J Neurol (2008) 255 [Suppl 3]:711 DOI 10.

1007/s00415-008-3003-z

Richard Hughes

The role of IVIg in autoimmune neuropathies: the latest evidence

Abstract Guillain-Barr syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) are the major immune neuropathies. Although a detailed understanding of the pathogenesis of these conditions is not yet available, the multiple effects of IVIg on the immune
Prof. R. Hughes () Cochrane Neuromuscular Disease Review Group Dept. of Clinical Neuroscience Kings College London, Guys Hospital London, SE1 1UL, UK E-Mail: richard.a.hughes@kcl.ac.uk

and inflammatory process recommend it as an agent worthy of investigation in these diseases. Following recent research, IVIg is now recommended as a first-line treatment option for moderate or severe GBS to be administered within two weeks of disease onset. With regard to CIDP, a Cochrane review demonstrated significant short-term improvements in disability and impairment with IVIg. The ICE (IGIV CIDP Efficacy trial) study group undertook the largest ever trial of IVIg for CIDP, which demonstrated for the first time the long-term efficacy of IVIg. The results of this ICE trial demonstrated the effi-

cacy of IVIg in CIDP, with a significantly higher response rate versus placebo after 24 weeks of treatment (P = 0.0002). Furthermore, long-term maintenance with IVIg also significantly reduced the rate of relapse (P < 0.011). On the basis of available data, IVIg can be recommended as a first-line treatment option for GBS and CIDP. For MMN, although the evidence for IVIg is limited, there is no evidence to recommend other treatments. Key words IVIg GuillainBarr syndrome (GBS) chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

Introduction
Recent research has shed some light on the mechanisms that underlie the pathogenesis of the major immune neuropathies, Guillain-Barr syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). In particular, antibodies to gangliosides have been identified in patients with the axonal forms of GBS, in the related condition of Fisher syndrome, and in MMN. There is good evidence from animal models and in vitro studies that antibodies to ganglioside GM1 or GD1a cause the acute motor axonal neuropathy form of GBS and those antibodies to ganglioside GQ1b which occur in Fisher syndrome damage the motor nerve terminal axon and the overlying terminal Schwann cell. However, these conditions probably arise from a combination of B and T-cell mediated immunity triggered by a

preceding bacterial or viral infection. T-cell activation is necessary to render the blood-nerve barrier permeable to antibodies and is especially marked in the acute inflammatory demyelinating polyradiculoneuropathy (AIDP) form of GBS and in CIDP. In animal models of AIDP, the dominant autoantigens are the myelin proteins P2, P0 and PMP22 but there is only limited evidence for the importance of immunity to these proteins in human disease. A possible exception is that antibodies to P0 are present in 20 % of patients with CIDP [10]. Although a detailed understanding of the pathogenesis of AIDP, CIDP and MMN is not yet available, the multiple effects of IVIg on the immune and inflammatory process recommend it as an agent worthy of investigation in these diseases.
JON 3003

Guillain-Barr Syndrome
Guillain-Barr syndrome is a serious condition with an incidence of one to four cases per 100,000 people. Some 30 % of patients require ventilation and about 5 % die. Patients exhibit progressive weakness reaching its nadir within four weeks. After a plateau phase of variable length, most patients begin to improve and in many recovery is substantial although there is a high incidence of persistent fatigue [14]. The use of plasma exchange (PE) for GBS has previously been evaluated in a Cochrane review [15]. Overwhelming benefit of PE in disability grade improvement after four weeks was demonstrated in several trials, while full muscle strength recovery after one year was also more common in patients treated with PE. These data illustrate that both short and long-term benefits can be seen with PE. Kleyweg et al. examined the use of IVIg in six bedbound patients with GBS: four improved, while the two that did not showed severe axonal degeneration, leading the authors to suggest that the response to IVIg may be comparable to PE results should be confirmed in a large trial [11]. Since PE had by then become established as the gold standard treatment, subsequent trials had to compare IVIg with PE rather than with placebo for ethical reasons. The first large trial of IVIg was completed in 1992 and reported marginal benefit of IVIg over PE [16]. The evidence base has now grown and has been summarised in a Cochrane review; there was no significant difference in efficacy, judged by change on a seven point disability scale after four weeks [7]. In the long-term, there was also no significant difference between the two treatments in terms of the number of patients dead or disabled after 12 months [8]. However, treatment was discontinued significantly more commonly with PE than with IVIg [7]. Surprisingly, there was no evidence from the review that serious adverse events were more common with PE than with IVIg, although in one trial multiple adverse events were significantly more common with PE than with IVIg [16]. These results have led to IVIg being recommended as a first-line treatment option for moderate or severe GBS within two weeks after onset. Because it is simpler and more readily available than PE, it is the preferred treatment for this indication and is licensed for this use in Europe. However, several questions still remain with regard to treatment. For example, it is not known whether patients with Fisher syndrome (which tends to improve on its own) or mild disease should be treated. Similarly, it is unknown how to treat patients who present two weeks after the onset of disease; the IVIg trials evaluated in the Cochrane review all comprised patients who were randomized within two weeks of disease onset. Finally, there is much uncertainty over the value of a second course of IVIg for patients who remain bed-bound

two or three weeks later after the first. This is the most urgent priority for future trials.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy

CIDP is an acquired demyelinating neuropathy of presumed autoimmune origin. According to the most recent diagnostic criteria, defined by the joint task force of the EFNS and the PNS in 2006, CIDP patients exhibit chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least two months, combined with absent or reduced tendon reflexes in all extremities [1]. Short-term treatment trials have been performed with corticosteroids, PE and IVIg, while immunosuppressant drugs are often used in patients with inadequate responses to these treatments. Following on from the first use of IVIg as a treatment for idiopathic thrombocytopenic purpura (ITP) in the early 1980s, Vermeulen et al. reported observational studies suggesting that IVIg is beneficial in CIDP [9, 21]. Later, van Doorn et al. conducted a small albumin placebo-controlled randomized trial, which demonstrated a significant beneficial effect when IVIg was given to patients with CIDP who were receiving regular IVIg and thought to be responding to it [17]. However, when the same investigators carried out a parallel group randomized trial in treatment-nave participants, they obtained disappointing results [18]. They suggested that this may have been due to an imbalance at baseline in important prognostic factors between the treatment groups. Eventually, a 2003 Cochrane review of four clinical trials, including the first negative trial, showed significant shortterm improvements in disability and impairment with IVIg [20]. Despite this evidence, IVIg has not yet been licensed for use in CIDP in Europe or the USA.

The ICE trial

Design
The ICE (IGIV CIDP Efficacy trial) study group has undertaken the largest ever trial of IVIg for CIDP [6]. The objective of this randomized, double-blind, placebocontrolled study was to evaluate the efficacy of IVIg (Gamunex, Talecris Biotherapeutics) compared with placebo on patient disability after up to six months of treatment. The trial involved 117 patients from 33 different centers in Europe, Israel, North America and South America. The first period of the study was a 24-week, double-blind period with a response-conditional crossover phase followed by a 24-week, re-randomized double-blind extension period.

The trial had the following design: After the screening period of 10 days, patients were randomized to receive eight infusions, three weeks apart, of either Gamunex (loading dose 2 g/kg, maintenance dose 1 g/kg) or placebo (0.1 % albumin) At the time of randomisation, clinical and neurophysiological measurements were taken for each patient The clinical measurements were repeated every three weeks at each treatment, and at the end of the first 24week period The main outcome measure used was the adjusted INCAT (inflammatory neuropathy cause and treatment) scale. Adjustment was made by excluding one point changes in upper limb function between 0 and 1 in order to ensure all 1 point step changes were clinically meaningful. The overall INCAT score is the sum of the scores of the arm and leg disability scales (Fig. 1) [5]. If patients did not improve or deteriorated by more than 1 point on the adjusted INCAT scale during the first period, they were crossed over to the alternate treatment and received the full 24 weeks of that treatment Patients that had crossed over were subsequently discontinued from the trial if their adjusted INCAT score failed to improve by 1 or more points relative to their score at cross-over At the end of either the six-month first period or crossover phase patients that had responded to treatment (i.e. completed 24 weeks of treatment and adjusted INCAT score had improved by 1 point) were re-randomized in the blinded extension period to receive Gamunex or placebo The treatment and assessment schedule in the 24week extension period was the same as in the first period, except that there was no loading dose [6].

Key inclusion criteria for the study included: 18 years of age with documented CIDP; overall INCAT score of 29 and substantial disability in upper or lower-limb function; no IVIg, PE or steroids within three months prior to screening; no myelopathy, central demyelination or persisting deficits from stroke.

Results
The primary endpoint of the study was the percentage of responders to Gamunex versus. placebo in the first treatment period. Responders were those who improved from baseline by 1 point or more in the adjusted INCAT disability score (excluding a change between 0 and 1 in the upper limb score) and maintained this improvement until week 24. Fig. 2 shows the statistically significant higher response rate of 54 % in the Gamunex-treated patients (n = 59), compared to 21 % in the placebo group (n = 58) (P = 0.0002). Other findings of the study were: Seventy eight percent of the original placebo-treated group crossed over to Gamunex in the first period of the study, compared to 39 % of the original Gamunex group that crossed over to placebo. Seventy four patients completed the 24-week blinded treatment (first period or crossover period) and were re-randomized and treated during the extension phase. Of the 74 patients entering the extension phase, 43 were re-randomized to receive Gamunex, while 31 received placebo. A significantly lower relapse rate was observed in patients re-randomized to Gamunex versus placebo: six (14 %) of 43 patients treated with Gamunex relapsed versus 11 (35 %) of 31 patients treated with placebo (P = 0.011).

INCAT Disability Scale Arm Disability 0 = No upper limb problems 1 = Symptoms, in 1 arm or both arms, not aecting ability to perform any of following functions: doing all zippers and buttons, washing or brushing hair, using knife and fork together, handling small coins 2 = Symptoms, in 1 arm or both arms, aecting but not preventing any of functions listed above 3 = Symptoms, in 1 arm or both arms, preventing 1 or 2 of functions listed above 4 = Symptoms, in 1 arm or both arms, preventing 3 or all of functions listed above, but some purposeful movements still possible 5 = Inability to use either arm for any purposeful movement

INCAT Disability Scale Leg Disability 0 = Walking not aected 1 = Walking aected, but walks independently outdoors 2 = Usually uses unilateral support (stick, single crutch, 1 arm) to walk outdoors 3 = Usually uses bilateral support (sticks, crutches, frame, 2 arms) to walk outdoors 4 = Usually uses wheelchair to travel outdoors, but able to stand and walk few steps 5 = Restricted to wheelchair, unable to stand and walk few steps with help

Fig. 1 The INCAT scale [5]

10

60 50 Responders, % 40 30 20 10 0 Gamunex (n=59) n=32 21 54 P<0.001

drawal if the adjusted INCAT score failed to improve by more than 1 point from the crossover baseline). In addition, the extension period was designed to assess sustained treatment benefit. The data from the ICE study confirm and strengthen the conclusion of the Cochrane review that the relative rate of short-term improvement in disability with IVIg is nearly three times that seen with placebo, so that the number needed to treat is three, a highly significant difference [20]. Moreover, the data also showed long-term benefit from treatment with IVIg in CIDP.

Placebo (n=58)

Other neuropathies
Multifocal motor neuropathy (MMN) is an autoimmune demyelinating neuropathy with slowly progressive weakness and multifocal conduction block in motor but not sensory nerve fibres. There is limited clinical trial evidence to support the clinical impression that IVIg is beneficial in about 70 % of patients. A Cochrane review found four randomized controlled trials comprising a total of only 34 participants [19]. Nevertheless meta-analysis showed a significant improvement in strength in patients treated with IVIg compared to placebo-treated patients, while there was also an improvement, albeit not significant, in disability score when patients were treated with IVIg as compared to placebo. IVIg is the only treatment which has been demonstrated to be beneficial in the treatment of this condition, and its use is appropriate in most cases. Paraprotein-associated demyelinating neuropathy (PDN) is another rare condition in which the use of IVIg has been investigated. Several different types of PDN exist, including MGUS IgM PDN with anti-myelin associated glycoprotein antibodies, and MGUS IgG or IgA PDN with CIDP-like illness. Two small randomized trials of IVIg have shown some evidence of short-term benefit in MGUS IgM PDN with anti-myelin associated glycoprotein antibodies but more long-term evidence is needed to establish the role of IVIg in treatment of this condition [2, 3]. The disease course of some PDN patients with IgG and IgA paraprotein closely resembles that of CIDP and these patients may be expected to respond to IVIg in the same way that patients with CIDP without a paraprotein respond. IVIg has been tried in several other forms of peripheral neuropathy, including proximal diabetic, paraneoplastic and vasculitic neuropathy, but its usefulness has not been proven by randomized controlled trials and therefore it cannot be routinely recommended [4, 12, 13].

Fig. 2 Response to IVIg in the ICE trial

In a further analysis confined to the 57 Gamunex responders entering the extension phase, 31 were rerandomized to receive Gamunex, while 26 received placebo. A significantly lower relapse rate was observed in patients re-randomized to Gamunex versus placebo: four (13 %) of 31 patients treated with Gamunex relapsed versus 11 (45 %) of 26 patients treated with placebo (P = 0.006) Gamunex had a good safety profile and was well tolerated throughout the first period, crossover phase, and extension period. Few patients discontinued the study because of adverse events: one (2 %) patient from each treatment group during the first period; two (4 %) patients treated with IVIg during the crossover period; and one (3 %) patient treated with placebo during the extension phase. Serious adverse events occurred in six of 113 (5 %) patients who were being treated with Gamunex and eight of 95 % (8 %) patients who were receiving placebo [6].

Conclusions
The results of the ICE study, the largest randomized, placebo-controlled trial ever conducted in CIDP, increase the body of evidence supporting the use of IVIg in CIDP by nearly 50 %. The efficacy of Gamunex in CIDP was clearly demonstrated with a significantly higher response rate versus placebo after up to 24 weeks of treatment (P = 0.0002). Furthermore, long-term maintenance with Gamunex also significantly reduced rate of relapse (P < 0.011). This was the first time that the long-term efficacy of IVIg had been demonstrated. Gamunex was shown to be well tolerated throughout the study. The study design was unique and rigorous, requiring an early treatment response during first period (within the first three to six weeks) to avoid lengthy exposure to ineffective therapy (i.e. minimising exposure to the inferior regimen). There was also a rigorous requirement for discontinuation in the crossover phase (i.e. patient with-

Conclusion
On the basis of available data, IVIg can be recommended as a first-line treatment option for GBS and CIDP. PE in

11

GBS and PE or corticosteroids in CIDP are also treatment options. For MMN, although the evidence for IVIg is limited, there is no evidence to recommend any other treatments and corticosteroids are harmful, so IVIg is the only option. Treatment for patients with PDN varies depending on the type of PDN, but IVIg may be suitable in the CIDP-like cases. Finally, anecdotal evidence exists

for the use of IVIg in several peripheral neuropathies, but no controlled trials have thus far been conducted.
Conflict of interest The author or his Department has received lecture honoraria and consultancy fees from Talecris, LFB, Kedrion, CSL Behring and Octapharma, all of whom manufacture immunoglobulin for intravenous use.

References
1. PNS JTFotEat. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies (2006) Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst 11:919 2. Comi G, Roveri L, Swan A, Willison H, Bojar M, Illa I, Karageorgiou C, Nobile-Orazio E, van den Bergh P, Swan T, Hughes R, Aubry J, Baumann N, Hadden R, Lunn M, Knapp M, Leger JM, Bouche P, Mazanec R, Meucci N, van der Meche F, Toyka K (2002) A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J Neurol 249:13701377 3. Dalakas MC, Quarles RH, Farrer RG, Dambrosia J, Soueidan S, Stein DP, Cupler E, Sekul EA, Otero C (1996) A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann Neurol 40:792795 4. Donofrio PD (2003) Immunotherapy of idiopathic inflammatory neuropathies. Muscle Nerve 28:273292 5. Hughes R, Bensa S, Willison H, Van den Bergh P, Comi G, Illa I, NobileOrazio E, van Doorn P, Dalakas M, Bojar M, Swan A (2001) Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 50:195201 6. Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, Hartung HP, Latov N, Merkies IS, van Doorn PA (2008) Intravenous immune globulin (10 % caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 7:136144 7. Hughes RA, Raphael JC, Swan AV, van Doorn PA (2006) Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane Database Syst Rev: CD002063 8. Hughes RA, Swan AV, Raphael JC, Annane D, van Koningsveld R, van Doorn PA (2007) Immunotherapy for Guillain-Barre syndrome: a systematic review. Brain 130:22452257 9. Imbach P, Barandun S, dApuzzo V, Baumgartner C, Hirt A, Morell A, Rossi E, Schoni M, Vest M, Wagner HP (1981) High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1: 12281231 10. Kazatchkine MD, Kaveri SV (2001) Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 345:747755 11. Kleyweg RP, van der Meche FG, Meulstee J (1988) Treatment of GuillainBarre syndrome with high-dose gammaglobulin. Neurology 38:16391641 12. Krendel DA, Costigan DA, Hopkins LC (1995) Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 52:10531061 13. Levy Y, Uziel Y, Zandman G, Rotman P, Amital H, Sherer Y, Langevitz P, Goldman B, Shoenfeld Y (2005) Response of vasculitic peripheral neuropathy to intravenous immunoglobulin. Ann N Y Acad Sci 1051:779786 14. Newswanger DL, Warren CR (2004) Guillain-Barre syndrome. Am Fam Physician 69:24052410 15. Raphael JC, Chevret S, Hughes RA, Annane D (2001) Plasma exchange for Guillain-Barre syndrome. Cochrane Database Syst Rev:CD001798 16. van der Meche FG, Schmitz PI (1992) A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. Dutch Guillain-Barre Study Group. N Engl J Med 326:11231129 17. van Doorn PA, Brand A, Strengers PF, Meulstee J, Vermeulen M (1990) Highdose intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a doubleblind, placebo-controlled, crossover study. Neurology 40:209212 18. van Doorn PA, Vermeulen M, Brand A, Mulder PG, Busch HF (1991) Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy. Clinical and laboratory characteristics associated with improvement. Arch Neurol 48:217220 19. van Schaik IN, van den Berg LH, de Haan R, Vermeulen M (2005) Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database Syst Rev:CD004429 20. Van Schaik IN, Winer JB, De Haan R, Vermeulen M (2002) Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev: CD001797 21. Vermeulen M, van der Meche FG, Speelman JD, Weber A, Busch HF (1985) Plasma and gamma-globulin infusion in chronic inflammatory polyneuropathy. J Neurol Sci 70: 317326