Interferon Beta Treatment Research Articles

Patients with multiple sclerosis who develop immunogenicity to interferon-beta have distinct transcriptomic and proteomic signatures prior to treatment which are associated with disease severity

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.

Reevaluating the role of interferon-beta in psoriasis pathogenesis: A registry-based self-controlled study.

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.

Association of magnetic resonance imaging phenotypes and serum biomarker levels with treatment response and long-term disease outcomes in multiple sclerosis patients.

The aim was to evaluate whether magnetic resonance imaging (MRI) phenotypes defined by inflammation and neurodegeneration markers correlate with serum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in relapsing-remitting multiple sclerosis (RRMS) patients; and to explore the role of radiological phenotypes and biomarker levels on treatment response and long-term prognostic outcomes. Magnetic resonance imaging scans from 80 RRMS patients were classified at baseline of interferon-beta (IFNβ) treatment into radiological phenotypes defined by high and low inflammation and high and low neurodegeneration, based on the number of contrast-enhancing lesions, brain parenchymal fraction and the relative volume of non-enhancing black holes on T1-weighted images. Serum levels of NfL and GFAP were measured at baseline with single molecule array (Simoa) assays. MRI phenotypes and serum biomarker levels were investigated for their association with IFNβ response, and times to second-line therapies, secondary-progressive MS (SPMS) conversion and Expanded Disability Status Scale (EDSS) 6.0. Mean (SD) follow-up was 17 (2.9) years. Serum NfL levels and GFAP were higher in the high inflammation (p = 0.04) and high neurodegeneration phenotypes (p = 0.03), respectively. The high inflammation phenotype was associated with poor response to IFNβ treatment (p = 0.04) and with shorter time to second-line therapies (p = 0.04). In contrast, the high neurodegeneration phenotype was associated with shorter time to SPMS (p = 0.006) and a trend towards shorter time to EDSS 6.0 (p = 0.09). High serum NfL levels were associated with poor response to IFNβ treatment (p = 0.004). Magnetic resonance imaging phenotypes defined by inflammation and neurodegeneration correlate with serum biomarker levels, and both have prognostic implications in treatment response and long-term disease outcomes.

Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis.

Multiple Sclerosis (MS) has a complex pathophysiology that involves genetic and environmental factors. DNA methylation (DNAm) is one epigenetic mechanism that can reversibly modulate gene expression. Cell specific DNAm changes have been associated with MS, and some MS therapies such as dimethyl fumarate can influence DNAm. Interferon Beta (IFNβ), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFNβ reduces disease burden in MS is not fully understood and little is known about the precise effect of IFNβ treatment on methylation. The objective of this study was to determine the changes in DNAm associated with INFβ use, using methylation arrays and statistical deconvolutions on two separate datasets (total ntreated = 64, nuntreated = 285). We show that IFNβ treatment in people with MS modifies the methylation profile of interferon response genes in a strong, targeted, and reproducible manner. Using these identified methylation differences, we constructed a methylation treatment score (MTS) that is an accurate discriminator between untreated and treated patients (Area under the curve = 0.83). This MTS is time-sensitive and in consistent with previously identified IFNβ treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFNβ treatment recruits the endogenous anti-viral molecular machinery. Finally, statistical deconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFNβ induced methylation changes. In conclusion, our study shows that IFNβ treatment is a potent and targeted epigenetic modifier in multiple sclerosis.

Evaluation of the Relationship between Vitamin D Receptor Gene Polymorphisms and Multiple Sclerosis Patients Who Responsive or non-Responsive to Treatment with Beta Interferon

Introduction: Multiple Sclerosis is a chronic, inflammatory disorder of the central nervous system, which leads to demyelination of nerves. Treatment with interferon beta is one of the best approaches to reduce recurrence and progression of the disease. The aim of this study is to search for the relationship between 4 polymorphisms FokIrs10735810, TaqIrs731236, ApaIrs797532 and BsmIrs1544410 located in the vitamin D receptor in MS patients responsive and non-responsive to interferon beta treatment and pave the way for the correct and fast administration of the appropriate drug, as well as reducing time, cost and lack of success in treatment.
 Methods: The type of study is observational and the study method is case-control. Blood samples were taken from 200 MS patients who were treated with interferon (100 responders and 100 non-responders). Using PCR-RFLP technique, the samples were subjected to enzymatic digestion with restriction enzymes ApaI, FokI, TaqI and BsmI. The data were evaluated using SPSS version 16, SNP Analyzer and Prism software, and K-tests and logistic regression.
 Results: A significant difference in the genotypic and allelic frequencies of ApaI (p=0.68), BsmI (p=0.65), FokI (p=0.57) and TaqI (p=0.50) polymorphisms in the patients between the two responsive and non-responsive groups to treatment was not observed.
 Conclusion According to our findings, there was no significant correlation between ApaI, FokI, TaqI and BsmI polymorphisms located in vitamin D receptor gene and response to treatment.

Recurrent encephalopathy associated with pegylated beta-interferon treatment

A 62-year-old woman with a history of multiple sclerosis (MS) presented with recurrent episodes of confusion, dysarthria and gait difficulties. These episodes occurred about 3 days after administration of pegylated interferon-beta-1a (Plegridy®) and resolved spontaneously in around 4 days. The brain MRI scan, laboratory findings and cerebrospinal fluid analysis during these episodes were negative for other causes of encephalopathy. She discontinued treatment with interferon and was started on teriflunomide, experiencing no recurrence of symptoms. We believe that interferon was responsible for this patient's recurrent encephalopathic syndrome, possibly due to its effects on inflammatory cytokines and endothelial dysfunction.

Early spinal cord pseudoatrophy in interferon-beta-treated multiple sclerosis.

Brain pseudoatrophy has been shown to play a pivotal role in the interpretation of brain atrophy measures during the first year of disease-modifying therapy in multiple sclerosis. Whether pseudoatrophy also affects the spinal cord remains unclear. The aim of this study was to analyze the extent of pseudoatrophy in the upper spinal cord during the first 2 years after therapy initiation and compare this to the brain. A total of 129 patients from a prospective longitudinal multicentric national cohort study for whom magnetic resonance imaging scans at baseline, 12 months, and 24 months were available were selected for brain and spinal cord volume quantification. Annual percentage brain volume and cord area change were calculated using SIENA (Structural Image Evaluation of Normalized Atrophy) and NeuroQLab, respectively. Linear mixed model analyses were performed to compare patients on interferon-beta therapy (n= 84) and untreated patients (n= 45). Patients treated with interferon-beta demonstrated accelerated annual percentage brain volume and cervical cord area change in the first year after treatment initiation, whereas atrophy rates stabilized to a similar and not significantly different level compared to untreated patients during the second year. These results suggest that pseudoatrophy occurs not only in the brain, but also in the spinal cord during the first year of interferon-beta treatment.

Cerebrovascular reactivity in multiple sclerosis is restored with reduced inflammation during immunomodulation

Cerebrovascular reactivity (CVR) reflects the capacity of the brain’s vasculature to increase blood flow following a vasodilatory stimulus. Reactivity is an essential property of the brain’s blood vessels that maintains nutrient supplies in the face of changing demand. In Multiple Sclerosis (MS), CVR may be diminished with brain inflammation and this may contribute to neurodegeneration. We test the hypothesis that CVR is altered with MS neuroinflammation and that it is restored when inflammation is reduced. Using a breath-hold task during functional Magnetic Resonance Imaging (MRI), we mapped grey matter and white matter CVRs (CVRGM and CVRWM, respectively) in 23 young MS patients, eligible for disease modifying therapy, before and during Interferon beta treatment. Inflammatory activity was inferred from the presence of Gadolinium enhancing lesions at MRI. Eighteen age and gender-matched healthy controls (HC) were also assessed. Enhancing lesions were observed in 12 patients at the start of the study and in 3 patients during treatment. Patients had lower pre-treatment CVRGM (p = 0.04) and CVRWM (p = 0.02) compared to HC. In patients, a lower pre-treatment CVRGM was associated with a lower GM volume (r = 0.60, p = 0.003). On-treatment, there was an increase in CVRGM (p = 0.02) and CVRWM (p = 0.03) that negatively correlated with pre-treatment CVR (GM: r = − 0.58, p = 0.005; WM: r = − 0.60, p = 0.003). CVR increased when enhancing lesions reduced in number (GM: r = − 0.48, p = 0.02, WM: r = − 0.62, p = 0.003). Resolution of inflammation may restore altered cerebrovascular function limiting neurodegeneration in MS. Imaging of cerebrovascular function may thereby inform tissue physiology and improve treatment monitoring.

Serum IgG levels to Epstein-Barr and measles viruses in patients with multiple sclerosis during natalizumab and interferon beta treatment

BackgroundPatients with multiple sclerosis (MS) demonstrate higher seroprevalence of Epstein-Barr virus (EBV) and increased anti-EBV IgG levels in serum compared with healthy controls. Intrathecal antibody production to measles virus (MeV)...

Urokinase, CX3CL1, CCL2, TRAIL and IL-18 induced by interferon-β treatment.

To identify serum proteins associated with MS and affected by interferon beta treatment. Plasma samples from 29 untreated relapsing-remitting MS patients and 15 healthy controls were investigated with a multiplexed panel containing 92 proteins related to inflammation. Follow-up samples were available from 13 patients at 1 and 3months after initiation of treatment with interferon beta-1a. Ten proteins were differentially expressed in MS patients. Five of these were altered by treatment with IFN-β 1a: uPA, CX3CL1, CCL2, TRAIL and IL18. CCL2 and TRAIL were confirmed to be modulated with interferon beta treatment in MS. As novel findings, we now report that uPA and CX3CL1 were differentially expressed in MS and increased after IFN-beta-1a treatment. Conflicting results have been reported on how interferon beta affects IL-18.

The Influence of Depression and Anxiety on Neurological Disability in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS), affecting mostly young-aged people. As a chronic incurable disease, in most cases, it can lead to progressive neurological impairment and severe disability. Depression and anxiety are major distress factors for MS patients, being considerably aggravating elements for their functional capacity. In this study, we analysed the mood disorder distribution and the possible correlations between depression, anxiety, automatic negative thoughts, and MS disability. We took into consideration 146 MS patients, who completed a series of questionnaires: Beck Depression Inventory II (BDI-II), Endler Multidimensional Anxiety Scales-State (EMAS-S), and Automatic Thoughts Questionnaire (ATQ). The Expanded Disability Status Scale (EDSS) was used to measure the neurological disability. Of all patients, 30.1% had symptoms for depression and 11% presented suicidal thoughts. After analysing the correlation index between each variable, we found that there is a mild positive correlation between depression and the EDSS score and between anxiety and the EDSS score. A difference is found in the test scores according to the type of the MS disease. Also, automatic negative thoughts are strongly correlated with depression and anxiety, but do not mediate the path between psychological comorbidities and neurological impairment. Sociodemographic features and interferon-beta treatment were not related to the intensity of the mood disorders. The study suggests that depression and anxiety are frequently encountered among MS patients and these mental disfunctions have an impact on their disability. A proper identification of these risk factors may improve the quality of life for these patients.

DDX39A interacts with LGP2 to inhibit RLR responses

Abstract RIG-I-like receptors (RLRs) are DEAD-box helicases and cytoplasmic pathogen recognition receptors that recognize and bind to nonself/viral RNA and trigger innate antiviral immunity. RLRs are essential for the detection of RNA virus infection and include RIG-I, MDA5, and LGP2. LGP2 has been implicated as RIG-I or MDA5 co-factor to regulate their activity. We conducted a yeast 2-hybrid (Y2H) screen (using LGP2 as bait) of a human hepatic cDNA library to identify protein binding partners of LGP2. Identified proteins were validated as LGP2 interactors through overexpression and co-immunoprecipitation assays of LGP2 binding. DDX39A, a DEAD Box helicase protein with known roles in RNA splicing, was identified as a binding partner. DDX39A overexpression was found to inhibit interferon-beta production from RLR-signaling in a cell-based ligand-free model in a dose-dependent manner. Further, in a cell-based interferon beta-promoter-luciferase assay model of Sendai virus (SenV) infection, DDX39A and LGP2 synergistically inhibited promoter activity. Similar results were seen in a cell-based NFkB-luciferase assay of the same system. Endogenous expression of DDX39A was assayed through the Huh7 human hepatoma cell line system with various stimuli including viral infection with SenV and Interferon-beta treatment showing that DDX39A is constitutively expressed in those cells. Structure-function mutants of DDX39A and LGP2 were used to determine the protein domains and functions required for interaction via co-immunoprecipitation assays. Through these studies, we will define the interactions between LGP2 and DDX39A, and reveal the roles these proteins have as co-factors in RLR signaling.

Interferon-Beta-Induced Headache in Patients with Multiple Sclerosis: Frequency and Characterization.

BackgroundStudies have shown that interferon-beta (IFN-β) treatment is associated with headaches in patients with multiple sclerosis (MS). Headaches can affect quality of life and overall function of patients with MS. We examined the frequency, relationships, patterns, and characteristics of headaches in response to IFN-β in patients with relapsing-remitting multiple sclerosis (RRMS).Patients and MethodsThis study was a prospective, longitudinal analysis with 1-year follow-up. The study comprised 796 patients with RRMS treated with IFN-β (mean age 30.84±8.98 years) at 5 tertiary referral center outpatient clinics in Egypt between January 2015 and December 2017. Headaches were diagnosed according to the International Classification of Headache Disorders ICHD-3 (beta version), and data were collected through an interviewer-administered Arabic-language-validated questionnaire with an addendum specifically designed to investigate the temporal relationship between commencement of interferon treatment, and headache onset and characteristics.ResultsTwo hundred seventy-six patients had pre-existing headaches, and 356 experienced de novo headaches. Of 122 patients who experienced headaches before IFN-β treatment, 55 reported headaches that worsened following onset of IFN-β treatment. In patients with post-IFN-β headaches, 329 had headaches that persisted for >3 months, 51 had chronic headaches, and 278 had episodic headaches, and 216 of these patients required preventive therapies. Univariate analysis showed a >6- and an approximately 5-fold increased risk of headache among those treated with intramuscular (IM) INF-β-1a (OR 6.51; 95% CI: 3.73–10.01; P-value <0.0001) and 44 μg of SC INF-β-1a (OR 5.44; 95% CI: 3.15–9.37; P-value <0.0001), respectively, compared with that in patients who received 22 μg of SC INF-β-1a.ConclusionInterferon-β therapy aggravated pre-existing headaches and caused primary headaches in patients with MS. Headache risk was greater following treatment with IM INF-β-1a and 44 μg SC INF-β-1a.

Cerebrospinal fluid inflammatory biomarkers predicting interferon-beta response in MS patients.

Background and Aims:Interferon beta (IFNb) is a safe first-line drug commonly used for relapsing-remitting (RR)-MS. Nevertheless, a considerable proportion of patients do not respond to IFNb treatment. Therefore, until now, a number of studies have investigated various markers that could predict the patients who would respond to IFNb therapy. The objective of this study was to identify reliable biomarkers to predict the efficacy of IFNb treatment in MS.Methods:In a group of 116 patients with clinically isolated syndrome (CIS) and RR-MS, we explored the association between CSF detectability of a large set of proinflammatory and anti-inflammatory molecules at the time of diagnosis and response to IFNb after the first year of treatment. The absence of clinical relapses, radiological activity and disability progression (NEDA-3) was assessed at the end of 1-year follow up. The results were compared with those obtained in additional groups of CIS and RR-MS patients treated with other first-line drugs (dimethyl fumarate and glatiramer acetate).Results:CSF undetectability of macrophage inflammatory protein (MIP)-1α was the main predictor of reaching NEDA-3 status after 1 year of IFNb treatment. Moreover, detectable platelet-derived growth factor (PDGF) was associated with higher probability of reaching NEDA-3. Conversely, no associations with the CSF molecules were found in the two other groups of patients treated either with dimethyl fumarate or with glatiramer acetate.Conclusion:MIP-1α and PDGF could potentially represent suitable CSF biomarkers able to predict response to IFNb in MS.

B cell function impacts the efficacy of IFN-β therapy in EAE

Recent studies identified that interferon beta (IFN-β) treatment skews B-cells towards a regulatory phenotype in multiple sclerosis. To assess B cell involvement during IFN-β therapy, we compared IFN-β treatment in a B cell-independent model and a B cell-dependent model of experimental autoimmune encephalomyelitis (EAE). We show that in B cell-independent EAE, IFN-β ameliorates neuroinflammation. Conversely, in B cell-dependent EAE, IFN-β has no effect on disease. Effective IFN-β therapy in B cell-independent EAE was associated with reduced inflammatory T cells in the CNS and skewed splenic B cells towards an immature population and away from a germinal center population. These immune cell populations were unchanged in B cell-dependent EAE. Finally, we found that IFN-β increased marginal zone B cells in both EAE models. These findings indicate that B cell function impacts IFN-β efficacy during neuroinflammation.

ACCELERATED DEVELOPMENT OF PULMONARY ARTERIAL HYPERTENSION IN THE SETTING OF ABATACEPT THERAPY

SESSION TITLE: Pulmonary Vascular Disease SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/22/2019 3:45 PM - 4:45 PM INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare and debilitating disease, commonly related to connective tissue disease (CTD), idiopathic or hereditary in nature or due to certain drugs. New medications have been acknowledged as being a risk factor for developing PAH.There are case reports of some biologic drugs as a possible risk factor. Abatacept is a chimeric protein that inhibits T-lymphocyte activation and is used as a biologic drug to treat autoimmune diseases. We present a patient with PAH and acceleration of symptoms after initiation of Abatacept for underlying autoimmune disease. CASE PRESENTATION: We present a 46-year-old woman with mixed connective tissue disease and rheumatoid arthritis for 5 years, who presented with six weeks of rapidly progressed dyspnea on exertion, orthopnea and pedal edema. She had been evaluated 2 months prior, while on Infliximab, for mild intermittent dyspnea for the past 6 months and noted to have normal pulmonary function and echocardiogram. She was subsequently switched to Abatacept due to a intolerance with Infliximab. A month after initiation of this medication her dyspnea worsen and she presented 10 weeks after with severe dyspnea. Echocardiogram revealed moderate right ventricle (RV) dilation and estimated pulmonary artery systolic pressure (PASP) of 93 mmHg and right atrial pressure (RAP) of 15 mmHg. Pulmonary embolism was ruled out. Right heart catheterization (RHC) measured a mean PAP of 50 mmHg and PVR of 20 Woods units. PAH was diagnosed with WHO functional class 3. Abatacept was discontinued as a potential risk factor that accelerated symptoms.Combination therapy was initiated with Tadalafil, Ambrisentan and Furosemide, and her WHO functional class improved to 1. Repeat echocardiogram at 6 months showed PASP: 35 mmHg, RAP: 3 mmHg with normal RV size and function and markedly improved six-minute walk distance. DISCUSSION: PAH is an uncommon debilitating disease with nonspecific symptoms, making early diagnosis challenging. This makes identification of risk factors for development and progression of PAH crucial. CTD is a well-established risk factor as are certain medications. With the growing use of biologic drugs for CTD therapy, these drugs as risk factors for PAH might grow as well. To the best of our knowledge this is the second case reported with Abatacept potentially accelerating PAH symptoms in the setting of treatment for CTD. CONCLUSIONS: In an era of increasing biologic agents use in patients with CTD, who are already at risk for PAH, physicians need to be aware of this potential association. Reference #1: Promislow, S. et al. Pulmonary arterial hypertension associated with abatacept treatment for rheumatoid arthritis: A case report. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2018 Reference #2: Gibbson, E. et al Reversible pulmonary arterial hypertension associated with interferon-beta treatment for multiple sclerosis. Can Respir J. 2015 DISCLOSURES: No relevant relationships by Selvin Jacob, source=Web Response No relevant relationships by Ginny Marmolejos, source=Web Response No relevant relationships by Kartik Ramakrishna, source=Web Response

Effect of Interferon-Beta Treatment on the Proportion of T Helper 17 Cells and Related Cytokines in Multiple Sclerosis: A Meta-Analysis.

T helper 17 (Th17) cells and related cytokines are important in multiple sclerosis (MS), which have become the new therapeutic targets of MS. In published studies, the effect of interferon-β (IFN-β) on the proportion of Th17 cells and related cytokines in MS patients remains controversial. We did a meta-analysis to assess the role of IFN-β on Th17 cells and related cytokines in MS patients. Compared with control subjects, MS patients with IFN-β treatment had a lower proportion of Th17 cells in CD4+ T cells of peripheral blood [-1.49 (-2.96 to -0.02)], interleukin (IL)-17 level [-1.08 (-1.77 to -0.40)], and IL-23 level [-1.63 (-2.59 to -0.68)] in serum. The results showed that IFN-β can reduce the proportion of Th17 cells, the levels of IL-17 and IL-23 in serum of MS.

Evaluation of Association between Flu-Like Syndrome Induced by Beta Interferon Drug and Required Drug Response in Patients with Multiple Sclerosis

Background: Beta interferon is one of the important drugs for multiple sclerosis. Its common side effects are flu-like symptoms caused by drug injection. The purpose of this study was to evaluate the possibility of predicting the response rate of this drug based on the flu-like drug reaction.Materials and Methods: This case-control study performed in Loghman Hakim hospital in Tehran in 2017 and 110 patients with multiple sclerosis under beta interferon treatment studied. Patients were divided into two groups with and without flu-like drug reaction. A neurology resident according to the patient’s history and patient records filled in the questionnaires. The results of the two groups were compared by SPSS 16 software.Results: A total of 110 patients including 31 patients with flu-like drug reaction and 79 non-complicated patients were evaluated. These patients included 32 males and 78 females with an average age of 35.55 years. The mean duration of beta interferon use was 4.33 years in the case group and 4.34 years in the control group. Finally, a significant correlation between the flu-like drug reaction and the optimal response in the first year treatment was found (p=0.026). In addition, cause of drug discontinuation had significant correlation with presence of flu like drug reaction (p=0.028). There was no significant correlation between the disease annual attacks rate and flu like drug reaction.Conclusion: Flu-like drug reaction is a common complication of interferon beta drugs, which has a therapeutic difference in patients with and without this drug reaction.

DNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins, which strongly argues for involvement of epigenetic factors. We observe highly similar peripheral blood mononuclear cell-based methylomes in 45 MS-discordant monozygotic twins. Nevertheless, we identify seven MS-associated differentially methylated positions (DMPs) of which we validate two, including a region in the TMEM232 promoter and ZBTB16 enhancer. In CD4 + T cells we find an MS-associated differentially methylated region in FIRRE. Additionally, 45 regions show large methylation differences in individual pairs, but they do not clearly associate with MS. Furthermore, we present epigenetic biomarkers for current interferon-beta treatment, and extensive validation shows that the ZBTB16 DMP is a signature for prior glucocorticoid treatment. Taken together, this study represents an important reference for epigenomic MS studies, identifies new candidate epigenetic markers, and highlights treatment effects and genetic background as major confounders.

Long-term disability outcomes in relapsing-remitting multiple sclerosis: a 10-year follow-up study.

The aim of this study is to assess the impact of interferon (IFN) beta treatment on the development of worsening disability in relapsing-remitting (RR) multiple sclerosis (MS) patients in the single-center observation cohort. This is a prospective study of 236 IFN-beta-treated and 183 untreated RRMS patients recruited consecutively at the Clinic of Neurology in Belgrade (Serbia). Out of this original cohort, 10-year follow-up data were available for 233 IFN-beta-treated and 131 untreated subjects. The median time since recruitment was 9.7years. IFN-beta treatment significantly delayed (p < 0.001) the time to reach each of the clinical outcomes (secondary progression-SP, EDSS scores 4 and 6) since recruitment. Time from the first visit to SP was reached after 9.7years for IFN-beta-treated vs. 7.8years for untreated patients. The delay for the development of EDSS score ≥ 4 from the first visit was 1.6years (8.7years for IFN-beta-treated vs. 7.1years for untreated patients). Time from the first visit to EDSS score of 6 was reached after 9.8years for IFN-beta-treated vs. 8.8years for untreated patients. The IFN-beta-treated group showed significant reduction (p < 0.001) in the risk of conversion to SP when compared with untreated patients (HR = 0.22). There was also a significant difference in reaching EDSS scores 4 and 6 (p < 0.001), in favor of the IFN-beta-treated group (HR = 0.40 and HR = 0.27, respectively). Comparison of outcomes in our IFN-beta-treated vs. untreated RRMS patients suggests that this treatment may delay development of long-term disability in MS.