Is Multiple Sclerosis A Disease That Requires Frequent Interferon-ß Dosing?
J Neurol 2004 Sep;251 Suppl 4:IV13-IV24
University of Turin, Department of NeuroScience, 10126, Turin, Italy
The three currently available Interferon-ß products for the treatment of patients with Relapsing/Remitting Multiple Sclerosis (RRMS) are administered according to different regimens.
Placebo-controlled clinical trials support the efficacy of both alternate-day Interferon-ß-1b (Betaferon) and once-a-week Interferon-ß-1a (Avonex), but benefits to patients are probably dependent on the regimen used.
Once-weekly administration, perceived to have fewer adverse events and greater convenience, may improve compliance, whereas frequent administration might enhance efficacy.
However, more frequent administration is also associated with an increase in NeutrAlizing AntiBody (NAB) production, relative to once weekly treatment.
The issue of NABs is complex, and their clinical relevance, if any, has yet to be fully assessed. Pharmacological evidence suggests that the effects of Interferon-beta on a number of biological markers is maximized when administered every 48 hours.
This might arise as a result of sustained activity in the intracellular molecular signalling pathways regulating beta Interferon-induced Gene expression.
Some evidence suggests that the increase in biological effect at higher more frequent doses is mirrored by improvements in clinical and MRI outcome measures.
Two recent comparative studies demonstrated significantly better clinical and Magnetic Resonance Imaging outcomes in patients with RRMS receiving alternate-day high-dose Interferon-ß-1b (250 micro g subcutaneously).
Or, three-times-weekly high-dose Interferon-ß-1a compared to those receiving once weekly low-dose Interferon ß-1a (30 micro g intramuscularly).
Despite some methodological drawbacks, these studies indicate that the benefits of high-dose frequently administered Interferon-beta on relapse rate are seen soon after beginning treatment. Therefore, it seems appropriate to begin the treatment of RRMS with this dosing regimen.
Assessing Treatment Effects On Axonal Loss-Evidence From MRI Monitored Clinical Trials
J Neurol 2004 Sep;251 Suppl 4:IV6-IV12
VU Medical Centre, Department of Diagnostic Radiology, De Boelelaan 1117, 7057, Amsterdam 1007 MB, The Netherlands
Magnetic Resonance Imaging (MRI) is a collection of very sensitive and versatile techniques for detecting Multiple Sclerosis (MS) related damage in the Central Nervous System.
Each technique is characterized by a particular combination of sensitivity, tissue and pathological specificity, and technical requirements that enable diverse aspects of MS to be explored.
MRI techniques also offer the possibility of quantitatively assessing the effects of therapeutic interventions, and to correlate these effects to clinical outcomes.
Of special interest are newer MR techniques that correlate more strongly with disability than Gadolinium-enhancement and T2 lesion load, and this review focuses on T1 HypoIntense lesions, MR Spectroscopy, and Brain Atrophy as surrogate markers of Axonal Loss, and their application in randomized clinical trials.
Several disease-modifying therapies appear to have differential effects on Inflammation, DeMyelination and Axonal Loss as judged by MRI, illustrating the unique capability of MRI to interrogate the pathophysiology of MS.
At the same time it illustrates the difficulties in understanding the mechanisms leading to Axonal Loss and persistent clinical deficit.
J Neurol 2004 Sep;251 Suppl 4:IV2-IV5
Brain Research Institute, University of Vienna, Division of NeuroImmunology, Spitalgasse 4, 1090, Vienna, Austria
Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System, associated with primary destruction of Myelin sheaths. Axons are relatively well preserved, although they too are injured in the development of the lesions.
While inflammation and DeMyelination induce Neurological deficit, which is in part reversible, the destruction of Axons, when past the threshold of compensation, is always accompanied by irreversible clinical deficits.
The mechanisms leading to tissue injury in MS are complex and heterogenous. They involve direct CytoToxicity mediated by T-Lymphocytes, specific AntiBodies and Complement as well as toxic products of Macrophages.
In addition, in a small subset of patients a genetically determined increased susceptibility of the Central Nervous System tissue for Immune mediated damage appears to play a role.
Since the pathogenetic pathways of DeMyelination and tissue damage vary between different MS patients, their identification by ParaClinical Markers is of critical importance for diagnosis and therapeutic management.
McCormack PL, Scott LJ
Adis International Inc., Yardley, Pennsylvania, USA
Interferon-ß-1b (Betaseron((R)), Betaferon((R))) is a Non-Glycosylated recombinant human Interferon-ß approved for high-frequency, SubCutaneous (SC) administration in the treatment of Multiple Sclerosis (MS).
Its mechanism of action is unknown, but may involve modulation of the AutoImmune pathogenic processes of MS.
In a randomized, double-blind trial in patients with Relapsing/Remitting MS (RRMS), SC Interferon-ß-1b 250 micro g (8 million International Units [MIU]) every other day reduced the annual relapse rate and increased the proportion of relapse-free patients compared with placebo.
It also reduced relapse severity, hospitalizations, and disease activity assessed by Magnetic Resonance Imaging (MRI), and increased the time to first relapse. Progression of disability showed a trend towards reduction relative to placebo and baseline, but did not reach statistical significance.
SC Interferon-ß-1b 250 micro g every other day was shown in a randomized trial to be superior to intramuscular (IM) Interferon-ß-1a 30 micro g (6 MIU) once weekly with respect to reductions in relapse-related parameters, disability progression and MRI-assessed disease activity.
In patients with Secondary/Progressive MS (SPMS), SC Interferon-ß-1b 250 micro g every other day slowed progression of the disease relative to placebo in one randomized, double-blind trial, but not in another.
In both studies, Interferon-ß-1b 250 micro g recipients had fewer relapses and less MRI-assessed disease activity than placebo recipients. The difference in primary outcome may reflect differences in patient entry criteria.
Interferon-ß-1b is generally well tolerated and the common adverse events (e.g. injection site reactions, Asthenia and an Influenza-Like Symptom Complex) are clinically manageable.
In a randomized trial, the tolerability of SC Interferon-ß-1b 250 micro g every other day was generally similar to that of IM Interferon-ß-1a 30 micro g once weekly, except for higher incidences of injection site reactions and Neutralizing Anti-Interferon-ß AntiBodies with SC Interferon-ß-1b.
In conclusion, SC Interferon-ß-1b 250 micro g every other day reduces the frequency and severity of relapses and MRI measures of disease activity and may delay the progression of disability in RRMS.
The drug appeared to be more effective than, and as well tolerated as, IM Interferon-ß-1a 30 micro g once weekly. Interferon-ß-1b also has positive effects on relapse rates and disease activity in patients with SPMS, although its effects on disease progression remain uncertain.
The drug is generally well tolerated, and the common adverse events are clinically manageable. Thus, Interferon-ß-1b is a valuable first-line therapy for patients with RRMS and a potentially useful option in those with SPMS.
Potassium Channels In T-Lymphocytes : Therapeutic Targets For AutoImmune Disorders?
Vianna-Jorge R, Suarez-Kurtz G
Instituto Nacional de Cancer, Divisao de Farmacologia, Coordenacao de Pesquisa, Rio de Janeiro, BrazilDepartamento de Farmacologia Basica e Clinica, Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Human peripheral blood T-Lymphocytes possess two types of K+ Channels: the Voltage-gated Kv1.3 and the Calcium-activated IKCa1 Channels.
The use of Peptidyl Inhibitors of Kv1.3 and IKCa1 indicated that these Channels are involved in the maintenance of Membrane Potential and that they play a crucial role in Ca+ signaling during T-Cell activation.
Thus, in vitro blockade of Kv1.3 and IKCa1 leads to inhibition of Cytokine production and Lymphocyte proliferation.
These observations prompted several groups of investigators in academia and pharmaceutical companies to characterize the expression of Kv1.3 and IKCa1 in different subsets of human T-Lymphocytes and to evaluate their potential as novel targets for ImmunoSuppression.
Recent in vivo studies showed that chronically activated T-Lymphocytes involved in the pathogenesis of Multiple Sclerosis present unusually high expression of Kv1.3 Channels and that the treatment with selective Kv1.3 Inhibitors can either prevent or ameliorate the symptoms of the disease.
In this model of Multiple Sclerosis, blockade of IKCa1 Channels had no effect alone, but improved the response to Kv1.3 Inhibitors.
In addition, the expression of Kv1.3 and IKCa1 Channels in human cells is very restricted, which makes them attractive targets for a more cell-specific and less harmful action than what is typically obtained with classical ImmunoSuppressants.
Studies using high-throughput toxin displacement, (86)Rb-efflux screening or Membrane Potential assays led to the identification of Non-Peptidyl small molecules with high affinity for Kv1.3 or IKCa1 channels.
Analysis of structure-function relationships in Kv1.3 and IKCa1 Channels helped define the binding sites for Channel Blockers, allowing the design of a new generation of small molecules with selectivity for either Kv1.3 or IKCa1, which could help the development of new drugs for safer treatment of AutoImmune Diseases.
Finn TP, Jones RE, Rich C, Dahan R, Link J, David CS, Chou YK, Offner H, Vandenbark AA
J NeuroSci Res 2004 Oct 1;78(1):100
Veterans Affairs Medical Center, NeuroImmunology Research, Portland, Oregon
Susceptibility to Multiple Sclerosis (MS) is associated genetically with Human Leucocyte Antigen (HLA) Class II Alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these Alleles contribute to MS through an enhanced ability to present Encephalitogenic Myelin Peptides to pathogenic T-Cells.
HLA-DRB1*1502, which contains Glycine instead of Valine at position 86 of the P1 Peptide-binding pocket, is apparently not genetically associated with MS.
To identify possible differences between these Alleles in their Antigen-Presenting function, we determined if T-Cell responses to known DRB1*1501-restricted Myelin Peptides might be diminished or absent in Transgenic (Tg) DRB1*1502-expressing mice.
We found that Tg DRB1*1502 mice had moderate to strong T-Cell responses to several Myelin Peptides with favorable DRB1*1501 binding motifs, notably Myelin Oligodendrocyte GlycoProtein (MOG)-35-55 (which was also Encephalitogenic), ProteoLipid Protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG Peptides.
These Peptides, with the exception of MOG-194-208, were also Immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to Peptides with unfavorable DRB1*1501 binding motifs.
Overall, none of the DRB1*1501-restricted Myelin Peptides tested selectively lacked Immunogenicity in association with DRB1*1502.
These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of Antigen-Presenting by DRB1*1502.
At least for this set of Myelin Peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.
Copyright 2004 Wiley-Liss, Inc.