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Over the past decade, preclinical and clinical research have confirmed the essential role of interferons for effective host immunological responses to malignant cells. Type I interferons (IFNα and IFNβ) directly regulate transcription of >100 downstream genes, which results in a myriad of direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on the tumour. New insights into endogenous and exogenous activation of type I interferons in the tumour and its microenvironment have given impetus to drug discovery and patient evaluation of interferon-directed strategies. When combined with prior observations or with other effective modalities for cancer treatment, modulation of the interferon system could contribute to further reductions in cancer morbidity and mortality. This Review discusses new interferon-directed therapeutic opportunities, ranging from cyclic dinucleotides to genome methylation inhibitors, angiogenesis inhibitors, chemoradiation, complexes with neoantigen-targeted monoclonal antibodies, combinations with other emerging therapeutic interventions and associations of interferon-stimulated gene expression with patient prognosis - all of which are strategies that have or will soon enter translational clinical evaluation.

It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS)., Objective: We examined the impact of CIITA polymorphisms -168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments., Methods: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS)., Results: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA -168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA -168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA -168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS., Conclusion: These data suggest that CIITA -168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management.

Background: Multiple sclerosis (MS), a chronic progressive, demyelinating, inflammatory disease, affects 2.5 million people worldwide. Approximately 63% of cases are classified as relapsing-remitting MS (RRMS) at the time of diagnosis. The aim of this cost-utility analysis is to evaluate alemtuzumab vs interferon beta (intramuscular [IM] interferon beta-1a, subcutaneous [SC] interferon beta-1a, SC interferon beta-1b, and SC pegylated interferon beta-1a) in previously treated, and vs SC interferon beta-1a, fingolimod, and natalizumab in untreated RRMS patients to determine the incremental cost-effectiveness ratio among the treatment alternatives as prices, the route, and the frequency of administration of considered products vary significantly., Methods: The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained). Markov modeling with a 10-year time horizon was carried out. During each 3-month cycle, patients maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS), or showed EDSS progression in SPMS; experienced relapses; suffered from an adverse event (AE); changed treatment; or died. A published network meta-analysis (NMA) was used for indirect comparison. The possibility of a therapy switch was considered. Clinical input data and resource utilization data were derived from the literature. Costs were extracted from price lists published in Austria and were calculated from the payer's perspective., Results: In treatment naïve patients, alemtuzumab is associated with costs of €132,663 and 5.25 QALYs in a 10-year time horizon. Costs for SC interferon beta amount to €164,159 and generate 4.85 QALYs. Also, in the pre-treated patients, alemtuzumab dominated comparators by accumulating higher total QALYs (4.88) and lower total costs (€137.409) compared to interferon beta-1a (€200.133), fingolimod (€240.903), and natalizumab (€247.758)., Conclusion: The analysis shows that alemtuzumab is a cost-saving alternative to treat RRMS in pre-treated and therapy naïve patients. From the patient perspective, alemtuzumab improves quality-of-life.

Background: Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue., Methods: The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model., Results: 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores., Conclusions: This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

INF-β has been widely used to treat patients with multiple sclerosis (MS) in relapse. Accurate prediction of treatment response is important for effective personalization of treatment. Microarray data have been frequently used to discover new genes and to predict treatment responses. However, conventional analytical methods suffer from three difficulties: high-dimensionality of datasets; high degree of multi-collinearity; and achieving gene identification in time-course data. The use of Elastic net, a sparse modelling method, would decrease the first two issues; however, Elastic net is currently unable to solve these three issues simultaneously. Here, we improved Elastic net to accommodate time-course data analyses. Numerical experiments were conducted using two time-course microarray datasets derived from peripheral blood mononuclear cells collected from patients with MS. The proposed methods successfully identified genes showing a high predictive ability for INF-β treatment response. Bootstrap sampling resulted in an 81% and 78% accuracy for each dataset, which was significantly higher than the 71% and 73% accuracy obtained using conventional methods. Our methods selected genes showing consistent differentiation throughout all time-courses. These genes are expected to provide new predictive biomarkers that can influence INF-β treatment for MS patients.

Background: Current treatments for relapsing remitting multiple sclerosis (RRMS) reduce inflammation, but have a partial or modest effect on disability. This effect may require a much longer follow-up than standard trial design, in particular in RRMS with relatively-preserved functional reserve. We aimed to assess the long-term clinical evolution of RRMS patients exposed to atorvastatin in two trials (ACTIVE and ARIANNA)., Methods: We retrospectively looked at 69 participants randomized with atorvastatin or placebo as add-on therapy to interferon-beta for 24 months at a single MS centre. We recorded relapses, 1-point EDSS progression and progression to EDSS 4.0. Cox regression was performed for these three questions. A Poisson regression model was used to evaluate the association between atorvastatin treatment and annualized relapse rate (ARR)., Results: After 8.4 ± 2.3 (3.7-11.9) years from trial, the use of atorvastatin was associated with reduced risk of 1-point EDSS progression (HR = 0.440; 95%CI = 0.225-0.861; p = 0.017), and of EDSS 4.0 (HR = 0.310; 95%CI = 0.123-0.784; p = 0.013). We found no significant association between atorvastatin and relapses., Discussion: These data suggest that a delayed treatment effect may be seen with atorvastatin added to interferon-beta, eight years after entering the clinical trials. Long-term follow-up of trial cohorts should be mandated., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a central nervous system autoimmune disease characterized by demyelination. Autoreactive T cells mainly interferon gamma (IFN-γ) producing T helper cells (Th1) have an important role in MS pathogenesis. Silymarin is a unique blend produced from milk thistle (Silybum marianum) plant which its imunomodulatory role has been indicated in studies. In the present study, the effects of silymarin on isolated Th1 cells were investigated in newly diagnosed MS patients and those who received betaferon. PBMCs were separated from newly diagnosed and IFN-β-treated MS patients. The Th1 cell isolation from PBMCs was performed using a human Th1 cell isolation kit. Th1 cells were cultured in the presence of silymarin (50, 100, and 150 μM for 48, 72, and 120 h). Th1 cell proliferation and CD69 expression were assessed by flow cytometry. Also, IFN-γ production and T-bet gene expression were measured by ELISA and real-time PCR respectively. In vitro cultured Th1 cells showed that silymarin suppresses Th1 cell proliferation dose and time dependently in newly diagnosed and IFN-β-treated MS patients in comparison to DMSO control. Also, CD69 expression as an early activation marker was changed after Th1 cell treatment with different doses of silymarin at different times. T-bet gene expression was significantly decreased in Th1 cells isolated from newly diagnosed and IFN-β-treated RRMS patients after treatment with silymarin compared to DMSO control. Additionally, IFN-γ production by Th1 cells was decreased after treatment silymarin in newly diagnosed patients; however, in IFN-β treated after 48-h treatment with silymarin, IFN-γ concentration was decreased at concentrations of 100 and 150 μM, and after 120 h, a significant increase was observed in the IFN-γ level at a concentration of 100 μM in comparison with DMSO. Our findings here clearly show that silymarin is an effective regulator for Th1 response in vitro condition. It not only suppresses Th1 proliferating activity but also inhibits T-bet gene expression and IFN-γ production by these cells.

Drug-Induced Pulmonary Arterial Hypertension (PAH) represents a well-known entity, predominantly related to anorexigens. Interferon-β (IFN) is considered to be a drug with a possible risk of inducing PAH. We report a patient with Multiple Sclerosis treated with IFN-β who diagnosed with PAH and her course of disease under specific PAH drug therapy. A review of the literature in IFN-β-induced PAH is provided., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Although Zika virus (ZIKV) can be transmitted sexually and cause congenital birth defects, immune control mechanisms in the female reproductive tract (FRT) are not well characterized. Here we show that treatment of primary human vaginal and cervical epithelial cells with interferon (IFN)-α/β or IFN-λ induces host defense transcriptional signatures and inhibits ZIKV infection. We also assess the effects of IFNs on intravaginal infection of the FRT using ovariectomized mice treated with reproductive hormones. We find that mice receiving estradiol are protected against intravaginal ZIKV infection, independently of IFN-α/β or IFN-λ signaling. In contrast, mice lacking IFN-λ signaling sustain greater FRT infection when progesterone is administered. Exogenous IFN-λ treatment confers an antiviral effect when mice receive both estradiol and progesterone, but not progesterone alone. Our results identify a hormonal stage-dependent role for IFN-λ in controlling ZIKV infection in the FRT and suggest a path for minimizing sexual transmission of ZIKV in women.

Our aim was to quantify circulating B cell subsets; immature/transitional, naïve, CD27 - and CD27 + memory cells and plasmablasts, in relapsing-remitting multiple sclerosis patients treated with IFN-β. The most relevant findings were a significant increase of plasmablasts and a decrease of immature/transitional B cells, resulting in a decreased ratio between those cells in relapse RRMS, together with an increase of CD27 - and CD27 + IgM + memory B cell subsets in both phases of the disease. These alterations point to an active B cell response, particularly in relapse, and the above referred ratio could constitute a good biomarker of relapse in patients that underwent IFN-β treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Importance: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition., Objective: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition., Design, Setting, and Participants: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up., Exposures: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017)., Main Outcome and Measure: Conversion to objectively defined secondary progressive MS., Results: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1)., Conclusions and Relevance: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

Objective: Multiple sclerosis (MS) is a multifactorial chronic disease that affects the central nervous system (CNS). Toll-like receptors (TLRs) play a central role in cytokine production after pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) and contribute to CNS damage in MS patients. Here, we evaluated the effects of interferon (IFN)-β treatment in TLR2 and TLR4-dependent cytokine production and mRNA expression in whole-blood cell cultures from MS patients., Methods: We evaluated cytokine production by ELISA from whole-blood cell culture supernatants and mRNA expression by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs)., Results: In patients treated with IFN-β, tumor necrosis factor (TNF)-α production after exposure to TLR2 agonist (Pam3Cys) was lower than in healthy controls and untreated MS patients. However, IFN-β treatment had no significant effect on TNF-α production after TLR4 agonist (LPS) stimulation. On the other hand, interleukin (IL)-10 production was increased in TLR4- but not in TLR2-stimulated whole-blood cell culture from MS patients under IFN-β treatment when compared to the controls. No differences in TNF-α or IL-10 mRNA expression in PBMCs from healthy controls and untreated or treated MS patients were detected, although PBMCs from treated patients presented higher levels of IL-32γ mRNA than those from controls., Conclusions: Our data suggest that IFN-β treatment alters the TLR-dependent immune response of PBMCs from MS patients. This may contribute to the beneficial effects of IFN-β treatment., (© 2019 S. Karger AG, Basel.)

Interferons-beta (IFN-β) along with glatiramer acetate is one of the most commonly used disease modifying treatment (DMT) of multiple sclerosis (MS) associated with effectiveness and acceptable safety profile. At the same time, therapy with IFN-β has a number of limitations associated with a high frequency of injections and production of neutralizing antibodies. The development of the pegylated form of IFN-β (PEG-IFN-β) is aimed at resolving these issues. This article reviewed the mechanism of action, efficacy, safety and tolerability of PEG-IFN-β in the treatment of MS.

Infection with Human Immunodeficiency Virus (HIV)-1 continues to cause HIV-associated neurocognitive disorders despite combined antiretroviral therapy. Interferons (IFNs) are important for any antiviral immune response, but the lasting production of IFNα causes exhaustive activation leading eventually to progression to AIDS. Expression of IFNα in the HIV-exposed central nervous system has been linked to cognitive impairment and inflammatory neuropathology. In contrast, IFNβ exerts anti-inflammatory effects, appears to control, at least temporarily, lentiviral infection in the brain and provides neuroprotection. The dichotomy of type I IFN effects on HIV-1 infection and the associated brain injury will be discussed in this review, because the underlying mechanisms require further investigation to allow harnessing these innate immune factors for therapeutic purposes.

Background: Autoantibodies against glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) cause chylomicronemia by blocking the ability of GPIHBP1 to bind lipoprotein lipase (LPL) and transport the enzyme to its site of action in the capillary lumen., Objective: A patient with multiple sclerosis developed chylomicronemia during interferon (IFN) β1a therapy. The chylomicronemia resolved when the IFN β1a therapy was discontinued. Here, we sought to determine whether the drug-induced chylomicronemia was caused by GPIHBP1 autoantibodies., Methods: We tested plasma samples collected during and after IFN β1a therapy for GPIHBP1 autoantibodies (by western blotting and with enzyme-linked immunosorbent assays). We also tested whether the patient's plasma blocked the binding of LPL to GPIHBP1 on GPIHBP1-expressing cells., Results: During IFN β1a therapy, the plasma contained GPIHBP1 autoantibodies, and those autoantibodies blocked GPIHBP1's ability to bind LPL. Thus, the chylomicronemia was because of the GPIHBP1 autoantibody syndrome. Consistent with that diagnosis, the plasma levels of GPIHBP1 and LPL were very low. After IFN β1a therapy was stopped, the plasma triglyceride levels returned to normal, and GPIHBP1 autoantibodies were undetectable., Conclusion: The appearance of GPIHBP1 autoantibodies during IFN β1a therapy caused chylomicronemia. The GPIHBP1 autoantibodies disappeared when the IFN β1a therapy was stopped, and the plasma triglyceride levels fell within the normal range., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Percentages of blood CD19+CD5+ B cells and CD8+perforin+ T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice., Methods: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values., Results: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19+CD5+ B cell and 0.89 (CI: 0.85-0.93) for CD8+ perforin+ T cell quantification; Spearman r was 0.92 (0.89-0.95; p <0.0001) and 0.92 (0.88-0.95; p <0.0001) respectively. All centres obtained z-scores≤0.5 for both biomarkers., Conclusion: Homogenous percentages of CD19+CD5+ B cells and CD8 perforin+ T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: The two-year study of the efficacy of Ifnb-1B (infibeta) in patients with relapsing-remitting (RRS) and secondary progressive multiple sclerosis (SPMS) in the Moscow region with the criteria NEDA-3., Material and Methods: Three hundred patients, 81 men and 219 women, aged from 18 to 67 years, including 227 with RRS and 73 with SPMS, were studied. The duration of disease was from 0.5 to 39 years, the level of neurological deficit on EDSS scale was from 1 to 6.5 points. All patients received infibeta., Results and Conclusion: During the treatment with infibeta, the chance of exacerbation decreased by an average of 39.4 times (OR 39.4 95% CI; 16.6-122.7) during the first year, by 35.3 times (OR 35.3; 95% CI 13.5-131,2) during the second year. A statistically significant decrease in the probability of exacerbation is also confirmed in the conditional logistic regression model (p<0.001). MRI revealed the signs of exacerbation and progression of the disease only in 11.5% of patients; 54.9% of the patients met the criteria NEDA-3. The highest efficacy of infibeta is noted in patients with RRS, more than 3 / 4 of them responded to therapy with the absence of both clinical and MRI signs of exacerbation and increase in neurodegeneration. Thus, a good clinical result is achieved in patients with RRS and SPMS treated with infibeta. When using the NEDA-3 criteria, a positive result is achieved in more than half of patients.

Background: Hepatitis C virus (HCV) is a single-stranded RNA (ribonucleic acid) virus that has the potential to cause inflammation of the liver. The traditional definition of acute HCV infection is the first six months following infection with the virus. Another commonly used definition of acute HCV infection is the absence of HCV antibody and subsequent seroconversion (presence of HCV antibody in a person who was previously negative for HCV antibody). Approximately 40% to 95% of people with acute HCV infection develop chronic HCV infection, that is, have persistent HCV RNA in their blood. In 2010, an estimated 160 million people worldwide (2% to 3% of the world's population) had chronic HCV infection. The optimal pharmacological treatment of acute HCV remains controversial. Chronic HCV infection can damage the liver., Objectives: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of acute HCV infection through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead we assessed the comparative benefits and harms of different interventions versus each other or versus no intervention using standard Cochrane methodology., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to April 2016 to identify randomised clinical trials on pharmacological interventions for acute HCV infection., Selection Criteria: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with acute HCV infection. We excluded trials which included previously liver transplanted participants and those with other coexisting viral diseases. We considered any of the various pharmacological interventions compared with placebo or each other., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on the available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE., Main Results: We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months.There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I 2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I 2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons.Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital., Authors' Conclusions: Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.

Objectives: Although interferon-beta is an established drug for relapsing remitting multiple sclerosis (RRMS), its impact on neuronal activity is not well understood., Methods: We investigated 15 patients with RRMS by [ 18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) to assess cerebral metabolic rate of glucose (CMR glc ) before interferon-beta therapy. Further, we performed clinical and neuropsychological investigations. In nine patients, these investigations were repeated after 6 months of therapy. Ten healthy controls were also studied., Results: We found no significant differences in absolute CMR glc between patients and controls, or in patients before and during treatment. However, during treatment, relative regional glucose metabolism (rCMRl glc ) was decreased in cerebellum and increased in parts of left inferior parietal, temporo-occipital, frontal cortical areas, left striatum and right insula. In untreated patients, higher fatigue was associated with lower rCMRl glc in portions of left posterior cingulate cortex, and higher depression was associated with lower rCMRl glc within the left superior temporal sulcus. In the pooled sample, higher depression was associated with higher rCMRl glc in parts of the right precuneus., Conclusions: Our results indicate effects of IFN-beta treatment on cerebellar, cortical and subcortical neuronal function. Moreover, more severe fatigue and depression in untreated patients seem to be associated with reduced neuronal activity in left posterior cingulate cortex and left superior temporal cortex, respectively., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Our goal was to compare subjects treated with glatiramer acetate (GA) and interferon-beta (IFN-β) in terms of long-term clinical outcomes., Methods: Subjects enrolled in the CLIMB who initiated either GA or IFN-β within five years of disease onset and prior to 2008 were identified (n = 150 for GA and n = 144 for IFN-β). The two treatment groups were compared in terms of long-term clinical outcomes: time to EDSS 4, time to EDSS 6 and EDSS score seven years after treatment initiation. Baseline confounders included in our analysis were age, gender, disease duration, attacks in the previous year, EDSS prior to treatment initiation, and year of treatment initiation. The groups were compared using three approaches to handle confounders: multiple regression adjusting for confounders, adjustment for the propensity score, and inverse probability of treatment weighting. In addition, we assessed potential predictors of differential treatment response using multiple regression models including appropriate interaction terms., Results: Subjects initially treated with GA had a slightly higher hazard of reaching EDSS 4 and EDSS 6, but the difference between the groups was not statistically significant (adjusted HR for EDSS 4 = 1.48; 95% CI: 0.77,2.84; p = .24; adjusted HR for EDSS 6 = 1.46; 95% CI: 0.70,3.05; p = .316). For the EDSS score at year 7, there was also only a small difference between the groups. Subjects treated with GA had a longer time until treatment cessation (adjusted HR = 0.70; 95% CI: 0.53,0.93; p = .012). The interaction models did not show strong evidence for the baseline predictors being associated with treatment response., Conclusions: Subjects treated with glatiramer acetate and interferon-beta had similar long-term clinical course., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The direct comparative evidence on treatment effects of available multiple sclerosis (MS) disease-modifying therapies (DMTs) is limited, and few studies have examined the benefits of DMTs on employment outcomes. We compared the effects of DMTs used in the previous 5 years on improving the work attendance, amount of work and work productivity of people with MS., Methods: The Australian MS Longitudinal Study collected data from participants on DMTs usage from 2010 to 2015 and whether DMTs contributed to changes in employment outcomes. We classified 11 DMTs into three categories based on their clinical efficacy (β-interferons and glatiramer acetate as category 1; teriflunomide and dimethyl fumarate as category 2; fingolimod, natalizumab, alemtuzumab and mitoxantrone as category 3). Each DMT used by a participant was treated as one observation and analysed by log-multinomial regression., Results: Of the 874 participants included, 1384 observations were generated. Those who used category 3 (higher efficacy) DMTs were 2-3 times more likely to report improvements in amount of work, work attendance and work productivity compared with those who used category 1 (classical injectable) DMTs. Natalizumab was associated with superior beneficial effects on patient-reported employment outcomes than fingolimod (RR=1.76, 95% CI 1.02 to 3.03 for increased work attendance and RR=1.46, 95% CI 1.02 to 2.10 for increased work productivity)., Conclusions: Those using the higher efficacy (category 3) DMTs, particularly fingolimod and natalizumab, reported significant increases in amount of work, work attendance and work productivity, suggesting they have important beneficial effects on work life in people with MS., Competing Interests: Competing interests: The authors have no conflicts of interest to declare., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Within the last decade, many changes have been made to the management of patients with multiple sclerosis (MS). The aim of our study was to investigate the global impact of all these changes on the disease's course., Materials and Methods: This single-centre study was carried out on patients with multiple sclerosis (pwMS) who started treatment with first-line disease-modifying therapies. We have compared three large cohorts of patients with MS diagnosis, for three consecutive periods within July 2001, August 2001-December 2005, and January 2006-September 2011., Results: A total of 1068 relapsing-remitting pwMS cases were included. Patients in the last cohort began treatment earlier (P < 0.0001), started more frequent treatment with high-dose interferon beta or glatiramer acetate (P < 0.0001), and had experienced a more frequent treatment escalation strategy (P = 0.004) than patients in other cohorts. The multivariate analysis adjusted for baseline characteristics showed that pwMS of the last cohort had a high probability of showing no evidence of disease activity (NEDA3) at 4 years (OR 3.22, 95% CIs 1.89-5.47; P < 0.0001). These results were confirmed in a propensity score analysis., Conclusions: Our study showed an improvement over the last 15 years in the treatment response; this observation can be associated to a paradigm shift in MS treatment strategies., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Multiple sclerosis (MS) as a chronic autoimmune demyelinating disorder of the central nervous system has been associated with numerous genetic and environmental factors among them are functional variants within the angiotensin I converting enzyme (ACE) gene., Methods: In the present study, we genotyped the rs4359 (C/T) and rs1799752 (Insertion (I)/Deletion (D)) of this gene in 391 MS patients and 380 age- and sex-matched controls., Results: We found significant overrepresentation of the I allele of the rs1799752 in MS patients compared with healthy subjects (Adjusted P value = 0.03, OR (95% CI) = 1.28 (1.05-1.57). The same allele was associated with MS risk in co-dominant and dominant models (Adjusted P values of 0.007 and 0.002 respectively). The allele and genotype frequencies of the rs4359 were not significantly different between cases and controls. Moreover, the I allele of the rs1799752 was significantly overrepresented in MS patients who were irresponsive to IFN-β compared with healthy subjects (Adjusted P value = 0.04, OR (95% CI) = 1.57 (1.08-2.29)). The same allele was associated with irresponsiveness to IFN-β in dominant model (Adjusted P value = 0.02, OR (95% CI) = 2.32 (1.22-4.42))., Conclusion: The present study provides further evidences for the role of ACE in MS risk or response of patients to IFN-β treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.)

Adipokines secreted by fatty tissue have inflammatory properties and are suggested biomarkers of MS disease activity. To assess this, 88 MS patients were followed with nine repeated measurements of leptin and adiponectin and 12 magnetic resonance imaging (MRI) scans for two years; six months without any immunomodulatory treatment followed by 18 months during interferon-beta (IFNB) treatment. Serum levels of leptin dropped and adiponectin increased upon initiation of IFNB-therapy, but were not associated with clinical or MRI disease activity or with treatment response. Our findings indicate that leptin and adiponectin are not useful as biomarkers of MS disease activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-β) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs' recommended dosages., Methods: We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-β and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis., Results: We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs., Conclusions: Meta-analyses confirmed that IFN-β and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear 'winner' across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness., Review Registration: PROSPERO CRD42016043278 .

Objective: Little is known about disease-modifying treatments (DMTs) for multiple sclerosis (MS) and infection risk in clinical practice. We examined the association between DMTs and infection-related medical encounters., Methods: Using population-based administrative data from British Columbia, Canada, we identified MS cases and followed them from their first demyelinating event (1996-2013) until emigration, death or study end (December 2013). Associations between DMT exposure (by DMT generation or class) and infection-related physician or hospital claims were assessed using recurrent time-to-events models, adjusted for age, sex, socioeconomic status, index year and comorbidity count. Results were reported as adjusted HRs (aHRs)., Results: Of 6793 MS cases, followed for 8.5 years (mean), 1716 (25.3%) were DMT exposed. Relative to no DMT, exposure to any first-generation DMT (beta-interferon or glatiramer acetate) was not associated with infection-related physician claims (aHR: 0.96; 95% CI 0.89 to 1.02), nor was exposure to these drug classes when assessed separately. Exposure to any second-generation DMT (oral DMT or natalizumab) was associated with an increased hazard of an infection-related physician claim (aHR: 1.47; 95% CI 1.16 to 1.85); when assessed individually, the association was significant for natalizumab (aHR: 1.59; 95% CI 1.19 to 2.11) but not the oral DMTs (aHR: 1.17; 95% CI 0.88 to 1.56). While no DMTs were associated with infection-related hospital claims, these hospitalisations were also uncommon., Conclusion: Exposure to first-generation DMTs was not associated with an altered infection risk. However, exposure to the second-generation DMTs was, with natalizumab associated with a 59% increased risk of an infection-related physician claim. Continued pharmacovigilance is warranted, including an investigation of the DMT-associated infection burden on patient outcomes., Competing Interests: Competing interests: FZ, EK and YZ report no disclosures. JMAW receives research funding from the Michael Smith Foundation for Health Research/The Koehle Family Foundation. CE receives research funding from the Canadian Institutes of Health Research, Saskatchewan Health Research Foundation and the Multiple Sclerosis Society of Canada. JDF receives research funding from the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society and the Dalhousie Medical Research Foundation, consultation and distribution royalties from MAPI Research Trust, as well as speaker honoraria and travel expenses from EMD Serono (2013 and 2014). RAM receives research funding from the Canadian Institutes of Health Research, Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Research Manitoba, the Consortium of MS Centers, Crohn’s and Colitis Canada and the Waugh Family Chair in Multiple Sclerosis and has conducted clinical trials funded by Sanofi-Aventis. HT is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She has received research funding from the Multiple Sclerosis Society of Canada, the Michael Smith Foundation for Health Research Scholar, the National Multiple Sclerosis Society, the Canadian Institutes of Health Research and the UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014, 2015 and 2016), Bayer Pharmaceuticals (2010), Teva Pharmaceuticals (2011), ECTRIMS (2011, 2012, 2013, 2014 and 2015), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014) and American Academy of Neurology (2013, 2014, 2015 and 2016). Unless otherwise stated, all speaker honoraria are either declined or donated to an MS charity or used as an unrestricted grant for use by her research group., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Primary Sjögren's syndrome (pSS) represents a chronic, systemic autoimmune disorder, characterized by lymphocytic infiltration of exocrine glands, inducing compromised secretory function and tissue destruction. Increasing evidence had revealed that inflammatory mediators, such as nitric oxide (NO) and pro-inflammatory cytokines, are critical in the development and perpetuation of pSS systemic manifestations. In our current study, we aimed to investigate the ex vivo immunomodulatory effect of interferon (IFN)-β on iNOS expression, as well as on pro-inflammatory (tumor necrosis factor (TNF)-α, interleukin (IL)-6) and immunoregulatory (IL-10) cytokine production. Furthermore, we examined potential associations between the influence of IFN-β treatment on NO production, and pSS clinical and serological manifestations., Methods: In 41 pSS patients documented for their clinical and serological features, NO and cytokines levels were measured by the Griess method and enzyme-linked immunosorbent assay, respectively. Inducible nitric oxide synthase expression was analyzed by fluorescence immunostaining assay, using peripheral blood mononuclear cells (PBMCs) isolated from healthy controls and pSS patients., Results: Our results revealed a strong down-modulating effect of IFN-β in the secretion of pro-inflammatory mediators including TNF-α, IL-6, and NO production. Interestingly, IFN-β exerts an increase in IL-10 levels. The most suppressive effect exerted by IFN-β on NO production was importantly reported for patients with neurological manifestation. This immunomodulatory effect of IFN-β on NO production is highly related to the decrease of inducible nitric oxide synthase (iNOS) expression., Conclusion: Our findings highlight a consistent ex vivo inhibitory effect of IFN-β on pro-inflammatory cytokine production and NO pathway in pSS patients. Our data suggest that IFN-β could represent a potential candidate for targeting inflammation during pSS.

Background: Multiple Sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are acquired demyelinating syndromes of the central nervous system more frequently in young adults and their beginning before 18 years of age is rare. They are autoimmune diseases with distinct pathophysiology, clinical presentation, treatment and prognoses. During childhood these conditions often present similar clinical features and differential diagnosis among pNMOSD, pMS and acute disseminated encephalomyelitis (ADEM) is still difficult at disease onset. The aim of this article is to describe the epidemiologic and clinical features, to evaluate the response to treatment and to compare the mains characteristics between the patients with MS and NMOSD who had the first event prior to 18 years of age followed at the Universidade Federal de São Paulo (UNIFESP)., Methods: Retrospective analysis of patients with MS and NMOSD who started the disease before 18 years of age followed for at UNIFESP. All patients fulfilled the McDonald 2010 criteria for MS and the IPND 2015 criteria or 2006 diagnostic criteria for NMOSD. For treatment analysis, we select patients with a follow-up of more than 6 months., Results: Sixty-eight patients fulfilled the inclusion criteria for MS and were selected for analysis. Mean age of onset was 15 years, 73.5% were female and the mean follow-up was 6.7 years. Mean annualized relapse rate (aRR) observed was 0,82 relapse/year and mean progression index (PI) was 0.31 EDSS points/year. The multivariate analysis showed a significant association between the EDSS on first appointment and total number of relapses with neurological disabilities in long term in patients with MS. The treatment with interferon-beta (IFN-β) and glatiramer acetate (GA) was safe and patients treated with high dose IFN-β and GA had a statistically significant reduction in disability progression. Eleven patients fulfilled the inclusion criteria for NMOSD: mean age of onset was 14 years, 72.7% were female and the mean follow-up was 6.3 years. Mean aRR observed was 1.5 relapse/year and mean PI was 2.2 EDSS points/year. The treatment with azathioprine was safe and significant halts disability progression. Patients with NMOSD reached EDSS 6 prior than those with MS., Conclusions: Pediatric demyelinating diseases in Brazil are similar to the diseases described abroad. In patients with pMS, the EDSS score at the first appointment and the total number of relapses were associated with poor prognosis. NMOSD is more severe than MS in pediatric patients. Treatment with DMD and azathioprine was well tolerated and effective in reducing relapse rate and disability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We aimed to investigate whether NLR family, pyrin domain containing 3 (NLRP3) polymorphisms are associated with the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. A total of 14 NLRP3 polymorphisms were genotyped in a cohort of 665 relapsing-remitting MS patients recruited across 5 centers and classified into responders and non-responders according to clinical-radiological criteria after 1 year of IFNβ treatment. A meta-analysis failed to demonstrate significant associations between the response to IFNβ and NLRP3 polymorphisms. These findings do not support a role of polymorphisms located in the NLRP3 gene and the response to IFNβ in MS patients.

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab., Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed., Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results., Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.

Background and Purpose: To assess long-term treatment effectiveness of disease-modifying therapy (DMT) initiated early in disease course versus later treatment start., Methods: We included all Danish patients with multiple sclerosis (MS) treated with DMT through two nationwide population-based MS registries. Patients were categorized as early treated if treatment started within 2 years after the first MS symptom (n = 2316) and later treated if treatment started between 2 and 8 years after clinical onset (n = 1479). We compared time from treatment start to progression to an Expanded Disability Status Scale (EDSS) score of 6 and mortality between cohorts as hazard ratio (HR) using a Cox proportional hazards model with adjustment for stabilized inverse probability of treatment weights. Several sensitivity analyses were conducted., Results: The median follow-up time of 3795 patients was 7.0 (range 0.6-19.5) years for the EDSS score of 6 outcome and 10.4 (range 1.2-20.1) years for the mortality outcome. Patients with later treatment start showed a 42% increased hazard rate of reaching an EDSS score of 6 compared with the early-treated patients [HR, 1.42; 95% confidence interval (CI), 1.18-1.70; P < 0.001]. When stratified by sex, the increased hazard among later-treated women persisted (HR, 1.53; 95% CI, 1.22-1.93; P < 0.001), whereas the HR was lower in men (1.25; 95% CI, 0.93-1.69; P = 0.15). Mortality was increased by 38% in later starters (HR, 1.38; 95% CI, 0.96-1.99; P = 0.08)., Conclusions: Patients who started treatment with DMT later reached an EDSS score of 6 more quickly compared with patients who started early and the delay showed a tendency to shorten time to death. Our results support the use of early treatment., (© 2018 EAN.)

Background: Suboptimal persistence with injectable disease-modifying therapies (iDMTs; interferon beta-1a/b, glatiramer acetate) is common in patients with relapsing forms of multiple sclerosis (MS), reducing the effectiveness of these agents. Adherence to, and persistence with, an effective therapy is important for patient populations at increased risk of rapid disease progression. African-American individuals with multiple sclerosis may experience a more aggressive disease course than Caucasian patients, with a greater risk of developing ambulatory difficulties and other disabilities, and may also have a diminished response to some disease-modifying therapies compared with patients of other ethnicities. Retention on oral fingolimod and on iDMTs was evaluated in a post hoc analysis of data from African-American patients in the parallel-group, 48-week 'Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease modifying thErapies in adults with Relapsing-remitting Multiple Sclerosis' (PREFERMS)., Methods: In PREFERMS, patients with relapsing-remitting MS aged 18-65 years with an Expanded Disability Status Scale score ≤6 enrolled at 117 US study sites were treatment-naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day:preselected iDMT) using an interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier, for efficacy or safety reasons only. The primary outcome was patient retention on randomized treatment over 48 weeks. In this post hoc analysis of African-American patients in PREFERMS, outcome variables included rate of patient retention on randomized treatment, reasons for discontinuing randomized treatment, patient-reported treatment satisfaction, and safety. Clinical and radiographic outcomes such as annualized relapse rate, brain volume loss, and lesion count changes were also investigated., Results: In PREFERMS, 141 of 875 patients (16.1%) randomized to a study drug were African-American. Analysis of data for the full analysis set of 67 patients receiving fingolimod and 69 receiving iDMTs showed that the retention rate over 48 weeks was significantly higher with fingolimod than with iDMTs (80.6% [n = 54] vs 30.4% [n = 21]; between-group difference: 50.2%; 95% confidence interval 35.8-64.6%; p < 0.0001). The most common treatment switch was from an iDMT to fingolimod for injection-related reasons, and patient satisfaction was greater with fingolimod than with iDMTs. Adverse events were consistent with the respective prescribing information for each treatment., Conclusion: In PREFERMS, fingolimod was associated with better treatment retention than iDMTs in African-American patients. Optimal outcomes in the management of multiple sclerosis depend on good persistence with treatment, and this is particularly important in patient populations at increased risk of a rapidly progressing disease course., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1., Methods: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed., Results: Patients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006)., Conclusion: Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups.

Background: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population., Methods: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate., Results: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T 2 -weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient)., Conclusions: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .).

While cancer immunotherapy has gained much deserved attention in recent years, many areas regarding the optimization of such modalities remain unexplored, including the development of novel approaches and the strategic combination of therapies that target multiple aspects of the cancer-immunity cycle. Our own work involves the use of gene transfer technology to promote cell death and immune stimulation. Such immunogenic cell death, mediated by the combined transfer of the alternate reading frame (p14ARF in humans and p19Arf in mice) and the interferon-β cDNA in our case, was shown to promote an antitumor immune response in mouse models of melanoma and lung carcinoma. With these encouraging results, we are now setting out on the road toward translational and preclinical development of our novel immunotherapeutic approach. Here, we outline the perspectives and challenges that we face, including the use of human tumor and immune cells to verify the response seen in mouse models and the incorporation of clinically relevant models, such as patient-derived xenografts and spontaneous tumors in animals. In addition, we seek to combine our immunotherapeutic approach with other treatments, such as chemotherapy or checkpoint blockade, with the goal of reducing dosage and increasing efficacy. The success of any translational research requires the cooperation of a multidisciplinary team of professionals involved in laboratory and clinical research, a relationship that is fostered at the Cancer Institute of Sao Paulo.

Objective: To study the efficacy of interferon beta (IFNβ) and glatiramer acetate (GA) related to the presence of oligoclonal M bands (OCMB) in the cerebrospinal fluid in relapsing-remitting multiple sclerosis (RRMS)., Method: This is an observational, multicenter and retrospective study with prospectively collected data of patients that started treatment with IFNβ or GA. Treatment decision was made blinded to the OCMB status. Time to first attack after starting therapy was compared by using Kaplan-Meier curves, and adjustment by Cox regression analysis was performed., Results: Two hundred and fifty-six patients entered in the study (141-55% received IFNβ; 115-45% received GA). After a mean follow-up of 41 and 65 months, 54.7% of patients remained free from further attacks (RF). The proportion of RF patients was higher in the GA group than in the IFNβ group (72.2 vs. 40.4%, p < 0.001). The IFNβ patients with OCMB+ presented the poorest response, 31.3% RF vs. 48.1% in IFNβ without OCMB, p = 0.03., Conclusion: OCMB in CSF could be a biomarker of treatment response in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the central nervous system (CNS). Neuroinflammation and oxidative stress are involved in the pathogenesis of MS, promoting tissue damage and demielinization. Current research findings suggest that melatonin has antioxidant and neuroprotective effects. The aim of this study was to evaluate the efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing-remitting multiple sclerosis (RRMS). 36 patients diagnose with RRMS treated with Interferon β-1b (IFNβ-1b) were enrolled in a double bind, randomized, placebo controlled trial. The experimental group received orally 25 mg/d of melatonin for 6 months. After melatonin administration, we observed a significant decrease in serum concentration of pro-inflammatory cytokines and oxidative stress markers; 18% for TNF-α (p <0.05), 34.8% for IL-1β (p <0.05), 34.7% for IL-6 (p <0.05), 39.9% for lipoperoxides (LPO) (p <0.05) and 24% for nitric oxide catabolites (NOC) levels (p <0.05), compared with placebo group. No significant difference in clinical efficacy outcomes were found between groups. Melatonin treatment was well tolerated and we did not observe significant differences in rates of side effects between the two groups. We concluded that melatonin administration during 6 months period is effective in reducing levels of serum pro-inflammatory cytokines and oxidative stress markers in patients with RRMS. These data support future studies evaluating the safety and effectiveness of melatonin supplementation in RRMS patients., (Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.)

IFN-β is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-β for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-β 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-α or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-β reversed the TNF-α/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-β improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

Purpose: This study explored the superiority of temozolomide (TMZ) + interferonβ (IFNβ) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design., Experimental Design: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m 2 , daily) followed by TMZ maintenance (100-200 mg/m 2 /day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNβ + RT arm intravenously received IFNβ (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8)., Results: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNβ + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNβ + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%., Conclusions: TMZ + IFNβ + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

Objective: To compare treatment effectiveness and persistence in relapsing-remitting multiple sclerosis patients who initiated rituximab versus glatiramer acetate (GA) or interferon-beta (IFN-β)., Methods: A total of 461 patients from the Swedish MS registry in the rituximab arm were propensity score matched on a 1:2 basis with 922 patients from the IFN-β/GA comparator, between April 2005 and November 2015. Annualised relapse rate (ARR) was compared using the Poisson method. A marginal Cox model was used to analyse time to first relapse, 3-month confirmed disability progression and treatment discontinuation in the matched sample. A signed-rank test was used to compare Expanded Disability Status Scale (EDSS) change from baseline., Results: Rituximab was associated with a reduction in ARR (0.003; 95% confidence interval (CI) = 0.001, 0.009) relative to IFN-β/GA (0.026; 95% CI = 0.020, 0.033) ( p < 0.001). Rituximab was associated with an 87% reduction in the relapse rate (hazard ratio (HR) = 0.13; 95% CI = 0.04, 0.41) and an 85% reduction in the discontinuation rate (HR = 0.15; 95% CI = 0.11, 0.20) relative to IFN-β/GA. EDSS regression from baseline was greater in the rituximab group at 12 and 24 months., Conclusion: Rituximab appears to be superior to first-generation disease-modifying treatments (DMTs) with respect to relapse control and tolerability, whereas superiority on disability outcomes is less clear.

A 42-year-old man was diagnosed with cStage IIIb malignant melanoma and underwent resection. After interferon-beta therapy, 18-fluorodeoxyglucose-positron emission tomography/computed tomography ( 18 F-FDG PET/CT) showed multiple lung metastases, and he received nivolumab (2 mg/kg) every 3 weeks, resulting in a total of 17 cycles. After treatment, 18 F-FDG PET/CT showed a significant decrease in the size of the metastases, but he had a Grade 4 alanine aminotransferase (ALT) elevation. Liver histology revealed drug-induced liver damage. Therefore, we performed steroid half-pulse therapy followed by oral methylprednisolone, but his ALT level did not completely recover to the normal range even after five months. We herein report a case with specific, sustained liver injury induced by nivolumab as an immune-related adverse events.

Background: Multiple sclerosis (MS) is a chronic, progressive autoimmune disease of the central nervous system in which inflammation plays a key role in the induction, development, and progression. Most of the MS patients present with relapsing-remitting (RR) form, characterized by flare-ups followed by periods of recovery. Many inflammatory and anti-inflammatory cytokines have been proposed as backers in MS pathogenesis, and the balance between these differing cytokines can regulate MS severity. Interferon (IFN)-β, a current disease-modifying therapy for MS, has demonstrated beneficial effects in reducing disease severity in MS patients. However, its immunoregulatory and anti-inflammatory actions in MS are not wholly understood. The aim of the study was to define, in clinically stable patients with RR-MS, the serum concentration of several cytokines, canonical or not, and their modulation by IFN-β therapy., Methods: Relapsing-remitting-MS patients were enrolled and diagnosed according to revised Mc Donald Diagnostic Criteria. A set of cytokines [including non-canonical neurotransmitter acetylcholine (ACh) and adipokines] and B-cell differentiation molecules, as potential biomarkers, were evaluated in 30 non-treated RR-MS patients compared to 30 IFN-β-treated MS patients and 30 age, gender, and body mass index-matched healthy controls (HC)., Results: Naïve MS patients showed significantly higher levels of interleukin (IL)-1β, IL-12/IL-23p40, IL-18, high-mobility group box protein-1, and IL-18 binding protein (IL-18BP) than MS-treated patients ( p  < 0.001 for all) and HC ( p  < 0.01). IFN-β therapy has significantly downmodulated IL-1β, IL-12/IL-23p40, IL-18 to normal levels ( p  < 0.001), whereas it has decreased IL-18BP ( p  < 0.001). ACh was significantly higher in the IFN-β-treated than HC and non-treated MS patients ( p  < 0.001). No significant differences were observed either in adipokines concentration or in B-cell-associated molecules among the three study groups., Conclusion: Although more experimental evidence are required, we speculate that the efficacy of treatment of MS with IFN-β is mediated, at least in part, by its ability to work on several levels to slow down the disease progression. Proposed actions include the modulation of IL-1-inflammasome axis and modulation of ACh, B-cell activating factor/a proliferation-inducing ligand system, and several adipokines.

Objective: To review the evidence supporting the European Union marketing authorization of drugs for multiple sclerosis (MS) and assess how far postmarketing research addresses information gaps at the time of approval., Methods: Through its database, we identified drugs approved by the European Medicines Agency and gathered data on pivotal trials from the European Public Assessment Reports and corresponding publications. We searched Medline, Embase, Cochrane Library, and trial registries for postmarketing randomized controlled trials testing the drugs identified in any form of the disease., Results: Since approval of interferon and glatiramer up to 2017, the Agency has examined 10 drugs for the treatment of MS, and 8 were included in this study: alemtuzumab, daclizumab, dimethyl fumarate, fampridine, fingolimod, peginterferon-β-1a, natalizumab, and teriflunomide. We analyzed 16 pivotal trials enrolling almost 16,000 participants. Eleven compared new drugs to placebo, 5 to interferon-β-1a. Annualized relapse rate was the primary outcome in two-thirds and coprimary with disability progression in the 2 studies of alemtuzumab. Of the 52 postmarketing trials, 24 reported final results and 28 were ongoing, terminated, or completed but no results were available. None directly compared the approved drugs, thus leaving their respective therapeutic values unknown. Data on the prevention of disease progression were scarce: none of the disease-modifying drugs showed any effect on disability progression., Conclusion: The lack of comparative evidence and data on clinical effectiveness hamper the assessment of therapeutic value and place in therapy of drugs approved for MS., (© 2018 American Academy of Neurology.)

Background: Beta-interferon (IFN-β) and glatiramer acetate (GA) have been evaluated in people with clinically isolated syndrome (CIS) with the aim to delay a second clinical attack and a diagnosis of clinically definite multiple sclerosis (CDMS). We systematically reviewed trials evaluating the short- and long-term clinical effectiveness of these drugs in CIS., Methods: We searched multiple electronic databases. We selected randomised controlled studies (RCTs) conducted in CIS patients and where the interventions were IFN-β and GA. Main outcomes were time to CDMS, and discontinuation due to adverse events (AE). We compared interventions using random-effect network meta-analyses (NMA). We also reported outcomes from long-term open-label extension (OLE) studies., Results: We identified five primary studies. Four had open-label extensions following double-blind periods comparing outcomes between early vs delayed DMT. Short-term clinical results (double-blind period) showed that all drugs delayed CDMS compared to placebo. Indirect comparisons did not suggest superiority of any one active drug over another. We could not undertake a NMA for discontinuation due to AE. Long-term clinical results (OLE studies) showed that the risk of developing CDMS was consistently reduced across studies after early DMT treatment compared to delayed DMT (HR = 0.64, 95% CI 0.55, 0.74). No data supported the benefit of DMTs in reducing the time to, and magnitude of, disability progression., Conclusions: Meta-analyses confirmed that IFN-β and GA delay time to CDMS compared to placebo. In the absence of evidence that early DMTs can reduce disability progression, future research is needed to better identify patients most likely to benefit from long-term DMTs.

Background: The risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis (MS) patients is related to serum anti-JCV antibody (JCVAb) index. However, the correlation of JCVAb index with other disease-modifying treatments (DMTs) is not well understood., Objective: In this study, we investigated the JCVAb seropositivity rate/JCVAb indexes and its correlation with clinical profiles in Japanese MS patients, and the relationship between JCVAb indexes and DMTs., Methods: JCVAb indexes were measured in 149 serum samples from 105 patients with MS. JCVAb indexes and seropositivity, and their correlation with age, sex, disease duration, Kurtzke expanded disability status scale and the duration of the DMTs were evaluated in each patient., Results: JCVAb was positive in 73 of 105 MS patients. Within 40 fingolimod-treated patients, 27 were positive for JCVAb and JCVAb indexes were positively correlated with the duration of fingolimod treatment. No significant relation was found between JCVAb indexes and the duration of treatment for the other disease-modifying drugs., Conclusion: JCVAb seropositivity was comparatively high in Japanese MS patients. Fingolimod treatment is likely to increase serum JCVAb index, possibly leading to the development of PML. Therefore, it is advised that JCVAb index should be serially monitored during fingolimod treatment to decrease PML risk.