Interferon beta in relapsing–remitting multiple sclerosis

Background and objective Long–term observational studies may provide additional information about the behaviour of different drugs in the post–marketing period. We present the data of our cohort of relapsing–remitting multiple sclerosis (RRMS) patients treated with interferon beta (IFNβ). Methods We analysed RRMS patients followed for at least 2 years. From 1995, we initiated therapy with IFNβ.As they became available, patients were allocated to one of the IFNs at standard doses (IFNβ–1b, IFNβ–1a i. m. or IFNβ–1a s. c.). Each patient was included in a follow–up protocol containing demographic and baseline clinical data. Results Between 1995 and 2004, 382 patients have completed at least 2 years of follow–up. Significant differences at entry were observed. Patients on IFNβ–1b had a higher disease activity and disability at baseline than those on IFNβ–1a i. m. or IFNβ–1a s. c. A significant reduction in the relapse rate was observed for the three drugs (70 % for IFNβ–1b, 64% for IFNβ–1a i. m. and 74 % for IFNβ–1a s. c.). We observed a sustained progression of disability in 11% of patients on IFNβ–1b, 17% on IFNβ–1a i. m. and 19% on IFNβ–1a s. c.; and at four years of follow–up in 24% of patients on IFNβ–1b, 23% on IFNβ–1a i. m. and 35% on IFNβ–1a s. c. No unexpected major adverse events were observed with any of the drugs. Conclusions Interferon beta is safe and well tolerated. The various registered interferon beta drugs provide a comparable efficacy in a large non–selected cohort of RRMS patients.     

The combination of cyclophosphamide plus interferon beta as rescue therapy could be used to treat relapsing–remitting multiple sclerosis patients

The aim of the present study was to evaluate the efficacy of the combination of cyclophosphamide (CTX) and interferon beta (IFN β) in a group of relapsing remitting (RR) multiple sclerosis (MS) patients who experienced treatment failure during IFN β therapy. It is the general experience that immunomodulatory agents (IMA) are only partially effective in RR patients. Recent data on the efficacy of immunosuppressive therapies for these patients are encouraging. The anti–inflammatory and immunosuppressive effects of CTX have been utilized to treat selected cases of multiple sclerosis with a progressive and worsening course as rescue therapy. Thirty RR MS patients with clinically defined MS who experienced treatment failure during IFN β therapy (2 or more relapses per year or 1.5 EDSS point worsening in one year) were enrolled in the study and treated with CTX iv pulse therapy added to IFN β and followed up for 24 months. As primary endpoints we evaluated the yearly relapse rate. We also evaluated the percentage of patients free of relapses and of EDSS variations. We analysed the results at one year before entry (T0: IFN β alone), 12 (T1) and 24 (T2) months after entry. Brain MRI was performed at T0, at T1 and T2. The 30 RR patients who had experienced a high number of relapses (r r =1.4) at T0 showed a significant improvement in yearly relapse rate (rr = 0.4) at T1 and a further improvement (rr = 0.17) at T2 (p < 0.001). The percentage of patients free of relapse was 70% at T2 (p < 0.0001). EDSS score changed from 2.6±1.23 at T0 to 2.2 ± 1.5 at T2, showing only a trend of improvement.No significant variation of MRI lesion load and no severe adverse events were recorded during the study. These data showed that the combination of CTX plus IFN β halted the progression of disease in active and deteriorating MS patients suggesting the necessity of RCTs to test the efficacy of this combination therapy in active RRMS patients or in patients who experienced treatment failure in response to disease modifying drugs (DMDs).     

Does interferon beta therapy affect survival of multiple sclerosis patients?

Multiple sclerosis (SM) is a chronic inflammatory and degenerative disease of the central nervous system. Its etiology has not been fully elucidated. For approximately 20 years, drugs have been used, successfully modifying the natural course of relapsing-remitting SM. One of them is interferon beta. Research outcomes of 16- and 21-year-retrospective follow-up of patients who participated in the pivotal interferon beta-1b trial were reported in 2010 and 2012, respectively. After 21 years, mortality rate among patients treated in the first 5 years with interferon beta-1b at a dose of 250 μg was significantly lower, irrespective of the cause, as compared to the placebo-controlled group. Interferon beta-1b administered during the first 5 years of the study decreased the risk of death by 46.8% as compared to the placebo patients. Moreover, the studies also confirmed safety of long-term interferon beta-1b therapy. However, not much is known about the effect of interferon beta-1a on patients’ survival – the available data are presented in the article.     

Interferon beta inhibits the Th17 cell-mediated autoimmune response in patients with relapsing–remitting multiple sclerosis

Interferon (IFN)β has been used over the past decades as an effective first-line therapy against relapsing–remitting multiple sclerosis (RR MS), however its in vivo operative mechanisms of action are not fully understood. Current advances in our understanding of the development of the autoimmune response, including its induction by a recently discovered Th17 cell lineage, may allow us to identify the biomarkers of this effective therapy. Our in vitro human studies have characterized IFNβ’s immunoregulatory effects on Th17 cell differentiation. IFNβ inhibited IL-1β, IL-23 and transforming growth factor (TGF)-β (which induce Th17 cell differentiation), and induced IL-27, IL-12p35 and IL-10 (which suppress it) in dendritic cells (DCs) and B-cells. The effect on IL-1β, IL-23 and IL-27 production in DCs was mediated by the up-regulation of Toll-like receptor (TLR)7 and its downstream signaling molecules. IFNβ’s direct effect on naïve T-cells suppressed in vitro Th17 differentiation by inhibiting Th17 cell lineage markers (retinoic acid-related orphan nuclear hormone receptor (ROR)c, IL-17A, IL-23R and CCR6), and by inducing IL-10 production by CD4 cells, which constrains Th17 cell expansion. Our results have identified novel therapeutic mechanisms of IFNβ, which inhibit Th17 cell differentiation in the context of the autoimmune response in MS.     

Neutralising antibodies to interferon β in multiple sclerosis

Abstract Interferon beta (IFNβ) therapy for multiple sclerosis (MS) is associated with a potential for the development of neutralising antibodies (NAbs) that negatively affect therapy. Several factors influence the development of NAbs, such as lack of complete sequence homology with the endogenous IFNβ sequence, frequency of administration, level of dose and formulation of IFNβ. Taken together, the evidence that NAb status reduces clinical efficacy in MS patients is strong. Standardised assays for NAbs are lacking, and titres vary over time. NAb testing is a critical component of care for MS patients because it provides information on one of the most important factors determining clinical responsiveness to IFNβ therapy. This expert panel report attempts to move the field towards resolution of the remaining issues and considers several aspects of NAbs, including their clinical relevance, factors influencing immunogenicity, assays to quantify NAbs and the definition of clinically relevant titres.     

The distribution of magnetic resonance imaging response to interferonβ–1b in multiple sclerosis

Whereas the effect of interferons (IFNs) on magnetic resonance imaging (MRI) outcome measures in patients with multiple sclerosis (MS) has been convincingly shown, little work has been done to define the between-patient heterogeneity of treatment response. Our aim was to assess the distribution of the effect of IFNbeta-1b in terms of reduction of active T2 lesions in patients with MS. Using a fixed and a random effects model, we investigated the distribution of active T2 lesions reduction over a three-year follow up in response to treatment with 250 mcg IFNbeta-1b every other day in 695 patients with a complete MRI data-set of the 718 (97 %) enrolled in the European, multicenter, randomised, double-blind, placebo-controlled trial of secondary progressive MS. The two statistical models consistently showed that the between-patient response to IFNbeta-1b, in terms of reduction of active T2 lesions, is highly heterogeneous. Whereas treated patients have a high probability (more than 65%) of showing an active T2 lesion reduction equal to or greater than 60%, there is also a 7% probability for treated patients not to show any reduction of MRI-detected disease activity during the course of the trial or even to have an increase of T2 active lesions. This study might be regarded as a first step toward the definition of markers potentially useful to identify IFNbeta treatment responders and non-responders with regard to T2 lesion activity.     

Metabolite changes in early relapsing–remitting multiple sclerosis

Previous in vivo proton magnetic resonance spectroscopic imaging (¹H–MRSI) studies have found reduced levels of N–acetyl–aspartate (NAA) in multiple sclerosis (MS) lesions, the surrounding normal–appearing white matter (NAWM) and cortical grey matter (CGM), suggesting neuronal and axonal dysfunction and loss. Other metabolites, such as myoinositol (Ins), creatine (Cr), choline (Cho), and glutamate plus glutamine (Glx), can also be quantified by ¹H–MRSI, and studies have indicated that concentrations of these metabolites may also be altered in MS. Relatively little is known about the time course of such metabolite changes. This preliminary study aimed to characterise changes in total NAA (tNAA, the sum of NAA and N–acetyl–aspartyl–glutamate), Cr, Cho, Ins and Glx concentrations in NAWM and in CGM, and their relationship with clinical outcome, in subjects with clinically early relapsing–remitting MS (RRMS). Twenty RRMS subjects and 10 healthy control subjects underwent ¹H–MRSI examinations yearly for two years. Using the LCModel, tNAA, Cr, Cho, Ins and Glx concentrations were estimated both in NAWM and CGM.At baseline, the concentration of tNAA was significantly reduced in the NAWM of the MS patients compared to the control group (–7%, p = 0.003), as well as in the CGM (–8.7%, p = 0.009). NAWM tNAA concentrations tended to recover from baseline, but otherwise tissue metabolite profiles did not significantly change in the MS subjects, or relatively between MS and healthy control subjects. While neuronal and axonal damage is apparent from the early clinical stages of MS, this study suggests that initially it may be partly reversible. Compared with other MR imaging measures, serial ¹H–MRSI may be relatively less sensitive to progressive pathological tissue changes in early RRMS.     

Cognitive linguistic deficits in relapsing–remitting multiple sclerosis

Background: Recent years have witnessed increasing reports of language dysfunction associated with the neuropathology of multiple sclerosis (MS). Although linguistic compromise is not traditionally thought to be a significant clinical manifestation of MS, a number of published case and group reports have uncovered the presence of higher-level language and isolated general language deficits in samples of patients with both chronic progressive and relapsing–remitting (RR) subtypes of the disease. To the present day however, the precise nature and extent of a language compromise in MS remains largely controversial and unclear.

Aims: The present study aims to profile the cognitive linguistic abilities of a cohort of fifteen RR-subtype MS patients against an age- and education-matched group of neurologically normal control participants.

Methods & Procedures: MS participants were assessed using a comprehensive battery of cognitive linguistic assessments targeting general and higher-level language behaviours.

Outcomes & Results: The results revealed reduced performance on higher-level language subtests including: listening comprehension (making inferences), oral expression (recreating sentences), semantic absurdities and definitions. For the general language behaviours, a reduced performance was found for spontaneously elicited speech, repetition and naming.

Conclusions: The findings are suggestive of both expressive language and higher-level language dysfunction in RR subtype MS and highlight deficits in linguistic organisation, retrieval mechanisms and semantic manipulation and processing.     

Treatment response scoring systems to assess long-term prognosis in self-injectable DMTs relapsing–remitting multiple sclerosis patients

Background and objectives

Different treatment response scoring systems in treated MS patients exist. The objective was to assess the long-term predictive value of these systems in RRMS patients treated with self-injectable DMTs.

Methods

RRMS-treated patients underwent brain MRI before the onset of therapy and 12 months thereafter, and neurological assessments every 6 months. Clinical and demographic characteristics were collected at baseline. After the first year of treatment, several scoring systems [Rio score (RS), modified Rio score (MRS), MAGNIMS score (MS), and ROAD score (RoS)] were calculated. Cox-Regression and survival analyses were performed to identify scores predicting long-term disability.

Results

We included 319 RRMS patients. Survival analyses showed that patients with RS > 1 and RoS > 3 had a significant risk of reaching an EDSS of 4.0 and 6.0 The score with the best sensitivity (61%) was the RoS, while the MRS showed the best specificity (88%). The RS showed the best positive predictive value (42%) and the best accuracy (81%).

Conclusions

The combined measures integrated into different scores have an acceptable prognostic value for identifying patients with long-term disability.

Thus, these data reinforce the concept of early treatment optimization to minimize the risk of long-term disability.

     

Early use of fingolimod is associated with better clinical outcomes in relapsing–remitting multiple sclerosis patients

Journal of Neurology - Multiple sclerosis (MS) is a chronic autoimmune disease with huge heterogeneity in terms of clinical course, disease severity and treatment response. The need for a tailored...     

Parity and disability progression in relapsing–remitting multiple sclerosis

Journal of Neurology - It is unclear whether parity and increasing parity are risk factors for long-term disability progression in relapsing–remitting multiple sclerosis. Furthermore, data on...     

Correction to: Treatment response scoring systems to assess long-term prognosis in self-injectable DMTs relapsing–remitting multiple sclerosis patients

Journal of Neurology -     

Is in utero early-exposure to interferon beta a risk factor for pregnancy outcomes in multiple sclerosis?

Objective   

There exist controversial and discrepant results on the risk of spontaneous abortions and teratogenesis induced by interferon treatment in people with MS.Aim of this study is to evaluate risks of the administration of INFβ related not only to the foetus, but also to children development up to 12-months developmental milestones.     

Brain atrophy as a non-response predictor to interferon-beta in relapsing–remitting multiple sclerosis

Abstract

Background:

Several predictors for treatment failure to interferon-beta (IFN-beta) have been proposed; however, brain atrophy has not been well studied.

Methods:

In this prospective and longitudinal study, all consecutive relapsing–remitting multiple sclerosis (RRMS) patients treated with sc IFN-beta-1a were included. Confirmed disability progression or a new relapse between weeks 48 and 144 after beginning with IFN-beta was considered as treatment non-response. EDSS progression, relapses, number of active lesions at 1 year (new or enlarging T2-weighted plus gadolinium-enhancing lesions, categorized in > 2 or ≤ 2), and brain parenchymal fraction (%BVC) volume change within the initial year of treatment were used as predictive factors. Cox regression model was adjusted for age, gender, and disease duration.

Results:

Seventy-one patients were included (71·8% female) with a follow-up of 144 weeks. Thirty-four (48%) fulfilled criteria of non-response to IFN-beta treatment. The model showed: (1) relapses+disability progression: HR = 4·6, 95% IC: 3·1–6·7 (P < 0·001); (2) relapses+BVC decrease: HR = 4·1, 95% IC: 3·2–7·3 (P = 0·001); (3) relapses+disability progression+new active lesions: HR = 10·1, 95% IC: 7·1–15·2 (P < 0·001); and (4) relapses+disability progression+new active lesions+BVC decrease: HR = 14·4, 95% IC: 11·4–21·2 (P < 0·001).

Conclusions:

Adding BVC measures to previously described predictive failure factors may increase sensitivity to early identify non-responder patients to IFN-beta-1a in the second and third years of therapy.     

Comparative analysis of dimethyl fumarate and fingolimod in relapsing–remitting multiple sclerosis

Journal of Neurology - Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing–remitting multiple...