Haas J, Maas-Enriquez M, Hartung HP
Mult Scler 2005 Oct;11(5):562-7
Jewish Hospital, Department of Neurology, Berlin, Germany
Use of Intravenous ImmunoGlobulins (IVIG) has been recommended for treatment of RRMS if first line therapy with Interferon-beta or Glatiramer Acetate is not tolerated, or if contraindications exist.
This consensus recommendation is based on the demonstration of efficacy and tolerability of IVIG in four randomized controlled trials (RCTs).
The impact of non-randomized observational trials on evidence-based recommendations for treatment is still under discussion.
In order to evaluate the transferability of study results derived from RCTs into a routine practice setting, we carried out a retrospective data analysis on patients with RRMS who had been treated with IVIG during the last five years.
Data sets from 308 out of 1122 screened patients were available for analysis.
Treatment with IVIG resulted in a 69% reduction of the mean annual relapse rate (ARR) (calculated over two years) from 1.74+/-1.15 before IVIG treatment to 0.53+/-0.61 after start of IVIG treatment.
Mean Expanded Disability Status Scale (EDSS) values remained stable throughout the observation period. The results of this observational study were similar to the results of previous RCTs with IVIG.
J Neurol 2005 Sep;252(Supplement 3):iii44-iii50
Heinrich-Heine-Universitat, Department of Neurology, Moorenstrasse 5, 40225, Dusseldorf, Germany
The use of Interferon-beta (IFN-ß) in the treatment of Multiple Sclerosis (MS) has not changed greatly since its introduction.
However, two new treatment paradigms have recently emerged: initiation of treatment as early in the course of the disease as possible and the use of higher doses with greater frequency to gain maximum therapeutic effect.
The rationale for early treatment comes from evidence showing that early and irreversible pathology exists in very early stages of Relapsing/Remitting MS (RRMS).
Often, before significant disability is apparent and continues during remission. In addition, irreversible axonal damage begins early in the course of MS.
Two relatively short-term studies indicate that it is possible to delay the onset of MS by early treatment with low-dose IFN-ß-1a.
The BENEFIT (Betaferon((R))/Betaseron((R)) in Newly Emerging MS For Initial Treatment) study is being undertaken to investigate whether early intervention with a high-dose and more frequent administration of IFN-ß-1b (250 microg [8 MIU] every other day [eod]) has the ability to affect long-term clinical and Magnetic Resonance Imaging (MRI) outcomes even more favorably.
In addition, together with its follow-up study, BENEFIT will address the open question of long-term effects of early treatment on disease progression.
Results from the pivotal IFN-ß-1b study, together with data from PRISMS (Prevention of Relapses and Disability by Interferon-ß-1a Subcutaneously in Multiple Sclerosis) showed the presence of a dose-response relationship for IFN-ß in the treatment of RRMS.
This finding was confirmed by the results of INCOMIN (Independent Comparison of Interferons) and EVIDENCE (Evidence of Interferon Dose-response: European North American Comparative Efficacy).
Direct comparative studies of high-dose (250 microg IFN-ß-1b, 44 microg IFN-ß-1a), high-frequency versus lower dose (30 microg IFN-ß-1a) and less frequent IFN-ß regimens.
Results from a pilot study in patients with RRMS have indicated that increasing the dose of IFN-ß-1b to 500 microg (16 MIU) had a more pronounced biological effect compared with the standard 250 microg dose.
The BEYOND (Betaferon((R))/Betaseron((R)) Efficacy Yielding Outcomes of a New Dose) study is being undertaken to investigate whether IFN-ß-1b 500 microg eod is superior to the standard 250 microg eod dose in treatment-naive patients with RRMS.
A third treatment arm will provide a comparison with Glatiramer Acetate 20mg subcutaneously once daily.
Short-Lived Plasma Blasts Are The Main B-Cell Effector Subset During The Course Of Multiple Sclerosis
Cepok S, Rosche B, Grummel V, Vogel F, Zhou D, Sayn J, Sommer N, Hartung HP, Hemmer B
Brain 2005 Jul;128(Pt 7):1667-76
Heinrich Heine-University, Department of Neurology, Duesseldorf, Germany
Multiple Sclerosis is a chronic Inflammatory and DeMyelinating disorder of the CNS with an unknown Etiology. Although Intrathecal ImmunoGlobulin G (IgG) synthesis is a key feature of the disease, little is still known about the B-Cell response in the CNS of Multiple Sclerosis patients.
We analyzed the phenotype and kinetics of different B-Cell subsets in patients with Multiple Sclerosis, infectious disease (IND) and Non-Inflammatory Neurological Disease (NIND).
B-Cells were detected in the CSF of Multiple Sclerosis and IND patients, but were largely absent in NIND patients.
In the CSF, the majority of B-Cells had a phenotype of Memory B-Cells and short-lived Plasma Blasts (PB); Plasma Cells were absent from the compartment.
The proportion of PB was highest in Multiple Sclerosis patients and patients with acute CNS infection.
While PB disappeared rapidly from the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the disease course in Multiple Sclerosis patients.
CSF PB numbers in Multiple Sclerosis patients strongly correlated with Intrathecal IgG synthesis and Inflammatory Parenchymal Disease activity as disclosed by MRI.
This study identifies short-lived Plasma Blasts as the main effector B-Cell population involved in ongoing active inflammation in Multiple Sclerosis patients.
Regional Lobar Atrophy Predicts Memory Impairment In Multiple Sclerosis
Benedict RH, Zivadinov R, Carone DA, Weinstock-Guttman B, Gaines J, Maggiore C, Sharma J, Tomassi MA, Bakshi R
AJNR Am J NeuroRadiol 2005 Aug;26(7):1824-31
SUNY Buffalo School of Medicine, Department of Neurology, Buffalo, NY 14203, USA
Background And Purpose
In recent studies, measures of Whole Brain Atrophy were strongly correlated with NeuroPsychological testing, explaining more variance than measures of lesion burden in patients with Multiple Sclerosis.
The relationship between Regional Lobar Atrophy and Cognitive Impairment is yet to be examined. We endeavored to assess the clinical significance of Regional Lobar Atrophy in Multiple Sclerosis.
In a cross-sectional study, we evaluated 31 patients with Multiple Sclerosis with Brain MR imaging and NeuroPsychological testing. Impairment was determined by comparison with demographically matched healthy controls.
MR imaging generated measures of lesion burden (Fluid-Attenuated Inversion Recovery HyperIntense volume), general Atrophy (Brain Parenchymal Fraction), Central Atrophy (Lateral Ventricle Volume), and Lobar Atrophy (Regional Brain Parenchymal Fraction of Frontal, Temporal, Parietal, and Occipital Lobes in each Hemisphere).
NeuroPsychological testing emphasized measures of Processing Speed and Memory, because these are commonly affected in Multiple Sclerosis.
Patients with Multiple Sclerosis showed significant Atrophy and impairment on all NeuroPsychological tests. Regional Atrophy accounted for the most variance in all regression models predicting Memory performance.
Left Temporal Atrophy was the primary predictor of Auditory/Verbal Memory (partial r's = 0.55-0.61), and both left and Right Temporal Atrophy predicted Visual/Spatial Memory performance (Partial r's = 0.51-0.67).
Models predicting learning consistency retained Frontal Lobe Atrophy measures (partial r's = 0.44-0.68). Central and General Atrophy measures were the primary predictors in modeling Processing Speed (Partial r's = 0.42-0.64).
Regional Atrophy accounts for more variance than lesion burden, Whole Brain Atrophy, or Lateral Ventricle Volume in predicting Multiple Sclerosis-associated Memory Dysfunction.
Disruption Of The Interaction Of T-Cells With Antigen-Presenting Cells By The Active Leflunomide Metabolite Teriflunomide: Involvement Of Impaired Integrin Activation And Immunologic Synapse Formation
Zeyda M, Poglitsch M, Geyeregger R, Smolen JS, Zlabinger GJ, Horl WH, Waldhausl W, Stulnig TM, Saemann MD
Arthritis Rheum 2005 Sep;52(9):2730-9
Medical University of Vienna, Vienna, Austria
Leflunomide, a potent disease-modifying AntiRheumatic drug of the Isoxazole class, exhibits AntiInflammatory, AntiProliferative, and ImmunoSuppressive effects by largely unknown mechanisms, although alterations of Pyrimidine synthesis have been proposed.
Successful Immune responsiveness requires T-Cell activation by interaction with Antigen-Presenting Cells (APCs), and Integrin activation and formation of an Immunologic Synapse (IS).
In this study, we evaluated the impact of the active Leflunomide metabolite Teriflunomide on T-Cell Integrin activation, evolution of the IS, and Antigen-specific formation of stable T-Cell/APC conjugates.
Effects of pharmacologic concentrations of Teriflunomide on CD3/CD28- and Lymphocyte function-associated Antigen 1-induced signal transduction and activation of primary human T-Cells were investigated.
Furthermore, T-Cells were stimulated with SuperAntigen- and Antigen-pulsed APCs to study relocalization of molecules to the IS and T-Cell/APC conjugate formation.
Teriflunomide inhibited T-Cell Receptor (TCR)/CD3-mediated Calcium mobilization, but other critical T-Cell signaling events, including activation of MAPK and NF-kappaB, remained unaltered.
In contrast, inhibition of TCR/CD3-triggered ß1,2 Integrin avidity and Integrin-mediated costimulation (outside-in signaling) by Teriflunomide revealed a striking interference with Integrin function that was independent of altered Pyrimidine synthesis.
Moreover, Teriflunomide abolished molecule relocalization to the IS and induction of T-Cell/APC conjugates.
These data show that the active metabolite of Leflunomide prevents the interaction of T-Cells with APCs to form an IS.
Since IS formation is crucial for eliciting an Immune Response, this novel mechanism could underlie the beneficial effects of Leflunomide in Immune-mediated disorders such as Rheumatoid Arthritis.
Alternatives To Current Disease-Modifying Treatment In MS: What Do We Need And What Can We Expect In The Future?
Kappos L, Kuhle J, Gass A, Achtnichts L, Radue EW
J Neurol 2004 Sep;251 Suppl 5:v57-v64
University Hospital, Department of Neurology, Kantonsspital, 4031, Basel, Switzerland
Disease-Modifying Treatments (DMTs) for Multiple Sclerosis (MS) are now widely available, and their beneficial effects on relapse rates, Magnetic Resonance Imaging outcomes and, in some cases, relapse-related disability have been shown in numerous clinical studies.
However, as these treatments are only partially effective in halting the MS disease process, the search for improved treatment regimens and novel therapies must continue.
Strategies to improve our therapeutic armamentarium have to take into account the different phases or parts of the pathogenesis of the disease.
Available treatments address systemic Immune dysfunction, Blood-Brain Barrier permeability and the inflammatory process in the Central Nervous System.
Currently, patients who fail to respond adequately to first-line DMTs are often considered as candidates for intensive ImmunoSuppression with cytostatic agents or even autologous Stem Cell Transplantation. However, new approaches are being developed.
Combination therapies offer an alternative approach that may have considerable potential to improve therapeutic yield and, although likely to present considerable challenges in terms of trial design, this certainly seems to be a logical step forward in view of the complex pathology of MS.
Several new drugs are also being developed with the aim of providing more effective, convenient and/or specific modulation of the inflammatory component of the disease.
These treatments include humanised MonoClonal AntiBodies such as the Anti-VLA-4 AntiBody Natalizumab, Inhibitors of IntraCellular activation, signalling pathways and T-Cell proliferation, and oral ImmunoModulators such as Sirolimus, Teriflunomide or Statins.
There remains, however, an urgent need for treatments that protect against DeMyelination and Axonal Loss, or promote ReMyelination/regeneration.
Due to the chronicity of MS, the therapeutic window for Neuroprotective Agents is wider than that following stroke or acute Spinal Cord injury, and may therefore allow the use of some drugs that have proven disappointing in other situations.
Novel potential NeuroProtective agents such as alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Antagonists and Ion-Channel Blockers will be entering Phase II trials in MS in the near future, and it is hoped that these agents will mark the start of a new era for DMTs for MS.
Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H
Brain 2005 Nov;128(Pt 11):2705-12
Medical University of Vienna, Center for Brain Research, Vienna, Austria
Focal DeMyelinated plaques in White Matter, which are the hallmark of Multiple Sclerosis pathology, only partially explain the patient's clinical deficits. We thus analyzed global Brain pathology in Multiple Sclerosis, focusing on the Normal-Appearing White Matter (NAWM) and the Cortex.
Autopsy tissue from 52 Multiple Sclerosis patients (acute, Relapsing/Remitting, Primary and Secondary/Progressive Multiple Sclerosis) and from 30 controls was analyzed using quantitative morphological techniques.
New and active focal inflammatory DeMyelinating lesions in the White Matter were mainly present in patients with acute and Relapsing Multiple Sclerosis, while Diffuse injury of the NAWM and Cortical DeMyelination were characteristic hallmarks of Primary and Secondary/Progressive Multiple Sclerosis.
Cortical DeMyelination and injury of the NAWM, reflected by Diffuse Axonal injury with profound Microglia activation, occurred on the background of a global inflammatory response in the Whole Brain and Meninges.
There was only a marginal correlation between focal lesion load in the White Matter and Diffuse White Matter injury, or Cortical pathology, respectively.
Our data suggest that Multiple Sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed DeMyelinated plaques in the White Matter.
With chronicity, Diffuse inflammation accumulates throughout the Whole Brain, and is associated with slowly progressive Axonal Injury in the NAWM and Cortical DeMyelination.