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This study aimed to investigate the potential relationship between multiple sclerosis (MS) and coronavirus disease 2019 (COVID-19) outcomes using Mendelian randomization analysis. Specifically, it evaluates whether genetic factors, including the single-nucleotide polymorphism (SNP) rs10191329, influence the susceptibility of MS patients to three COVID-19 outcomes [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalized COVID-19, and severe COVID-19]. This study utilized genome-wide association study summary statistics from the International Multiple Sclerosis Genetics Consortium to conduct a Mendelian randomization analysis. SNPs strongly associated with MS were selected to examine their impact on COVID-19 outcomes. The analysis focused on identifying any causal associations between MS and COVID-19 severity, as well as assessing the role of interferon beta (IFNβ) treatment in modifying these outcomes. The results suggest a potential association between MS and an increased risk of COVID-19, but individuals carrying the rs10191329 SNP appeared less likely to develop severe COVID-19. This SNP, located within the DYSF-ZNF638 locus, may influence immune responses and MS severity, highlighting its relevance for personalized treatment strategies. Importantly, no significant causal relationship was found between IFNβ treatment and the three COVID-19 outcomes, indicating that the findings in treated patients differ from those observed in untreated patients. This suggests that IFNβ may offer protective effects against SARS-CoV-2 in MS patients. These findings underscore the importance of genetic factors, such as rs10191329, in shaping the clinical outcomes of MS patients in the context of COVID-19. Further research should explore targeted therapies and personalized approaches for managing MS during the ongoing pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Liang, Sheng and Zhang.)

Preclinical data suggest that type I interferon (IFN) responsiveness is essential for the antitumor effects of radiotherapy (RT). However, its clinical value remains unclear. This study aimed to explore this from a clinical perspective. In cohort 1, data from 152 hepatocellular carcinoma (HCC) patients who received RT were analyzed. Blood samples were taken 1 day before and 2 weeks after RT. RT was found to increase serum levels of IFN-β (a subtype of IFN-I) in HCC patients (3.42 ± 1.57 to 5.51 ± 2.11 pg/ml, P < 0.01), particularly in those with favorable responses. Higher post-RT serum IFN-β levels (≥4.77 pg/ml) were associated with better progression-free survival (HR = 0.58, P < 0.01). Cohort 2 included 46 HCC patients, including 23 who underwent preoperative RT and 23 matched control HCC who received surgical resection without RT. Formalin-fixed paraffin-embedded samples were obtained. Neoadjuvant RT significantly increased IFN-β expression in tumor tissues compared to direct surgery (8.13% ± 5.19% to 15.10% ± 5.89%, P < 0.01). Higher post-RT IFN-β (>median) indicated better disease-free survival (P = 0.049). Additionally, increased CD11c+MHCII+CD141+ antigen-presenting cell subsets and CD103+CD39+CD8+ tumor-infiltrating lymphocytes were found in the higher IFN-β group (P = 0.02, P = 0.03), which may contribute to the favorable prognosis in higher IFN-β group. Collectively, these findings suggest that IFN-β response activated by radiation may serve as a prognostic biomarker for HCC patients undergoing RT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Interferon beta (IFNβ) is a member of the type-1 interferon family and has various immunomodulatory functions in neuropathological conditions. Although the level of IFNβ is low under healthy conditions, it is increased during inflammatory processes to protect the central nervous system (CNS). In particular, microglia and astrocytes are the main sources of IFNβ upon inflammatory insult in the CNS. The protective effects of IFNβ are well characterized in reducing the progression of multiple sclerosis (MS); however, little is understood about its effects in other neurological/neurodegenerative diseases. In this review, different types of IFNs and their signaling pathways will be described. Then we will focus on the potential role and therapeutic effect of IFNβ in several CNS-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury, prion disease and spinocerebellar ataxia 7., Competing Interests: Declaration of competing interest All authors have nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a chronic immune-mediated and heterogeneous disease characterized by demyelination, axonal damage, and physical and cognitive impairment. Recent studies have highlighted alterations in the microbiota of people with MS (pwMS). However, the intricate nature of the disease and the wide range of treatments available make it challenging to identify specific microbial populations or functions associated with MS symptoms and disease progression. This study aimed to characterize the microbiota of pwMS treated with the oral drug teriflunomide (TF) and compare it with that of pwMS treated with beta interferons (IFNβ), pwMS treated with no previous disease modifying therapies (naïve), and healthy controls. Our findings demonstrate significant alterations in both the composition and function of the gut microbiota in pwMS that are further influenced by disease-modifying therapies. Specifically, oral treatment with TF had a notable impact on the gut microbiota of pwMS. Importantly, the dysregulated microbial environment within the gut was associated with symptoms commonly experienced by pwMS, including fatigue, anxiety, and depression., Competing Interests: Declaration of competing interest The authors declare that they do not have conflicts of interest. The founding sponsors had no role in the design of the study or the decision to publish the results., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mounting evidence links systemic innate immunity with cancer immune surveillance. In advanced metastatic castration-resistant prostate cancer (mCRPC), Black patients have been found to have increased inflammatory markers and longer survival after sipuleucel-T (sip-T) therapy, an FDA-approved, autologous cell therapy. We hypothesized these differences may be explained by previously reported ancestral differences in pattern recognition receptor signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality. We discovered that peripheral blood mononuclear cell IFN-β responses to Toll-like receptor 1/2 (TLR1/2), a sensor of bacterial and gut microbiome constituents, associated with significantly longer survival after sip-T therapy in two separate cohorts of men with mCRPC (discovery cohort: n = 106, HR = 0.12; P = 0.019; validation cohort: n = 28, HR < 0.01; P = 0.047). Higher IFN-β induction after TLR1/2 stimulation was associated with lower HRs than biomarkers of vaccine potency and other prognostic factors in mCRPC. TLR1/2-dependent cytokine induction was stronger in Black individuals (1.2-fold higher for IFN-β; P = 0.04) but was associated with survival independently of race or numbers of vaccine-induced tumor antigen-specific T cells. IFN-β responses to TLR1/2 signaling correlated with increased numbers of IFN-γ producing T cells after broad, tumor antigen-independent stimulation. Thus, peripheral innate immunity differs by race, may predict survival after sip-T, and associates with peripheral T-cell functionality in men with mCRPC., Significance: The identification of factors that determine successful cancer immunotherapy, particularly in refractory tumor types like mCRPC, is urgently needed: both to identify patients that may benefit from such therapies and to uncover routes to sensitize patients with cancer to immunotherapy. Our work links functional peripheral immune responses with race and survival after cellular immunotherapy in men with mCRPC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: To investigate the association between infections and disability worsening in people with multiple sclerosis (MS) treated with either B-cell depleting therapy (rituximab) or interferon-beta/glatiramer acetate (IFN/GA)., Methods: This cohort study spanned from 2000 to 2021, using data from the Swedish MS Registry linked to national health care registries, comprising 8,759 rituximab and 7,561 IFN/GA treatment episodes. The risk of hospital-treated infection was estimated using multivariable Cox models. The association between infections and increase in Expanded Disability Status Scale (EDSS) scores was assessed using a doubly robust generalized estimating equations model. Additionally, a piece-wise exponential model analyzed events of increased disability beyond defined cut-off values, controlling for relapses, and MRI activity., Results: Compared with IFN/GA, rituximab displayed increased risk of both inpatient- and outpatient-treated infections (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.50-2.90 and HR, 1.37; 95% CI, 1.13-1.67, respectively). An inpatient-treated infection was associated with a 0.19-unit increase in EDSS (95% CI, 0.12-0.26). Degree of worsening was greatest for progressive MS, and under IFN/GA treatment, which unlike rituximab, was more commonly associated with MRI activity. After controlling for relapses and MRI activity, inpatient-treated infections were associated with disability worsening in people with relapsing-remitting MS treated with IFN/GA (HR, 2.01; 95% CI, 1.59-2.53), but not in those treated with rituximab., Interpretation: Compared to IFN/GA, rituximab doubled the infection risk, but reduced the risk of subsequent disability worsening. Further, the risk of worsening after hospital-treated infection was greater with progressive MS than with relapsing-remitting MS. Infection risk should be considered to improve long term outcomes. ANN NEUROL 2024;96:694-703., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity., Competing Interests: Declaration of competing interest MA is now employed by Nxera Pharma UK, Translational Sciences, Granta Park Steinmetz Building, Cambridge, United Kingdom. KEW is now employed by Nucleome Therapeutics, Oxford, United Kingdom. EKH has received honoraria/research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has served as a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; has been supported by the Czech Ministry of Education – project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107) – funded by the European Union-Next Generation EU. RF has received speaker honoraria and hospitality from Merck, Biogen, TEVA, Novartis, Genzyme, Abbvie, Merz and Ipsen. PN has received speaker honoraria and consultant fees from Biogen, Novartis, Merck, and Roche. The remaining authors (LC, PD, CC, IPT, ECJ) declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome., Methods: Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses., Results: A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%., Discussion: In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred., Classification of Evidence: This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Mendelian susceptibility to mycobacterial disease (MSMD) is caused by approximately 21 genetic defects, including a mutation in Interferon-Gamma Receptor 1 (IFNGR1). IFNGR1 deficiency leads to a loss of cellular responsiveness to type II Interferon (IFN-γ), which plays a significant role in controlling intracellular bacteria. This study explored the response of IFN-β therapy in a patient with partial IFNGR1 deficiency to treat invasive mycobacterial infection. The biological therapy was used successfully as an adjuvant to anti-mycobacterial medications to treat a 17-year-old girl with partial IFNGR1 deficiency who presented with a recurrent mycobacterial infection that extended to her central nervous system, which resulted in clinical and radiological improvement. This report suggests that activation of type I IFN through Signal Transducers and Activators of Transcription1 (STAT1) could bypass the early IFN-γ signaling defects and activate IFN-γ production. For that reason, IFN-β might be used as a beneficial adjuvant therapy for managing extensive central nervous system mycobacterial infection, especially in patients with IFNGR1 deficiency., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Interferon-beta has been suggested as a trigger of psoriasis, yet a systematic investigation is lacking. This study aimed to assess the risk of developing psoriasis following interferon-beta treatment, utilizing a pharmaco-epidemiological approach to investigate the role of interferon-beta in psoriasis pathogenesis. We included all treatment-naïve patients with multiple sclerosis (MS) in Denmark who initiated interferon-beta treatment for MS from January 1996 to June 2023. These patients were compared to a control cohort of patients with MS treated with other disease-modifying drugs. We compared the incidence rates of psoriasis before and during the treatment. Data for this study were extracted from the Danish MS Registry and integrated with information from other national Danish health registries. Among 7174 patients treated with interferon-beta, the incidence rate of psoriasis post-treatment initiation was slightly higher (2.01 per 1000 person-years) compared to the rate prior to treatment (1.67 per 1000 person-years). This increase did not achieve statistical significance (P = 0.53), with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 0.68-2.13). The control cohort showed an increase in psoriasis incidence post-treatment initiation (3.12 per 1000 person-years) compared to prior (1.11 per 1000 person-years), with an IRR of 2.80 (95% CI 1.36-4.77, P = 0.0038). This registry-based self-controlled study does not support the theory that interferon-beta acts as a trigger for psoriasis development., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

The aim of the present study was to investigate the impact of CCR5 Δ32 and CTLA-4 polymorphisms on the response to IFN-β treatment in our cohort of MS patients from Croatia and Slovenia. Genomic DNA was obtained from 295 MS patients (230 female; 65 male) classified as responders ( n = 173) and non-responders ( n = 122) based on clinical criteria for treatment efficacy. Genotyping was performed via PCR/PCR-RFLP. No significant differences in the genotype/allele frequencies of CCR5Δ32 and CTLA-4 +49 A/G were detected between male responders and non-responders. A significantly higher prevalence ( p = 0.039) of the CTLA-4 +49 AA genotype was found in female responders (42.1%) compared to non-responders (28.9%). Using multiple forward regression analysis, the CTLA-4 +49 AA genotype significantly predicted a positive response to IFN-β therapy in females ( p = 0.011) and contributed to 4.5% of response variability. Furthermore, the combined presence of the CCR5Δ32 wtwt/CTLA-4 +49 AA genotype significantly predicted a positive response to treatment in females ( p = 0.025). The age at disease onset, pretreatment relapse rate, and baseline EDSS score were not reliable predictors of treatment response in MS patients. Our results indicate that the presence of the CCR5Δ32 polymorphism was not associated with the response to IFN-β treatment, whereas the CTLA-4 +49 polymorphism showed a positive correlation with an optimal response in female patients.

Background: The mechanisms of the function of interferon beta (IFN-β) and natalizumab (NTZ) in multiple sclerosis (MS) patients have not yet been fully understood. Over the past decades, many studies have been conducted to evaluate gene expression changes especially regulatory non-coding RNAs such as microRNAs (miRNAs) following therapy in MS patients., Objective: To assess the changes in the expression of miR-20b in MS patients treated with IFN-β or NTZ., Methods: Sixty patients with relapsing-remitting MS (RRMS) and 30 healthy controls (HCs) were enrolled. The patients were categorized as untreated (N=20), IFN-β-treated (N=20), and NTZtreated (N=20). For the expression analysis, real-time PCR was performed on the whole blood. The bioinformatic tools were applied for signaling pathways enrichment analysis of miR-20b targetome., Results: The relative expression of miR-20b was significantly downregulated in the untreated patients compared with the HCs (-1.726-fold, p<0.001), while IFN-β-treated and NTZ-treated patients showed no statistical difference compared with the HCs (0.733-fold, p=0.99 for IFN-β and 1.025-fold, p=0.18 for NTZ). This indicates the restoration of miR-20b expression to normal level in the treated patients. Additionally, in silico analysis demonstrated that the Jak-STAT signaling pathway is enriched with miR-20b targets (p<0.0001)., Conclusion: Our findings suggest that the positive effects of IFN-β and NTZ in the RRMS patients could be potentially mediated by returning miR-20b expression to baseline.

Background: Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression., Objectives: To investigate whether the failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics., Methods: We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t 0 , and constant hazard ratio (HR) after time = t 0 . We selected the best-fitting t 0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset., Results: The time-dependent Cox model revealed a significant benefit of treatment delayed by t 0  = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43-0.98), p  = 0.041), and delayed by t 0  = 2 years for the PROMISE study (HR = 0.65, (0.42-0.99), p  = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p  < 0.001., Conclusion: The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment., Competing Interests: Declaration of Conflicting InterestsMaria Pia Sormani has received personal compensation for consulting services and for speaking activities from Merck, Novartis, Roche, Sanofi, Bristol-Meyer Squibb, Immunic and Biogen. The other author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique model to address the immuno-stimulatory properties of RT on a systemic level. We prospectively analyzed the IFNβ plasma levels and lymphocyte counts (LCs) of rectal adenocarcinoma patients before and after treatment with scRT (n = 22) and lcRT (n = 40). Flow cytometry was conducted to assess the effects on lymphocytic subpopulations in a subset of 20 patients. A statistically significant increase in the post-RT IFNβ plasma levels was noted in patients undergoing scRT ( p = 0.004). Improved pathological tumor regression was associated with elevated post-RT IFNβ levels ( p = 0.003). Although all patients experienced substantial lymphopenia after treatment, the post-RT LC of patients treated with scRT were significantly higher compared to lcRT ( p = 0.001). Patients undergoing scRT displayed significantly lower percentages of regulatory CD4+/CD25+ T-cells after therapy ( p = 0.02). scRT enables effective stimulation of the IFN-type-I pathway on a systemic level and confers decreased lymphocytic cytotoxicity and limited regulatory T-cell activation compared to lcRT, supporting its increasing role in immuno-RT trials.

Objective: Multiple sclerosis (MS) is a multifactorial inflammatory and autoimmune condition that lead to chronic neurodegeneration and central nervous system (CNS) demyelination that mainly affects young adults. The incidence and prevalence rate of MS considerably vary in ethnicities and geographic regions and affecting women more than men. Interferon-β (IFN-β) is the first-line disease management for MS, while the majority of affected members does not respond to the IFN-β. Numerous recent studies shown a significant relationship between genetic variations and responsiveness to the IFN-β. Therefore, determining the genetic differences in the drug response could help determine precise treatment strategies., Methods: The genotyping of the rs7298096 polymorphism (SNP) and NINJ2 gene expression were assessed in 99 responders and 106 non-responder patients with IFN-β treated RRMS., Results: The distribution of rs7298096 SNP was significantly different in the responders and non-responder patients and the NINJ2 gene expression considerably increased in the non-responder patients compare to the responders. The NINJ2 gene expression level in the AA genotype of the non-responder group was higher than to the other genotypes of both groups., Conclusion: Our results showed that the NINJ2 gene expression level and rs7298096 genotype possibly affect the response to the IFN-β in patients with RRMS.

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-β on endophenotype 3-related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-β 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.

Background: Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system and is characterized by extensive brain damage and neurodegeneration. Immunological, genetic, and histological analyses of MS patients provide data in support of the concept that autoimmunity plays a crucial role in the condition's course. It has been proposed that MS may be treated with interferon (IFN)-β and other members of the type I family., Objective: Low levels of type I IFN in MS patients may affect immunological control, establish the threshold for an IFN therapeutic response, and be "primed" or "fixed" by IFN therapy., Methods: This study was conducted as a cross-sectional study. qRT-PCR was used to examine the expression of two critical IFN regulatory genes, IFI44 and MX1, in MS patients receiving IFN-β treatment., Results: The findings demonstrated a considerable rise in the expression of both genes in MS patients treated with IFN-β compared to those newly diagnosed with the illness. In addition, IFI44 and MX1 might be positively associated with their expression after IFN-β therapy and be regarded as IFN-β responsiveness indicators., Conclusion: The IFI44/MX1 axis could act as one of the crucial regulators of the disease following IFN-β treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: A limited subgroup of multiple sclerosis (MS) patients present with a longterm disease evolution characterized by a limited disease progression, known as benign MS (BMS). Chitinase 3-like-1 (CHI3L1) levels are sensitive to inflammatory processes and may play a role in the pathogenesis of MS. In this observational, cross-sectional study, we aimed to evaluate the implications of serum CHI3L1 and inflammatory cytokines in BMS patients treated with interferon β-1b for over a decade., Methods: We collected serum samples from 17 BMS patients and 17 healthy controls (HC) to measure serum CHI3L1 levels and a Th17 panel of inflammatory cytokines. Serum levels of CHI3L1 were analysed using the sandwich ELISA method and the Th17 panel was assessed using the multiplex XMap technology on a Flexmap 3D Analyzer., Results: Serum CHI3L1 levels did not differ significantly from HC. We identified a positive correlation between CHI3L1 levels and relapses during treatment., Conclusion: Our findings suggest that there are no differences in serum CHI3L1 levels between BMS patients and HC. However, serum CHI3L1 levels are sensitive to clinical inflammatory activity and may be associated with relapses in BMS patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Peginterferon β-1a (PEG-IFN-β-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-β-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-β-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-β-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-β-1a (statistical reference), glatiramer acetate, and SC IFN-β-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-β-1a (MPR = 0.92±0.1; Coeff=-0.08; p<0.01), compared with PEG-IFN-β-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-β-1a (9.1%; HR=3.35; p=0.01), compared with PEG-IFN-β-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-β-1a (AHR = 0.02±0.21; Coeff=0.01; p=0.97], and PEG-IFN-β-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-β-1a (€29.42±€47.83; Coeff=6.79; p=0.61), and PEG-IFN-β-1a (€23.91±€43.90)., Conclusions: SC PEG-IFN-β-1a and IFN-β-1a were used in relatively similar populations, while glatiramer acetate was preferred in older and more disabled patients. PEG-IFN-β-1a was associated with higher adherence and lower escalation rates toward more effective (and costly) DMTs.