Multiple sclerosis endophenotypes identified by high-dimensional blood signatures are associated with distinct disease trajectories.

One of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis (n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-ß on endophenotype 3-related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-ß exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient's blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.

Novel peripheral blood mononuclear cell mRNA signature for IFN-beta therapy responsiveness prediction in multiple sclerosis.

Interferon-beta (IFN-ß) is one of the classical drugs for immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS) patients, but the drug responsiveness of different patients varies. Currently, there is no valid model to predict IFN-ß responsiveness. This research attempted to develop an IFN-ß responsiveness prediction model based on mRNA expression in RRMS patient peripheral blood mononuclear cells. Peripheral blood mononuclear cell mRNA expression datasets including 50 RRMS patients receiving IFN-ß treatment were obtained from GEO. Among the datasets, 24 cases from GSE24427 were included in a training set, and 18 and 9 cases from GSE19285 and GSE33464, respectively, were adopted as two independent test sets. In the training set, blood samples were collected immediately before first, second, month 1, 12, and 24 IFN-ß injection, and the mRNA expression data at four time points, namely, two days, one month, one year and two years after the onset of IFN-ß treatment, were compared with pre-treatment data to identify IFN-stimulated genes (ISGs). The ISGs at the one-month time point were used to construct the drug responsiveness prediction model. Next, the drug responsiveness model was verified in the two independent test sets to examine the performance of the model in predicting drug responsiveness. Finally, we used CIBERSORTx to estimate the content of cell subtypes in samples and evaluated whether differences in the proportions of cell subtypes were related to differences in IFN-ß responsiveness. Among the four time points, one month was the time point when the training set GSE24427 and test set GSE33464 had the highest number of ISGs. Functional analysis showed that these one-month ISGs were enriched in biological functions such as the innate immune response, type-I interferon signalling pathway, and other IFN-ß-associated functions. Based on these ISGs, we obtained a four-factor prediction model for IFN-ß responsiveness including MX1, MX2, XAF1, and LAMP3. In addition, the model demonstrated favourable predictive performance within the training set and two external test sets. A higher proportion of activated NK cells and lower naive CD4/total CD4 ratio might indicate better drug responsiveness. This research developed a polygene-based biomarker model that could predict RRMS patient IFN-ß responsiveness in the early treatment period. This model could probably help doctors screen out patients who would not benefit from IFN-ß treatment early and determine whether a current treatment plan should be continued.

Utilization of peginterferon-ß-1a in the real-world practice for relapsing-remitting multiple sclerosis.

OBJECTIVE: Peginterferon ß-1a (PEG-IFN-ß-1a) is the most recent interferon beta formulation approved for treating relapsing-remitting multiple sclerosis (RRMS). We aim to describe the real-world utilization of PEG-IFN-ß-1a in RRMS and compare it with other injectable disease-modifying therapies (DMTs). PATIENTS AND METHODS: In this population-based study, we used 2015-2019 routinely collected healthcare data of the Campania region of Italy from National Healthcare System DMT prescriptions, inpatient and outpatient clinical records of hospitals in Campania, and the Federico II University MS clinical registry for a subset of patients. We included individuals with RRMS receiving new prescriptions of PEG-IFN-ß-1a [n=281; age = 38.8±12.3 years; females=70.5%; disease duration = 8.4±8.3 years; Expanded Disability Status Scale (EDSS) at baseline=2.0 (1.0-6.5)], glatiramer acetate [n=751; age = 46.0±11.4 years; females=67.1%; disease duration = 9.8±8.2 years; EDSS=4.0 (1.5-8.5)], and subcutaneous (SC) IFN-ß-1a [n=1,226; age = 39.7±11.7 years; females=66.5%; disease duration = 8.2±6.5 years; EDSS 2.5 (1.5-6.5)]. Adherence [medication possession ratio (MPR)], escalation to more effective DMTs, hospitalization rates and costs were measured. We used mixed-effect linear regression models (for adherence, hospitalization rates and costs) and Cox regression models (for escalation) to assess differences between PEG-IFN-ß-1a (statistical reference), glatiramer acetate, and SC IFN-ß-1a. All models included age, sex, previous treatment/untreated, year of treatment initiation, treatment duration, and adherence as covariates. RESULTS: Adherence was lower in glatiramer acetate (MPR = 0.91±0.1; Coeff=-0.11; p<0.01), and IFN-ß-1a (MPR = 0.92±0.1; Coeff=-0.08; p<0.01), compared with PEG-IFN-ß-1a (MPR = 1.01±0.1). The probability of escalating to more effective DMTs was higher for glatiramer acetate (14.9%; HR=4.09; p<0.01) and IFN-ß-1a (9.1%; HR=3.35; p=0.01), compared with PEG-IFN-ß-1a (4.9%). No differences in annualized hospitalization rates were identified between glatiramer acetate [annualized hospitalization rates (AHR) = 0.05±0.30; Coeff=0.02; p=0.31), IFN-ß-1a (AHR = 0.02±0.21; Coeff=0.01; p=0.97], and PEG-IFN-ß-1a (AHR = 0.02±0.24); however, monthly costs for MS admissions were higher for glatiramer acetate (€49.45±€195.27; Coeff=-29.89; p=0.03), compared with IFN-ß-1a (€29.42±€47.83; Coeff=6.79; p=0.61), and PEG-IFN-ß-1a (€23.91±€43.90). CONCLUSIONS: SC PEG-IFN-ß-1a and IFN-ß-1a were used in relatively similar populations, while glatiramer acetate was preferred in older and more disabled patients. PEG-IFN-ß-1a was associated with higher adherence and lower escalation rates toward more effective (and costly) DMTs.

The impact of metformin use on the outcomes of relapse-remitting multiple sclerosis patients receiving interferon beta 1a: an exploratory prospective phase II open-label randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disorder. Elevated levels of pro-inflammatory mediators and some oxidative stress parameters can accelerate the demyelination process. We aimed to investigate the efficacy and safety of metformin as an adjuvant therapy to interferon beta 1a (IFNß-1a) in relapsing-remitting multiple sclerosis (RRMS) patients. METHOD: Eighty RRMS patients were equally divided into 2 groups: the intervention group receiving IFNß-1a plus 2 gm of metformin once daily and the control group receiving IFNß-1a alone. Interleukin 17 (IL17), interleukin 22 (IL22), malondialdehyde (MDA), T2 lesions in magnetic resonance imaging (MRI) and expanded disability status scale (EDSS) were assessed at the baseline and then after 6 months. RESULTS: At baseline, there were no statistically significant differences between the two groups (p > 0.05). After 6 months, the change in the median (interquartile range) of the results for both the intervention and control group were; IL17 (- 1.39 (4.19) vs - 0.93 (5.48), p = 0.48), IL22 (- 0.14 (0.48) vs - 0.09 (0.6), p = 0.53), and EDSS (0 vs 0, p = 1), respectively. The mean (standard deviation) change in MDA for the intervention and control group was - 0.93 (2.2) vs - 0.5 (2.53), p = 0.038, respectively. For MRI results, 21 patients had stationary and regressive course and 1 patient had a progressive course in the intervention arm vs 12 patients had stationary and regressive course and 4 had a progressive course in the control arm, p = 0.14. CONCLUSION: Adding metformin to IFNß-1a demonstrated a potential effect on an oxidative stress marker (MDA). However, there is no statistically significant effect on immunological, MRI and clinical outcomes. We recommend larger scale studies to confirm or negate these findings. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT05298670, 28/3/2022.

Antitumor activity of pegylated human interferon ß as monotherapy or in combination with immune checkpoint inhibitors via tumor growth inhibition and dendritic cell activation.

Type I interferons (IFN), especially human IFN alpha (IFNα), have been utilized for antitumor therapy for decades. Human interferon beta (IFNß) is rarely used for cancer treatment, despite advantages over IFNα in biological activities such as tumor growth inhibition and dendritic cell (DC) activation. The utilization of pegylated human IFNß (PEG-IFNß), as monotherapy or in combination with immune checkpoint inhibitors (ICIs) was evaluated in this study through in vivo efficacy studies in syngeneic mouse melanoma, non-small cell lung cancer (NSCLC), and colon adenocarcinoma (COAD) models resistant to immune checkpoint inhibitors (ICIs). In vitro comparative study of PEG-IFNß and pegylated IFNα-2b was performed in terms of tumor growth inhibition against human melanoma, NSCLC and COAD cell lines and activation of human monocyte-derived DCs (MoDCs). Our data demonstrate that the in vivo antitumor effects of PEG-IFNß are partially attributable to tumor growth-inhibitory effects and DC-activating activities, superior to pegylated IFNα-2b. Our findings suggest that utilizing PEG-IFNß as an antitumor therapy can enhance the therapeutic effect of ICIs in ICI-resistant tumors by directly inhibiting tumor growth and induction of DC maturation.

Assessing the duration of EDSS improvement after a therapy start: A novel approach applied to the long-term extension of the PRISMS study.

BACKGROUND: In a chronic and progressive disease such as multiple sclerosis (MS), the improvement on Expanded Disability Status Scale (EDSS) can be a transient event. Therefore, estimating the prevalence of disability improvement over time, accounting both for improvement incidence and duration, is of interest. The aim of this study was to show the application of a simple estimator for the proportion of patients with sustained improvement over time using data from the long-term extension of the PRISMS trial. METHODS: A total of 534 relapsing-remitting MS (RRMS) patients from the PRISMS trial were included. Patients with a baseline EDSS of 0 were excluded. Patients were randomized to placebo (n = 178), subcutaneous interferon beta-1a (sc IFN ß-1a) 22 µg (n = 181) or sc IFN ß-1a 44 µg (n = 175). At Year 2, patients receiving placebo were re-randomized to sc IFN ß-1a 22 µg or 44 µg (delayed sc IFN ß-1a) while patients receiving sc IFN ß-1a 22 µg or 44 µg continued their initial regimen. Patients were followed up for over 7 years post-randomization. Disability improvement was defined as a 1-point decrease in EDSS from baseline confirmed at 6 months. Prevalence of improvement was estimated as difference of Kaplan-Meier (KM) estimators while the cumulative incidence of improvement was calculated using the standard KM curves. RESULTS: No significant differences in cumulative incidence of EDSS improvement at 3 years between delayed sc IFN ß-1a (20.3%) and sc IFN ß-1a 22 µg (20.8%; p = 0.49) or 44 µg (21.3%; p = 0.33). When taking duration of improvement into account, the proportion of patients showing an improved condition after 3 years was 10.1% with delayed sc IFN ß-1a, 11.3% with sc IFN ß-1a 22 µg (p = 0.17) and 15.4% with sc IFN ß-1a 44 µg (p = 0.037) that was substantially maintained over the long term. CONCLUSIONS: With the use of this new statistical methodology, it is possible to estimate the time to improvement as well as the duration of improvement, information that is better suited to describing a non-final outcome like disability improvement. In this case, early sc IFN ß-1a 44 µg initiation had a greater proportion of patients with a sustained disability improvement over a long period of follow-up as compared to patients who had initially been randomized to placebo. In contrast, no significant differences on the cumulative incidence of improvement were observed.

Impact of interferon beta exposure on birth outcome and child development - Results from the post-authorisation safety study PRIMA.

BACKGROUND: Interferon beta therapies are well-established disease-modifying treatments for patients with relapsing multiple sclerosis (MS). Based on clinical evidence from two large cohort studies, both, the EMA and FDA updated the labels of the interferon beta class in terms of pregnancy and breastfeeding in 2019 and 2020, respectively. To complement pregnancy label updates with patient-reported real-world data, this study examined German pregnancy and outcome reports including available data on child development from women with MS treated with peginterferon beta-1a or intramuscular (IM) interferon beta-1a. METHODS: The post-authorisation safety study PRIMA included adult women diagnosed with relapsing-remitting MS or clinically isolated syndrome, who were treated with peginterferon beta-1a or IM interferon beta-1a before or during pregnancy and registered in the marketing authorisation holder's MS Service center patient support program. In the prospective part of the study, conducted from April to October 2021, data on developmental milestones of the newborns were collected via telephone interview from mothers reporting live births. RESULTS: In total, 426 women were enrolled, reporting 542 pregnancies that resulted in 466 live births. A total of 162 women completed the questionnaire for 192 live births (53.1% male). Newborns had Apgar scores indicative of healthy infants. Weight, length and head circumference at birth and physical growth curves up to 48 months lay within the expected range of the German general population. Most newborn screenings and examinations during check-ups were inconspicuous over the study period of 48 months. Out of 158 breastfed infants, 112 (70.9%) were breastfed exclusively until month 5. CONCLUSION: Study results confirmed former reports indicating that exposure to interferon beta therapies during pregnancy or lactation had no adverse effects on intrauterine growth and child development over the study period, which covered the first 4 years of life. These real-world data obtained within the scope of a patient support program for peginterferon beta-1a or IM interferon beta-1a corroborate German and Scandinavian registry data and support the label update of all interferon beta therapies. REGISTRATION: NCT04655222, EUPAS38347.

Interferon Beta-1a versus Glatiramer Acetate: Changes of Innate Immunity in a Group of Women with Multiple Sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations. METHODS: Sixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD). RESULTS: A statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10-20%. CONCLUSION: Innate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

The value of Interferon ß in multiple sclerosis and novel opportunities for its anti-viral activity: a narrative literature review.

Interferon-beta (IFN-ß) for Multiple Sclerosis (MS) is turning 30. The COVID-19 pandemic rejuvenated the interest in interferon biology in health and disease, opening translational opportunities beyond neuroinflammation. The antiviral properties of this molecule are in accord with the hypothesis of a viral etiology of MS, for which a credible culprit has been identified in the Epstein-Barr Virus. Likely, IFNs are crucial in the acute phase of SARS-CoV-2 infection, as demonstrated by inherited and acquired impairments of the interferon response that predispose to a severe COVID-19 course. Accordingly, IFN-ß exerted protection against SARS-CoV-2 in people with MS (pwMS). In this viewpoint, we summarize the evidence on IFN-ß mechanisms of action in MS with a focus on its antiviral properties, especially against EBV. We synopsize the role of IFNs in COVID-19 and the opportunities and challenges of IFN-ß usage for this condition. Finally, we leverage the lessons learned in the pandemic to suggest a role of IFN-ß in long-COVID-19 and in special MS subpopulations.

Association of age and inflammatory disease activity in the pivotal natalizumab clinical trials in relapsing-remitting multiple sclerosis.

BACKGROUND: Focal inflammatory disease activity in relapsing-remitting multiple sclerosis (RRMS) diminishes with increasing age. Here we use patient-level data from randomised controlled trials (RCTs) of natalizumab treatment in RRMS to investigate the association of age and inflammatory disease activity. METHODS: We used patient-level data from the AFFIRM (natalizumab vs placebo in relapsing-remitting MS, NCT00027300) and SENTINEL (natalizumab plus interferon beta vs interferon beta in relapsing remitting MS, NCT00030966) RCTs. We determined the proportion of participants developing new T2 lesions, contrast-enhancing lesions (CELs) and relapses over 2 years of follow-up as a function of age, and investigated the association of age with time to first relapse using time-to-event analyses. RESULTS: At baseline, there were no differences between age groups in T2 lesion volume and number of relapses in the year before inclusion. In SENTINEL, older participants had a significantly lower number of CELs. During both trials, the number of new CELs and the proportion of participants developing new CELs were significantly lower in older age groups. The number of new T2 lesions and the proportion of participants with any radiological disease activity during follow-up were also lower in older age groups, especially in the control arms. CONCLUSIONS: Older age is associated with a lower prevalence and degree of focal inflammatory disease activity in treated and untreated RRMS. Our findings inform the design of RCTs, and suggest that patient age should be taken into consideration when deciding on immunomodulatory treatment in RRMS.

Disease-modifying therapies and cost-of-illness progression among people newly diagnosed with multiple sclerosis: a national register-based cohort study covering treatment initiation with interferons, glatiramer acetate or natalizumab.

OBJECTIVES: Disease-modifying therapies (DMTs) can slow disease progression in multiple sclerosis (MS). The objective of this study was to explore the cost-of-illness (COI) progression among newly diagnosed people with MS in relation to the first DMT received. DESIGN AND SETTING: A cohort study using data from nationwide registers in Sweden. PARTICIPANTS: People with MS (PwMS) in Sweden first diagnosed in 2006-2015, when aged 20-55, receiving first-line therapy with interferons (IFN), glatiramer acetate (GA) or natalizumab (NAT). They were followed up through 2016. OUTCOME MEASURES: Outcomes (in Euros, €) were: (1) secondary healthcare costs: specialised outpatient and inpatient care including out-of-pocket expenditure, DMTs including hospital-administered MS therapies, and prescribed drugs, and (2) productivity losses: sickness absence and disability pension. Descriptive statistics and Poisson regression were computed, adjusting for disability progression using the Expanded Disability Status Scale. RESULTS: 3673 newly diagnosed PwMS who were treated with IFN (N=2696), GA (N=441) or NAT (N=536) were identified. Healthcare costs were similar for the INF and GA groups, while the NAT group had higher costs (p value<0.05), owing to DMT and outpatient costs. IFN had lower productivity losses than NAT and GA (p value>0.05), driven by fewer sickness absence days. NAT had a trend towards lower disability pension costs compared with GA (p value>0.05). CONCLUSIONS: Similar trends over time for healthcare costs and productivity losses were identified across the DMT subgroups. PwMS on NAT maintained their work capacity for a longer time compared with those on GA, potentially leading to lower disability pension costs over time. COI serves as an objective measure to explore the importance of DMTs in maintaining low levels of progression of MS over time.

Global DNA Methylation and Hydroxymethylation Levels in PBMCs Are Altered in RRMS Patients Treated with IFN-ß and GA-A Preliminary Study.

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS) due to an autoimmune attack on axonal myelin sheaths. Epigenetics is an open research topic on MS, which has been investigated in search of biomarkers and treatment targets for this heterogeneous disease. In this study, we quantified global levels of epigenetic marks using an ELISA-like approach in Peripheral Blood Mononuclear Cells (PBMCs) from 52 patients with MS, treated with Interferon beta (IFN-ß) and Glatiramer Acetate (GA) or untreated, and 30 healthy controls. We performed media comparisons and correlation analyses of these epigenetic markers with clinical variables in subgroups of patients and controls. We observed that DNA methylation (5-mC) decreased in treated patients compared with untreated and healthy controls. Moreover, 5-mC and hydroxymethylation (5-hmC) correlated with clinical variables. In contrast, histone H3 and H4 acetylation did not correlate with the disease variables considered. Globally quantified epigenetic DNA marks 5-mC and 5-hmC correlate with disease and were altered with treatment. However, to date, no biomarker has been identified that can predict the potential response to therapy before treatment initiation.

Interferon-ß modulates microglial polarization to ameliorate delayed tPA-exacerbated brain injury in ischemic stroke.

Tissue plasminogen activator (tPA) is the only FDA-approved drug for the treatment of ischemic stroke. Delayed tPA administration is associated with increased risks of blood-brain barrier (BBB) disruption and hemorrhagic transformation. Studies have shown that interferon beta (IFNß) or type I IFN receptor (IFNAR1) signaling confers protection against ischemic stroke in preclinical models. In addition, we have previously demonstrated that IFNß can be co-administered with tPA to alleviate delayed tPA-induced adverse effects in ischemic stroke. In this study, we investigated the time limit of IFNß treatment on the extension of tPA therapeutic window and assessed the effect of IFNß on modulating microglia (MG) phenotypes in ischemic stroke with delayed tPA treatment. Mice were subjected to 40 minutes transient middle cerebral artery occlusion (MCAO) followed by delayed tPA treatment in the presence or absence of IFNß at 3h, 4.5h or 6h post-reperfusion. In addition, mice with MG-specific IFNAR1 knockdown were generated to validate the effects of IFNß on modulating MG phenotypes, ameliorating brain injury, and lessening BBB disruption in delayed tPA-treated MCAO mice. Our results showed that IFNß extended tPA therapeutic window to 4.5h post-reperfusion in MCAO mice, and that was accompanied with attenuated brain injury and lessened BBB disruption. Mechanistically, our findings revealed that IFNß modulated MG polarization, leading to the suppression of inflammatory MG and the promotion of anti-inflammatory MG, in delayed tPA-treated MCAO mice. Notably, these effects were abolished in MG-specific IFNAR1 knockdown MCAO mice. Furthermore, the protective effect of IFNß on the amelioration of delayed tPA-exacerbated ischemic brain injury was also abolished in these mice. Finally, we identified that IFNß-mediated modulation of MG phenotypes played a role in maintaining BBB integrity, because the knockdown of IFNAR1 in MG partly reversed the protective effect of IFNß on lessening BBB disruption in delayed tPA-treated MCAO mice. In summary, our study reveals a novel function of IFNß in modulating MG phenotypes, and that may subsequently confer protection against delayed tPA-exacerbated brain injury in ischemic stroke.

Preclinical efficacy of oncolytic VSV-IFNß in treating cancer: A systematic review.

Background: Cancer incidence and mortality are increasing rapidly worldwide, necessitating further investigation into developing and optimizing emergent cancer therapies. Oncolytic viruses such as vesicular stomatitis virus encoding interferon ß (VSV-IFNß) have attracted considerable attention, as they offer great efficacy and safety profiles. This systematic review aimed to determine and compare the efficacy profile between VSV-IFNß and non-treatment controls in preclinical cancer models. Methodology: The Embase and Medline databases were systematically searched for relevant studies using related key terms and Medical Subject Headings (MeSH). Titles, abstracts, and full texts were screened, and data from eligible articles were extracted by two groups independently and in duplicate (two reviewers per group). Disagreements were resolved by a fifth independent reviewer. The included articles were all preclinical (translational) in vivo English studies that investigated and compared the efficacy profile between VSV-IFNß and non-treatment controls in animal models. The risk of bias among the studies was assessed by two reviewers independently and in duplicate using SYRCLE's risk-of-bias tool for animal studies; disparities were addressed by a third independent reviewer. Results: After employing relevant MeSH and key terms, we identified 1598 articles. A total of 87 articles were either duplicates or conference proceedings and were thus excluded. Following title and abstract screening, 37 articles were included in the full-text assessment. Finally, 14 studies met the eligibility criteria. Forty-two experiments from the included studies examined the potential efficacy of VSV-IFNß through different routes of administration, including intratumoral, intraperitoneal, and intravenous routes. Thirty-seven experiments reported positive outcomes. Meanwhile, five experiments reported negative outcomes, three and two of which examined intratumoral and intravenous VSV-IFNß administration, respectively. Conclusion: Although the majority of the included studies support the promising potential of VSV-IFNß as an oncolytic virus, further research is necessary to ensure a safe and efficacious profile to translate its application into clinical trials. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022335418.

Retrospective analysis of effectiveness of fingolimod in real life setting in Turkey (REFINE).

BACKGROUND: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. METHODS: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients' database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. RESULTS: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. DISCUSSION: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

Polymorphism in interferon alpha/beta receptor contributes to glucocorticoid response and outcome of ARDS and COVID-19.

BACKGROUND: The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN ß) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN ß, and therefore, we aimed at finding the reason behind this. METHODS: We first sequenced the genes encoding the IFN α/ß receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier:  NCT02622724 , November 24, 2015) in which the patients were randomized to receive an intravenous injection of IFN ß-1a (144 patients) or placebo (152 patients). Genetic background was analyzed against clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. Thereafter, we tested the influence of the genetic background on IFN α/ß receptor expression in lung organ cultures and whether, it has any effect on transcription factors STAT1 and STAT2 involved in IFN signaling. RESULTS: We found a novel disease association of a SNP rs9984273, which is situated in the interferon α/ß receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN ß treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN ß and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database. CONCLUSIONS: The distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids.

Impact of COVID-19 on prescribing patterns and treatment selection of disease modifying therapies in multiple sclerosis.

BACKGROUND: Certain classes of multiple sclerosis (MS) disease modifying therapies (DMTs) have been associated with an increased risk of severe COVID-19, resulting in prescribers considering changes in their practice habits during the COVID-19 pandemic. This study assessed for differences in prescribing patterns of DMTs along with the reason(s) for modification of therapy over time. METHODS: A retrospective review of medical records at Johns Hopkins Health System was performed. The timeframe of the study, April 2019 to December 2021, was divided into three subcategories: pre-pandemic (April 2019-March 2020), pre-vaccine availability (April 2020-March 2021), and post-vaccine availability (April 2021-December 2021). Patients were identified through dispense reports from the pharmacy dispensing system, and prescribing report from the health-system electronic health record (EHR). The health-system EHR was also utilized to conduct chart reviews for a subset of patients that had a modification in their therapy during the specified timeframes. The study included adult patients that were prescribed at least one DMT through the Johns Hopkins Pharmacy Services during the study timeframe and those who stayed on their DMT for at least 2 months without tolerability issues. Descriptive statistics were used to compare the prescribing practices during the timeframes with the percentage of prescribing for each type of treatment and to assess the percentage of patients that switched therapies in the different time periods. RESULTS: Based on prescribing report data, 670 patients were prescribed a DMT during the pre-pandemic period with infusion therapies being the most prescribed therapies during this timeframe (38%), followed by oral therapies at 35%. In comparison, a total of 620 patients were prescribed a DMT during pre-vaccine pandemic and the percentage of prescriptions of infusion therapies decreased to 28% (-10%) during this timeframe, whereas oral prescriptions increased to 42% (+7%). These trends continued during the post-vaccine timeframe where infusion therapies decreased to 26% (-12%) and oral therapies increased to 43% (+8%) in reference to the pre-pandemic period. Prescribing patterns of self-injectable therapies remained stable throughout the 3 timeframes. A dispensing report cohort of 500 patients were randomly selected for chart reviews to assess therapy modifications due to COVID-19. The percentage of therapy change due to COVID-19 increased to 45.2% during pre-vaccine period and remained at 38.4% during post-vaccine period when compared to the pre-pandemic reference period. The majority of changes due to COVID-19 were delays in infusion therapies (96% during pre-vaccine, and 94% during post-vaccine), not medication changes. CONCLUSION: Prescribing patterns and therapy modifications of DMTs for MS patients were impacted by COVID-19, with the greatest changes observed for the infusion therapies, including reduction in percentage of infusion prescriptions and delays in infusion therapies. Prescribing patterns of lower efficacy self-injectable therapies (interferon-beta and glatiramer acetate) remained stable. The outcomes of this study provide background for future outcomes-focused research studies in MS.

Patient-reported outcomes are the strongest predictors of disease disability in intramuscular interferon ß-1a users.

Introduction: Patient-reported outcomes (PROs) are valuable measures for routine clinical care of people with multiple sclerosis (pwMS). Materials: 646 pwMS treated with interferon-ß-1a (IFN-ß-1a) were retrospectively included from the New York State Multiple Sclerosis Consortium. Clinical and PRO data at enrollment and 3 year follow-up were collected. PwMS with stable disease and disability worsening were matched (1:1) based on age, Expanded Disability Status Scale (EDSS) scores and disease duration. Disability worsening was determined based on trial criteria. Results: PwMS with future EDSS worsening had higher baseline and follow-up timed-25-foot walk (6.6 vs 5.5 s; 9.1 vs 5.5 s; p < 0.001) when compared with stable pwMS. Worsening pwMS reported higher baseline difficulties in getting up (odds ratio [OR] = 2.4; p = 0.009), climbing stairs (OR = 1.6; p = 0.024) and standing (OR = 2.2; p < 0.001). Worsening pwMS reported greater lower limb limitations (OR = 2.3; p = 0.004) and fatigue (OR = 1.8; p = 0.002). Conclusion: Higher fatigue and lower limb functional limitations are significant predictors of future disability worsening in pwMS.

A large retrospective study was carried out on people with multiple sclerosis (PwMS) being treated with intramuscular interferon-ß medication from the New York State Multiple Sclerosis Consortium. The aim of the study was to look at whether patient-reported and clinical measures could be used early on to predict whether PwMS have worsening of their disease. The study demonstrated that patient-reported levels of limitations in multiple physical and mental symptoms can predict future worsening in objectively quantified disability in PwMS who take intramuscular interferon-ß medication. Reported limitations in lower extremities and fatigue were the most predictive of future disability worsening.

Stability and Activity of Interferon Beta to Treat Idiopathic Pulmonary Fibrosis with Different Nebulizer Technologies.

Background: Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by lung scarring, which results in breathing difficulty. Currently, patients with IPF exhibit a poor survival rate and have access to very limited therapeutic options. Interferon beta (IFN-ß) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis, and it has also been shown to exhibit therapeutic potential in IPF. However, clinical use of IFN-ß did not lead to improved overall survival in IPF patients in existing studies. One possibility is the limited efficiency of IFN-ß delivery through intravenous or subcutaneous injection. Materials and Methods: The aerosol particle size distribution was determined with a laser diffraction particle size analyzer to characterize the droplet size and fine particle fraction generated by three types of nebulizers: jet, ultrasonic, and mesh. A breathing simulator was used to assess the delivery efficiency of IFN-ß, and the temperature in the medication reservoirs was monitored with a thermocouple during nebulization. To further evaluate the antifibrotic activity of IFN-ß pre- and postnebulization, bleomycin (BLM)- or transforming growth factor-beta (TGF-ß)-treated human lung fibroblast (HLF) cells were used. Cell viability was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Transwell migration assay and Q-PCR analysis were used to evaluate cell migration and the myofibroblast differentiation ability, respectively. IFN-ß protein samples were prepared using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) sample loading buffer, and the expression of IFN-ß was assessed by western blotting. Results: Among the current drug delivery systems, aerosolized medication has shown increased efficacy of drug delivery for treating respiratory diseases when compared with parenteral drugs. It was found that neither the structural integrity nor the biological function of nebulized IFN-ß was compromised by the nebulization process of the mesh nebulizer. In addition, in BLM dose-response or TGF-ß-induced lung fibroblast proliferation assays, these effects could be reversed by both parenteral and inhaled IFN-ß nebulized with the mesh nebulizer. Nebulized IFN-ß with the mesh nebulizer also significantly inhibited the migration and myofibroblast differentiation ability of TGF-ß-treated HLF cells. Conclusions: The investigations revealed the potential efficacy of IFN-ß in the treatment of IPF with the mesh nebulizer, demonstrating the higher efficiency of IFN-ß delivered through the mesh nebulizer.