IntraVenous ImmunoGlobulin (IVIG)

Neurology 2008 Jul 22;71(4):265-7

IntraVenous ImmunoGlobulin in Relapsing/Remitting Multiple Sclerosis: a dose-finding trial

PRIVIG Study Group; UBC MS/MRI Research Group
Fazekas F, Lublin FD, Li D, Freedman MS, Hartung HP, Rieckmann P, Sørensen PS, Maas-Enriquez M, Sommerauer B, Hanna K
Medical University of Graz, Department of Neurology, Auenbruggerplatz 22, A-8036 Graz, Austria

Objective
Several studies have reported a reduction of relapses after the long-term administration of IV ImmunoGlobulin (IVIG) to patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

But they were mostly small and differed in terms of predefined outcome variables and treatment regimen.

We therefore set out to test two different doses of a new formulation of ImmunoGlobulin termed IGIV-C 10% for suppression of both clinical and MRI disease activity as well as safety.

Methods
One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial.

Forty-four and 42 patients received treatment with 0.2 and 0.4 g/kg of IGIV-C 10%, and 41 patients received an equal volume of placebo (0.1% albumin) every 4 weeks for 48 weeks.

The primary endpoint was the proportion of relapse-free patients. The main secondary endpoint was lesion activity assessed by 6-weekly MRI.

Results
Baseline variables were similar in IVIG- and placebo-treated groups.

After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%).

And there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks.

There were no significant between-group differences in the rates of adverse events.

Conclusion
Although IV ImmunoGlobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg.

This result seriously questions the utility of IVIG for the treatment of Relapsing/Remitting Multiple Sclerosis.

PMID# 18645164

NeuroDegener Dis 2008;5(1):8-15

Intravenous polyclonal human ImmunoGlobulins in Multiple Sclerosis

Soelberg Sorensen P
Danish MS Research Center, Copenhagen University Hospital, Rigshospitalet, Department of Neurology, Copenhagen, Denmark

IntraVenous ImmunogGlobulin (IVIG) is an established therapy for DeMyelinating Diseases of the Peripheral Nervous System. IVIG exerts a number of effects that may be beneficial in Multiple Sclerosis (MS).

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

In patients with a first episode of DeMyelinating Disease, IVIG delays the time to the second relapse and thereby to the diagnosis of definite MS.

In patients with an acute MS relapse, IVIG as add-on therapy to MethylPrednisolone does not make remission of symptoms faster or more complete.

IVIG does not seem to be of any benefit to chronic visual or motor symptoms in MS.

In Secondary/Progressive MS, IVIG has not shown any effect on disease progression, relapses or new Magnetic Resonance Imaging lesions.

Experimental studies in the MS model Experimental Autoimmune Encephalomyelitis in rats demonstrate that IVIG has to be administered at the time of induction of a relapse in order to be effective.

In conclusion, IVIG can be considered as a second-line treatment to approved therapies for Relapsing/Remitting MS, but the ideal dosage of IVIG still needs to be determined.

In order to be a first-line treatment for MS, the beneficial effect should be confirmed in a large-scale placebo-controlled survey, or in a study comparing the effect with approved therapies for Relapsing/Remitting MS using appropriate clinical and Magnetic Resonance Imaging outcome measures.

Copyright (c) 2008 S. Karger AG, Basel.

Mult Scler 2007 Nov;13(9):1107-17

IntraVenous ImmunoGlobulin in Primary and Secondary/Chronic/Progressive Multiple Sclerosis: a randomized placebo controlled multicenter study

Pöhlau D, Przuntek H, Sailer M, Bethke F, Koehler J, König N, Heesen C, Späth P, Andresen I
Multiple Sclerosis Center, Kamillus-Klinik Asbach, Department of Neurology, Germany

In patients with Relapsing/Remitting Multiple Sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability.

In patients with Chronic/Progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies.

This trial investigated the influence of IVIG in Primary (PPMS) and Secondary (SPMS) Chronic/Progressive MS.

Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months.

Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the Expanded Disability Status Scale (EDSS) sustained for 3 months, and 2) the improvement of Neurological functions defined by a patient's best EDSS score.

Secondary endpoints were: the proportion of patients with sustained progression, the relapse rate, the assessment of Fine Motor Skills, Visual Evoked Potentials, Contrast Sensitivity, Depression and Quality Of Life.

Analysis of the Intention-To-Treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406).

When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant.

There was no IVIG-mediated improvement in Neurological functions.

In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396).

PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score.

In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028).

The difference was significant in PPMS (P=0.016), but not in SPMS patients.

In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression.

In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups.

Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated.

It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favor of IVIG treatment in patients with SPMS.

J Neurol Sci 2007 Aug 15;259(1-2):61-6

IntraVenous ImmunoGlobulin in MS: promise or failure?

Fazekas F, Strasser-Fuchs S, Hommes OR
Medical University Graz, Department of Neurology, Auenbruggerplatz 22, A-8036 Graz, Austria

There is an established role for IntraVenous ImmunoGlobulin (IVIG) in the treatment of certain Neurologic Autoimmune Disorders which affect the Peripheral Nervous System and a variety of ImmunoModulatory properties of IVIG have been proposed.

This prompted an intense research into the efficacy of IVIG in Central Nervous System Autoimmune Disorders and until now several well-controlled clinical trials have been performed in different stages and phenotypes of Multiple Sclerosis (MS).

The results were mixed. Speculations that IVIG might be able to reverse fixed Neurologic deficits from MS could not be confirmed.

Adding IVIG to the conventional treatment of MS relapses with high-dose IVMP also did not provide any additional benefits. Similarly, trials failed to establish a role for IVIG in the treatment of Secondary or Primary/Progressive MS.

Most consistent beneficial results with a reduction of relapse rates and a slowing of disability have been obtained in Relapsing/Remitting MS including Clinically Isolated Syndromes.

Although a most recent study did not confirm a reduction of disease activity based on clinical and MRI findings.

Trial results also suggest that IVIG might serve to suppress an increased recurrence of relapses immediately after delivery.

Consequently, IVIG treatment may be considered as second line option for these indications.

Although there is still uncertainty regarding the actual mechanism(s) of action and optimal dosage of this treatment.

AutoImmunity 2006 Sep;39(6):513-7

Long term safety of IVIg therapy in Multiple Sclerosis: 10 years experience

Katz U, Kishner I, Magalashvili D, Shoenfeld Y, Achiron A
Center for AutoImmune Diseases, The Chaim Sheba Medical Center, Department of Internal Medicine B, Tel HaShomer, 52621, Israel

Multiple Sclerosis (MS) is a chronic DeMyelinating Disease of the Central Nervous System. The majority of MS patients have a Relapsing/Remitting course with progressive Neurological disability that accumulates over the years.

IntraVenous ImmunoGlobulin (IVIg) has demonstrated benefit in the treatment of some patients with Relapsing/Remitting MS.

Concerns about adverse events of IVIg, mainly Acute Renal Failure and Thromboembolic events have been raised in the medical literature.

We examined the adverse events profile of IVIg treatment in a large cohort of 293 Relapsing/Remitting MS patients:

Treated with an initial loading dose of IVIg (0.4 g/Kg body weight/day, for 5 consecutive days) and additional booster dose infusions (0.4 g/Kg body weight/booster dose, every 6 weeks) as a maintenance treatment.

A total of 9,281 IVIg infusions were administered within a mean treatment period of 3.8 +/- 3.5 years (3 months-10 years). The main adverse event during the loading dose period was headache, occurring in 12.6% of the patients.

The annual rate of any adverse event during the IVIg maintenance period was 4.4% during the first year and had a trend to decrease with every passing year of treatment.

Adverse events during the loading dose did not predict adverse events during the maintenance phase. No severe adverse events were recorded.

We conclude that IVIg is a safe therapy in MS either for short or for long-term periods.