Multiple Sclerosis Disease-modifying Therapies Research Articles

Interferon β for Multiple Sclerosis.

Despite that the availability of new therapeutic options has expanded the multiple sclerosis (MS) disease-modifying therapy arsenal, interferon β (IFN-β) remains an important therapy option in the current decision-making process. This review will summarize the present knowledge of IFN-β mechanism of action, the overall safety, and the short- and long-term efficacy of its use in relapsing remitting MS and clinically isolated syndromes. Data on secondary progressive MS is also provided, although no clear benefit was identified.

Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches.

Multiple sclerosis (MS) is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies (DMTs) for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.

Beneficial effects of oral administration of C-Phycocyanin and Phycocyanobilin in rodent models of experimental autoimmune encephalomyelitis

The only three oral treatments currently available for multiple sclerosis (MS) target the relapsing forms of the disease and concerns regarding efficacy, safety and tolerability limit their use. Identifying novel oral disease-modifying therapies for MS, targeting both its inflammatory and neurodegenerative components is still a major goal. AimThe scope of this study was to provide evidence that the oral administration of C-Phycocyanin (C-PC), the main biliprotein of the Spirulina platensis cyanobacteria and its tetrapyrrolic prosthetic group, Phycocyanobilin (PCB), exert ameliorating actions on rodent models of experimental autoimmune encephalomyelitis (EAE). Main methodsEAE was induced in Lewis rats using the spinal cord encephalitogen from Sprague Dawley rats and in C57BL6 mice with MOG35–55 peptide. Clinical signs, motor function, oxidative stress markers, cytokine levels by ELISA and transmission electron microscopy analysis were assessed. Key findingsEither prophylactic or early therapeutic administration of C-PC to Lewis rats with EAE, significantly improved clinical signs and restored the motor function of the animals. Furthermore, C-PC positively modulated oxidative stress markers measured in brain homogenate and serum and protected the integrity of cerebral myelin sheaths as shown by transmission electron microscopy analysis. In C57BL/6 mice with EAE, PCB orally improved clinical status of the animals and reduced the expression levels of brain IL-6 and IFN-γ proinflammatory cytokines. SignificanceThese results, for the first time, support the fact that both C-PC and PCB administered orally could potentially improve neuroinflammation, protect from demyelination and axonal loss, which may be translated into an improved quality of life for MS patients.

Disease-Modifying Therapies for Multiple Sclerosis: A Systematic Literature Review of Cost-Effectiveness Studies.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. MS is considered incurable; however, disease treatment has advanced significantly over the past several decades with the introduction of disease-modifying therapies (DMTs). The current study reviewed the cost-effectiveness analyses of DMTs in relapsing-remitting MS (RRMS) patients. A systematic literature search of bibliographic databases was conducted to identify economic evaluations published after 2007. The relevant population, intervention, comparators, outcomes, and study design (PICOS) were considered. The outcomes of interest were incremental cost-effectiveness ratios (ICERs), net monetary benefits, incremental benefits, and incremental costs. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement was used to assess the reporting quality of published studies. A total of 1370 potentially relevant citations were identified, of which 33 published articles and four Health Technology Assessment (HTA) reports prepared for the UK were included in the final analysis. Almost all studies were based on a health economic model and considered RRMS as the phase of disease at study entry. The studies were conducted in 10 different countries, with approximately 50% based in the US. Study outcomes were rarely comparable due to the different settings, input data, and assumptions. Even within the same country, the discrepancy between study criteria was considerable. The compliance with reporting standards of the CHEERS statement was generally high. Internationally, a large number of health economic assessments of DMTs in RRMS were available, yielding difficult to compare, and at times conflicting, results.

Treatment satisfaction across injectable, infusion, and oral disease-modifying therapies for multiple sclerosis

BackgroundThe recent approval of oral disease-modifying therapies (DMTs) for multiple sclerosis (MS) has provided patients with a new route of therapy administration. Little research has compared patients’ experiences with and perceptions of injectable, infusion and oral MS therapies. MethodsThree hundred fifty-seven treated MS patients enrolled in the CLIMB study completed the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM provides information regarding perceived effectiveness, side effects, convenience and overall satisfaction. The patients were treated with either interferon beta-1a intramuscular (IFNβ−1a IM) (n = 40), interferon beta-1a subcutaneous (IFNβ−1a SC) (n = 45), glatiramer acetate (GA) (n = 118), natalizumab (NTZ) (n = 44), fingolimod (n = 66), or dimethyl fumarate (BG-12) (n = 44). Multivariable linear regression models were used to compare treatment satisfaction across all DMTs and between patients treated with injectable (n = 203), infusion (n = 44), and oral (n = 110) DMTs. All models were adjusted for sex, age, EDSS, and time on treatment. ResultsPatients taking oral DMTs reported significantly higher convenience scores compared to patients taking either injectable or infusion DMTs. The adjusted difference in the mean overall convenience score was 26.87 (95% CI: 21.4, 32.34) for the comparison of orals and injectables and 17.53 (95% CI: 11.15, 23.9) for the comparison of orals and infusion. In addition, the proportion of patients reporting a side effect was significantly lower for orals compared to injectables (adjusted OR= 0.35; 95% CI: 0.18, 0.68) and infusion compared to injectables (adjusted OR= 0.14; 95% CI: 0.05, 0.35). ConclusionPatients reported treatment with the oral medications as more convenient than the injectable and infusion DMTs.

Brain volume loss is present in Japanese multiple sclerosis patients with no evidence of disease activity

No evidence of disease activity-3 (NEDA-3), defined as absence of clinical relapse, disability progression, and brain magnetic resonance imaging (MRI) activity, has emerged as the therapeutic target of disease-modifying therapy for multiple sclerosis (MS). However, recent studies have revealed that NEDA-3 might not be sufficient to prevent cognitive deterioration and predict long-term disability. In addition to NEDA-3, brain atrophy has recently been recognized as a pivotal biomarker that is closely associated to disability in patients with MS. This retrospective observational study included 22 Japanese MS patients with relatively mild disease (median expanded disability status scale = 1.75). Fifteen patients (68%) received disease-modifying therapy (DMT), including interferon (IFN)-β (n = 6), IFN-β, or azathioprine followed by fingolimod (n = 4), fingolimod (n = 4), and IFN-β followed by natalizumab (n = 1). It revealed that 14 (64.6%) patients achieved NEDA-3 in the 2-year observational period. However, nine (64.3%) of the patients with NEDA-3 were revealed to have a significant BVL, defined as ≥ 0.4% per year. Importantly, these nine patients included all patients receiving IFN-β therapy (n = 6), whereas patients without BVL included none of these patients. Conversely, patients treated with fingolimod following IFN-β did not have significant BVL. These results indicate that evaluation of NEDA-4 is encouraged especially in patients with IFN-β therapy in MS clinical practice in Japan although Japanese MS patients have generally been thought to possess a milder disease including brain atrophy compared to their Western counterparts.

Effects of fingolimod on cortical excitability in relapsing-remitting multiple sclerosis examined using paired-pulse TMS–EEG

Background: It has been shown that fingolimod, a disease-modifying therapy for multiple sclerosis (MS), modulates cortical neural excitability, by affecting glutamatergic drive, in treated MS patients. The development of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) has allowed for the assessment of functional neurotransmission in vivo.

Acute disseminated encephalomyelitis: prognostic value of early follow-up brain MRI.

Patients with acute disseminated encephalomyelitis (ADEM) are presumed to have radiological monophasic disease, but this is uncertain since follow-up brain MRI is not routinely performed. We aimed to ascertain combined radiological and clinical monophasic disease in ADEM patients and to assess whether performing early (<6months) follow-up brain MRI has prognostic value for subsequent multiphasic disease. We retrospectively studied the medical records of patients initially diagnosed with ADEM (years 2000-2014) at the Massachusetts General Hospital, USA. A neuroimaging specialist, masked to clinical events, reviewed all available brain MRIs. We included 62 patients (25 male; 30 pediatric; median clinical follow-up 3years) and classified them into two subgroups: (1) clinically monophasic (no new, recurrent or worsening neurological symptoms >3months after onset) (n=45), and (2) clinically multiphasic (clinical relapse >3months after onset) (n=17). All clinically monophasic patients with brain MRI follow-up (n=30) also had radiological monophasic disease a median of 2years after ADEM onset. New lesions (58 vs. 14%) and persistent lesions (100 vs. 18%) on early brain MRI [available in 40 patients (65%)], as well as clinical flares (53 vs. 20%), were more common in clinically multiphasic versus monophasic patients. These early follow-up data allowed us to predict multiphasic disease with reasonable accuracy in a multivariable model (AUC=0.73). We conclude that performing early follow-up brain MRI routinely in ADEM patients would aid clinicians in predicting multiphasic disease and may stratify patients who would benefit from initiation of disease-modifying therapy for multiple sclerosis.

Persistence to disease-modifying therapies for multiple sclerosis in a Canadian cohort.

PurposeTo examine the long-term persistence to the first-line injectable disease-modifying therapies (DMTs) for multiple sclerosis (MS) and to identify the factors associated with nonpersistence.Patients and methodsWe used population-based administrative data from Manitoba, Canada. All adult subjects who were diagnosed with MS and dispensed a first-line injectable DMT (beta-interferon-1b, beta-interferon-1a, and glatiramer acetate) between 1996 and 2011 and had a minimum of 1 year of follow-up were included. The primary outcome was the median time to discontinuation of any DMT. The associations between potential predictors and persistence were estimated using multivariable Cox-proportional hazard models.ResultsOverall, 721 subjects were followed for a median of 7.8 years (interquartile range 6.1). The median time to discontinuation of all first-line DMTs was 4.2 years (25th and 75th percentile: 1.7, 10.6 years). Of the 451 (62.6%) subjects who discontinued their DMT during the study period, 259 (57.4%) eventually resumed or restarted a DMT. Subjects who were younger when starting a DMT, had prior MS-related hospitalizations, were more recently diagnosed with MS, or had a greater lag time between their MS diagnosis and DMT initiation were more likely to discontinue therapy.ConclusionOver half of the individuals receiving a DMT for MS in Manitoba remained on therapy for at least 4 years. DMT discontinuation occurred in 60% of the cohort, but most restarted a DMT within 1 year. While not all of the factors identified with discontinuing DMT are modifiable, they may help practitioners enhance MS care by identifying individuals who may be at particular risk for DMT discontinuation.

Minocycline for Early Multiple Sclerosis

Minocycline showed early promise as a disease-modifying therapy for multiple sclerosis (MS) with favorable pricing. In this multicenter study,

Retrospective review on the prevalence of lymphopenia in patients aged 55 years and over taking oral disease-modifying therapies for multiple sclerosis (P5.371)

Retrospective review on the prevalence of lymphopenia in patients aged 55 years and over taking oral disease-modifying therapies for multiple sclerosis (P5.371)

Persistence with multiple sclerosis disease-modifying therapies is highest when switching to fingolimod compared with other oral and injectable therapies: a retrospective US claims database analysis (P2.397)

Persistence with multiple sclerosis disease-modifying therapies is highest when switching to fingolimod compared with other oral and injectable therapies: a retrospective US claims database analysis (P2.397)

Adherence to disease-modifying therapies for multiple sclerosis and subsequent hospitalizations.

The aim of this study was to examine the association between optimal adherence to first-line disease-modifying therapies (DMT) for multiple sclerosis (MS) and hospitalizations. We used population-based administrative data from three Canadian provinces. All individuals receiving DMT (interferon-B-1b, interferon-B-1a, or glatiramer acetate) between January 1, 1996, and December 31, 2011 (British Columbia); March 31, 2012 (Manitoba); or March 31, 2014, (Saskatchewan) were included. Adherence was estimated for the first year of DMT (year 0), using the medication possession ratio (MPR). The association between optimal adherence (MPR≥80%) and all-cause and MS-specific hospitalizations in the subsequent 1, 2, and 5years was assessed using Hurdle Poisson and logistic regression. Rate and odds ratios were adjusted (aRR and aOR) for sociodemographic factors and prior health-care utilization. Overall, 4746 subjects were followed for a mean 7.8 (SD 4.0) years; 3598 (76%) were women. Optimal DMT adherence was achieved in 3564/4746 (75.1%) subjects. Subsequent all-cause and MS-specific hospitalizations were lower for subjects with optimal versus suboptimal adherence, but none reached statistical significance (1-year period, aRR=0.77, 95%CI: 0.47-1.26; aOR=0.80, 95%CI: 0.52-1.25). Similar findings were observed in the 2-year and 5-year periods. Prior health-care utilization (hospitalizations and medications) was associated with future hospitalizations; for every additional medication class, the 5-year all-cause hospitalization rate and likelihood of an MS-specific hospitalization increased by 5% and 11%, respectively (aRR=1.05, 95%CI: 1.02-1.07; and aOR=1.11, 95%CI: 1.07-1.14). Hospitalization rates were lower in subjects with optimal DMT adherence, but findings were not statistically significant. Prior hospitalization and polypharmacy were associated with increased risk for future hospitalizations in MS. Copyright © 2017 John Wiley & Sons, Ltd.

Monitoring the Course of MS With Optical Coherence Tomography.

Retinae of patients with multiple sclerosis (MS), as part of the central nervous system (CNS), display inflammatory and neurodegenerative changes. There is increasing evidence suggesting that retinal changes, and in particular neurodegeneration, mirror global CNS alterations in MS. Spectral domain optical coherence tomography (SD-OCT) is an inexpensive, rapid, non-invasive, and reproducible imaging technique that generates high-resolution images of tissues such as the retina. An advantage of SD-OCT over magnetic resonance imaging techniques in the assessment of neurodegeneration may be its sensitivity to capture changes at the individual patient level. Several studies demonstrate that changes within the inner retina (primarily as a reflection of optic neuropathy), as assessed by OCT, correlate with reduced quality of life, visual dysfunction, and global disability in MS. Moreover, longitudinal studies suggest that inner retinal thinning is an early phenomenon in MS and that retinal thinning may occur independent of previous symptomatic episodes of optic neuritis, significantly correlating with inflammatory disease. Preliminary studies suggest that MS disease-modifying therapies may have differential effects on OCT-determined rates of retinal atrophy, supporting a potential utility for OCT to investigate the neuroprotective benefits of disease-modifying therapies in MS, as well as an outcome in trials of putatively neuroprotective strategies.

Conjoint analysis to understand preferences of patients with multiple sclerosis for disease-modifying therapy attributes in Spain: a cross-sectional observational study

ObjectiveTo assess patients’ preferences for a range of disease-modifying therapy (DMT) attributes in multiple sclerosis (MS).DesignA cross-sectional observational study.SettingThe data reported were from 17 MS units throughout Spain.ParticipantsAdult patients with...

Risk factors for non-adherence to disease-modifying therapy in pediatric multiple sclerosis

Background: Adherence to disease-modifying therapies (DMTs) in pediatric multiple sclerosis (MS) is not well understood. We examined the prevalence and risk factors for poor adherence in pediatric MS. Methods: This cross-sectional study recruited youth with MS from 12 North American pediatric MS clinics. In addition to pharmacy-refill data, patients and parents completed self-report measures of adherence and quality of life. Additionally, patients completed measures of self-efficacy and well-being. Factor analysis and linear regression methods were used. Results: A total of 66 youth (mean age, 15.7 years) received MS DMTs (33% oral, 66% injectable). Estimates of poor adherence (i.e. missing >20% of doses) varied by source: pharmacy 7%, parent 14%, and patient 41%. Factor analysis yielded two composites: adherence summary and parental involvement in adherence. Regressions revealed that patients with better self-reported physical functioning were more adherent. Parents were more likely to be involved in adherence when their child had worse parent-reported PedsQL School Functioning and lower MS Self-Efficacy Control. Oral DMTs were associated with lesser parental involvement in adherence. Conclusion: Rates of non-adherence varied by information source. Better self-reported physical functioning was the strongest predictor of adherence. Parental involvement in adherence was associated with worse PedsQL School Functioning and lower MS Self-Efficacy-measured confidence in controlling MS.

Update on disease-modifying therapies for multiple sclerosis

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system (CNS). It predominantly affects young women and is one of the most common causes of disability in...

Changes in first-line injectable disease-modifying therapy for multiple sclerosis: predictors of non-adherence, switching, discontinuation, and interruption of drugs.

This study was aimed to describe changes of Disease-Modifying Treatments (DMT) in an Italian cohort of patients with multiple sclerosis (MS) and to identify predictors of therapeutic modifications. Patients with MS and treated with the first-line injectable DMT (interferons-IFNs or glatiramer) between 1/7/2009 and 31/10/2012 were selected from administrative databases of the MS Center of Cagliari (Sardinia, Italy). Socio-demographic, therapeutic, and clinical information was collected in the 6months preceding the index date. All patients were followed for 36months to evaluate therapeutic changes in terms of non-adherence, switch, temporary discontinuation, and permanent interruption. Predictors of changes were estimated by multivariable regression models. Data on 1698 patients were collected: glatiramer was prescribed in 27% of cases, IFNβ-1b in 22%, IFNβ-1a-im in 20%, IFNβ-1a-sc-44mcg in 19%, and IFNβ-1a-sc-22mcg in 12%. Non-adherence was observed in 25% of cases, therapeutic switch in 30%, discontinuation in 37%, and permanent interruption in 28%. The risk of non-adherence was higher for IFNβ-1b, compared with IFNβ-1a-im (adjOR=1.73). Therapeutic switch occurred especially in patients recently diagnosed (each year from diagnosis causes a decrease of this risk adjHR=0.97); the risk of discontinuation was higher with EDSS=4-6 and 7-9 (adjHR=1.52 and 4.42, respectively). The risk of permanent interruption increased with the augmentation of disability (adjHR=1.67 and 5.43 for EDSS 4-6 and 7-9). This study mirrored a detailed framework of DMT prescription and identified factors related to changes in the MS therapy. These findings could support healthcare providers in the evaluation and maximization of benefits associated with a long-term DMT.

Pharmacogenetic Biomarkers to Predict Treatment Response in Multiple Sclerosis: Current and Future Perspectives.

Disease-modifying therapies (DMTs) have significantly advanced the treatment of relapsing multiple sclerosis (MS), decreasing the frequency of relapses, disability, and magnetic resonance imaging lesion formation. However, patients' responses to and tolerability of DMTs vary considerably, creating an unmet need for biomarkers to identify likely responders and/or those who may have treatment-limiting adverse reactions. Most studies in MS have focused on the identification of pharmacogenetic markers, using either the candidate-gene approach, which requires prior knowledge of the genetic marker and its role in the target disease, or genome-wide association, which examines multiple genetic variants, typically single nucleotide polymorphisms (SNPs). Both approaches have implicated numerous alleles and SNPs in response to selected MS DMTs. None have been validated for use in clinical practice. This review covers pharmacogenetic markers in clinical practice in other diseases and then reviews the current status of MS DMT markers (interferon β, glatiramer acetate, and mitoxantrone). For a complex disease such as MS, multiple biomarkers may need to be evaluated simultaneously to identify potential responders. Efforts to identify relevant biomarkers are underway and will need to be expanded to all MS DMTs. These will require extensive validation in large patient groups before they can be used in clinical practice.

Multiple sclerosis: Is there a safe time to discontinue therapy in MS?

As yet, no clear strategy has been developed for discontinuation of disease-modifying therapy in multiple sclerosis. A recent observational study adds new information, but the most informative patient groups are still to be assessed comprehensively, and several questions need to be addressed in prospective studies.