How Responsive Is The Multiple Sclerosis Impact Scale (MSIS-29)? A Comparison With Some Other Self Report Scales
Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ
J Neurol NeuroSurg Psychiatry 2005 Nov;76(11):1539-43
Peninsula Medical School, Derriford Hospital, Plymouth, Devon PL6 8DH, UK
To compare the responsiveness of the Multiple Sclerosis Impact Scale (MSIS-29) with other self report scales in three Multiple Sclerosis (MS) samples using a range of methods.
To estimate the impact on clinical trials of differing scale responsiveness.
We studied three discrete MS samples: consecutive admissions for rehabilitation; consecutive admissions for steroid treatment of relapses; and a cohort with Primary/Progressive MS (PPMS).
All patients completed four scales at two time points: MSIS-29; Short Form 36 (SF-36); Functional Assessment of MS (FAMS); and General Health Questionnaire (GHQ-12).
(1) the responsiveness of each scale in each sample (effect sizes):
(2) the relative responsiveness of competing scales within each sample (relative efficiency):
(3) the differential responsiveness of competing scales across the three samples (relative precision); and
(4) the implications for clinical trials (samples size estimates scales to produce the same effect size).
We studied 245 people (64 rehabilitation; 77 steroids; 104 PPMS). The most responsive physical and psychological scales in both rehabilitation and steroids samples were the MSIS-29 physical scale and the GHQ-12.
However, the relative ability of different scales to detect change in the two samples was variable. Differing responsiveness implied more than a twofold impact on sample size estimates.
The MSIS-29 was the most responsive physical and second most responsive psychological scale. Scale responsiveness differs notably within and across samples, which affects sample size calculations. Results of clinical trials are scale dependent.
Cutting Edge: Macrophage Migration Inhibitory Factor Is Necessary For Progression Of Experimental Autoimmune Encephalomyelitis
Powell ND, Papenfuss TL, McClain MA, Gienapp IE, Shawler TM, Satoskar AR, Whitacre CC
J Immunol 2005 Nov 1;175(9):5611-4
Department of Molecular Virology, Immunology, and Medical Genetics
Macrophage Migration Inhibitory Factor (MIF) has been implicated in the pathogenesis of Inflammatory and Autoimmune Diseases. The role of MIF in the progression of Experimental Autoimmune Encephalomyelitis (EAE) was explored using MIF(-/-) mice.
Wild-type mice showed a progressive disease course, whereas MIF(-/-) mice exhibited acute signs but no further progression of clinical disease.
MIF(-/-) mice displayed markedly elevated CortiCosterone levels and significant decreases in the Inflammatory Cytokines TNF-, IFN-γ, IL-2, and IL-6 before, during, and after EAE onset.
Taken together, these findings support that MIF is an important mediator of EAE progression through GlucoCorticoid antagonism and up-regulation of the inflammatory response.
Natalizumab Induction and Maintenance Therapy for Crohn's Disease
Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P
International Efficacy of Natalizumab as Active Crohn's Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group
N Engl J Med 2005 Nov 3;353(18):1912-1925
Mayo Clinic, Rochester, Minn 55905, USA
Natalizumab, a humanized MonoClonal AntiBody against alpha(4) Integrin, inhibits Leukocyte adhesion and migration into inflamed tissue.
We conducted two controlled trials to evaluate Natalizumab as induction and maintenance therapy in patients with active Crohn's Disease.
In the first trial, 905 patients were randomly assigned to receive 300 mg of Natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10.
In the second trial, 339 patients who had a response to Natalizumab in the first trial were randomly reassigned to receive 300 mg of Natalizumab or placebo every four weeks through week 56.
The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).
In the first trial, the Natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks.
Continuing Natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P< 0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo.
Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the Natalizumab group in the second trial.
In an open-label extension study, a patient treated with Natalizumab died from Progressive Multifocal Leukoencephalopathy, associated with the JC virus, a human PolyomaVirus.
Induction therapy with Natalizumab for Crohn's Disease resulted in small, nonsignificant improvements in response and remission rates.
Patients who had a response had significantly increased rates of sustained response and remission if Natalizumab was continued every four weeks.
The benefit of Natalizumab will need to be weighed against the risk of serious adverse events, including Progressive Multifocal Leukoencephalopathy. (Clinical Trials, gov numbers, NCT00032786 and NCT00032799.)
Copyright 2005 Massachusetts Medical Society.
Azathioprine And Interferon-beta-1a In Relapsing/Remitting Multiple Sclerosis Patients: Increasing Efficacy Of Combined Treatment
Lus G, Romano F, Scuotto A, Accardo C, Cotrufo R
Eur Neurol 2004;51(1):15-20
Faculty of Medicine of the Second University of Naples and the Centro Interuniversitario di Ricerca in NeuroScienze, Department of Neurological Sciences, Naples, Italy
Current treatments of Relapsing/Remitting Multiple Sclerosis (RRMS) with ImmunoSuppressive or ImmunoModulatory drugs have been shown to modify the course of the disease in a significative number of patients.
However, in many cases, the response to either Interferon-beta (IFN-ß) or Azathioprine (AZA) treatments was not satisfactory and new therapeutic approaches are needed.
We studied clinical and MRI efficacy, safety and tolerance of AZA and IFN-ß-1a combined therapy in 23 patients with clinically definite RRMS, who had not previously been responsive to either monotherapies.
Our cases were divided into three subgroups:
- 8 previously untreated patients (subgroup A) with at least 2 years of natural course of the disease
- 8 patients (subgroup B) previously treated with AZA for 2 years and
- 7 patients (subgroup C) previously treated with IFN-ß-1a for 2 years. The baseline Expanded Disability Status Scale (EDSS) ranged from 2 to 4 in all subgroups
All patients completed 2 years of combined treatment with a dose of AZA adjusted to reduce Lymphocyte count down to 1,000 +/- 100/microl in association with IFN-ß-1a at a dose of 6 MIU every other day.
The mean number of relapses during the combined treatment period was significantly lower than that observed before combined therapy in all the three subgroups.
Also, the mean Delta EDSS score was significantly lower during combined treatment than in monotherapy in subgroups B and C.
Moreover, after 2 years of combined treatment, the number of new T1 HypoIntense lesions, the number and volume of proton density/T2 HyperIntense lesions and the Gadolinium enhancement of T1 HypoIntense lesions were significantly lower than before combined treatment.
After 2 years of treatment, this combination therapy appears to be safe and well tolerated and no serious side effects were reported.
Despite some limitations of our study design, the information regarding efficacy, safety and tolerance of the association of AZA and IFN-ß is most encouraging.
Copyright 2004 S. Karger AG, Basel
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 humanized 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.
Clinical Stabilization And Effective B-Lymphocyte Depletion In The CerebroSpinal Fluid And Peripheral Blood Of A Patient With Fulminant Relapsing/Remitting Multiple Sclerosis
Stuve O, Cepok S, Elias B, Saleh A, Hartung HP, Hemmer B, Kieseier BC
Arch Neurol 2005 Oct;62(10):1620-3
Heinrich-Heine University, Department of Neurology and Institute of Diagnostic Radiology, Dusseldorf, Germany
The Anti-CD20 Monoclonal AntiBody Rituximab effectively depletes B-Lymphocytes and has been successfully used in the therapy of Immune-mediated disorders of the Peripheral Nervous System.
A limited effect of Rituximab on B-Lymphocytes in the CerebroSpinal Fluid compartment of patients with Primary/Progressive Multiple Sclerosis (MS) was recently reported.
To determine the effect of Rituximab on clinical, Magnetic Resonance Imaging, and Immunological variables in a patient with Relapsing/Remitting MS.
A patient with Relapsing/Remitting MS was treated with Rituximab.
The patient was repeatedly examined clinically and by Magnetic Resonance Imaging. The frequency of peripheral blood and CerebroSpinal Fluid B-Lymphocytes was assessed by flow cytometry before, during, and after Rituximab therapy.
Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on Magnetic Resonance Imaging were also reduced. B-Lymphocytes were depleted in the Cerebrospinal Fluid and peripheral blood.
Our data demonstrate beneficial clinical effects of Rituximab in Relapsing/Remitting MS, mediated through modulation of Humoral Systemic and Central Nervous System intrinsic immune responses.
Clinical trials should determine optimal therapeutic strategies for patients with Relapsing/Remitting MS.
Clinical Presentation Of Primary /Progressive Multiple Sclerosis 10 Years After The Incidental Finding Of Typical Magnetic Resonance Imaging Brain Lesions: The Subclinical Stage Of Primary/Progressive Multiple Sclerosis May Last 10 Years
McDonnell GV, Cabrera-Gomez J, Calne DB, Li DK, Oger J
Mult Scler 2003 Mar;9(2):204-9
Vancouver Hospital & Health Sciences Centre at UBC Hospital, Multiple Sclerosis Clinic, Vancouver, BC, Canada
Subclinical Multiple Sclerosis (MS) has been identified incidentally at autopsy; apparently unaffected individuals with an affected twin have demonstrated Magnetic Resonance Imaging (MRI) changes consistent with MS.
And 'MRI relapses' are several times more common than clinical relapses.
A 39-year-old, right-handed man underwent MRI and PET scanning in 1986 as a 'normal' control in a Parkinson's Disease study, where his father was the proband.
MRI indicated multiple areas of abnormal signal intensity in a PeriVentricular and Gray-White Matter junction distribution.
Repeated clinical evaluations over the next 10 years were unchanged until 1996, when he complained of progressive weakness of the right foot and clumsiness in the right hand.
MRI now indicated a further area of high signal intensity in the Right Posterior Cord at the level of C5/C6.
There was mild Pyramidal distribution weakness in the right leg with an Extensor Plantar Response on the same side.
Over the next five years there has been mild progression in Weakness and Fatigue and intermittent Lhermitte's Phenomenon.
At no stage has there been a history of relapse, CerebroSpinal Fluid examination was normal and Evoked Responses (Visual and SomatoSensory) are normal.
This case demonstrates the phenomenon of SubClinical MS, unusually supported by prolonged clinical and MRI follow-up.
The patient eventually became symptomatic nine years after MRI diagnosis and is following a Primary/Progressive course.
Although MRI is known to be sensitive in identifying subclinical 'attacks', the pattern illustrated here may actually be quite typical of Primary/Progressive MS.
And, is compatible with the later onset seen in this subgroup of patients.