Rudick RA, Cutter GR, Baier M, Weinstock-Guttman B, Mass MK, Fisher E, Miller DM, Sandrock AW
Mult Scler 2005 Dec;11(6):626-34
Mellen Center for Multiple Sclerosis Treatment and Research, The Cleveland Clinic Foundation, Department of Neurology, OH 44195, USA
Two methods were used to estimate the long-term impact of Disease-Modifying Drug Therapy (DMDT) in patients with Relapsing Multiple Sclerosis (MS) who completed a placebo-controlled, randomized clinical trial of Interferon-beta-1a (IFN-ß-1a).
The study cohort consisted of patients with ambulatory Relapsing MS who had previously participated in a placebo-controlled clinical trial for two years.
At its end, patients were managed in an unstructured fashion by their Neurologists and re-evaluated at an average of 6.1 years after the end of the trial.
Follow-up evaluation was obtained for 93% of the 172 eligible patients.
Because study inclusion criteria required that all patients have an Expanded Disability Status Scale (EDSS) score of < or = 3.5 at entry, disability progression at follow-up was defined as EDSS > or = 6.0.
Two methods were used to estimate the expected proportions that reached EDSS > or = 6.0 at follow-up. Estimates were compared with observed proportions.
Method 1 used progression rates observed during the two-year phase III clinical trial and the percentage of time that patients were on DMDT during the follow-up period.
Method 2 used progression rates from a natural history comparison group of Relapsing/Remitting MS patients.
At the eight-year follow-up, 42.0% of the original placebo patients and 29.1% of the original IFN-ß-1a patients reached an EDSS > or = 6.0, an observed treatment effect of approximately 30%.
Using method 1, it was estimated that 36.3% of the original placebo patients and 27.6% of the original IFN-ß-1a patients should have reached an EDSS > or = 6.0. Use of the natural history control group (method 2) predicted less plausible outcomes.
Estimated proportions of patients reaching the endpoint were 63.3% for the original placebo group and 55.8% for the original IFN-ß-1a group.
Treatment effect sizes of 75-90% would be required to match estimates from method 2 with the observed outcome.
The paucity of data on the long-term treatment of patients with MS may be aided by applying these or similar methods to vigorously followed cohorts of patients.
FTY720, A New Class Of ImmunoModulator, Inhibits Lymphocyte Egress From Secondary Lymphoid Tissues And Thymus By Agonistic Activity At Sphingosine 1-Phosphate Receptors
Pharmacology & Therapeutics Volume 108, Issue 3 , December 2005, Pages 308-319
Mitsubishi Pharma Corporation, Research Laboratory III (Immunology), Pharmaceuticals Research Unit, Research and Development Division, Japan
FTY720 is the first of a new ImmunoModulator class: Sphingosine 1-Phosphate (S1P) Receptor Agonist.
In 1994, an ImmunoSuppressive natural product, ISP-I (myriocin), was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp.
The chemical modification of ISP-I yielded a new compound, FTY720, which has more potent ImmunoSuppressive activity and less toxicity than ISP-I does.
FTY720 has been shown to be highly effective in experimental AlloTransplantation models and Autoimmune Disease models.
A striking feature of FTY720 is the induction of a marked decrease in peripheral blood T- and B-Cells at doses that show ImmunoSuppressive activity in these models.
Reportedly, FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinase 2 in vivo, and FTY720-P acts as a potent agonist at S1P receptors.
Recently, it has been suggested that FTY720-P internalizes S1P1 on Lymphocytes and thereby inhibits the migration of Lymphocytes toward S1P.
Thus, it is likely that the reduction of circulating Lymphocytes by FTY720 is due to the inhibition of S1P/S1P1-dependent Lymphocyte egress from Secondary Lymphoid tissues and Thymus.
Because FTY720 displays a novel mechanism of action that has not been observed with other ImmunoSuppressive agents and shows a synergism with Cyclosporin A (CsA) and Tacrolimus.
It is presumed that FTY720 provides a useful tool for the prevention of transplant rejection and a new therapeutic approach for Autoimmune Diseases including Multiple Sclerosis and Rheumatoid Arthritis.
Audoin B, Fernando KT, Swanton JK, Thompson AJ, Plant GT, Miller DH
Brain 2006 Apr;129(Pt 4):1031-9
Institute of Neurology, University College London, NMR Research Unit, Department of NeuroInflammation, London, UK; Institute of Neurology, University College London, Department of NeuroInflammation, London, UK; Centre de Resonance Magnetique Biologique et Medicale (CRMBM) and Service de Neurologie, Hopital de la Timone, Marseille, France
Patients with Clinically Isolated Syndromes suggestive of Multiple Sclerosis have evidence for abnormality in Normal-Appearing Gray Matter detected using the Magnetization Transfer Ratio (MTR), a quantitative MRI measure.
One potential mechanism for the decreased Gray Matter MTR (GM MTR) observed is trans-synaptic morphological abnormality secondary to DeMyelinating lesions that are in an anatomically linked pathway but remote location.
We investigated this potential association by studying the location of abnormalities using voxel-based analysis of GM MTR maps in a group of 80 patients studied within 6 months of presenting with isolated Optic Neuritis and compared the findings with those seen in 50 age- and sex-matched healthy controls.
Occipital Cortex and whole Brain analysis comparing all Optic Neuritis patients and controls revealed a selective decrease of MTR bilaterally in the Visual Cortex in patients [Brodmann area (BA) 17].
Whole Brain analysis of patients fulfilling the McDonald criteria for Multiple Sclerosis (n = 20) showed a lower MTR compared to controls bilaterally in the Visual Cortex (BA 17/18), left Hippocampus, bilateral superior Temporal Gyrus, bilateral Lenticular Nuclei and the right Cerebellum.
There was no significant difference in the percentage of Gray Matter between patients and controls in the regions of abnormal MTR detected in the Visual Cortex.
The intrinsic MTR decrease seen in patients suggests that there are structural changes in the Visual Cortex following an attack of Optic Neuritis.
Potential mechanisms for this include Trans-Synaptic Neuronal Degeneration and Cortical Synaptic morphological changes; such abnormalities may also contribute to MTR abnormalities observed in the Normal-Appearing Gray Matter in Multiple Sclerosis.
Gupta S, Solomon JM, Tasciyan TA, Cao MM, Stone RD, Ostuni JL, Ohayon JM, Muraro PA, Frank JA, Richert ND, McFarland HF, Bagnato F
Mult Scler 2005 Dec;11(6):658-68
National Institute of Neurological Disorders and Stroke, NIH, NeuroImmunology Branch, Bethesda, MD 20892, USA
Interferon-beta (IFN-ß) reduces the number and load of new Contrast-Enhancing Lesions (CELs) in patients with Multiple Sclerosis (MS).
However, the ability of IFN-ß to reduce lesion sizes and re-enhancements of pre-existing CELs has not been examined extensively.
Activity of Contrast Re-Enhancing Lesions (Re-CELs) and contrast single-enhancing lesions (S-CELs) were monitored in ten patients with Relapsing/Remitting (RR) MS.
These patients underwent monthly post-contrast Magnetic Resonance Imaging (MRIs) for an 18-month natural history phase and an 18-month therapy phase with subcutaneous IFN-ß-1b, totaling 37 images per patient.
The activity was analyzed using the first image as a baseline and registering subsequent active monthly images to the baseline. There was a 76.4% reduction in the number of CELs with IFN-ß therapy.
The decrease was greater (P = 0.003) for S-CELs (82.3%) than for Re-CELs (57.4%). S-CELs showed no changes in durations of enhancement and maximal lesion sizes with treatment.
Exclusively for Re-CELs, IFN-ß-1b significantly decreased maximal lesion sizes, total number of enhancement periods and total months of enhancement.
Thus, IFN-ß appears to be effective in reducing the degree of severity of inflammation among Re-CELs, as reflected by their reduced maximal lesion sizes and durations of enhancement.
Prognostic Factors In MultiDisciplinary Rehabilitation Treatment In Multiple Sclerosis: An Outcome Study
Grasso MG, Troisi E, Rizzi F, Morelli D, Paolucci S
Mult Scler 2005 Dec;11(6):719-24
Fondazione Santa Lucia-IRCCS, Rome, Italy
The aim of this outcome study was to evaluate the effectiveness and prognostic factors of inpatient multidisciplinary rehabilitation treatment in patients with Multiple Sclerosis (MS).
We analyzed 230 consecutive inpatients with MS admitted to an MS rehabilitation ward who followed an individualized, goal-oriented, multidisciplinary rehabilitation program.
Every patient was submitted to a Neurological Examination and evaluated by means of Kurtzke's Expanded Disability Status Scale (EDSS), with its Functional Systems (FS), Barthel Index (BI) and the Rivermead Mobility Index (RMI).
We observed an effectiveness (percentage of potential improvement achieved during rehabilitation) of nearly 16% on BI and 8% on RMI, corresponding to an improvement in 124 patients (54%) on BI and 113 patients (49%) on RMI.
Basal EDSS (beta = -0.32, P < 0.001), Cognitive status (beta = -0.15, P < 0.05) and disease duration (beta = -0.13, P < 0.05) were negatively associated with effectiveness of treatment on BI (adjusted R2 = 0.176).
Whereas effectiveness on RMI was correlated only with the EDSS score (beta = -0.34, P < 0.001, adjusted R2 = 0.113).
In the logistic regression analysis, the absence of severe Sphincteric disturbances was correlated with the probability of improvement on BI that was nearly twice as high (OR =2.25, 95% CI 1.24-4.08) as that of other patients.
Moreover, patients without severe Cognitive deficits showed a similar probability (OR =2.37, 95% CI 1.05-5.33) of improvement on RMI.
The results of this study provide further evidence that intensive multidisciplinary rehabilitation in MS is effective in the majority of MS patients and that early treatment may favor functional recovery.
De Ridder D, Ost D, Van der Aa F, Stagnaro M, Beneton C, Gross-Paju K, Eelen P, Limbourg H, Harper M, Segal JC, Fowler CJ, Nordenbo A
Mult Scler 2005 Dec;11(6):694-9
University Hospitals KU Leuven, Department of Urology, Belgium
AntiCholinergics and intermittent catheterization are the cornerstones of Bladder management in early Multiple Sclerosis (MS).
In advanced MS however, Bladder management is based more on tradition than on evidence. Nurses seem to deal with catheter problems and chronic incontinence.
Despite the abundant use of indwelling catheters, there is a lack for guidelines on catheter-induced problems. The psychosexual and social impact of Bladder problems in advanced MS is often neglected.
The international multidisciplinary special interest group on Sexual, Urological and Bowel Dysfunction in MS (SUBDIMS) as a special interest group of the Rehabilitation in Multiple Sclerosis (RIMS) was confronted with a high variability in practice and a lack of guidelines.
A literature review was prepared during three multidisciplinary expert meetings. This review will be the basis of further initiatives to improve the Urological treatment of patients with advanced MS.
CD26+ CD4+ T-Cell Counts And Attack Risk In Interferon-Treated Multiple Sclerosis
Sellebjerg F, Ross C, Koch-Henriksen N, Sorensen PS, Frederiksen JL, Bendtzen K, Sorensen TL
Mult Scler 2005 Dec;11(6):641-5
The MS Clinic, Copenhagen University Hospital, Glostrup, Denmark
Biomarkers that allow the identification of patients with Multiple Sclerosis (MS) with an insufficient response to ImmunoModulatory treatment would be desirable, as currently available treatments are only incompletely efficacious.
Previous studies have shown that the expression of CD25, CD26 and CCR5 on T-Cells is altered in patients with active MS.
We studied the expression of these molecules by flow cytometry in patients followed for six months during ImmunoModulatory treatment.
In Interferon-beta (IFN-ß)-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26+ CD4+ T-Cell counts above median.
And, this risk was independent of the risk conferred by Neutralizing Anti-IFN-ß AntiBodies.
CD26+ CD4+ T-Cell counts may identify patients with MS at increased risk of attack during treatment with IFN-ß.