IntraVenous ImmunoGlobulin (IVIG)

IntraVenous ImmunoGlobulin (IVIG) is an established therapy for a number of NeuroImmune Disorders, including Guillain-Barre Syndrome and chronic Inflammatory DeMyelinating PolyNeuropathy.

IVIG exerts a number of effects that may be beneficial in Multiple Sclerosis (MS): reduction of Inflammation, inhibition of Macrophages, and promotion of ReMyelination.

Four double-blind trials have been performed of IVIG in Relapsing/Remitting MS. A meta-analysis of the four trials has shown that IVIG reduces the relapse rate, new MRI lesions, and disease progression.

IVIG does not seem to be of any benefit in chronic Visual or Motor symptoms in MS. In Secondary/Progressive MS, IVIG has not shown effect on disease progression, relapses or new MRI lesions.

In conclusion, IVIG is an alternative second-line treatment to approved therapies in Relapsing/Remitting MS, but the ideal dosage of IVIG still needs to be determined.

IntraVenous ImmunoGlobulin(IVIg) is a ImmunoModulating therapy to administer a relatively high dose of human ImmunoGlobulins to a number of AutoImmune Diseases.

Clinical trials of IVIg for Neurological Disorders including AutoImmune Peripheral Neuropathy were carried out since the later of 1980's, and the efficacy of IVIg for such diseases was proved.

In recent years the effectiveness of IVIg for Multiple Sclerosis (MS) has been reported in several randomized controlled trials(RCTs).

MS patients in the trials were given ImmunoGlobulin or placebo every month or two months for more than half a year. IVIg in particular is beneficial in prevention a recurrence of Relapsing/Remitting MS and in improvement of MRI findings in a part of RCTs.

However, IVIg does not recognize the distinct effectiveness in progression of Secondary/Progressive MS yet. Some problems, for example, optimal dose or dosage frequency are unsolved.

Generally a adverse effect of IVIg in MS patient is slightness and the continuation treatment of IVIg is tolerate for most patients.

Now, in Europe where a clinical trial goes ahead, IVIg might be considered the therapy for MS when a already established treatment for MS such as Interferon-ß is not effective or not be able to use.

On the other hand, unfortunately the effectiveness of IVIg for MS could not be recognized by RCT executed in Japan.

IntraVenous ImmunoGlobulins are used in the treatment of different AutoImmune Diseases. Recent trials suggest their efficacy in Relapsing/Remitting Multiple Sclerosis.

We report the results of an efficacy and safety trial using monthly intravenous injections of ImmunoGlobulins for patients with Secondary/Progressive Multiple Sclerosis.

Eighteen patients in clinical progression, who have been previously treated with ImmunoModulatory or ImmunoSuppressive Drugs, were given monthly IntraVenous ImmunoGlobulin infusions (0.4 g/kg/d for 5 days). At the beginning, the mean EDSS score was 6.77.

At the end of the study, an improvement of EDSS was noted in 61.1 p. cent of patients, with less than 1 and 0.75 for Secondary and Primary/Progressive Diseases respectively. No worsening was reported.

Surprisingly, some patients had partial improvement of Neurological functions which were considered as sequelae. Indications for IntraVenous ImmunoGlobulins in the treatment of the Multiple Sclerosis need to be evaluated.

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

Owing to its AntiInflammatory properties, IVIG may be beneficial in the treatment of acute relapses and in prevention of new relapses. By promoting ReMyelination, IVIG could have a beneficial effect on disability and disease progression.

Four double-blind trials in Relapsing/Remitting MS have demonstrated that IVIG reduces the relapse rate and the number of Gadolinium enhancing lesions, and in this respect seems comparable to established therapies in Relapsing/Remitting MS, i.e. Interferon-ß and Glatiramer Acetate.

The doses of IVIG that have been used for treatment in Relapsing/Remitting have varied 10-fold, and the ideal dosage of IVIG for treating MS still needs to be determined.

Three studies have been performed to assess the effect of IVIG on chronic Visual Impairment or established Motor Symptoms in MS. None of these trials could confirm that established symptoms in MS can be reversed by IVIG.

In Secondary/Progressive MS, a large randomized placebo-controlled trial has recently shown that IVIG is without beneficial effects in this phase of the disease.

In conclusion, IVIG is a valuable alternative for treatment of Relapsing/Remitting MS 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.

Background
Some patients with Multiple Sclerosis (MS) do not show a clear improvement of acute relapses after treatment with Intravenous MethylPrednisolone (IVMP).

We compared the efficacy of the combination of IntraVenous ImmunoGlobulins (IVIg) and IVMP with the standard treatment of IVMP alone in promoting recovery from moderate to severe acute relapses in MS.

Methods
Patients with Clinically Definite MS having a relapse with at least a one point increase in Kurtzke's Expanded Disability Status Scale (EDSS) in comparison to the preattack EDSS were randomized to IVMP-IVIg or IVMP-placebo treatment.

The primary outcome criterion was the EDSS grade at four weeks.

A preplanned interim analysis was performed after inclusion of 19 consecutive MS patients to evaluate the sample size necessary for a larger trial.

Findings
Both groups had improved one point on the EDSS four weeks after start of treatment (P = 0.81) and one of the stopping rules of the interim analysis was fulfilled.

There were also no differences in secondary outcomes: EDSS at eight and 12 weeks, time to improve > or = 1 EDSS points, difference in Scripps Score and Ambulation Index.

Five patients in the IVMP-IVIg group and two in the IVMP group had a new relapse in the six month follow-up.

Interpretation
Our study could not show superiority of IVMP-IVIg in the treatment of moderate to severe acute relapses in MS.

Background
Several double-blind placebo-controlled trials of Relapsing/Remitting Multiple Sclerosis have shown beneficial effects of IntraVenous ImmunoGlobulin (IVIG) on relapse rate and disability.

The European Study on Intravenous ImmunoGlobulin in Multiple Sclerosis set out to test IVIG in the Secondary/Progressive phase of the disease.

Methods
318 patients with Clinically Definite Secondary/Progressive Multiple Sclerosis (mean age 44 years [SD 7]) were randomly assigned IVIG 1 g/kg per month (n=159) or an equivalent volume of placebo (Albumin 0.1%; n=159) for 27 months.

After baseline investigation, clinical assessments were made every 3 months and MRI was repeated after 12 months and 24 months.

The primary outcome was confirmed worsening of disability as defined by the time to first confirmed progression on the Expanded Disability Status Scale (EDSS). Analyses were by intention to treat.

Findings
19 patients in the IVIG group and 39 in the placebo group terminated study treatment prematurely but were included in the analyses.

IVIG treatment had no beneficial effect on time to confirmed EDSS progression (hazard ratio 1.11 [95% CI 0.80-1.53] for IVIG versus placebo). The annual relapse rate was 0.46 in both groups.

No significant differences between the treatment groups were found in any of the other clinical outcome measures or in the change of T₂-lesion load over time.

The treatment was generally well tolerated, although deep venous Thrombosis, Pulmonary Embolism, or both occurred in seven patients with risk factors for Thromboembolism (IVIG six, placebo one).

Interpretation
Treatment with IVIG in this study did not show any clinical benefit and therefore cannot be recommended for patients with Secondary/Progressive Multiple Sclerosis.

The aim of the study was to evaluate the efficacy and safety of Interferon-ß-1a (Avonex) and IntraVenous ImmunoGlobulin (IVIG) in clinical practice for the treatment of Relapsing/Remitting Multiple Sclerosis.

Avonex is the most common disease-modifying therapy used in Iran due to its ease of administration.

IVIG is also frequently used due to its alleged effectiveness and fewer side effects. Eighty patients were selected and prospectively monitored according to a predefined protocol.

They were then randomized to receive either weekly intramuscular injections of Avonex or 0.4 g/kg monthly IVIG in a single blind fashion and following an attack of exacerbation which was treated with Steroids.

Basal relapse rate and Expanded Disability Status Scale (EDSS) were similar in both groups of patients (p > 0.4). Seventy-two patients remained in the study.

The annual relapse rate consistently decreased from 0.95 +/- 0.41 to 0.60 +/- 0.67 ( approximately 32%, p < 0.001) for 34 patients treated with Avonex and from 1.05 +/- 0.34 to 0.55 +/- 0.46 for 38 patients in the IVIG group ( approximately 47%, p < 0.001).

EDSS decreased by 0.4 units in IVIG-treated patients (p < 0.001) and remained stable (0.2 < p < 0.3) in the Avonex arm.

This study confirms the relative efficacy of both treatments with better safety profile for IVIG in the studied Iranian population. However, the results are very preliminary ones, due to limited numbers of patients and only 12 months of treatment.

Copyright (c) 2004 S. Karger AG, Basel.

IntraVenous ImmunoGlobulin (IVIG) is an established treatment of Immune-mediated DeMyelinating Neuropathy.

Since IVIG possesses multiple ImmunoModulatory and anti-inflammatory properties, IVIG therapy may represent a way of interfering with the disease process in Multiple Sclerosis (MS).

In the MS animal model Experimental Autoimmune Encephalomyelitis (EAE), infusions of IVIG significantly reduced disease symptoms as well as the underlying CNS pathology.

IVIG was only effective in EAE when administered in a prophylactic treatment protocol, since IVIG infusions during the established phase of EAE did not alter the disease course or the degree of inflammation found in the Central Nervous System.

IVIG also has the potential to act through Myelin repair mechanisms as evidenced by work done in the Theilers murine Encephalomyelitis Virus model of DeMyelination.

Together these observations have led to certain expectations for IVIG as a treatment for MS, and have resulted in various clinical trials.

Several controlled trials report beneficial effects of IVIG on relapse rate, new MRI lesions, and disease progression in Relapsing/Remitting MS, while a ReMyelinating effect of IVIG has not been documented. IVIG is, therefore, presently regarded as a second-line therapy of MS.

Background
Monthly application of high-dose IntraVenous ImmunoGlobulin (IVIG) to patients with Secondary/Progressive Multiple Sclerosis (MS) showed no clinical benefit in the European Study on Immunoglobulin in MS (ESIMS).

Magnetic Resonance Imaging (MRI) results may provide insights into the morphologic consequences of such treatment.

Methods
A total of 318 patients (mean age 44 +/- 7 years) were enrolled in 31 European and Canadian centres and treated monthly with 1 g/kg body weight of IVIG or equivalent amounts of albumin 0.1% for 27 months.

MRI was performed at baseline and after 12 and 24 months and comprised of conventional dual-echo T₂-weighted and T₁-weighted scans before and after application of 0.1 mmol/kg Gd-DTPA.

Results
Similar to clinical variables, MRI measures at baseline were well comparable between treatment groups except for a somewhat lower mean number of contrast-enhancing lesions and number of active scans in IVIG-treated patients.

Over the trial period there was almost no change of the T₂-lesion load and the 'black hole' volume in both treatment groups and the cumulative number of contrast-enhancing lesions were similar.

There was only a trend for fewer new or enlarged T₂-lesions in IVIG patients, which disappeared after correction for the imbalance in the number of contrast-enhancing lesions at baseline.

Brain Volume in terms of a partial Cerebral fraction decreased significantly less with IVIG than placebo treatment (final visit: -0.62 -/+ 0.88% versus -0.88 +/- 0.91%; P=0.009).

This difference remained statistically significant with correction for active lesions at baseline (P=0.02) and was seen primarily in male patients and those with an Expanded Disability Status Scale score > or = 6 and no relapses in the two years before the study.

Conclusion
The absence of significant differences in conventional MRI measures between both treatment groups parallels the negative clinical results of ESIMS.

The causes for and possible long-term clinical effects of a lower rate of Brain volume loss in IVIG patients should be explored further.

High-dose IntraVenous ImmunoGlobulins (IVIG) have become a successful new treatment regimen in Neurological Autoimmune Diseases.

Most autoimmune disorders are heterogeneous, implicating Cellular and Humoral Immune Mechanisms, and this pathogenesis also applies to MS.

Many in vivo and in vitro experimental studies have shown that IVIG can therapeutically interfere with the Immune System at several levels, but only some are likely to be relevant in MS.

Clinical trials of IVIg have investigated the effect on different disease courses and stages of MS.

Data show that IVIg have beneficial effects in Relapsing/Remitting disease, but probably no effect during the Secondary/Progressive phase.

IVIG are, therefore, currently considered in some countries as second line treatments for patients with Relapsing/Remitting disease when first-line drugs are not tolerated.

Despite promising data from animal experiments that IVIG may induce ReMyelination, human treatment trials have not demonstrated a clinically relevant improvement.

The Immunomodulatory treatment of Multiple Sclerosis (MS) with high-dose IntraVenous ImmunoGlobulins (IVIG) has been discussed with some controversy in the context of evidence-based medicine.

The recent publication of eight trials investigating several aspects of MS has shed some more light on the role of IVIG treatment in MS.

Here we summarize and critically discuss the new data in the context of previous studies on this treatment.

In Relapsing/Remitting MS, IVIG remain a second-line treatment when other licensed treatments are not possible.

Currently there is no role for IVIG in Secondary/Progressive MS. Similarly, the use of IVIG during an acute relapse shows no benefit in addition to standard Steroid treatment.

The initiation of IVIg therapy after a Clinically Isolated Syndrome has delayed the occurrence of definite MS, and this may become a new indication.

Furthermore, previous data suggesting that IVIG can reduce the incidence of postpartal relapses have been substantiated.

However, those trials unfortunately lack appropriate internal control groups. By and large, previous recommendations for the use of IVIG in MS are supported by the new data.

Treatment of Neurological Disorders with IntraVenous ImmunoGlobulin (IVIG) is an increasing feature of practice for an expanding range of indications.

This article reviews the current literature regarding the role of IVIG treatment in Multiple Sclerosis (MS) and summarizes recommendations for the use of IVIG in different courses and clinical subsets of the disease.

Principally based on the results of four randomized, double-blind, placebo-controlled trials (RCTs) and a corresponding meta-analysis.

The amount of evidence for the efficacy of IVIG treatment is currently most convincing for the Relapsing/Remitting course of MS (RRMS).

Nevertheless, it lags clearly behind that for beta-Interferon due to smaller study sizes, partial deficits in study design and not established optimal dosage.

This prompted the basis for a consensus statement in some countries to recommend IVIG as second-line treatment in RRMS.

When other licensed therapies (i. e., beta-Interferon, Glatiramer Acetate) are individually not tolerated due to side effects or concomitant disease.

Recent evidence indicates that IVIG is also effective in Clinically Isolated Syndrome (CIS) and should be considered as a therapeutic option, particularly when licensed ImmunoTherapy can not be offered.

During an acute relapse additional IVIG administration to established Steroid treatment showed no benefit.

Despite promising experimental data on promotion of ReMyelination, fixed chronic deficits were not reversed or improved by long-term IVIG treatment either.

Currently there is no indication for IVIG treatment in the Chronic/Progressive disease stages.

Since a large and well-designed RCT failed to show any beneficial effect in patients with Secondary/Progressive MS (SPMS) and data derived from Primary/Progressive MS (PPMS) are still pending.

However, preliminary results of a so far unpublished RCT including patients with PPMS and SPMS suggest a strong trend towards a beneficial effect in PPMS.

So far, IVIG is the only therapy investigated for reducing postpartum relapses, whereas ImmunoModulatory Drugs are contraindicated during pregnancy and lactation period.

Data evaluating the peripartal use of IVIG along with the positive results of the trials in RRMS justify postpartal IVIG treatment.

Particularly for mothers, who choose to breastfeed, under consideration of the recommendations specified for the Relapsing/Remitting disease course.

As recently shown IVIG administration right from the early weeks of pregnancy appears to be a promising strategy, but cannot be recommended from the viewpoint of evidence-based medicine.