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.     

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.     

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...     

The association between cognition and motor performance is beyond structural damage in relapsing–remitting multiple sclerosis

Journal of Neurology - Previous studies demonstrated an association between motor and cognitive performance in multiple sclerosis (MS). However, disease-related brain damage might represent a...     

Intracortical excitability in patients with relapsing–remitting and secondary progressive multiple sclerosis

We designed this study to investigate possible correlations between variables measuring primary motor cortex excitability detected by single and paired-pulse transcranial magnetic stimulation (TMS) and the severity of clinical manifestations in patients with multiple sclerosis (MS). Thirty patients with MS in remission, 16 with relapsing–remitting (RR), 14 with secondary progressive disease (SP) and 17 healthy subjects participated in the study. In each subject, the central motor conduction time (CMCT) was calculated, and single-pulse and paired-pulse TMS at 3 and 10 ms interstimulus intervals was delivered over the primary motor cortex of the dominant hemisphere to measure the amplitude of motor-evoked potentials (MEPs), motor threshold (MTh), intracortical inhibition (ICI) and facilitation (ICF). Correlations were determined between the patients’ TMS findings and magnetic resonance imaging (MRI) (lesion load) and clinical features (expanded disability status scale, EDSS score). EDSS scores were significantly higher in SPMS than in RRMS patients. The MTh was significantly higher, and the MEP was significantly smaller in SPMS patients than in RRMS patients and control subjects. All patients had longer CMCTs than healthy subjects. In all patients, paired-pulse TMS elicited an inhibited test MEP at the 3-ms ISI and a facilitated test MEP at the 10 ms ISI. Post hoc analysis showed that ICI was significantly lower in SPMS patients than in those with RRMS and healthy subjects. EDSS scores correlated significantly with TMS measures (MEP, ICI, CMCT and MTh), but not with MRI lesion load. It was found that intracortical excitability as measured with TMS differs according to the clinical course of MS; it remains normal in patients with low EDSS scores and is altered in patients with high EDSS scores.     

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...     

Spinal cord lesions are frequently asymptomatic in relapsing–remitting multiple sclerosis: a retrospective MRI survey

Journal of Neurology - Spinal cord (SC) involvement correlates with poor prognosis in patients with multiple sclerosis (MS). Nevertheless, there is no consensus on the use of SC-MRI at follow-up,...     

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.     

MR imaging and cognitive correlates of relapsing–remitting multiple sclerosis patients with cerebellar symptoms

Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system, frequently associated with cognitive impairments. Damages of the cerebellum are very common features of patients with MS, although the impact of this clinical factor is generally neglected. Recent evidence from our group demonstrated that MS patients with cerebellar damages are characterized by selective cognitive dysfunctions related to attention and language abilities. Here, we aimed at investigating the presence of neuroanatomical abnormalities in relapsing–remitting MS patients with (RR-MSc) and without (RR-MSnc) cerebellar signs. Twelve RR-MSc patients, 14 demographically, clinically, and radiologically, matched RR-MSnc patients and 20 controls were investigated. All patients underwent neuropsychological assessment. After refilling of FLAIR lesions on the 3D T1-weighted images, VBM was performed using SPM8 and DARTEL. A correlation analysis was performed between VBM results and neuropsychological variables characterizing RR-MSc patients. Despite a similar clinical status, RR-MSc patients were characterized by more severe cognitive damages in attention and language domains with respect to RR-MSnc and controls. With respect to controls, RR-MSnc patients were characterized by a specific atrophy of the bilateral thalami that became more widespread (including motor cortex) in the RR-MSc group (FWE < 0.05). However, consistent with their well-defined neuropsychological deficits, RR-MSc group showed atrophies in the prefrontal and temporal cortical areas when directly compared with RR-MSnc group. Our results demonstrated that RR-MS patients having cerebellar signs were characterized by a distinct neuroanatomical profile, mainly involving cortical regions underpinning executive functions and verbal fluency.     

Normal plasma antithrombin activity in patients with relapsing–remitting and secondary progressive multiple sclerosis

Objective

Multiple sclerosis (MS) is an inflammatory disease characterized by multifocal areas of central nervous system (CNS) demyelination. Activation of coagulation factors and fibrin deposition are observed around CNS blood vessels in experimental autoimmune encephalomyelitis, an animal model of MS. Antithrombin (AT) is a potent anticoagulant with remarkable anti-inflammatory properties, and its inhibitory effects on coagulation and inflammation may play a role in the pathogenesis and clinical course of MS. We studied the association between plasma AT activity and clinical forms of MS.

Patients and methods

A total of 69 patients, 37 with relapsing–remitting and 32 with secondary progressive MS, were included in the study. A control group (CG) of 34 normal subjects was also studied. Plasma AT activity (Stachrom ATIII) was quantified using a chromogenic activity assay with normal reference values ranging from 70% to 120% of AT activity.

Results

We found no difference between plasma AT levels in patients and those in CG. We also found no association of AT levels with activity of disease, duration of disease progression, level of neurological disability, and treatment.

Conclusion

We found no association between plasma AT activity and RRMS or SPMS. It remains to be studied whether exists or not an association between abnormal plasma AT activity and other MS forms.     

Acute posterior multifocal placoid pigment epitheliopathy after alemtuzumab treatment for relapsing–remitting multiple sclerosis

Journal of Neurology -     

Risk factors for lymphopenia in patients with relapsing–remitting multiple sclerosis treated with dimethyl fumarate

Journal of Neurology - To identify risk factors for DMF-induced lymphopenia and characterize its impact on T lymphocyte subsets in MS patients. We performed a retrospective analysis of 194 RRMS...     

Differences in systemic and central nervous system cellular immunity relevant to relapsing–remitting multiple sclerosis

In order to elucidate the differences between systemic and central nervous system (CNS) immunity that are relevant to exacerbations of multiple sclerosis (MS), paired peripheral blood and cerebrospinal fluid (CSF) samples obtained from 36 non-treated patients with relapsing-remitting MS (RRMS) were simultaneously examined using flow cytometry to determine the percentages of functional lymphocyte subsets, as well as enzyme-linked immunosorbent assays for measuring soluble immune mediators.Active RRMS patients (n = 27) were characterized by an increase in CD4+ CXCR3+ Th1 cells in blood as compared with inactive patients (n = 9), and this parameter was inversely correlated with plasma levels of IL-10 and IL- 12p70. In contrast, an increase in the percentage of CD4+ CD25+ cells and a decrease in the percentage of CD8+ CD11a(high) cells were features of CSF samples from those with active RRMS. Further, CSF CD4+ CD25+ cells had a close association with leukocyte counts as well as albumin and CXCL10 levels in the CSF, and, thus, could be useful as a measure for inflammatory reactions in the CNS. On the other hand, CD8+ CD11a(high) cells may function as immunoregulatory cells, as their percentage in the CSF showed a positive correlation with CSF levels of the anti-inflammatory cytokine IL-4. These findings suggest that MS relapses occur in a combination with altered cell-mediated immunity that differs between the peripheral blood and CSF compartments, while measurement of lymphocyte subsets may be helpful for monitoring disease status.     

Vitamin D and disability in relapsing–remitting multiple sclerosis in patients with a Mexican background

Previous studies of multiple sclerosis (MS) patients have reported an inverse correlation between disability, the number of relapses and vitamin D levels in mostly white patients. It is unclear if this relationship has the same behavior in individuals with Hispanic backgrounds. To determine the relationship between vitamin D serum levels and disability in a sample of Hispanics of a Mexican background with relapsing–remitting multiple sclerosis (RRMS). A cross-sectional study was conducted on 50 RRMS individuals of Mexican background. The Expanded Disability Status Scale (EDSS) score, progression index (PI) and annual relapse rate (ARR) were recorded for each patient. Vitamin D levels were assessed during the summer. Pearson’s test was used to evaluate the relationship between vitamin D and EDSS, PI, ARR, and duration of disease evolution. Most patients were females (n = 29, 58%). The mean vitamin D level was 22.3 (± 6.4) ng/ml; the mean EDSS score was 2.2 (± 0.7), ARR 1.3 (± 0.5) and PI1.08 (± 0.6). No correlation was found between vitamin D levels and EDSS scores, ARR, PI or duration of disease. Moderate negative association between vitamin D levels and EDSS was found just in females (<0.0001). No correlation between vitamin D levels and disability was found in this sample of RRMS Mexicans. Longitudinal studies are needed to better understand the impact of Vitamin D in disability and multiple time points.     

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.