IntraVenous ImmunoGlobulin (IVIG)

We wanted to assess whether IntraVenous ImmunoGlobulin (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.

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.

Ten patients with Relapsing/Remitting Multiple Sclerosis were treated with IntraVenous ImmuneGlobulin, 0.4 g/kg per day for 5 consecutive days, and then with additional booster doses of ImmuneGlobulin of 0.4 g/kg, once every 2 months, for the next 12 months.

Ten untreated patients with Relapsing/Remitting Multiple Sclerosis who were matched with the study patients for age, disease duration, and number of attacks per year served as controls. ImmunoGlobulin treatment was well tolerated, with no side effects.

The exacerbation rate decreased from 3.7 +/- 1.2 exacerbations per year before treatment to 1.0 +/- 0.7 exacerbations per year during the treatment in the ImmuneGlobulin-treated patients, while it remained unaltered in the controls.

The post treatment Kurtzke Expanded Disability Status Scale score decreased from a mean of 4.45 to 4.15, whereas in controls it increased from 3.55 to 3.75.

The results suggest that ImmuneGlobulin suppresses the ongoing pathologic process in Multiple Sclerosis and may be a promising treatment to prevent disease exacerbations.

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 were chosen in order to assess the primary end point
• Sustained improvement
  • (assessed at month 6, confirmed at month 9)
• 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 Extended 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.

Experimental studies and open clinical trials have suggested IntraVenous ImmunoGlobulin (IVIG) as a potentially effective treatment of Multiple Sclerosis (MS).

The Austrian Immunoglobulin in Multiple Sclerosis (AIMS) study tested this assumption by examining 148 patients with Relapsing/Remitting MS in a randomized, double-blind, placebo controlled fashion (75 IVIG, 73 placebo).

Monthly administration of IVIG in a dosage of 0.15-0.20 g/kg over a period of 2 years slowed the progression of or even reversed disability.

As evident in a total of 24% of patients and almost halved the number of relapses in comparison to placebo treatment.

Therapeutic efficacy was noted within the first 6 months of treatment and was not correlated to the severity of disability (mild Neurological Signs without disability to ambulatory with assistance) at study entry.

Overall the magnitude of treatment effects of IVIG was comparable to that reported for Interferon-ß- and Copolymer-1.

Further ongoing studies will have to clarify the future role of IVIG in the treatment of MS, in particular in the Progressive forms of the disease.

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 I.V.IG in MS, we conducted an open-label, unblinded protocol of IVIG 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.

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

Four double-blind trials in Relapsing/Remitting MS have demonstrated that IVIG may reduce the relapse rate, progression and the number of gadolinium-enhancing lesions.

However, these trials were smaller than the pivotal trials of Interferon-beta and Glatiramer Acetate, and therefore, we performed a meta-analysis of the four trials.

In order to provide an overall assessment of the benefits of IVIG in Relapsing/Remitting Multiple Sclerosis, in comparison with other drugs currently available for treatment of disease activity in MS.

The meta-analysis showed a significant beneficial effect on:
1. Annual relapse rate (effect size -0.5; P = 0.00003)
2. Proportion of relapse-free patients (0.29 difference; P = 2.1 x 10-8)
3. Change in Expanded Disability Status Scale (EDSS) score (effect size: 0.25; P = 0.04)
4. A trend towards a reduction in the proportion of patients who deteriorated (P = 0.03).

Each single study in the meta-analysis had its weaknesses, but all studies were positive regarding their primary end-point.

The results yield concordant evidence for reduction of relapse rate and progression. The ideal dosage of IVIG for treating MS needs still to be determined.

In conclusion, IVIG may be a valuable alternative for treatment of Relapsing/Remitting MS, but can presently not be considered as a first-line treatment.

IVIG could be considered in patients who do not tolerate or are unwilling to take the approved injectable medications, but additional studies are needed to establish the role of IVIG in the management of Multiple Sclerosis.

Multiple Sclerosis (MS) is characterized by intra-Blood-Brain Barrier ImmunoGlobulin synthesis that persists lifelong.

SubCellular fractionation and two-dimensional ElectroPhoresis were used in conjunction with Immune precipitation and ImmunoBlotting to identify Antigenic Determinants for this ImmunoGlobulin.

We report that 2', 3'-Cyclic Nucleotide 3'-Phosphodiesterase (CNP), a protein associated with Oligodendrocyte/Myelin membranes, also present in Lymphocytes and Retina, is one major target for the Humoral Response.

AntiBodies to CNP are detected in Sera of 74% of MS patients. The AntiBodies are IgM and are present in Serum in high Titer as well as in CerebroSpinal Fluid.

The AntiBody response is temporally persistent, consistent with Systemic Immune Activation and persistent Antigenic stimulation. Moreover, CNP is isolated as an Immune complex from MS Brain.

CNP is expressed as two isoforms, with CNPII identical to CNPI but with a 20-Amino Acid extension at the Amino terminus of CNPII; however, the AntiBody response is exclusively restricted to CNPI.

In contrast, both isoforms bind the C3 Complement, providing a plausible mechanism in MS Central Nervous System (CNS) for Opsonization of Myelin membrane CNP, mediated via the C3 Receptor, and Phagocytosis of CNP-Ig Immune complexes, mediated by membrane Ig Fc Receptors of Macrophages and CNS Microglia.

Macrophage Inflammatory Protein - 1 (MIP-1) and MIP-1ß are, distinct but highly homologous CC Chemokines, produced by a variety of host cells in response to various external stimuli, and share affinity for CCR5.

To better elucidate the role of these CC Chemokines in Adaptive Immunity, we have characterized the affects of MIP-1alpha and MIP-1ß on Cellular and Humoral Immune Responses.

MIP-1 stimulated strong Antigen (Ag)-specific Serum IgG and IgM responses, while MIP-1ß promoted lower IgG and IgM, but higher Serum IgA and IgE AntiBody (Ab) responses.

MIP-1 elevated Ag-specific IgG1 and IgG2b followed by IgG2a and IgG3 subclass responses, while MIP-1ß only stimulated IgG1 and IgG2b subclasses. Correspondingly, MIP-1ß produced higher Titers of Ag-specific Mucosal secretory-IgA Ab levels when compared to MIP-1.

Splenic T-Cells from MIP-1- or MIP-1ß- treated mice displayed higher Ag-specific Th1 (IFN-γ) as well as selective Th2 (IL-5 and IL-6) Cytokine responses than did T-Cells from control groups.

Interestingly, Mucosally derived T-Cells from MIP-1ß-treated mice displayed higher levels of IL-4 and IL-6 compared to MIP-1-treated mice. However, MIP-1 effectively enhanced Ag-specific Cell-mediated Immune Responses.

In correlation with their selective effects on Humoral and Cellular Immune Responses, these Chemokines also differentially attract CD4⁺ versus CD8⁺ T-Cells and modulate CD40, CD80, and CD86 expressed by B220⁺ Cells as well as CD28, 4-1BB, and gp39 expression by CD4⁺ and CD8⁺ T-Cells in a dose-dependent fashion.

Taken together, these studies suggest that these CC Chemokines differentially enhance Mucosal and Serum Humoral as well as Cellular Immune Responses.

Polyclonal ImmunoGlobulins for IntraVenous use (IVIg) are a potent ImmunoModulator and have been shown to be effective in several Immune-mediated diseases. This includes Inflammatory DeMyelinating Diseases of the Central Nervous System (CNS) like Multiple Sclerosis (MS).

Besides their ImmunoModulatory function, IVIg have been proposed to enhance ReMyelination based on studies in the animal model of Theiler's Murine Encephalomyelitis Virus (TMEV).

Disappointingly, recent treatment trials in patients with MS have failed to demonstrate repair of longstanding deficits.

Since the clinical trials have used IVIg that contained nearly exclusively IgG, whereas the most pronounced effect in TMEV was seen with IgM, this could be a possible explanation for the negative outcome in the MS trials.

Here we have examined the effects of a new PolyClonal IgM preparation (IVIgM) on cultured Oligodendrocyte Precursor Cells (OPCs).

To achieve successful ReMyelination, OPCs proliferate, migrate, and differentiate into mature myelinating Oligodendrocytes.

IVIgM and commercial IVIg preparations had no influence on proliferation and differentiation of either isolated OPCs or OPCs in coculture with Microglia.

In contrast, IVIgM inhibited the proliferation of OPCs in mixed Glial cultures containing Astrocytes and Microglia.

This was not seen in cultures treated with IVIg, Albumin, or Interferon-gamma (IFN-γ), suggesting that this is a specific effect of IVIgM.

Differentiation was slightly delayed by IVIgM in mixed Glial cultures, but this was not statistically significant and Interferon-γ had a similar effect.

These results underline the importance of IgM in influencing OPCs and corroborate the in vivo findings that PolyClonal IgM are more potent than IgG in their capacity to influence ReMyelination.

The exact mechanism of how this modulation of OPCs is achieved remains unknown, but a complex interaction among all cells present in the CNS has to be postulated.

Objective
To determine whether IV ImmunoGlobulin (IVIg) reverses chronic Visual Impairment in MS patients with Optic Neuritis (ON).

Methods
In this double-blind, placebo-controlled Phase II trial, 55 patients with persistent Acuity Loss after ON were randomized to receive either IVIg 0.4 g/kg daily for 5 days followed by three single infusions monthly for 3 months, or placebo.

Results
The trial was terminated by the National Eye Institute because of negative results when 55 of the planned 60 patients had been enrolled.

Fifty-two patients completed the scheduled infusions, and 53 patients completed 12 months of follow-up.

Analysis of this data indicated that a difference between treatment groups was not observed for the primary outcome measure, improvement in logMAR Visual scores at 6 months (p = 0.766).

Exploratory secondary analyses suggested that IVIg treatment was associated with improvement in Visual function (including logMAR visual scores at 6 months and visual fields at 6 and 12 months) in patients with clinically stable MS during the trial.