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Background and Objective: Patients' perceptions and experiences of medication efficacy, medication adverse events, dosing frequency, and dosing complexity have been found to influence adherence to injectable disease-modifying treatments (DMTs) in patients with multiple sclerosis (MS). The aim of this study was to quantify patient preferences for features of injectable DMTs for MS., Methods: Adult patients in the United States (US) with a self-reported diagnosis of MS completed an online discrete-choice experiment survey to assess preference for a number of features of a hypothetical injectable DMT. Patients chose hypothetical treatments in paired comparisons, where each treatment was described by features or attributes, including the number of years until disability progression, the number of relapses in the next 4 years, injection time, the frequency of injections, the occurrence of flu-like symptoms (FLS), and severity of injection-site reactions. Random-parameters logit regression parameters were used to calculate preference weights of attribute levels and the relative importance of changes in treatment features., Results: Of the 205 patients who completed the survey, 192 provided sufficient data for analysis. The results indicated a broad range of tradeoffs that patients would be willing to make. With regard to this, the relative importance of an improvement in the number of years until disability progression from 1 to 2 (i.e., vertical distance between preference weights for these attribute levels) was 0.9 [95% confidence interval (CI) 0.5-1.2], the relative importance of this change was approximately equivalent to that of an improvement from 12 injections per month to two (mean 0.8, 95% CI 0.4-1.2), or approximately equivalent to a decrease from four to one relapses in the next 4 years (mean 0.8, 95% CI 0.5-1.2), or FLS 3 days after every injection to 3 days after some injections (mean 1.0, 95% CI 0.6-1.4)., Conclusions: These results suggest that an improvement in treatment efficacy may be as important as a reduction in injection frequency or a reduction in some adverse events for patients who self-administer injectable DMTs for MS. Understanding the preferences of patients who use injectable treatments will inform the development of such treatments, which may in turn improve patient medication adherence and well-being.

Multiple sclerosis (MS) is a recurrent inflammatory disease of the central nervous system, which ultimately causes substantial disability in many patients. A key clinical feature of this disease is the occurrence of relapses, consisting of episodes of neurological dysfunction followed by periods of remission. This review considers in detail the importance of the occurrence of relapses to the ultimate course of MS and the impact of relap setreatment (both acutely and prophylactically) on the long-term outcome for individuals. The ultimate goal of therapy in MS is the reduction of long-term disability. Clinical trials in MS, however, typically only extend for a very short time period compared to the time it takes for disability to evolve. Consequently, short-term outcome measures that are associated with, and predict, future disability need to be identified. In this regard, not only are relapses a characteristic feature of MS, they have also been proven to be associated with the occurrence of long-term disability. Moreover, treatments that reduce the number and severity of these attacks improve the long-term prognosis., (Copyright © 2016. Published by Elsevier B.V.)

Background: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women., Methods: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204., Findings: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy., Interpretation: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial., Funding: National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Importance: Varicella-zoster virus (VZV) infections increasingly are reported in patients with multiple sclerosis (MS) and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell-mediated immunity., Objective: To assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated patients and provide recommendations for prevention and management., Design, Setting, and Participants: Rates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female patients aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated., Interventions: In clinical trials, patients received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all patients received fingolimod, 0.5 mg/d (total exposure of 54,000 patient-years at the time of analysis)., Main Outcomes and Measures: Calculation of the incidence rate of VZV infection per 1000 patient-years was based on the reporting of adverse events in the trials and the postmarketing setting., Results: Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 patient-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for patients receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation., Conclusions and Relevance: Rates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the patient's VZV immune status before initiating fingolimod therapy and immunization for patients susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.

Fingolimod treatment initiation is associated with a transient slowing of heart rate and atrioventricular conduction. This report presents first-dose fingolimod effects (0.5mg or 1.25mg) on cardiac parameters using phase 3 FREEDOMS, FREEDOMS II and TRANSFORMS pooled study data (n=3635 patients). Vital signs were recorded hourly for ≥6h; 12-lead electrocardiogram (ECG) was obtained at baseline and at 6h post-dose. Clinical events were graded at the first-dose administrator׳s discretion. At screening, on day 1 and at month 3, 1073 patients underwent 24-h ambulatory electrocardiogram monitoring. A transient decrease in mean measured heart rate occurred 4-5h after the first dose, with a maximum reduction of 8 (fingolimod 0.5mg) and 11 beats per minute (fingolimod 1.25mg) below baseline. Symptomatic bradycardia at treatment initiation was reported in 0.6% (fingolimod 0.5mg) and 2.1% (fingolimod 1.25mg) of patients; events were typically mild or moderate in severity, and most resolved spontaneously. Atrioventricular (AV) conduction delays were observed in a few patients (Wenckebach (Mobitz type I) second-degree AV block, fingolimod 0.5mg, 0.2%; 1.25mg, 1%: 2:1 AV block fingolimod, 0.5mg, 0%; 1.25mg, 0.2% on ECG 6-h post-dose). These were usually well tolerated and first occurred within 6h of dosing. Consistent with its effects on atrial myocytes, fingolimod treatment initiation induced a transient slowing of heart rate and AV conduction. However, symptomatic bradycardia and second-degree AV block were uncommon and did not require intervention., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Clinical trials have generated a wealth of data on the safety profile of interferon β-1b for patients with multiple sclerosis (MS). In general, interferon β-1b has not been associated with serious or life-threatening side effects during long-term treatment. Flu-like symptoms, injection site reactions, depression, and elevated liver transaminases were the most common adverse events in clinical trials. This review will discuss the rates of these and other common adverse events observed in 3 clinical trials of interferon β-1b: BENEFIT, BEYOND, and the 16-year Long-Term Follow-up (LTF) of the pivotal interferon β-1b trial in MS, as well as how these adverse events may influence patient and physician decision making when selecting a disease-modifying therapy. In addition, we will discuss the effects of interferon β-1b on mortality in the 16-year and 21-year LTF studies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS)., Design: Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy., Patients: The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin., Interventions: Statin effects on in vitro and in vivo interferon-beta-induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity., Results: In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P < .001), interferon regulatory factor 1 protein by 30% (P=.006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy-induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium- dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation., Conclusions: High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.

A 42-year-old African American woman with a 5-year history of neuromyelitis optica was found to have an incongruous homonymous hemianopia. Optical coherence tomography (OCT) showed corresponding left homonymous hemimacular thinning. Magnetic resonance imaging of the brain demonstrated a demyelinating lesion in the left optic tract (OT) just anterior to the lateral geniculate nucleus and diffusion tensor magnetic resonance tractography confirmed axonal fiber loss in the left OT. This case illustrates the complementary and confirmatory roles of visual field testing, macular OCT, and neuroimaging in an OT lesion, which caused selective hemimacular thinning through retrograde degeneration.

Objective: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci., Methods: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease., Results: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1)., Interpretation: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS., (Copyright © 2011 American Neurological Association.)

Fingolimod is the first oral agent approved in the USA for the treatment of relapsing forms of multiple sclerosis. Fingolimod is a sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phosphate receptors on lymphocytes, resulting in a downregulation of the receptor and a reversible sequestration of lymphocytes in lymphoid tissue. Effector memory T cells are not sequestered so that immune surveillance may be minimally affected. Two large-scale Phase III clinical trials have demonstrated the efficacy of fingolimod compared with placebo and intramuscular interferon β-1a in relapsing-remitting multiple sclerosis. Due to its mechanism of action, fingolimod administration may be associated with first-dose bradycardia and macular edema. Therefore, patients should be observed for 6 h at the time of their first dose and undergo ophthalmologic evaluation prior to treatment initiation and at 3-4 months after initiation.

Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3(+)CD14(+) monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon beta-treated relapsing-remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4( +) T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon beta is beneficial in multiple sclerosis; why so remains unclear. Interferon beta-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon beta and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis.

Objective: This article describes the design of and difficulties inherent in the execution of a long-term, observational trial that sought to assess the validity of short-term measures of multiple sclerosis (MS) (eg, relapse rate, inflammatory lesions) for long-term disease outcomes., Methods: In the original double-blind, placebo-controlled interferon (IFN)-p1b study, 372 patients with relapsing-remitting MS (Expanded Disability Status Scale score 0.0-5.5) were randomly assigned to IFN-beta1b 50 ug (n = 125), IFN-beta1b 250 microg (n = 124), or placebo (n = 123) for 2 years. These patients were recruited 16 years later for participation in this long-term follow-up (LTF) study, which had no exclusion criteria or drug interventions., Results: The 11 centers identified 88.2% (328/372) of the original study patients at LTF; however, 10.8% (n = 40) refused to participate and 9.4% (n = 35) were deceased. Detailed evaluations were available for 260 patients, which included 7 deceased patients. No differences in demographic or baseline disease characteristics were found between individuals who did and did not participate in the LTF. More patients randomly assigned to placebo in the original trial were deceased (20/123 [16.3%]) than those assigned to IFN-beta1b 50 microg (9/125 [7.2%]; uncorrected P = 0.044) or IFN-beta1b 250 microg (6/124 [4.8%]; uncorrected P = 0.003)., Conclusions: Although most patients (88.2%) were identified at LTF, ascertainment was incomplete. This was attributable to patients' refusal to participate, loss to follow-up, or death. Delays in the registration of death data and recent privacy legislation provided further barriers. Mortality was lower for patients originally randomized to receive IFN-beta1b rather than placebo. We recommend that all short-term trials on chronic diseases include provisions for LTF.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Interferon-beta (IFN-beta) therapy for MS is hypothesized to cause short-term and long-term changes in gene expression that shift the inflammation from Th1 to Th2. In vivo gene induction to define kinetics of response to IFN-beta therapy in a large cohort of MS patients is described. Differential gene expression in peripheral blood mononuclear cells (PBMCs) obtained from relapsing-remitting MS patients (RRMS) was assessed using high content microarrays. Rapid onset of gene expression appeared within 4 h of subcutaneous IFN-beta administration, returning to baseline levels at 42 h in clinically stable RRMS. IFN-beta therapy in vivo rapidly but transiently induced strong upregulation of genes mediating immune modulation, IFN signaling, and antiviral responses. RT-PCR showed significant patient-to-patient variation in the magnitude of expression of multiple genes, especially for IFN-beta-inducible genes, such as MxA, IRF7, and CCL8, a Th1 product. Variation among patients in IFN-beta-induced RNA transcription was not explained by neutralizing antibodies or IFN receptor expression. Surprisingly, genes regulated in vivo by IFN-beta therapy do not support a simple Th1 to Th2 shift. A complex interplay between both proinflammatory and anti-inflammatory immune regulatory genes is likely to act in concert in the treatment of RRMS.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). In the last 12 years, there has been a proliferation of studies elucidating the immune mechanisms that mediate tissue damage in MS. Interferons (IFNs) have an important role in regulating innate and adaptive immune responses. They decrease pro-inflammatory responses such as the autoimmunity in MS, but other autoimmune responses such as systemic lupus erythematosus (SLE) may be exacerbated. This review offers a general overview of the biological properties of IFNs, effects on immune cells, and clinical effectiveness in MS treatment. IFN signaling is complex, from receptor binding events to the generation of effector mechanisms that dampen inflammation. Immune cell function is altered in MS. IFN treatment of MS patients ameliorates immune dysfunction, but not completely. The incomplete resolution of immune dysfunction by IFNs partly explains their significant, but modest therapeutic effects. This observation also suggests that there are immune mechanisms in MS that are resistant to IFN therapy. In MS, abnormalities may exist at several points along the IFN signaling pathway, including molecular defects in the IFN second messenger system. Currently, several studies are ongoing evaluating ways of potentiating IFN effects. IFNs were the first agents to show clinical efficacy in treatment of MS. More than a decade of experience with IFNs has showed continued clinical efficacy over time. In the near future, IFNs will continue to play a major role in MS.

Recombinant Adenovirus and Adeno-associated virus (AAV) are highly effective vehicles for gene transfer into CNS cells. However, the duration of gene expression and the cytotoxicity to cells are quite different between these viral approaches. We initially investigated these distinctions by stereotaxically injecting both Adenovirus vector and AAV vectors expressing reporter genes into mouse hippocampus. The adenovirus vector induced a pronounced immune response with a marked increase in CD45 and MHC class I protein expression and transgene expression was shorter than six weeks. In contrast, with the AAV vector there was lower expression of CD45 and MHC class I immune activation markers, and longer expression of reporter gene (up to 12 months). To study the roles of human Apolipoprotein E (ApoE) alleles in the pathogenesis of Alzheimer's disease and other CNS diseases, we generated recombinant AAV-apoE alleles driven by the GFAP promoter and expressed them in the mouse brain of Alzheimer's disease mouse. High level ApoE expressions in mouse brain lasted for 12 months, and ApoE was specifically expressed in astrocytes. We demonstrate that AAV-GFAP-ApoE is valuable in studying the pathogenesis and in gene therapy for Alzheimer's disease and other CNS diseases.