Interferon Beta In Multiple Sclerosis Research Articles

Persistence, adherence, healthcare resource utilisation and costs for interferon Beta in multiple sclerosis: a population-based study in the Campania region (southern Italy)

BackgroundTo differentiate five formulations of Interferon Beta for the treatment of multiple sclerosis (MS) in clinical practice, by analysing persistence, adherence, healthcare resource utilisation and costs at population level.MethodsIn this population-based study, we included individuals with MS living in the Campania Region of Italy from 2015 to 2017, on treatment with intramuscular Interferon Beta-1a (Avonex® = 618), subcutaneous pegylated Interferon Beta-1a (Plegridy® = 259), subcutaneous Interferon Beta-1a (Rebif® = 1220), and subcutaneous Interferon Beta-1b (Betaferon® = 348; and Extavia® = 69). We recorded healthcare resource utilisation from administrative databases (hospital discharges, drug prescriptions, MS-related outpatients), and derived costs from the Regional formulary. We classified hospital admissions into MS-related and non-MS-related. Persistence (time to switch to other disease modifying treatments (DMTs)), and adherence (medication possession ratio (MPR) = medication supply obtained/medication supply expected during follow-up period) were calculated.ResultsPatients treated with Rebif® were younger, when compared with other Interferon Beta formulations (p < 0.01). The probability of switching to other DMTs was 60% higher for Betaferon®, 90% higher for Extavia®, and 110% higher for Plegridy®, when compared with Rebif® (p < 0.01). Plegridy® presented with 7% higher adherence (p < 0.01), and Betaferon® with 3% lower adherence (p = 0.03), when compared with Rebif®. The probability of MS-related hospital admissions was 40% higher in Avonex® (p = 0.03), 400% higher in Betaferon® (p < 0.01), and 60% higher in Plegridy® (p = 0.04), resulting into higher non-DMT-related costs, when compared with Rebif®.DiscussionInterferon Beta formulations presented with different prescription patterns, persistence, adherence, healthcare resource utilisation and costs, with Rebif® being used in younger patients and with less MS-related hospital admissions.

Multi-centre validation of a flow cytometry method to identify optimal responders to interferon-beta in multiple sclerosis

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

NLRP3 polymorphisms and response to interferon-beta in multiple sclerosis patients

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

Higher Serum Uric Acid Levels in Multiple Sclerosis Patients After Longterm Interferon Beta Treatment

Abstract Interferon beta is a safe and efficacious treatment for relapsing multiple sclerosis (MS). However, there is some evidence that uric acid, a scavenger of peroxynitrite, is involved in MS pathology and that increasing serum uric acid levels might have beneficial therapeutic effects. The aim of this study is to investigate serum uric acid levels in MS patients before and after long-term interferon beta treatment. Blood samples from 101 MS patients (53 receiving interferon beta 1a treatment and 48 receiving interferon beta 1b treatment; 28 male and 73 female; mean age at treatment onset 32,4±7,3 years; mean duration of disease at treatment onset 5,1±3,2 years; mean EDSS 2±1,3) before and after interferon beta treatment (mean treatment duration 3±2 years) were analysed. Serum uric acid levels were measured using a quantitative enzymatic assay (Elitech Diagnostic, Sees, France). MS patients had significantly increased serum uric acid levels after treatment compared with those at the beginning of treatment (272,31±78,21 μmol/l vs. 210,17±53,65 μmol/l; p=0,019, Wilcoxon Mann-Whitney U-test). We did not find significant differences in serum uric acid levels between the interferon beta 1a and interferon beta 1b groups (p=0.98). These results indicate that one of the beneficial effects of interferon beta in MS might be based on the elevation of serum uric acid levels as a natural scavenger of peroxynitrite.

Effect on Cognition of Estroprogestins Combined with Interferon Beta in Multiple Sclerosis: Analysis of Secondary Outcomes from a Randomised Controlled Trial.

Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-β) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. We investigated whether a combination of estroprogestins and IFN-β can improve cognition in women with MS. Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-β-1a (Rebif®, Merck Serono, Geneva, Switzerland) 44mcg three times a week (tiw) (group 1), subcutaneous IFN-β-1a 44mcg tiw plus ethinyl estradiol 20mcg and desogestrel 150mcg (Mercilon®, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-β-1a 44mcg tiw plus ethinyl estradiol 40mcg and desogestrel 125mcg (Gracial®, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao's Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined 'cognitive impairment'. At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p=0.03). The risk of developing cognitive impairment over 24months was lower in group 3 (p=0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p=0.03). This study suggests that the combination of high-dose estroprogestins and IFN-β may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised. Protocol Number NCT00151801, registered in ClinicalTrials.gov.

Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial.

Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity. The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity.

In Memoriam: Jean Lindenmann (1924-2015): A Circuitous Interfering Power in Neurology.

Sometimes, the intended consequences of scientific discovery are not the ones that ultimately have the greatest impact on humanity. This is certainly the case of the interferons, which were discovered jointly by Jean Lindenmann and Alick Isaacs in an attempt to elucidate the role of interferons in host innate immune responses against viral infections. Dr Lindenmann, a Swiss virologist who passed away on January 15, 2015, in Zurich, Switzerland, was an outstanding scientist whose contributions to the interferon field were groundbreaking. He joined Dr Isaacs in the mid-1950s as a postdoctoral fellow at the National Institute for Medical Research in Mill Hill in London, England. The purpose of his research was to study the nature of “viral interference.” When he commenced his work it was already established that incubation of a tissue or tissue culture with heatinactivated virus could prevent the replication of a virus that was subsequently added. Drs Lindenmann and Isaacs subsequently demonstrated that fluid conditioned for 24 hours with chick chorio-allantoic membranes exposed to inactivated virus could transfer this “interfering power” to fresh membranes, indicating that additional “interfering activity” had been generated.1 Dr Lindenmann then showed that a certain time lapse was required to obtain interference, suggesting that a new protein had to be generated to achieve this. Furthermore, dilution experiments indicated a linear relationship between the concentration of interferon and its antiviral potency.2 The seminal article reporting the discovery of interferons was published in 1957,3 which ultimately proved to be a family of proteins with a very high specific activity and a broad spectrum of biological effects. Dr Lindenmann returned to Zurich but did not pursue the purification and structural analysis of interferon. He was convinced that this task would be more or less rapidly accomplished by biochemists.4 In retrospect, this decision may appear misguided: Thousands of man-years later, in 1980, Ernest Knight remarked that “the best way to describe the progress in purification and characterization of the interferon proteins is that it has just begun.”5 At that time, the multiplic ity of interferon species and the low levels of production proved to be an almost unsurmountable barrier. Rather than purifying interferon, Dr Lindenmann explored its mechanism of action and identified a dominant autosomal gene, which he called Mx (now called Mx+), that mediated interferon-induced resistance aga ins t in f luenza and some othe r v i ruses . The Mx promoter is a powerful tool to direct controlled expression of a downstream gene and is now widely used in inducible gene expression in experimental mice.6 After 1980, research in the interferon field progressed rapidly as recombinant DNA technology clarified the relationship between the many interferon species and allowed the production of pure interferon on the kilogram scale. Most importantly, the generation of interferons on an industrial scale led to legitimate clinical applications. In 1987, Hillel Panitch, MD, and colleagues conducted a clinical trial with interferon gamma in patients with relapsingremitting multiple sclerosis (MS).7 At that time, many MS experts considered MS to be a viral, postviral, or paraviral disorder, which made interferon gamma a plausible intervention. Unexpectedly, a disproportionate number of patients displayed disease exacerbations, and bioassays detected an increase in circulating HLA-DR–positive monocytes in peripheral blood of recipients. These observations strongly suggested that MS disease exacerbations are immune mediated and not the consequence of viral illness. In contrast, interferon beta preparations have been approved and used for the treatment of MS for more than 20 years. The biological beneficial effects of interferon beta in MS, which include the reduction of disease attacks and brain lesions on magnetic resonance imaging, are pleiotropic and still incompletely understood. The recent approval of pegylated interferon beta-1a will likely ensure that they remain a mainstay of MS therapy for decades to come. Thus, Dr Lindenmann’s discovery not only opened up a new area of basic research, but also led to practical medical benefits. Those who knew Dr Lindenmann describe him as a gifted communicator who time and again delighted laymen and colleagues alike with his philosophical and historical discourses on scientific topics. Modest and unassuming, he kept out of the limelight toward which many another with his accomplishments would have striven. Jean Lindenmann

Gender effects on treatment response to interferon-beta in multiple sclerosis.

Gender appears to play a role in incidence and disease course of multiple sclerosis (MS). The objective was to determine whether male and female patients with MS respond differently to interferon-beta treatment in terms of reduction in relapse rates. We included all 2033 patients with relapsing-remitting MS who started treatment with interferon-beta from 1996 to 2003, identified from the Danish Multiple Sclerosis Treatment Register. We defined neutralizing antibody (NAb)-positive and NAb-negative periods in the single patient by the results of the NAb tests. Patients served as their own controls, and relapse rates were compared between NAb-negative and NAb-positive periods. NAbs significantly abrogated the interferon-beta treatment efficacy in both genders. The all-over women:men relapse rate ratio irrespective of NAb status was 1.47 (95%CI; 1.28-1.68). In a generalized linear Poisson models analysis with relapse counts as response variable, the main effects NAbs, sex, age at treatment start and number of relapses in 2 years before treatment start were strongly significant, but the effect of NAbs on relapse rates did not differ significantly between men and women. As NAbs influenced the on-treatment relapse rates strongly in both sexes but without statistical significant difference, there is no indication of different effects of interferon-beta in men or women.

Correction of Non-Response to Interferon-beta in Multiple Sclerosis (P01.203)

Correction of Non-Response to Interferon-beta in Multiple Sclerosis (P01.203)

Cell-Based Reporter Gene Assay for Therapy-Induced Neutralizing Antibodies to Interferon-Beta in Multiple Sclerosis

Patients with therapy-induced neutralizing antibodies (NAbs) to interferon-beta (IFN-β) have reduced responses to IFN-β treatment, resulting in higher relapse rates, increased magnetic resonance imaging activity, and a higher risk of disease progression. A functional assay was employed for both screening and titering of IFN-β NAbs utilizing a human cell line transfected with a luciferase reporter gene responsive to IFN-β. This assay demonstrated 100% sensitivity and specificity compared with the traditional cytopathic effect (CPE) assay and normal donor specimens. Additionally, 183 patients with multiple sclerosis (MS) undergoing therapy with IFN-β were tested in the reporter gene assay. Percent positivity for NAbs to the IFN-β was as follows: Avonex (1α) 26.5%, Rebif (1α) 34.1%, and Betaseron (1β) 31.8%. The IFN-β reporter gene assay showed excellent correlation with the well-established CPE assay offering clear advantages. The 50% false-positivity rate typically seen in enzyme-linked immunosorbent assays could be eliminated by using a functional assay for both screening and titering. Results can be reported within 20 h, and the cell line is cryopreserved, eliminating the need to maintain live viral and cell cultures. The use of this functional assay should be a valuable tool for detecting and monitoring the presence of NAbs in IFN-β-treated patients with MS.

Treatment With Interferon Beta for Multiple Sclerosis

TotheEditor:DrShirani andcolleagues suggested that interferonbeta treatmentwasnotassociatedwithareductioninprogression of long-term disability in patients with multiple sclerosis (MS). In contrast, long-term follow-up of a randomized controlled trialof interferonbeta-1breporteda60%to70%reduction in long-term disability and a 46% to 47% reduction in mortality. Although Shirani et al did not cite these studies, both reports used bias-reduction methods. Time zero was the same for all patients (either eligibility for interferon beta treatmentortrialentry)sothattherewasnoimmortaltimebias, andbothanalysesusedpropensityscore(covariate)adjustment. Through their study design, Shirani et al introduced an important source of selection bias. Although covariate adjustment was undertaken at time zero, this method does not adjust adequately for subsequent treatment decisions. Every patient who ultimately chose not to receive treatment began this option immediately after becoming eligible. If such a patient deteriorated, however, they may have been treated. Thus, only clinically stable patients would remain untreated whereas treated patients would begin therapy at staggered times after eligibility, depending on their clinical status. This bias cannot be overcome by using time-dependent covariates or covariate adjustment because, by definition, the no treatment group must survive the observation period untreated. This bias is indicated by the reversal in the hazard ratio (HR) direction when using the historical control group. Although interferon beta treatment was not statistically significantly associated with reaching an Expanded Disability Status Scale (EDSS) score of 6, the HR was increased compared with the contemporary controls (HR, 1.30; 95% CI, 0.921.83) and decreased compared with the historical controls (HR, 0.77; 95% CI, 0.58-1.02). Similarly, this selection bias in the contemporary control group is also suggested by the observed increase in HRs for the treatment and posttreatment intervals compared with the pretreatment interval (eFigure 5 in article). This pattern suggests that patients may have been followed up without interferon beta treatment until they worsened or that treatment may have been discontinued in those who progressed further. To avoid this bias, controls without access to treatment are necessary. Unfortunately, almost 20% of the historical controls in the study were excluded for having received interferon beta therapy during follow-up. Thus, even within the historical control group, untreated patients may have been selected for doing well without therapy.

Suspected autoimmune hepatitis and primary biliary cirrhosis unmasked by interferon-beta in a multiple sclerosis patient

The use of interferon-beta in multiple sclerosis is associated with various forms of hepatotoxicity, including autoimmune hepatitis and liver failure. We describe a case with features of autoimmune liver disease and primary biliary cirrhosis occurring during long-term treatment with interferon-beta in a patient with relapsing-remitting multiple sclerosis. This case highlights the importance of monitoring biochemical liver test results throughout interferon-beta treatment of multiple sclerosis.

Biological Effects of Neutralizing Antibodies Against Interferon beta in Multiple Sclerosis (on Behalf of the NABINMS Study Group) (S31.005)

Biological Effects of Neutralizing Antibodies Against Interferon beta in Multiple Sclerosis (on Behalf of the NABINMS Study Group) (S31.005)

IL28B polymorphisms are not associated with the response to interferon-beta in multiple sclerosis

Recent studies have revealed an association between interleukin 28B ( IL28B) and response to IFN-alpha treatment in hepatitis C patients. Here we investigated the influence of IL28B polymorphisms in the response to interferon-beta (IFNβ) in multiple sclerosis (MS) patients. We genotyped two SNPs of the IL28B gene (rs8099917 and rs12979860) in 588 MS patients classified into responders (n = 281) and non-responders (n = 307) to IFNβ. Combined analysis of the study cohorts showed no significant associations between SNPs rs8099917 and rs12979860 and the response to treatment. These findings do not support a role of IL28B polymorphisms in the response to IFNβ in MS patients.

Influence of the HLA-DRB1 Genotype on Antibody Development to Interferon Beta in Multiple Sclerosis

To determine relevant HLA-DRB1 alleles associated with the susceptibility of anti-interferon beta antibody development in a large patient cohort. In a case-control study, HLA-DRB1 genotyping was performed in a discovery cohort (n = 268) and a validation cohort (n = 825). Patients were recruited in Germany by primary care physicians and neurologists and were mainly of Northern European heritage. All patients had a diagnosis of multiple sclerosis and were receiving long-term interferon beta therapy. The antibody status to interferon beta was determined in all patients by capture enzyme-linked immunosorbent assay and in vivo myxovirus protein A assay and correlated with the HLA-DRB1 genotype. In the discovery and validation cohorts, HLA-DRB1*04:01, *04:08, *16:01 were identified as genetic markers that are associated with an increased risk of anti-interferon beta antibody development (P < .05). In addition, alleles with a protective potential were identified, including HLA-DRB1*03:01, *04:04, *11:04. However, after correction for multiple testing, protective alleles did not reach statistical significance. The HLA alleles identified in this study seem to be the major genetic determinant of antibody development, allowing the prediction of the individual risk of patients before initiation of therapy.

One‐year MRI scan predicts clinical response to interferon beta in multiple sclerosis

To define the predictive value of clinical and magnetic resonance imaging (MRI) characteristics in identifying relapsing-remitting multiple sclerosis (RR-MS) patients with sustained disability progression during interferon beta (IFNB) treatment. All patients receiving treatment with one of the available IFNB formulations for at least 1 year were included in this single-centre, prospective and post-marketing study. Demographic, clinical and MRI data were collected at IFNB start and at 1 year of therapy; patients were followed-up at least yearly. Poor clinical response was defined as the occurrence of a sustained disability progression of > or =1 point in the Expanded Disability Status Scale (EDSS) during the follow-up period. Out of 454 RR-MS patients starting IFNB therapy, data coming from 394 patients with a mean follow-up of 4.8 (2.4) years were analysed. Sixty patients were excluded because of too short follow-up. Less than 1/3 (30.4%) of the patients satisfied the criterion of 'poor responders'. Patients presenting new lesions on T2-weighted MRI scan after 1 year of therapy (compared with baseline) had a higher risk of being poor responder to treatment with IFNB during the follow-up period (HR 16.8, 95% CI 7.6-37.1, P < 0.001). An augmented risk increasing the number of lesions was observed, with a 10-fold increase for each new lesion. Developing new T2-hyperintense lesions during IFNB treatment was the best predictor of long-term poor response to therapy. MRI scans performed after 1 year of IFNB treatment may be useful in contributing to early identification of poor responders.

Interferons and autoimmune disorders

Interferons are ubiquitous cytokines produced by all mononuclear cell types in response to infection by a DNA or RNA virus. There are three major classes of interferons: type I or nonimmune interferons consist chiefly of interferons alpha produced by leukocytes and of interferon beta produced by fibroblasts, although there are several other less important variants; type II or immune interferon is interferon gamma, which is mainly produced by NK cells and T cells; and type III consists of the lambda interferons. Each type is characterized by a specific receptor and signal transduction pathway. Toll-like receptors (TLRs) on the cell membrane and endosomes recognize viruses and other microorganisms. Binding of DNA or RNA to endosomal TLRs generates a signal whose transduction pathways lead to molecules capable of binding to genes for various interferons, interleukin-1, and TNFα. Interferons can stimulate or inhibit up to 300 different genes encoding proteins involved in antiviral defense mechanisms, inflammation, adaptive immunity, angiogenesis, and other processes. The properties of interferons are used to treat a number of viral infections (e.g., hepatitis B and hepatitis C), inflammatory diseases (interferon beta for multiple sclerosis and interferon gamma for systemic sclerosis), and malignancies. Overactivation of the interferon pathways has been demonstrated in patients with systemic lupus erythematosus. The result is a characteristic pattern of mRNA expression known as the interferon signature. Interferon overactivation is related to inadequate clearance of apoptotic particles with accumulation of apoptosis products (DNA-CpG motifs and U-RNA). Similar abnormalities have been found in patients with primary Sjögren's syndrome, systemic sclerosis, and polymyositis, as well as in some cases of rheumatoid arthritis. Immunomodulation strategies designed to decrease interferon overactivity are being evaluated in patients with systemic lupus erythematosus.

A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis

The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-beta in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-beta for a minimum of 2 years and classified as responders and non-responders based on clinical criteria. A validation cohort of 30 multiple sclerosis patients was included in the study to replicate gene-expression findings. Before treatment, interferon-beta responders and non-responders were characterized by differential expression of type I interferon-induced genes with overexpression of the type interferon-induced genes in non-responders. Upon treatment the expression of these genes remained unaltered in non-responders, but was strongly upregulated in responders. Functional experiments showed a selective increase in phosphorylated STAT1 levels and interferon receptor 1 expression in monocytes of non-responders at baseline. When dissecting this type I interferon signature further, interferon-beta non-responders were characterized by increased monocyte type I interferon secretion upon innate immune stimuli via toll-like receptor 4, by increased endogenous production of type I interferon, and by an elevated activation status of myeloid dendritic cells. These findings indicate that perturbations of the type I interferon signalling pathway in monocytes are related to lack of response to interferon-beta, and type I interferon-regulated genes may be used as response markers in interferon-beta treatment.

Antibodies against interferon-beta in multiple sclerosis

We measured the frequency of binding antibody (BAB) and neutralizing antibody (NAB) against interferon-beta (IFN-β) in sera from 827 patients with relapsing-remitting multiple sclerosis (RRMS) using various IFN-β medications. Of the 827 patients, 363 (43.9%) had serum BAB after more than 12 months of IFN-β treatment. Of the 363 BAB-positive sera, we analyzed 137 for BAB using a myxovirus-resistant protein A (MxA) protein induction assay (ELISA) and an MxA messenger RNA (mRNA) induction assay (real-time polymerase chain reaction (PCR)). We obtained similar results for each serum in both NAB assays, indicating a good correlation between transcription and translation of MxA. We tested all 363 sera by real-time PCR, and NAB was present in 70.8% of BAB-positive sera, or 31.1% of the 827 patients with relapsing-remitting multiple sclerosis (RRMS). Real-time PCR offers several advantages for measuring NAB compared with the MxA protein induction enzyme-linked immunosorbent assay and should be used routinely for NAB among patients with MS using IFN-β treatment.

Reversible bilateral optic neuritis after Infliximab discontinuation in a patient with Crohn's disease

A relationship between inflammatory bowel disease and multiple sclerosis is supported by a higher than expected coexistence of these diseases among families and individuals. A 32 year-old male with Crohn's disease of the terminal ileum diagnosed 4 years ago and HLA-B27 negative bilateral sacroiliitis diagnosed 2 years ago, was admitted in our hospital because of an acute episode of blurred vision. In addition the patient complained for urine incontinence. Before this admission the patient was administered methylprednisolone and Infliximab induction treatment. During admission the diagnosis of multiple sclerosis-associated bilateral optic neuritis was made and Infliximab was discontinued. The patient was started on therapy with interferon-beta for multiple sclerosis, prednizolone and azathioprine for Crohn's disease and oxybutynin hydrochloride for urine incontinence. After 8 weeks of Infliximab discontinuation patient recovered totally from optic neuritis. This is a rare case of totally reversible bilateral optic neuritis associated with multiple sclerosis in a patient with Crohn's disease and sacroiliitis receiving also Infliximab induction therapy.