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ImmunoGlobulin (IVIG) Therapy
In Multiple Sclerosis


  1. ReMyelination as a future therapeutic principle in Multiple Sclerosis
    Nervenarzt 1998 Oct;69(10):841-50

  2. Unique AutoAntiBodies promote CNS ReMyelination
    Mult Scler 1998 Jun;4(3):217-21

  3. Assessing the outcome of treatment trials in Relapsing/Remitting Multiple Sclerosis
    J Neurol NeuroSurg Psychiatry 1998 Jun;64(6):726-9

  4. Combined ImmunoGlobulin and Azathioprine in R/R Multiple Sclerosis
    Eur Neurol 1998;39(3):178-81

  5. IntraVenous ImmunoGlobulin reduces MRI activity in Relapsing Multiple Sclerosis
    Neurology 1998 May;50(5):1273-81

  6. Failure of IV ImmunoGlobulin to arrest progression of Multiple Sclerosis: a clinical and MRI based study
    Mult Scler 1997 Dec;3(6):370-6

  7. IntraVenous ImmunoGlobulin therapy: effects of acute and chronic treatment in Multiple Sclerosis
    Mult Scler 1996 Jul;1(6):349-52

  8. IV ImmunoGlobulin treatment for Primary or Secondary Progressive Multiple Sclerosis
    Mult Scler 1997 Apr;3(2):149-52

  9. Trial of IntraVenous ImmunoGlobulin in Multiple Sclerosis: preliminary results
    Mult Scler 1997 Apr;3(2):145-8

  10. Treatment effects of monthly IntraVenous ImmunoGlobulin in Relapsing/Remitting Multiple Sclerosis: further analyzes of the Austrian ImmunoGlobulin in MS study
    Mult Scler 1997 Apr;3(2):137-41

  11. Promotion of endogenous ReMyelination in Multiple Sclerosis
    Mult Scler 1997 Apr;3(2):71-5




#1

Promoting ReMyelination As A Future Therapeutic Principle In Multiple Sclerosis?

Pohlau D, Aktas O, Epplen C, Hartung HP, Hoffmann V, Przuntek H
Nervenarzt 1998 Oct;69(10):841-50
Neurologische Klinik, Ruhr-Universitat Bochum am St. Josef Hospital
PMID# 9834472; UI# 99051537
Abstract

Multiple Sclerosis (MS), the most common Neurological AutoImmune Disorder diagnosed in young adults, is characterized by the repeated occurrence of DeMyelinating lesions within the Central Nervous System (CNS).

Promotion of ReMyelination in the Brain and Spinal Cord constitutes a potential strategy for therapeutic intervention in MS and other DeMyelinating Diseases.

    Three different principles are known to promote ReMyelination in the CNS of different animal models:
    1. Application of Growth Factors
    2. Transplantation of Myelin-Forming Cells
    3. IntraVenous ImmunoGlobulin (IVIg) Therapy

However, the systemic application of Growth Factors could be limited by effects on unaffected tissue.

For successful transplantation we still have the problem of homologous cells not tolerated by a Immunological different organism.

Currently the required combination of Growth Factors needed to cultivate human homologous cells is not known, so that cells suitable for transplantation are still not available.

Nevertheless, there is increasing evidence for beneficial effects of IVIg therapy on the promotion of ReMyelination in humans.

In this review we summarise recent findings on the regulation of Myelin sheath development and Oligodendrocyte differentiation, and discuss the presented strategies in the context of possible clinical application for the therapy of MS.



#2

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
Abstract

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.



#3

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
Abstract

Objectives
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.

Methods
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.

Conclusions
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.



#4

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
Abstract

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.



#5

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
Abstract

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.



#6

Failure of IntraVenous ImmunoGlobulin To Arrest Progression Of Multiple Sclerosis

A clinical and MRI based study

Francis GS, Freedman MS, Antel JP
Mult Scler 1997 Dec;3(6):370-6
Montreal Neurological Institute, Dept of Neurology and NeuroSurgery, Quebec, Canada
PMID# 9493636; UI# 98152630
Abstract

Due to the modest benefit, inconvenience and high cost of currently available therapies for MS, it is appropriate to seek alternative treatments.

Based on anecdotal evidence suggestive of benefit for IVIG in MS, we conducted an open-label, unblinded protocol of I.V.IG in nine MS patients.

The patients were given induction doses of IVIG followed by monthly boosters for 1 year and had clinical, MRI and CSF analyzes performed. Patients included were both Progressive and Relapsing.

There was no clinical benefit nor apparent MRI benefit utilizing this protocol.

During treatment the majority of patients continued to progress or have attacks and MRI demonstrated continued accumulation of T2-weighted lesions. CSF was unaffected by treatment.



#7

IntraVenous ImmunoGlobulin therapy: Effects Of Acute And Chronic Treatment In Multiple Sclerosis

Sorensen PS
Mult Scler 1996 Jul;1(6):349-52
National Univ Hospital, Copenhagen Multiple Sclerosis Clinic, Dept of Neurology, Denmark
PMID# 9345416; UI# 98005276
Abstract

High dose IntraVenous ImmunoGlobulin (IVIG) exerts several effects on the Immune System that could have a beneficial influence on the disease processes in Multiple Sclerosis (MS).

IVIG may be useful in treatment of acute exacerbations, in prevention of new relapses, and in promotion of ReMyelination.

Presently, the clinical evidence of effect of IVIG in MS is based on the results of small open trials, some of which, however, have been encouraging.

Confirmation of a beneficial effect of IVIG must await the results of placebo-controlled, double-blind trials currently ongoing in several centers. If effective, IVIG administration would be a valuable supplement to the existing treatment of MS.



#8

IVIG Treatment For Primary Or Secondary Progressive Multiple Sclerosis

Outline of a double-blind randomized, placebo-controlled trial.

Poehlau D, Federlein J, Postert T, Sailer M, Bethke F, Kappos L, Haas J, Przuntek H
Mult Scler 1997 Apr;3(2):149-52
Neurologische Uniklinik der Ruhr-Universitat Bochum am St. Josef Hospital, Germany
PMID# 9291171; UI# 97434948
Abstract

We present the design of a double-blind, randomized placebo-controlled phase III study to evaluate safety and efficacy of IVIG in the treatment of patients suffering from Primary or Secondary Chronic Progressive Multiple Sclerosis.

The primary endpoint is disability. Two measures of disability were chosen in order to assess the primary end point

  1. Sustained improvement (assessed at month 6, confirmed at month 9)
  2. Progression to increasing disability of the disease (sustained for 3 months) at any time during the course of this 2 years study.

The disability is measured by the Expanded Disability Status Scale (EDSS).

Secondary end points include the assessment of Visual function, functions of the Upper Extremity, Cognitive functions, Depression and Quality of Life.



#9

Trial Of IV ImmunoGlobulin In Multiple Sclerosis

Preliminary results

Sorensen PS, Wanscher B, Schreiber K, Blinkenberg M, Jensen CV, Ravnborg M
Mult Scler 1997 Apr;3(2):145-8
Rigshospitalet and The Danish Magnetic Resonance Center, Copenhagen Univ Hospital, Copenhagen Multiple Sclerosis Clinic, Dept of Neurology, Denmark
PMID# 9291170; UI# 97434947
Abstract

We enrolled 25 patients with Relapsing/Remitting or Relapsing/Progressive Multiple Sclerosis (MS) in a randomized placebo-controlled double-blind study of IntraVenous ImmunoGlobulin (IVIG).

IVIG 1 g/kg daily for 2 days was administered every 4 weeks for 24 weeks.

Seventeen patients completed the whole trial, whereas eight patients discontinued the trial; four during IVIG treatment and four on placebo.

Of the 17 patients who completed the trial, 11 had no exacerbations during IVIG treatment compared with only six on placebo (P=O.05).

The total number of exacerbations in the IVIG period was 11 and in the placebo period 15 (NS), and the number of severe exacerbations requiring treatment with IntraVenous MethylPrednisolone was four during treatment with IVIG and six on placebo (NS).

The results suggest that IVIG treatment may be of benefit for prevention of exacerbations in patients with Relapsing MS.



#10

Treatment Effects Of Monthly IntraVenous ImmunoGlobulin In R/R Multiple Sclerosis

Further Analyzes Of The Austrian ImmunoGlobulin In MS Study

Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B
Mult Scler 1997 Apr;3(2):137-41
Karl-Franzens University, Dept of Neurology, Graz, Austria
PMID# 9291168; UI# 97434945
Abstract

Recently, the Austrian ImmunoGlobulin in Multiple Sclerosis (AIMS) study showed patients with Relapsing/Remitting Multiple Sclerosis to benefit from repeated administration of IntraVenous ImmunoGlobulin (IVIg).

To provide a more detailed understanding of IVIG's action we performed further analyzes on the time course of treatment effects and in regard to the impact of clinical disability at study entry on patients' response to medication.

The AIMS trial was a randomized, placebo-controlled, double blind, multicenter trial.

It included 148 patients (IVIG: 75; placebo 73) who suffered from Relapsing/Remitting MS, were 15-65 years old and scored from 1-6 on the Expanded Disability Status Scale (EDSS).

IVIG was given over 2 years in a monthly dosage of 0.15-0.2 g/kg body weight.

Within the first 6 months of the trial clinical disability of IVIG treated patients improved significantly from a baseline EDSS of 3.33 +/- 1.38 to a score of 3.05 +/- 1.73 (P=0.002).

This improvement was retained over the subsequent 18 months of the trial (final EDSS: 3.09 +/- 1.62).

In contrast, placebo-treated patients showed a slight trend for deterioration over the study period (baseline EDSS: 3.37 +/- 1.67; final EDSS: 3.49 +/- 1.83).

IVIG treatment was associated with a significant reduction of relapses throughout the study which was independent of the patients' disability at baseline.

The observation of clinical improvement in the early phase of IVIG medication may suggest the activation of repair mechanisms.

Such as the promotion of ReMyelination while ImmunoRegulatory effects would be expected as the cause of fewer exacerbations throughout the AIMS study. These hypotheses need to be tested in future trials.



#11

Promotion Of Endogenous ReMyelination In Multiple Sclerosis

Lucchinetti CF, Noseworthy JH, Rodriguez M
Mult Scler 1997 Apr;3(2):71-5
Mayo Clinic Foundation, Dept of Neurology, Rochester, Minnesota, USA
PMID# 9291156; UI# 97434933
Abstract

Studies in both human and experimental models demonstrate that Myelin repair occurs in the Central Nervous System and is a normal physiologic response to Myelin injury.

However, ReMyelination in MS is often incomplete and limited.

The outcome of an actively DeMyelinating lesion depends on the balance between factors promoting Myelin destruction and Myelin repair.

Experimental models of CNS DeMyelination provide an opportunity to investigate the Morphologic, Cellular and Molecular mechanisms involved in ReMyelination.

This review focuses on experiments using the Theiler's virus model of DeMyelination which indicate that manipulation of the Immune Response has the potential to promote endogenous CNS ReMyelination and functional recovery in MS.



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