Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 123-130, 15 February 2003

The role of intravenous immunoglobulin in the treatment of multiple sclerosis

MS Research Unit, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark

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Abstract 

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 anti-inflammatory 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-beta 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.

Keywords:  Immunoglobulin G, Intravenous immunoglobulin, Multiple sclerosis, Controlled trials, Multiple sclerosis drug therapy, Relapses, Disease progression, MRI

 

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1. Introduction 

Intravenous immune globulin G (IVIG) has, during the recent years, become an established first-line treatment in a number of immune mediated diseases, including neurological disorders characterized by demyelination in the peripheral nervous system, i.e. Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy [1], [2], [3].

Multiple sclerosis (MS) is a chronic disease in the central nervous system characterised by immune mediated demyelination and axonal loss. In the majority of patients, a T-cell-mediated inflammation, induced by encephalitogenic T-cells and macrophages, leading to demyelination is the predominant pathogenic mechanism. However, at least in some patients, demyelinating antibodies and complement activation may be pathogenetically relevant. In a small proportion of the patients, demyelination is caused by a primary oligodendrocyte disorder. An early feature of the acute MS attack is a disruption of the blood–brain barrier causing a leak of immune mediators into the central nervous system. Release of pro-inflammatory cytokines are involved in the immune response directed against oligodendrocyte surface proteins and myelin proteins, which subsequently leads to disruption and phagocytosis of myelin by macrophages and to damage of axons. Several immunological disturbances have been observed in patients with active MS, including a reduced number of regulatory T-cells and increased number of activated pro-inflammatory CD4+ cells, and an increase in B-cells producing IgG antibodies against myelin proteins in the cerebrospinal fluid (CSF) [4], [5], [6], [7], [8], [9].

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2. Immunological properties of IVIG 

Commercial preparations of IVIG are made from plasma pools collected from several thousands of normal donors. Each gram of IVIG contains 4×1018 molecules and more than 107 different specificities. The effects of IVIG in MS could be mediated by several different mechanisms. IVIG contains anti-idiotypic antibodies that may neutralize circulating autoantibodies against myelin proteins and restore the physiological pattern of spontaneous fluctuations of the concentration of autoantibodies in plasma. IVIG can bind to surface receptors on B-cells and down-regulate antibody production. Blockade of the Fc receptors on macrophages could modulate the function of macrophages and inhibit macrophage-mediated phagocytosis of myelin [10], [11]. Additionally, IVIG can bind to specific epitopes of the T-cell receptor of certain regulatory T-cells and, thereby, cause suppression of inducer T-cells and B-cells [12], [13], [14]. Furthermore, IVIG can modify the balance between Th1 and Th2 subtypes of T-helper cells and thereby induce a modulation of cytokine production with down-regulation and/or neutralisation of pro-inflammatory cytokines (IL-1, IL-2, IL-6, interferon (INF)-γ, TNF-α, and IL-2 receptor) [15]. Moreover, commercial preparations of IVIG contain anti-inflammatory cytokines such as TGF-beta, but not pro-inflammatory cytokines such as INF-γ, or TNF-α [16]. Activation of complement is attenuated by IVIG, and IVIG may act as receptor for activated complement components and prevent their attachment to oligodendrocyte surface and myelin proteins [17], and thereby IVIG may inhibit complement-mediated demyelination. IVIG is capable to neutralise bacterial and viral superantigens that may cause activation of myelin specific encephalitogenic T-cells. Finally, in animal models IVIG promotes remyelination in demyelinating disorders [18], [19], [20], [21], [22], [23], [24].

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3. Access to the CNS 

It is still not known whether intravenous administration causes IgG to enter the CNS in sufficient amounts of to influence the local immune response within the MS lesion or if the effects of IVIG are confined to the blood circulation and the immune system outside the CNS [25]. A controlled study of IVIG in the treatment of MS reported a significant increase in the CSF IgG concentration during IVIG therapy and suggested that measurable amounts of IgG enters the CNS during IVIG treatment, or alternatively, that IVIG might induce an alteration of the intrathecal immune response [26].

More direct evidence of penetration of IVIG across the intact blood–brain barrier was provided by Bard et al. [27], who, in a mouse model of Alzheimer disease, administered mouse monoclonal antibodies against amyloid β-peptide intraperitoneally and subsequently could demonstrate the presence of the monoclonal IgG antibodies in brain sections.

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4. IVIG therapy in relapsing–remitting MS 

The majority of uncontrolled trials have shown some effect on disease activity with long-term treatment using rather small doses of gammaglobulins [28], [29], [30], [31], [32], [33], [34], [35], [36].

Four randomized, double-blind studies of IVIG in relapsing–remitting MS have been reported from Austria, Israel, Denmark and Poland, and all showed a beneficial effect on the disease activity. The studies were different in design and used different efficacy endpoints (Table 1).

Table 1. Design, patient characteristics, and treatment results of three published trials of IVIG in relapsing–remitting MS
StudyDesignAge (years)MS duration (years)EDSSMonthly IVIG dose (g/kg)Trial duration (months)Reduction in relapse ratea (%)Progression-free patientsb (%)Improvement in EDSSb (%)Deterioration in EDSSc (%)
Fazekas et al. (N=150)PG3773.30.22459†1717†7
Achiron et al. (N=40)PG3542.90.22463†35†133
Sorensen et al. (N=26)DC3553.52.06×24238†330

PG: parallel groups; DC: double cross-over.

a Difference IVIG compared with placebo.

b Difference in proportion IVIG–placebo.

c Difference in proportion placebo–IVIG.

† p<0.05.

The first published placebo-controlled trial was the Austrian study by Fazekas et al. [37], [38], who used a parallel group design and changes in EDSS as the primary efficacy measure. The study comprised 150 patients with relapsing–remitting MS, moderate disability (mean EDSS score 3.3), and at least two acute exacerbations during the previous 2 years, who were randomly assigned to treatment with either IVIG 0.15–0.20 g/kg/month or placebo for a period of 2 years (Table 1). The treatment was well tolerated, and 64 patients in the IVIG group and 56 patients in the placebo group completed the 2 years of treatment. Intention-to-treat analysis showed a significant reduction in impairment (EDSS −0.24) in IVIG-treated patients compared with an increase in impairment (EDSS 0.12) in the placebo group (p=0.008). Deterioration in disability, defined as an increase of at least 1.0 point in the EDSS score by the end of the study, occurred in 16% of the IVIG-treated patients and in 23% of placebo-treated patients. This difference was not statistically significant, but taken together with the proportion of patients who improved of one point or more on EDSS (31% in the IVIG group and in 14% in the placebo group), the difference between IVIG and placebo became statistically significant (p=0.04). However, the most prominent change was seen in the occurrence of relapses. The mean annual relapse rate fell during IVIG treatment from a pretreatment rate of 1.30 to 0.52, while the mean annual relapse rate during placebo treatment was 1.26 compared to 1.41 before the study period. This means a 59% reduction in the IVIG-treated group compared with the placebo group (p=0.004). The decrease in relapses was seen within the first 6 months after the start of IVIG treatment and was maintained throughout the study. Also the proportion of relapse-free patients was significantly higher in the IVIG group (53%) than in the placebo group (26%) (p=0.03). Adverse effects, using this low dose of IVIG, were infrequent and mild consisting of a transient rash after IVIG infusion in two patients and aggravation of a depression in one patient. MRI scans were not obtained in this study. Although the evaluation of EDSS and relapses was carried out by a blinded physician, the treating physician was aware of the treatment allocation that may have made it difficult to maintain blinding of all the patients during a 2-year study. The improvement in EDSS score in a considerable proportion of the patients has been ascribed to failure to maintain blindness in all patients [39].

In the Israeli study, Achiron et al. [40] used a parallel group design and employed the annual relapse rate as primary efficacy endpoint. They randomly assigned 40 patients with relapsing–remitting MS to treatment with either IVIG at a loading dose of 0.4 g/kg/day for 5 days followed by 0.4 g/kg every 2 months or placebo for 2 years [36], [37]. The patients had a mean EDSS score of 2.9 and had experienced between one and six relapses during the last 2 years before entering the study (Table 1). All patients but two completed the 2-year study, and only few and mild adverse events were reported. A highly significant reduction in the primary efficacy measure, the annual exacerbation rate, was observed in the IVIG group with a decline from 1.85 in the pretreatment period to 0.75 in the first year and to 0.42 in the second year (p<0.05). In the placebo group the annual relapse rate was 1.55 before the study and it was almost unchanged during the first year (1.80) and the second year (1.42) of the study. The 2-year reduction in relapse rate in the IVIG group was 63% compared to placebo. No significant differences were found in the mean change in EDSS score: −0.3 in the IVIG group and 1.97 in the placebo group. The proportion of patients who deteriorated by at least one point or more was lower in the IVIG-treated patients (13.7%) than in the placebo group (17.1%). MRI was performed before treatment and at the end of the second year. The evaluation of MRI lesions was made with the use of a self-composed scoring system based on the number and diameter of demyelinating plaques, yielding a score between 1 and 10. This method for assessment of brain MRI lesions, however, was rather insensitive compared to conventional measurements of T2 lesion volume. At the end of year 2, the mean MRI score was 3.82 in the IVIG group (baseline value 3.21) and 3.2 in the placebo group (baseline value 3.04) (p=0.51). Further, only 30 out of 40 patients were available for the final MRI, which may have contributed to the finding that IVIG had no impact on MRI.

The Danish study by Sorensen et al. [26], [41] used MRI as primary efficacy measure in a double-blind two period crossover study of IVIG 2 g/kg monthly or placebo during two 6-month treatment periods. Half of the patients were treated with IVIG for 6 months and after a 3-month washout period they were treated with placebo for 6 months. The other half of the patients was treated in the reverse order. Twenty-six patients with relapsing multiple sclerosis, an EDSS score at entry between 2 and 7, two or more relapses in the last year before entry, and at least five cerebral lesions on T2-weighted images on a screening MRI were included (Table 1). MRI was performed at monthly intervals during both 6-month treatment periods. In all, 18 patients completed the two period crossover study and constituted the per-protocol population. Twenty-one patients had at least one infusion and completed at least two MRI in the second treatment period and were available for the intention-to-treat analysis. In the per-protocol analysis, the mean number of gadolinium enhancing lesions per month decreased from 3.8 at baseline to 1.2 during IVIG and 3.2 during placebo, and the number of new enhancing lesions decreased from 3.8 at baseline to 1.0 during IVIG and 2.5 during placebo (p<0.01). Similar results were obtained in the intention-to-treat analysis. The reduction in mean number of new and total gadolinium-enhancing lesions during IVIG treatment compared with placebo were significantly reduced by approximately 60% (p<0.05). The percentage of patients with active scans decreased after 1 month of treatment with IVIG and remained stable thereafter during the 6-month period, whereas no changes were observed in the placebo treatment period. The median percentage change in T2 lesion load was −2.6 during IVIG and −0.4 during placebo (p=0.27). Although the study was not powered to show effect on clinical end-points, a trend (p=0.13) towards a reduction in the number of relapses was observed during IVIG treatment (11 relapses) compared with placebo (19 relapses). A significantly higher number of patients were exacerbation-free during treatment with IVIG (15) compared to placebo (7) (p=0.02). Although more patients improved in disability on IVIG than on placebo, no significant changes were observed in EDSS during IVIG or placebo treatment. This high dose of IVIG was associated with a high number of adverse events. Eczema, primarily on hand and feet, rashes, and infusion-related headache were the most commonly reported. Eight patients discontinued therapy; three patients withdrew having developed severe eczema, one patient encountered hepatitis C, one patient died of a pulmonary embolus as a complication to a deep venous thrombosis in the leg, one patient stopped therapy after several severe relapses, one patient withdrew his consent, and one patient emigrated.

The most recently published study from Poland by Lewanska et al. [42] used the annual relapse rate and the difference between pre-study relapse rate and relapse rate during the study period as primary clinical efficacy measures in a three-arm parallel group study comparing two different doses of IVIG and placebo. Forty-nine patients with clinical definite relapsing–remitting MS were allocated into three treatment groups: IVIG 0.2 g/kg (n=17), IVIG 0.4 g/kg (n=15) or placebo (n=17) given at monthly intervals for 12 months. Clinical examination and MRI were performed every 3 months during the study period. The clinical endpoints included annual relapse rate, proportion of relapse-free patients, mean changes in the EDSS score, and proportion of patients with worsening in clinical disability by 0.5 points on the EDSS, sustained for at least 3 months. MRI endpoints included changes in lesion volume on T2-weighted images and the mean number of gadolinium enhancing lesions on T1-weighted images every 3 months. The annual relapse rate was significantly lower in both IVIG groups (0.88 for 0.2 g/kg and 0.86 for 0.4 g/kg) compared to placebo (1.24). Neurological disability measured with EDSS decreased slightly in both the IVIG groups (0.03 and 0.07, respectively) and increased by 0.29 in the placebo group (p=0.01). The proportion of patients who worsened in the EDSS were 23.5% in the 0.2 g/kg IVIG group, 6.7% in the 0.4 g/kg IVIG group, compared with 47.1% in the placebo group. The total lesion volume on T2-weighted MRI increased by 13.6% in the placebo group, whereas it was almost unchanged both IVIG groups (0.4 g/kg −3.95% and 0.2 g/kg +3.6%). The mean number of Gd-enhancing lesions in the IVIG groups were reduced compared to the placebo group. However, the number of patients in each treatment arm was very low, and the study period only 12 months which make it difficult to interpret the results. Changes in EDSS were defined as increases or decreases by 0.5 points, and in the lower parts of the EDSS scale such changes would include random variations. Frequent MRI analyses of gadolinium-enhancing lesions showed considerable fluctuations making it difficult to evaluate the reduction in the mean number of lesions.

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5. IVIG in the prevention of post partum exacerbations 

Achiron et al. [43] used IVIG 0.4 g/kg/day for 5 consecutive days during the 1st, 6th and 12th week after childbirth to prevent childbirth-associated exacerbations in nine patients with a history of MS relapse 2 to 9 weeks after a previous delivery. None of the patients had exacerbations within the first 6 months after delivery.

In an open study, Hass treated 34 patients with IVIG 60 g within the first 3 days after delivery, of whom 18 patients with active disease before pregnancy received additionally 10 g IVIG monthly for 3 months. The exacerbation rate post partum was compared with the exacerbation rate after delivery in 227 patients from the European Pregnancy in Multiple Sclerosis Study (PRIMS). The two patient groups were comparable as to age, duration of disease, EDSS and relapse rate in the year before pregnancy. Both groups showed an increase in relapse rate after delivery, but the increase in the IVIG-treated patients was 33% lower than expected referring to the PRIMS data [44].

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6. IVIG for acute attacks of MS 

In 1986, Soukop and Tschabitscher [45] used IVIG (50 mg/kg) for treatment of acute exacerbations in 22 patients with relapsing–remitting MS. In 15 (68%) of the patients IVIG treatment improved neurological symptoms and signs, usually within 24 h, but the improvement persisted only 2 weeks after the end of treatment.

Recently, Sahlas et al. [46] reported effect of IVIG in two patients with acute disseminated encephalomyelitis refractory to treatment with methylprednisolone.

Nos et al. [47] studied the effect of IVIG on the blood–brain barrier in patients with an acute relapse. Using serial gadolinium-enhanced MRI they compared IVIG treatment with the combination of IVIG and prednisone and found that the combination of IVIG and prednisone dramatically decreased the enhancement on the serial scans, whereas IVIG alone did not have any effect on the degree of enhancement. This indicates that any beneficial influence of IVIG in acute relapses of MS is not mediated by improvement of the blood–brain barrier damage.

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7. IVIG for promotion of remyelination in MS 

The first attempt to utilize the remyelinating properties of IVIG demonstrated in animal studies was made by van Engelen et al. [48] who treated five patients with stable deficits in optic nerve function affecting eight eyes after optic neuritis. IVIG was administered as 0.4 g/kg daily for 5 days followed by 0.4 g/kg every 2 weeks for 3 months. Improvement in visual acuity, colour vision or visual evoked potentials was reported in five out of eight eyes.

Based on this open study, Noseworthy et al. [49] performed a double-blind randomized trial in 55 patients with persistent loss of visual acuity after optic neuritis. Patients were randomly allocated to receive either IVIG 0.4 g/kg daily for 5 days followed by 0.4 g/kg every 4 weeks for 3 months or placebo. Outcome measures were change in visual acuity at 6 months (and 12 months), change in visual fields, and change in visual evoked potentials. No difference between the treatment groups was observed in the primary outcome measure, improvement in visual acuity at 6 months, although a positive trend favouring IVIG was found at 12 months (p=0.132). IVIG administration did not improve visual fields or visual evoked potentials. Exploratory analysis suggested an interaction with disease activity: Patients with clinical stable disease during the trial showed improvement in visual acuity and visual fields.

In another trial, Noseworthy et al. [50] studied if administration of IVIG in patients with stable neurologic weakness was followed by changes in muscle strength, as an indirect measure of possible treatment-related remyelination. Sixty-seven patients with persistent muscle weakness that had been stable for 4 to 18 months were randomized to treatment with either IVIG 0.4 g/kg daily for 5 days followed by 0.4 g/kg every 2 weeks for 3 months or placebo. The primary outcome measure was change from baseline to 6 months in the mean percent of normal strength of muscles with apparently irreversible motor deficits (targeted neurologic deficits). Other outcome measures included disability scales and MRI in a subset of patients. The trial was discontinued prematurely at the time of an interim analysis when 64 patients had completed 3 months follow-up and 59 had completed 6 months follow-up. There was no difference in the degree of change in strength in the targeted muscles between the two treatment groups, and no beneficial effect of IVIG on relapse rate or impairment measures.

Stangel et al. [51] conducted a small placebo-controlled single crossover study of IVIG using changes in central motor conduction time as an indirect measure of central myelination. Ten patients with stable motor deficits were treated first with placebo and 6 weeks later with IVIG 0.4 g/kg on 5 consecutive days. No change in the primary outcome measure, the central motor conduction time, was found 6 weeks after each treatment. A small improvement was found in neurological rating scale after IVIG, but the change was not statistically significant compared with placebo.

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8. IVIG in the treatment of secondary progressive MS 

In an unpublished trial, Poehlau et al. studied 40 patients with secondary progressive MS randomly assigned to treatment with either IVIG 20 g or placebo every 2 weeks for 1 year. They reported that more patients showed improvement and fewer patients showed worsening in neurological disability during treatment with IVIG compared to placebo. They also found a significant reduction of 50% in the relapse rate and an improvement in visual evoked potentials during IVIG compared to a placebo (personal communication).

Recently, the European Study on IVIG in Multiple Sclerosis (ESIMS), a large placebo-controlled phase 3 trial of IVIG in the treatment of secondary progressive MS has been concluded. The aim of the study was to compare the effect of IVIG 1 g/kg with placebo administered every 4 weeks for 26 months on delay of clinical progression based on deterioration of EDSS score in patients with secondary progressive MS. The study comprised 318 patients with clinically active secondary progressive MS documented by deterioration of at least one EDSS point or progression of 0.5 EDSS points and at least 2 relapses during the past 2 years. The time to a confirmed treatment failure, defined as deterioration of one EDSS point if the initial EDSS was <6.0 or of 0.5 EDSS point if the initial EDSS was ≥6.0, was chosen as primary endpoint. Other endpoint included an outcome criteria composed of deterioration in EDSS and/or 20% worsening in the nine-hole-peg-test, mean change in EDSS, annual relapse rate, change in lesion volume on T2-weighted MRI, number of gadolinium enhancing lesions, and number of active MRI scans. A total of 260 patients completed the trial according to the protocol, but complete 27 months data were available for 286 patients. No significant differences between IVIG and placebo were found in the primary outcome measure, time to deterioration in EDSS, or in any other efficacy endpoint. Details of the design of the trial and preliminary results are presented in this volume of the journal [52].

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9. Discussion and conclusions 

IVIG has been used in a large range of dosages to treat MS patients in different stages of the disease in trials with diffrent endpoints (Table 2). From these trials it appears that there is concordant evidence of a beneficial effect of IVIG on relapses, disability and MRI changes in patients with relapsing–remitting MS. All four randomised studies were positive regarding the primary efficacy endpoint, and the results yield evidence for different types of endpoint, i.e. relapses, disability and gadolinium positive MRI lesions [26], [37], [40], [42]. However, each single study had its weaknesses, and apart from the study by Fazekas et al., the studies were small. Contrary to the results of most placebo-controlled trials in MS, the studies with changes in relapse rate as endpoint showed no reduction in the annual relapse rate in the placebo group, which would have been expected as a result of a regression to the mean. This would tend to overestimate the effect of IVIG compared to other therapies. Further, none of the studies have convincingly documented that IVIG reduces progression of disability measured as the time to sustained deterioration in the score on the EDSS or a beneficial effect on the lesion load on T2-weighted MRI. In a recent report of a subcommitte of the American Academy of Neurology on disease modifying therapies in MS it is stated that “the studies of IVIG, to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIG reduces the attack rate in RRMS. The current evidence suggest that IVIG is of little benefit with regard to slowing disease progression” [53]. However, it is not mentioned which studies have formed the basis of this statement. Although it is evident that the final conclusion regarding the benefit of IVIG in MS cannot be drawn from the presently published trials, it has to be emphasized that all studies in relapsing–remitting MS show converging evidence of a positive clinical effect.

Table 2. Dosage, clinical state or symptom, primary endpoints, and overall results in controlled trials of IVIG in MS
Study (reference no.)Clinical state/symptomNo. of patientsIVIG dosagePrimary endpointOverall result
Fazekas et al. [37]RRMS1500.2 g/kg/monthEDSS changesPositive
Achiron et al. [40]RRMS402+0.4 g/kg/2 monthRelapse ratePositive
Sorensen et al. [26]RRMS262 g/kg/monthNew MRI lesionsPositive
Lewanska et al. [42]RRMS490.2 and 0.4 g/kg/monthRelapse ratePositive
Hass [44]Post partum3460+10 g/monthRelapsesPositive
ESIMS [52]SPMS3181 g/kg/monthTime to progressionNegative
Noseworthy et al. [49]Optic neuritis552+0.4 g/kg/monthVisual acuityNegative
Noseworthy et al. [50]Fixed motor deficits672+0.4 g/kg/2 weekMuscle strengthNegative
Stangel et al. [51]Stable motor deficits102 g/kgMEPNegative

RRMS: relapsing–remitting MS; SPMS: secondary progressive MS; MEP: motor evoked potentials central conduction time.

It is difficult to compare the effect of IVIG with the effect of the approved therapies, interferon-beta and glatiramer acetate [54], [55], [56], [57], [58], [59]. The reduction in relapse rate in the IVIG studies appears to be greater than that seen in studies of interferon-beta and glatiramer acetate. However, the smaller sample size of the IVIG studies and the lack of reduction of relapse rate in the placebo group have to be taken in consideration. Regarding the effect on disease progression and MRI, data from the pivotal studies of interferon-beta and glatiramer acetate appear more robust and convincing. It is a major problem that the optimum dose of IVIG in relapsing–remitting MS has still not been determined. This has to be established in a sufficiently large dose-finding study in relapsing–remitting MS patients with appropriate clinical as well as MRI endpoints.

The results of trials in patients with fixed motor deficits or apparently permanent loss of visual acuity do not indicate that IVIG has clinically relevant remyelinating effect in MS.

The results of the ESIMS trial in secondary progressive MS has clearly shown that IVIG is not effective in this phase of the disease [52]. Other therapies have also failed to stop disease progression in this advanced stage of MS, but have shown effect on relapses and MRI endpoints [60], [61]. Thus, although it is evident that this phase of the disease is the less amenable to therapy, it is worrying that IVIG did not show any beneficial effect on the relapse rate or MRI.

In conclusion, IVIG is a valuable alternative to the established therapies in relapsing–remitting MS, but a number of questions regarding the efficacy of IVIG are still unanswered and IVIG cannot presently be regarded as a first line therapy in relapsing–remitting MS. IVIG has the advantage of requiring only monthly infusions, and has, in doses of 0.2 to 0.4 g/kg, only mild and infrequent side effects. Hence, IVIG is indicated in patients who are unwilling to perform frequent subcutaneous or intramuscular injections, in patients with relapsing–remitting MS who do not tolerate or have contraindications to the approved therapies, and could be considered in patients who do not seem to benefit from one of the established therapies.

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PII: S0022-510X(02)00343-X

Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 123-130, 15 February 2003

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