Interleukin 17 receptor in multiple sclerosis patients treated with interferon β-1a

Interleukin 17 (IL-17) and its receptor IL-17R1 produced by T-helper cells named Th17 are involved in the pathology of autoimmune diseases. In contrast to the at least partially explained role of IL-17 in pathology of multiple sclerosis, the significance of IL-17R in MS is unclear. Therefore we have studied the expression of IL-17R in the stable phase of multiple sclerosis treated by interferon β-1a. The studied material consisted of 20 MS patients with relapsing-remitting form of the disease, and fulfilling the diagnostic McDonald et al. criteria. The patients were treated subcutaneously every second day with 30 mg of interferon β -1a (Betaferon). The interleukin 17 receptor level was measured by the ELISA immunoassay test using RayBio human IL-17R ELISA kit. After three months of therapy with interferon β -1a the level of IL-17R was significantly higher than that established at the starting point. The level of IL-17R after 6 months of therapy was insignificantly higher than established in the previous study group (3 months of therapy). While it remains difficult to pinpoint the exact significance of upregulation of IL-17R in the early period of therapy, the present findings should be taken into account when considering the pharmacodynamics of interferon action in MS in view of the opinions on the crucial role of IL-17 in pathology of MS and suggestions that it may constitute a drug target in autoimmunological diseases.     

Axonal metabolic recovery in multiple sclerosis patients treated with interferon β–1b

Patients with multiple sclerosis (MS) can benefit from treatment with interferon β–1b. However, the mechanisms of action of this drug are incompletely understood and effects of interferon β–1b on axonal injury are not known. A measure of axonal injury can be obtained in vivo using magnetic resonance spectroscopy to quantify the resonance intensity of the neuronal marker, N-acetylaspartate (NAA). In a small pilot study, we performed combined magnetic resonance imaging and magnetic resonance spectroscopic imaging on 10 patients with relapsing-remitting MS before and 1 year after starting treatment with subcutaneous interferon β–1b. Resonance intensities of NAA relative to creatine (Cr) were measured in a large, central brain volume. These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline. NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5 % 12 months after the start of therapy [2.89 (0.24), p = 0.05], while NAA/Cr in the untreated group decreased, but not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months, p > 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03). Our data suggest that, in addition to losing axons, patients with chronic multiple sclerosis suffer from chronic, sublethal axonal injury that is at least partially reversible with interferon β–1b therapy. Received: 2 August 2000, Received in revised form: 11 December 2000, Accepted: 26 February 2001     

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...     

Health-related quality of life in patients with relapsing-remitting multiple sclerosis treated with subcutaneous interferon β-1a in Iran

Purpose: Multiple sclerosis (MS) requires long-term therapy and can affect many aspects of a patient's life, including quality of life. MS patients score lower on health-related quality of life (HRQoL) measures. The efficacy of subcutaneous interferon (IFN) β-1a has been extensively evaluated by using objective measures but its impact on HRQoL is currently unclear. In this observational study, we evaluated HRQoL of Iranian patients with relapsing-remitting MS (RRMS) treated with IFN β-1a by using short-form 36 (SF-36) and multiple sclerosis international quality of life (MusiQoL) questionnaires. Methods: Four hundred recruited RRMS patients were treated with human serum album free IFN β-1a for 1 year. Patients were required to fill in SF-36 and MusiQoL questionnaires at the first visit and at each follow-up visit. Expanded disability status scale (EDSS) evaluation was performed at baseline and at each visit. Comparisons in HRQoL between visits were calculated using Cohen's d effect size. The relationship between change in EDSS score and the score of each questionnaire was calculated using Pearson correlation coefficients. Results: Three-hundred and eighty three completed the study. Two-hundred and thirty nine were female. Mean (SD) age was 28.75 (±5.49). After 1 year, overall MusiQoL Index score effect size was ?0.16 and SF-36 physical component and mental component showed overall effect sizes of ?0.28 and ?0.53, respectively. Mean (range) EDSS change was 1 (1–4). Three-hundred and seventy four were clinically stable with mean (range) EDSS change of 0.1 (?2–0.5). Increase in EDSS was linked to a decrease in both MusiQoL and SF-36. Conclusion: We found that, HRQoL did not change significantly over the first year of therapy. Furthermore, decreases in HRQoL were inversely correlated with increases in EDSS score.     

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.     

Determinants of interferon β efficacy in patients with multiple sclerosis

Many patients with multiple sclerosis (MS) experience clinical relapses or progression of disability, or exhibit evidence of disease activity on MRI, despite the use of disease-modifying therapy. Although evidence clearly supports the efficacy of interferon β (IFN-β) in treating MS, the factors that determine the response to this drug in individual patients have not been fully elucidated. As more treatment options become available, the early identification of factors that can affect or predict the efficacy of agents in individual patients is important, because such knowledge facilitates early switching of treatment. Despite years of research and numerous reports of promising therapy markers for MS, few markers have emerged as clinically useful. Several studies suggest, however, that development of MRI lesions within 6-24 months after the initiation of IFN-β treatment predicts an unfavorable response. In addition, persistently high titers of neutralizing antibodies diminish or abrogate the therapeutic effects of IFN-β, and help to identify patients who do not respond. This Review highlights advances in research on the response to IFN-β in patients with MS and aims to provide a practical approach for incorporating clinical data, biological markers and MRI measures of disease activity into their therapeutic management.     

Magnetic resonance imaging outcome of new enhancing lesions in relapsing-remitting multiple sclerosis patients treated with interferon β1a

We investigated whether interferon-β_1a modifies the course of new enhancing lesions in relapsing-remitting multiple sclerosis. Sixty-eight patients were studied by monthly magnetic resonance imaging (MRI) in a pretest-posttest design including 6 months of observation and 6 months of treatment. We examined the course of new Gd-enhancing lesions on two consecutive scans during observation and during treatment. Lesions detected during treatment were also analyzed by MRI 1 year later for persistence of enhancement, persistence of T2 hyperintensity, development of T1 hypointensity, or disappearance. Among the enhancing lesions detected by observation and treatment MRI, respectively, Gd-enhancement persisted at 2 months in 20% and 3% (P < 0.001), T2 hyperintensity persisted in 86% and 63% (P < 0.03), and T1 hypointensity developed in 49% and 15% (P < 0.01). Progression to T1 hypointensity was significantly more frequent in larger lesions during both the observation and treatment periods (P < 0.01). No reenhancement of plaques was present at 1-year follow-up; a further reduction in T2 hyperintensity (63% vs. 39%) was observed while T1 hypointensity remained unchanged. Both the duration of Gd enhancement and the short-term MRI course of new enhancing lesions benefited by treatment with recombinant interferon-β_1a treatment. Received: 20 January 1998 Received in revised form: 17 July 1998 Accepted: 26 September 1998     

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

Journal of Neurology - Unfortunately, the given name and family name of first author was incorrectly tagged in the xml data, therefore it is abbreviated wrongly as “Morales FS” in...     

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.     

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.     

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.     

Can we predict flu-like symptoms in patients with multiple sclerosis treated with interferon-β?

Interferon-beta1b treatment in relapsing-remitting multiple sclerosis can frequently induce systemic side effects such as flu-like symptoms with fever. In vitro stimulation of peripheral blood leukocytes with interferon-beta1b before the beginning of therapy shows that patients who develop fever generally have increased levels of interleukin-6.     

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...     

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.     

Predictors of long–term clinical response to interferon beta therapy in relapsing multiple sclerosis

Objectives The aim of this study was to identify clinical, magnetic resonance imaging (MRI) and biological markers predictive of long–term clinical response to interferon beta (IFN beta) therapy in patients with relapsing–remitting multiple sclerosis (RRMS). Methods Sixty–eight patients treated with IFN beta were followed over a 6–year period. Relapse rate and disability progression were evaluated throughout the study. We considered suboptimal clinical response to be either the presence of sustained disability progression, or more than two relapses. Baseline and 12–month demographic, clinical and MRI findings, as well as the development of neutralizing antibodies (NAbs) against IFN beta during the first year of therapy were analyzed as predictors of long–term clinical outcome. Results "Black holes" on MRI were the best baseline predictor of disability progression (odds ratio [OR] 6.8; p < 0.001).At 1 year, both male gender (OR 4.9; p = 0.009) and NAbs (OR 7.3; p = 0.003) were independently associated with a high risk of developing subsequent disability. The presence of gadolinium enhancement, both at baseline (OR 4.7; p = 0.005) and on the 1–year MRI scan (OR 7.9; p = 0.002), was the unique variable associated with the number of relapses over the study period. Conclusions Variables assessable within the first year of treatment significantly influence relapse rate and disability progression in patients with RRMS treated with IFN beta. These findings may help clinicians to make decisions regarding therapy regimen over time, and highlight the need for a prognostic algorithm. The study was supported by Industria Farmaceutica Serono Italy.     

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.