MSON, DMT use and their interactions.

Maternal education has significant influence on progression in multiple sclerosis

ObjectiveThe identification of potential risk factors for disease severity is of great importance in the treatment of multiple sclerosis. The influence of socioeconomic status on progression in multiple sclerosis (MS) is sparsely investigated. Our aim was to investigate how socioeconomic status in adolescence influences disease progression in later life. MethodsA total of 1598 patients with multiple sclerosis from a well-defined population in Norway were included. Detailed information on disease progression, measured by expanded disability status scale (EDSS) and multiple sclerosis severity score (MSSS), were combined with data on socioeconomic factors. We used residency and parental level of education at patients’ age 16 and exposure to second-hand smoking as a measure of socioeconomic status in adolescence, adjusting for the same variables as well as use of disease modifying treatments at prevalence date 01.01.18. ResultsHigh maternal level of education at patients’ age 16 was significantly associated with less pronounced disease progression measured by MSSS (β-coefficient -0.58, p = 0.015), younger age and lower EDSS at disease onset, and shorter time from onset to diagnosis. No significant associations were found for paternal education level and MSSS. The use of any disease modifying treatment before prevalence date was significantly associated with disease progression (β-coefficient -0.49, p=0.004), while residence, current and second-hand smoking were not. ConclusionThis study on a population-based, real-world cohort shows that the parental level of education has a significant impact on a timely diagnosis of MS. In addition to disease modifying treatment, maternal level of education also had an impact on disease progression in later life.

Health care resource utilization and disease modifying treatment use in multiple sclerosis patients by age and insurance type

Objective The objective of this study was to describe and compare health care resource utilization (HCRU) and disease modifying treatment (DMT) use among US adults <65 years with multiple sclerosis (MS), across commercial and Medicare Advantage plans. Methods Medical and pharmacy claims data from commercial and Medicare Advantage with Part D (MAPD) plans were extracted for MS patients age 18 − 64 identified between 1 January 2014 and 31 May 2017. Comparisons were made between commercial and MAPD enrollees for all-cause HCRU and DMT use over 1 year, overall and by 5 year age groups. Results A total of 28,427 MS patients were identified; two-thirds (67%) had commercial coverage. MAPD patients had statistically significantly higher mean counts of all-cause inpatient, emergency room (ER) and ambulatory visits compared to commercial patients. The significant differences were evident in all age groups ≥30 years, except for ER visits in the 40–44 and 60–64 age groups. MAPD patients had statistically significantly lower prevalence of DMT use compared to commercial patients in all age groups starting at ≥35 years. Conclusion MAPD patients had a higher burden of medical HCRU compared to their commercially insured counterparts, most likely due primarily to their more advanced disease state and higher level of MS-related disability. Reasons for lower prevalence of DMT use among MAPD patients may include their more advanced disease state, older age and higher prevalence of comorbid conditions compared with commercially insured patients, as well as more restrictive formularies for MAPD vs. commercial plans. These findings suggest that there may be an opportunity for recently approved DMTs indicated for active secondary progressive MS to fulfill an unmet need for treatment among MS patients <65 years without contraindicated comorbid conditions who are enrolled in MAPD plans. Novel therapies under development to delay progression may help keep MS patients of working age in the work force.

A Neurodisparity Index of Nationwide Access to Neurological Health Care in Northern Ireland

Nationwide disparities in managing neurological patients have rarely been reported. We compared neurological health care between the population who reside in a Health and Social Care Trust with a tertiary neuroscience center and those living in the four non-tertiary center Trusts in Northern Ireland. Using the tertiary center Trust population as reference, neurodisparity indices (NDIs) defined as the number of treated patients resident in each Trust per 100,000 residents compared to the same ratio in the tertiary center Trust for a fixed time period. NDIs were calculated for four neurological pathways—intravenous thrombolysis (iv-tPA) and mechanical thrombectomy (MT) for acute ischemic stroke (AIS), disease modifying treatment (DMT) in multiple sclerosis (MS) and admissions to a tertiary neurology ward. Neurological management was recorded in 3,026 patients. Patients resident in the tertiary center Trust were more likely to receive AIS treatments (iv-tPA and MT) and access to the neurology ward (p < 0.001) than patients residing in other Trusts. DMT use for patients with MS was higher in two non-tertiary center Trusts than in the tertiary center Trust. There was a geographical gradient for MT for AIS patients and ward admissions. Averaged NDIs for non-tertiary center Trusts were: 0.48 (95%CI 0.32–0.71) for patient admissions to the tertiary neurology ward, 0.50 (95%CI 0.38–0.66) for MT in AIS patients, 0.78 (95%CI 0.67–0.92) for iv-tPA in AIS patients, and 1.11 (95%CI 0.99–1.26) for DMT use in MS patients. There are important neurodisparities in Northern Ireland, particularly for MT and tertiary ward admissions. Neurologists and health service planners should be aware that geography and time-dependent management of neurological patients worsen neurodisparities.

Incidence and clinical outcome of Coronavirus disease 2019 in a cohort of 11,560 Brazilian patients with multiple sclerosis

Background: Little information is available regarding the incidence and clinical outcome of the SARS-CoV2 infection in patients with multiple sclerosis (pwMS). Objective: To determine the incidence, clinical outcome, and impact of COVID-19 on pwMS. Methods: This observational study was prospectively performed on a cohort of pwMS (N = 11,560) followed up by 47 out of 51 Brazilian MS referral centers that registered pwMS with COVID-19 at the REDONE platform from 13 March to 4 June 2020. Results: The incidence of COVID-19 for pwMS patients was 27.7/10,000 patients and for the general population was 29.2/10,000 inhabitants. A total of 94 (77 women) pwMS patients, aged 40 ± 10.25 years, presenting 9.9 ± 8.6 years of MS disease duration, developed the COVID-19, most of them (87%) exhibited the mild form of the disease. Eighty (96%) patients maintained the use of MS disease-modifying treatment (DMT) during COVID-19 pandemic and 14 patients were not in use of DMTs. Conclusion: Incidence of COVID-19 in Brazilian pwMS was not different from those observed for the general Brazilian population. Most pwMS exhibited mild COVID-19, despite the maintenance of the underlying MS treatment.

Co-Occurrence of Neurodevelopmental Disorders in Pediatric Sickle Cell Disease.

The objective of this study is to retrospectively determine the co-occurrence, associated characteristics, and risk factors for neurodevelopmental disorders (NDD) in a pediatric sickle cell disease (SCD) clinic population. We investigated the co-occurrence and features of NDD in pediatric SCD through a retrospective cohort study conducted between July 2017 and January 2019. The participants were patients with SCD younger than 18 years of age identified from our institutions' clinic rosters and medical records databases. A total of 276 participants were eligible for study inclusion, and 65 participants were found to have various NDD. Children with SCD and NDD were more likely to have a history of multiple SCD-related complications in comparison to children with SCD without NDD. Children with SCD and NDD were more likely to use disease-modifying therapies in comparison to children with SCD without NDD (χ2 27.2, p < 0.001). Children with SCD and NDD have higher odds of having certain disease-related complications and higher use of disease-modifying treatments than children with SCD who do not have NDD. Screening and diagnoses of NDD may be relevant to clinical management of pediatric SCD.

Einfluss von Fatigue und kognitiven Einschränkungen auf die Inanspruchnahme von Gesundheitsleistungen, Arbeitsleistung und Lebensqualität (Utility)

Influence of fatigue and cognitive impairment on the use of health services, work performance and quality of life (utility): A study with 5,475 patients with multiple sclerosis in Germany Introduction: People with multiple sclerosis (MS) experience a number of neurological problems beyond the general outcome measures of relapses and disability that can independently affect costs and quality of life. Objectives: To investigate the effect of self-assessed fatigue and subjective cognitive impairment on direct healthcare consumption, work participation and utility in Germany. Methods: The study included 5,475 participants and investigated – in addition to all resource consumption – fatigue, cognitive impairment and the effect of MS while at work using visual analogue scales (VAS 0–10). The analysis controlled for gender, age, disease duration, education, disability, and use of disease-modifying treatments. Results: The level of fatigue and cognitive impairment was significantly and independently correlated with all resource utilisation, workforce participation and utility (p&lt;0.0001). For each VAS point increase in severity, the probability of working was reduced by 10.6% for cognitive impairment and 4.9% for fatigue, while utility decreased by 0.03 for each point. Work hours decreased in linear fashion with each point of increasing severity for both symptoms, while sick leave increased accordingly. Both symptoms significantly affected productivity at work. Conclusions: The effect of fatigue and impaired cognition on work capacity has been shown in an international study, but demonstrating their effect on resource consumption requires a large single-country sample. This German analysis demonstrates their effect on all economic resources, both direct and indirect.

Changing therapeutic strategies and persistence to disease-modifying treatments in a population of multiple sclerosis patients from Veneto region, Italy

BackgroundThe availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy. MethodsDemographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence. ResultsOf 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among second-line DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation. ConclusionThe use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors.

12th Post-ECTRIMS Meeting: review of the novelties from the 2019 ECTRIMS Congress (II).

Like every year, after the ECTRIMS Congress, renowned Spanish neurologists who are experts in multiple sclerosis presented the main novelties in research in this field at the Post-ECTRIMS Meeting. To summarise the content presented at the 12th edition of the Post-ECTRIMS Meeting, which took place in September 2019 in Sevilla and is presented in two parts. In this second part, the most recent evidence on the use of disease-modifying treatments during pregnancy is presented. Details are provided concerning the results of phase 3 clinical trials conducted to evaluate the efficacy and safety of two potential disease-modifying treatments for relapsing-remitting multiple sclerosis: ponesimod and ofatumumab. For the progressive forms, both available disease modifying treatments and others still in the research phase are reviewed. In the field of stem cell therapies, the article includes the results of the only clinical trial carried out to date comparing patients with relapsing-remitting multiple sclerosis treated with autologous haematopoietic stem cell transplantation and those treated with disease-modifying therapies. There are no important developments as regards symptomatic treatments, although the European Academy of Neurology has published a guide on palliative care. The various sources of information that collect pharmacovigilance data in the post-marketing setting are reviewed. Patients diagnosed in recent years tend to have less severe multiple sclerosis, probably due to the fact that it is diagnosed in its milder stages together with the steady increase in the number of treatments available.

Neurodevelopmental Disorders in Pediatric Sickle Cell Disease

Children with sickle cell disease (SCD) have an increased risk of neurological complications, including stroke, silent cerebral infarction, and cognitive deficits. Past research by others has also shown increased risk for neurodevelopmental disorders (NDD) in this population (PMID 19142770, 27038278). A previous study conducted by our group noted that only 22% of patients with SCD and NDD had a prior history of stroke (PMID 26149844). We investigated the prevalence and features of NDD in pediatric SCD through a retrospective chart review conducted between July 2017 and January 2019. The participants were patients with SCD identified from the Johns Hopkins Pediatric Hematology Harriet Lane Clinic roster and the Kennedy Krieger Institute medical records database. Children under 18 years of age with SCD were included in the study. A total of 396 patients were identified and reviewed for study inclusion. Analyses were completed using non-parametric tests (Wilcoxon-Mann-Whitney test, chi squared test) in Stata IC-13. Table 1 shows the characteristics of the clinic patient population. A total of 284 participants qualified for study inclusion and 78 participants (27%) were found to have various NDD. Children with SCD and NDD were more likely to have a history of seizure (OR=5.77, 95%CI:1.69-19.76, p&lt;0.006), stroke (OR=5.12, 95%CI:2.4-10.92, p&lt;0.001), dactylitis (OR=3.65, 95%CI:1.86-7.18, p&lt;0.001), pain crises (OR=2.96, 95%CI:1.56-5.63, p&lt;0.002), asthma (OR=2.46, 95%CI:1.38-4.36, p&lt;0.003), headache (OR=2.44, 95%CI:1.04-5.7, p&lt; 0.05), acute chest syndrome (OR=1.77, 95%CI:1.05-3, p&lt;0.04), or priapism (male patients only, OR=6.48, 95%CI:1.59-26.42, p&lt;0.01), in comparison to children with SCD without NDD. Children with SCD and NDD were more likely to have a history of hydroxyurea usage (OR=2.28, 95%CI:1.34-3.88, p&lt;0.003), in comparison to children with SCD without NDD. Children with SCD and NDD had significantly higher odds of receiving school support (OR=9.34, 95%CI:4.68-18.64, p&lt;0.001), in comparison to children with SCD without NDD. Figure 1 shows the prevalence of reported NDD in this clinic population. Table 2 shows the different subtypes of NDD in this clinic population. The most common NDD were language disorders and ADHD. Four (18%) of the children with language disorders had been seen by a speech and language pathologist at the hospital. There was no significant difference in the odds of having a history of stroke between children with a history of SCD and a language disorder and children with SCD without language/other NDD (OR=3.3, 95%CI:0.97-11.18, p=0.055). ADHD had a prevalence of 7% in this SCD clinic population. Eleven (52%) of the children with ADHD had been seen by a behavioral therapist. Eighteen (86%) children with ADHD had been seen by either a neurodevelopmental physician or pediatric neurologist. Of the children with SCD and ADHD, 13 (62%) were on an appropriate medication for ADHD, either a stimulant medication alone (57%), alpha agonist alone (5%), or both (5%). Children with SCD and ADHD had higher odds of having a stroke in comparison to children with SCD without NDD (OR=7.42, 95%CI:2.55-21.58, p&lt;0.001). In conclusion, children with SCD and NDD have higher odds of having certain disease-related complications and higher use of disease modifying treatments than children with SCD who do not have NDD. The higher use of disease-modifying treatments could be due to the association of the NDD with SCD-related complications and the need to provide these children with a higher level of care. We cannot determine causal or temporal relationships between these NDD and SCD-related complications from this research. Screening and diagnoses of NDD may be relevant to clinical management of pediatric SCD. Disclosures Lance: NIH: Research Funding; KKI: Research Funding. Shapiro:HRSA: Other: Training Grant; Mutual Funds: Other: may invest in health care organizations; Baltimore City Health Department: Consultancy; Maternal and Child Health Bureau: Other: Training Grant. Casella:Immunoarray Ltd.: Patents &amp; Royalties; Mast Pharmaceuticals: Consultancy; NIH: Research Funding.

Real-Life Outcome in Multiple Sclerosis in the Czech Republic.

Background Cohort studies and registries provide opportunities to estimate long-term outcome in multiple sclerosis. Objectives To describe changes in disability (EDSS), relapse activity, and health care consumption over the period 2008-2015 by combining two Czech cost-of-illness studies with disease data from the MS Center in Prague. Methods The combined dataset included 426 patients with a mean observation time of 8.3 years. A Cox proportional hazards model with time-varying covariates for treatment, disease course, and EDSS was applied to estimate the effect of treatment on the risk of progression to EDSS 4 and the risk of relapses. The use of health care resources (hospitalization, consultation, and tests) was compared between the two cross-sectional studies. Results Total health care costs appeared stable between 2008 and 2015, despite more intense use of disease-modifying treatments in 2015 (52% of patients versus 31% in 2008). 39% of patients starting treatment at EDSS 0-3 in 2008 progressed to EDSS 4 or higher by 2015, while 65% of patients starting at EDSS 0-2 remained stable. The number of relapses was associated with a higher risk of progression. In a marginal structural Cox model of the relapse risk, treatment with natalizumab or fingolimod was associated with a lower risk of relapse (hazard ratio 0.68, p<0.01). Treatment with natalizumab or fingolimod was associated with a lower risk of progression to EDSS 4. Conclusion Our results link relapses to progression and indicate that the newer treatments have a better effectiveness, despite difficulties caused by small a sample size, administrative rules guiding treatment, and absence of a random comparator group.

Validations of apomorphine-induced BOLD activation correlations in hemiparkinsonian rhesus macaques.

Identification of Parkinson's disease at the earliest possible stage of the disease may provide the best opportunity for the use of disease modifying treatments. However, diagnosing the disease during the pre-symptomatic period remains an unmet goal. To that end, we used pharmacological MRI (phMRI) to assess the function of the cortico-basal ganglia circuit in a non-human primate model of dopamine deficiency to determine the possible relationships between phMRI signals with behavioral, neurochemical, and histological measurements. Animals with unilateral treatments with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), that expressed stable, long-term hemiparkinsonism were challenged with the dopaminergic receptor agonist, apomorphine, and structure-specific phMRI blood oxygen level-dependent (BOLD) activation responses were measured. Behavioral, histopathological, and neurochemical measurements were obtained and correlated with phMRI activation of structures of the cortico-basal ganglia system. Greater phMRI activations in the basal ganglia and cortex were associated with slower movement speed, decreased daytime activity, or more pronounced parkinsonian features. Animals showed decreased stimulus-evoked dopamine release in the putamen and substantia nigra pars compacta and lower basal glutamate levels in the motor cortex on the MPTP-lesioned hemisphere compared to the contralateral hemisphere. The altered neurochemistry was significantly correlated with phMRI signals in the motor cortex and putamen. Finally, greater phMRI activations in the caudate nucleus correlated with fewer tyrosine hydroxylase-positive (TH+) nigral cells and decreased TH+ fiber density in the putamen. These results reveal the correlation of phMRI signals with the severity of the motor deficits and pathophysiological changes in the cortico-basal ganglia circuit.

Unmet needs and challenges for follow-up and treatment of autosomal dominant polycystic kidney disease: the paediatric perspective.

Awareness is growing that the clinical course of autosomal dominant polycystic kidney disease (ADPKD) already begins in childhood, with a broad range of both symptomatic and asymptomatic features. Knowing that parenchymal destruction with cyst formation and growth starts early in life, it seems reasonable to assume that early intervention may yield the best chances for preserving renal outcome. Interventions may involve lifestyle modifications, hypertension control and the use of disease-modifying treatments once these become available for the paediatric population with an acceptable risk and side-effect profile. Until then, screening of at-risk children is controversial and not generally recommended since this might cause psychosocial and financial harm. Also, the clinical and research communities are facing important questions as to the nature of potential interventions and their optimal indications and timing. Indeed, challenges include the identification and validation of indicators, both measuring and predicting disease progression from childhood, and the discrimination of slow from rapid progressors in the paediatric population. This discrimination will improve both the cost-effectiveness and benefit-to-risk ratio of therapies. Furthermore, we will need to define outcome measures, and to evaluate the possibility of a potential therapeutic window of opportunity in childhood. The recently established international register ADPedKD will help in elucidating these questions. In this review, we provide an overview of the current knowledge on paediatric ADPKD as a future therapeutic target population and its unmet challenges.

Cost Sharing of Disease-Modifying Treatments (DMTs) as Policy Lever to Improve DMTs’ Access in Multiple Sclerosis

ObjectivesTo understand the nonlinear relationship between out-of-pocket (OOP) payments and disease-modifying treatment (DMT) use and adherence, primarily to pinpoint the threshold at which the use of DMTs becomes price sensitive. MethodsIndividuals with more than two multiple sclerosis (MS) diagnoses (International Classification of Diseases, Ninth Revision code 340) were identified from the MarketScan database (2006–2009). Heterogeneity in treatment was normalized by calculating an annual OOP payment as the average OOP payment for purchasing a fixed basket of DMTs at the insurance plan level. A local linear regression with a model-based recursive partitioning algorithm was applied to explore the relationship between OOP and consequently lower DMT use and adherence as measured by days covered by DMT. ResultsWe identified the inflection points in annual OOP payments as $442 for DMT use and $890 for DMT adherence. For patients with annual OOP payments of more than $442, a $100-increase in OOP payment was associated with a decline of 0.6% in DMT use; for annual OOP payments of more than $890, a $100-increase in OOP payment was associated with two fewer days of DMT treatments. ConclusionsAlthough the use of DMTs and DMT adherence appeared unassociated with OOP payment below $442 and $890, respectively, an excessive OOP payment was a barrier to DMT access. This information can inform maximum monthly and yearly payment caps when designing valued-based insurance plans.

Using IMPrESS to guide policy change in multiple sclerosis

The International MultiPlE Sclerosis Study (IMPrESS) studied the significant impact of multiple sclerosis (MS) on the health and well-being of both people with the disease and their caregivers, along with its broader socioeconomic impact. Results confirmed that there is an urgent need to achieve better outcomes for people with MS. This paper uses results from the IMPrESS to present new international evidence on the socioeconomic burden of MS and discuss the merits of a likely paradigm shift in the management of MS towards the use of better (and more accurate) diagnostic follow-up to monitor disease progression and the earlier use of disease-modifying treatments (DMTs) to achieve better clinical, quality-of-life and socioeconomic results for individuals.

PRM35 - Comparing Different Data on Disease Burden In Multiple Sclerosis

Numerous studies exist on costs of multiple sclerosis (MS). Comparison of results, even with similar study methods, is challenging due to differences in the samples. We investigate methods for explaining and adjusting for differences between samples and results using two large cross-sectional data sets. In two methodologically very similar European cost-of-illness studies in MS, conducted in 2005 and 2015, patients had provided data on their disease, resource use, work productivity and health-related quality of life. Since disease severity was the strongest driver of costs (and utilities), we compared resource use for patients with mild MS only (Expanded Disability Status Scale 0-3), including 8351 patients from 6 countries. Patients in the 2015 study were older (2.8 years) and had longer disease duration (1.7 years). Employment rate in those below 65 years was lower (64% vs. 72%), possibly due to higher age and changes in economic conditions. The 3-month relapse rate was 32% lower, potentially a consequence of higher use of disease-modifying treatments (DMTs; 70% in 2015 vs. 57% in 2005), but also due to a sample with possibly more benign disease. The lower relapse rate might also have contributed to a lower rate of short-term sick leave (19% vs. 24%), hospitalisations (4% vs. 7%) and use of services (7% vs. 14%). However, these changes may also be a consequence of trends unrelated to MS such as more control on sick leaves, fewer inpatient admissions, and less service provision. When comparing patient samples and results in MS, it is not sufficient to control for disease severity alone. Additional factors need to be adjusted for to allow for appropriate comparisons of disease burden, including demographics, disease duration and disease course, as well as external factors such as changes in economic conditions and healthcare systems.

Factors associated with benign multiple sclerosis in the New York State MS Consortium (NYSMSC).

BackgroundThis retrospective analysis explored prognostic factors associated with a benign multiple sclerosis (BMS) disease course at baseline and over the 4-year follow-up.MethodsPatients from the centralized New York State Multiple Sclerosis Consortium registry were classified as having BMS according to 3 different criteria centered on disease duration and disability. Additional analyses explored prognostic factors associated with BMS using the most conservative disability criteria (Expanded Disability Status Scale ≤2 and disease duration ≥10 years).ResultsAmong 6258 patients who fulfilled eligibility criteria, 19.8 % to 33.3 % were characterized as having BMS, at baseline depending on classification criteria used. Positive prognostic factors for BMS at baseline included female sex (p < 0.0001) and younger age at onset (p < 0.0001); negative prognostic factors included progressive-onset type of MS and African-American race. Of the 1237 BMS patients (per most conservative criteria), 742 were followed for a median of 4 years to explore effect of disease-modifying treatment (DMT) on benign status. DMT (p = 0.009) and longer disease duration (p = 0.007) were the only significant positive predictors of maintaining BMS at follow-up. The protective effect was stronger for patients taking DMT at both enrollment and follow-up (OR = 0.71; p = 0.006).ConclusionsThere is a need for development of more reliable prognostic indicators of BMS. Use of DMT was significantly associated with maintaining a benign disease state.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0623-2) contains supplementary material, which is available to authorized users.

Predicting the End of Symptomatic Relapses and Disease Modifying Treatment Use Decisions in Progressive Multiple Sclerosis (S24.001)

Predicting the End of Symptomatic Relapses and Disease Modifying Treatment Use Decisions in Progressive Multiple Sclerosis (S24.001)

Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial

Acute demyelinating optic neuritis, a common feature of multiple sclerosis, can damage vision through neurodegeneration in the optic nerve and in its fibres in the retina. Inhibition of voltage-gated sodium channels is neuroprotective in preclinical models. In this study we aimed to establish whether sodium-channel inhibition with phenytoin is neuroprotective in patient with acute optic neuritis. We did a randomised, placebo-controlled, double-blind phase 2 trial at two UK academic hospitals in London and Sheffield. Patients with acute optic neuritis aged 18-60 years, presenting within 2 weeks of onset, with visual acuity of 6/9 or worse, were randomly assigned (1:1) by minimisation via a web-based service to oral phenytoin (maintenance dose 4 mg/kg per day if randomised before or on July 16, 2013, and 6 mg/kg per day if randomised on or after July 17, 2013) or placebo for 3 months, stratified by time from onset, centre, previous multiple sclerosis diagnosis, use of disease-modifying treatment, and use of corticosteroids for acute optic neuritis. Participants and treating and assessing physicians were masked to group assignment. The primary outcome was retinal nerve fibre layer (RNFL) thickness in the affected eye at 6 months, adjusted for fellow-eye RNFL thickness at baseline, analysed in a modified intention-to-treat population of all randomised participants who were followed up at 6 months. Safety was analysed in the entire population, including those who were lost to follow-up. The trial is registered with ClinicalTrials.gov, number NCT 01451593. We recruited 86 participants between Feb 3, 2012, and May 22, 2014 (42 assigned to phenytoin and 44 to placebo). 29 were assigned to phenytoin 4 mg/kg and 13 to phenytoin 6 mg/kg. Five participants were lost to follow-up, so the primary analysis included 81 participants (39 assigned to phenytoin and 42 to placebo). Mean 6-month RNFL thickness in the affected eye at 6 months was 81.46 μm (SD 16.27) in the phenytoin group (a mean decrease of 16.69 μm [SD 13.73] from baseline) versus 74.29 μm (15.14) in the placebo group (a mean decrease of 23.79 μm [13.97] since baseline; adjusted 6-month difference of 7.15 μm [95% CI 1.08-13.22]; p=0.021), corresponding to a 30% reduction in the extent of RNFL loss with phenytoin compared with placebo. Treatment was well tolerated, with five (12%) of 42 patients having a serious adverse event in the phenytoin group (only one, severe rash, was attributable to phenytoin) compared with two (5%) of 44 in the placebo group. These findings support the concept of neuroprotection with phenytoin in patients with acute optic neuritis at concentrations at which it blocks voltage-gated sodium channels selectively. Further investigation in larger clinical trials in optic neuritis and in relapsing multiple sclerosis is warranted. US National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland, Novartis, UK National Institute for Health Research (NIHR), and NIHR UCLH/UCL Biomedical Research Centre.