Unique AutoAntiBodies Promote Central Nervous System ReMyelination
Asakura K, Rodriguez M
Mult Scler 1998 Jun;4(3):217-21
Mayo Clinic and Foundation, Dept of Neurology, Rochester, Minnesota, USA
PMID# 9762677; UI# 98435425
In previous studies we demonstrated that the Humoral Immune Response directed against unique Central Nervous System (CNS) Antigens enhanced CNS ReMyelination in the Theiler's Virus experimental model of Multiple Sclerosis (MS).
To expand on this observation, a mouse IgM kappa MonoClonal AntiBody (mAb) which enhances CNS ReMyelination, was raised against normal mouse Spinal Cord homogenate.
Characterization of this mAb revealed that it is polyreactive towards variety of IntraCellular Antigens but also reacts to an unidentified surface Antigen on Oligodendrocytes.
The mAb is encoded by germline ImmunoGlobulin Genes without Somatic mutations consistent with the observation that it is a natural AutoAntiBody.
Recently we generated another mouse IgM kappa mAb raised against normal Spinal Cord homogenate, which also promotes CNS ReMyelination.
Further characterization revealed that both mAbs which promote ReMyelination have similar binding characteristics.
Conventionally Abs which recognize normal CNS components, especially Oligodendrocytes or Myelin, have been considered to be a disease marker or be involved in the PathoGenesis of MS.
However, we have identified a unique population of circulating AutoAntiBodies which are beneficial for Myelin repair.
Therefore this observation indicates the need to re-evaluate AutoAntiBody production against Myelin components in CSF and blood as markers of disease activity versus repair in MS.
Assessing The Outcome Of Treatment Trials In Relapsing/Remitting Multiple Sclerosis
Liu C, Li Wan Po A, Blumhardt LD
J Neurol NeuroSurg Psychiatry 1998 Jun;64(6):726-9
Univ Hospital, Faculty of Medicine, Division of Clinical Neurology, Nottingham, UK
PMID# 9647299; UI# 98309514
To review the outcome measures commonly used in phase III treatment trials of Relapsing/Remitting Multiple Sclerosis.
And, to introduce a method of data analysis which is clinically appropriate for the often reversible disability in this type of Multiple Sclerosis.
The conventional end point measures for disability change are inadequate and potentially misleading.
Those using the disability difference between study entry and completion do not take into account serial data or disease fluctuations.
Rigid definitions of "disease progression" based on two measurements of change in disability several months apart, do not assess worsening after the defined "end point".
Nor, the significant proportion of erroneous "treatment failures" which result from subsequent recovery from relapses that outlast the end point.
Assessing attacks merely by counting their frequency ignores the variation in magnitude and duration.
These problems can be largely circumvented by integrating the area under a disability-time curve (AUC).
A technique which utilizes all serial measurements at scheduled visits and during relapses to summarise the total Neurological Dysfunction experienced by an individual patient on any particular clinical scale during a study period.
The "summary measure" statistic AUC incorporates both transient and progressive disability into an overall estimate of the dysfunction that was experienced by a patient during a period of time.
It is statistically more powerful and clinically more meaningful than conventional methods of assessing disability changes.
Particularly for trials which are too short to expect to disclose major treatment effects on irreversible disability in patients with a fluctuating disease.
Combined ImmunoGlobulin & Azathioprine In Relapsing/Remitting Multiple Sclerosis
Kalanie H, Tabatabai SS
Eur Neurol 1998;39(3):178-81
Shahid Beheshti Univ of Medical Sciences, Mehr Hospital, Dept of Neurology, Tehran, Iran
PMID# 9605396; UI# 98266433
In an attempt to prevent exacerbations of Multiple Sclerosis, ImmunoGlobulin therapy was combined with Azathioprine (AZA).
IntraVenous ImmunoGlobulin (I.V.IG) 2 g/kg was given in divided doses over 3 consecutive days followed by monthly booster doses (0.2 g/kg) for 3 years to 38 patients with Relapsing/Remitting Multiple Sclerosis (MS).
In the 34 patients who completed the trial, the relapse rate decreased (from 1.7 relapses per year to 0 during the 3-year trial period).
The Kurtzke Expanded Disability Status Scale decreased from 3.4 +/- 0.72 to 3.0 +/- 0.70.
The results suggest that combined I.V.IG and AZA suppress the ongoing pathologic process in Relapsing/Remitting MS.
IntraVenous ImmunoGlobulin Reduces MRI Activity In Relapsing Multiple Sclerosis
Sorensen PS, Wanscher B, Jensen CV, Schreiber K, Blinkenberg M, Ravnborg M, Kirsmeier H, Larsen VA, Lee ML
Neurology 1998 May;50(5):1273-81
Copenhagen Univ Hospital, Dept of Neurology, Rigshospitalet, Denmark
PMID# 9595974; UI# 98255413
We wanted to assess whether IntraVenous ImmunoGlobulin G (IVIG) decreases disease activity on MRI in Relapsing MS.
Previous trials of IVIG in Relapsing/Remitting MS demonstrated a reduction of acute relapses, but these studies did not include MRI.
We treated 26 patients in a randomized, double-blind, crossover study of IVIG 1 g/kg daily or placebo on 2 consecutive days every month during two 6-month treatment periods.
The primary end point was the number of Gadolinium-enhancing lesions on monthly serial MRI.
Secondary efficacy variables were the occurrence of exacerbations, clinical Neurologic ratings, total MS lesion load on T2-weighted MRI, and multimodal Evoked Potentials.
Eighteen patients completed the entire trial; eight patients did not.
Twenty-one patients completed the first treatment period and at least two MRI examinations in the second treatment period and were included in the intention-to-treat analysis.
On serial MRI, we observed fewer enhancing lesions per patient per scan during IVIG treatment (median, 0.4; range, 0 to 9.3) than during placebo treatment (median, 1.3; range, 0.2 to 25.7; p = 0.03).
During IVIG treatment, 15 patients were exacerbation free compared with only 7 on placebo (p = 0.02). The total number of exacerbations in the IVIG period was 11 and in the placebo period, 19 (not significant).
None of the remaining secondary efficacy measures were significantly different between the two treatment periods.
The number of adverse events, in particular Eczema, was significantly higher during IVIG therapy than during placebo treatment.
These results suggest that IVIG treatment is beneficial to patients with Relapsing MS.