Aktuelle Neurologie 2007; 34(6): 342-347
DOI: 10.1055/s-2007-970910
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Einsatz intravenöser Immunglobuline in der Neurologie: Aktuelle Entwicklungen

Use of Intravenous Immunoglobulins in Neurological Diseases: An UpdateM.  Stangel1 , R.  Gold2
  • 1Neurologische Klinik, Medizinische Hochschule Hannover
  • 2Neurologische Klinik, St. Josefs Hospital, Klinikum der Ruhr Universität, Bochum
Further Information

Publication History

Publication Date:
03 July 2007 (online)

Zusammenfassung

In den letzten Jahren gab es beträchtliche Fortschritte in der Behandlung von neurologischen Autoimmunerkrankungen. Teil dieser Entwicklung war auch der Einsatz von hoch dosierten polyklonalen intravenösen Immunglobulinen (IVIg). Auf der Grundlage von randomisierten, plazebokontrollierten, doppelblinden Studien sind IVIg Mittel der ersten Wahl beim Guillain-Barré-Syndrom, der chronisch inflammatorischen demyelinisierenden Polyneuropathie (CIDP) und der multifokalen motorischen Neuropathie (MMN) geworden. Des Weiteren sind IVIg bei rascher Verschlechterung einer Myasthenia gravis indiziert und gelten als Mittel der zweiten Wahl bei Dermatomyositis, Stiff-Person-Syndrom und schwangerschaftsassoziierten bzw. postpartalen Schüben bei multipler Sklerose. Aufgrund der einfachen Handhabung und dem günstigen Nebenwirkungsprofil wurden IVIg sehr großzügig bei den meisten vermeintlich autoimmun vermittelten Erkrankungen eingesetzt oder bei Krankheiten ohne verfügbare zugelassene Therapie. Dies, und die strengen Auflagen für den Produktionsprozess haben zu einem Mangel an IVIg geführt mit der Konsequenz eines drastischen Kostenanstiegs. IVIg sollten daher entsprechend der verfügbaren Daten aus klinischen Studien eingesetzt werden. Wir geben hier eine Übersicht zum klinischen Einsatz und den aktuellen Empfehlungen für IVIg bei neurologischen Erkrankungen.

Abstract

Over the past decade we have observed considerable advances in the treatment of autoimmune-mediated disorders affecting the nervous system. Part of this development was the introduction of high-dose polyclonal intravenous immunoglobulins (IVIg). On the basis of randomised, placebo-controlled, double-blind clinical trials, IVIg has become the first line treatment for Guillain-Barré syndrome, chronic idiopathic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Furthermore, IVIg can serve as a rescue therapy for patients with rapidly worsening myasthenia gravis, and is a second-line therapy for dermatomyositis, stiff-person syndrome, and pregnancy- or post-partum-associated multiple sclerosis attacks. Due to the excellent safety profile and its uncomplicated administration, IVIg has been used very liberally for most diseases with a suspected autoimmune pathology or where there is no treatment available. This, and the strict licensing requirements, has led to a shortage in IVIg supply and a dramatic increase in costs. Therefore, IVIg should principally be used according to available data from controlled clinical trials. Here we review the clinical applications and recommendations for the use of IVIg in neurological diseases.

Literatur

  • 1 Imbach P, Barandun S, d'Apuzzo V. et al . High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood.  Lancet. 1981;  1 1228-1231
  • 2 Kazatchkine M D, Kaveri S V. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin.  N Engl J Med. 2001;  345 747-755
  • 3 Kazatchkine M D, Dietrich G, Hurez V. et al . V region-mediated selection of autoreactive repertoires by intravenous immunoglobulin (i. v. Ig).  Immunol Rev. 1994;  139 79-107
  • 4 Stangel M, Pul R. Basic principles of intravenous immunglobulin (IVIg) treatment.  J Neurol. 2006;  253, Suppl 5 V/18-V/24
  • 5 Clynes R. IVIg therapy: Interfering with interferon-γ.  Immunity. 2007;  26 4-6
  • 6 Nimmerjahn F, Ravetch J V. The antiinflammatory activity of IgG: the intravenous IgG paradox.  J Exp Med. 2007;  204 11-15
  • 7 Bruhns P, Samuelsson A, Pollard J W, Ravetch J V. Colony-stimulating factor-1-dependent macrophages are responsible for IVIg protection in antibody-induced autoimmune disease.  Immunity. 2003;  18 573-581
  • 8 Kaneko Y, Nimmerjahn F, Ravetch J V. Anti-inflammatory activity of immunoglobulin G resulting from sialylation.  Science. 2006;  313 670-673
  • 9 Siragam V, Crow A R, Brinc D. et al . Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells.  Nat Med. 2006;  12 688-692
  • 10 Park-Min K-H, Serbina N, Yang W. et al . FcgRIII-dependent inhibition of interferon-γ responses mediates suppressive effects of intravenous immune globulin.  Immunity. 2007;  26 67-78
  • 11 Buchwald B, Ahangari R, Weishaupt A, Toyka K V. Intravenous immunoglobulins neutralize blocking antibodies in Guillain-Barré syndrome.  Ann Neurol. 2002;  51 673-680
  • 12 Jacobs B C, O'Hanlon G M, Bullens R WM. et al . Immunoglobulins inhibit pathophysiologival effects of anti-GQ1b-positive sera at motor nerve terminals through inhibition of antibody binding.  Brain. 2003;  126 2220-2234
  • 13 Stangel M, Gold R. Hochdosierte intravenöse Immunglobuline in der Behandlung der Multiplen Sklerose. Update über neue Studien.  Nervenarzt. 2005;  76 1267-1272
  • 14 Trebst C, Stangel M. Promotion of remyelination by immunoglobulins: implications for the treatment of multiple sclerosis.  Curr Pharm Design. 2006;  12 241-249
  • 15 Meche F GA van der, Schmitz P IM. the Dutch Guillain-Barré study group . A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome.  N Engl J Med. 1992;  326 1123-1129
  • 16 Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group . Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome.  Lancet. 1997;  349 225-230
  • 17 Raphael J C, Chevret S, Harboun M, Jars-Guincestre M C. Intravenous immune globulins in patients with Guillain-Barre syndrome and contraindications to plasma exchange: 3 days versus 6 days.  J Neurol Neurosurg Psychiatry. 2001;  71 235-238
  • 18 van Koningsveld R, Schmitz P IM, van der Meché F GA. et al . Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: randomised trial.  Lancet. 2004;  363 192-196
  • 19 Mori M, Kuwabara S, Fukutake T, Hattori T. Intravenous immunoglobulin therapy for Miller Fisher syndrome.  Neurology. 2007;  68 1144-1146
  • 20 Hahn A F, Bolton C F, Zochodne D, Feasby T E. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study.  Brain. 1996;  119 1067-1077
  • 21 Mendell J R, Barohn R J, Freimer M L. et al . Randomised controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy.  Neurology. 2001;  56 445-449
  • 22 Hughes R AC, Bensa S, Willison H. et al . Randomized controlled trial of intravenous immunoglobulin (IVIg) versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy.  Ann Neurol. 2001;  50 195-201
  • 23 Federico P, Zochodne D W, Hahn A F. et al . Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study.  Neurology. 2000;  55 1256-1262
  • 24 Leger J M, Chassande B, Musset L. et al . Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double blind, placebo-controlled study.  Brain. 2001;  124 145-153
  • 25 van den Berg L H, Kerkhoff H, Oey P L. et al . Treatment of multifocal motor neuropathy with high dose intravenous immunoglobulins: a double blind, placebo controlled study.  J Neurol Neurosurg Psychiatry. 1995;  59 248-252
  • 26 Terenghi F, Cappellari A, Bersano A. et al . How long is IVIg effective in multifocal motor neuropathy?.  Neurology. 2004;  62 666-668
  • 27 Vucic S, Black K R, Siao Tick Chong P, Cros D. Multifocal motor neuropathy. Decrease in conduction block and reinnervation with long-term IVIg.  Neurology. 2004;  63 1264-1269
  • 28 Dalakas M C, Quarles R H, Farrer R G. et al . A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy.  Ann Neurol. 1996;  40 792-795
  • 29 Comi G, Roveri L, Swan A. et al . A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy.  J Neurol. 2002;  249 1370-1377
  • 30 Cook D, Dalakas M, Galdi A. et al . High-dose intravenous immunoglobulin in the treatment of demyelinating neuropathy associated with monoclonal gammopathy.  Neurology. 1990;  40 212-214
  • 31 Renaud S, Gregor M, Fuhr P. et al . Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies.  Muscle Nerve. 2003;  27 611-615
  • 32 Gajdos P, Chevret S, Clair B. et al . Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis.  Ann Neurol. 1997;  41 789-796
  • 33 Gajdos P, Tranchant C, Clair B. et al . Treatment of myasthenia gravis exacerbation with intravenous immunoglobulins.  Arch Neurol. 2005;  62 1689-1693
  • 34 Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis. A randomized controlled trial.  Neurology. 2007;  68 837-841
  • 35 Dalakas M C, Illa I, Dambrosia J M. et al . A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.  N Engl J Med. 1993;  329 1993-2000
  • 36 Cherin P, Pelletier S, Teixeira A. et al . Results and long-term follow-up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients.  Arthritis Rheumat. 2002;  46 467-474
  • 37 Jann S, Beretta S, Moggio M. et al . High-dose intravenous human immunoglobulins in polymyositis resistant to treatment.  J Neurol Neurosurg Psychiatry. 1992;  55 60-62
  • 38 Dalakas M, Koffman B, Fujii M. et al . A controlled study of IVIG combined with prednisone in the treatment of IBM.  Neurology. 2001;  56 323-327
  • 39 Dalakas M C, Sonies B, Dambrosia J. et al . Treatment of inclusion-body myositis with IVIg: A double-blind, placebo-controlled study.  Neurology. 1997;  48 712-716
  • 40 Walter M C, Lochmüller H, Toepfer M. et al . High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo controlled study.  J Neurol. 2000;  247 22-28
  • 41 Stangel M, Boegner F, Klatt C H. et al . A placebo-controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis.  J Neurol Neurosurg Psychiatry. 2000;  68 89-92
  • 42 Noseworthy J H, O'Brien P C, Weinshenker B G. et al . IV immunoglobulin does not reverse established weakness in MS. A double-blind, placebo-controlled trial.  Neurology. 2000;  55 1135-1143
  • 43 Sorensen P S, Haas J, Sellebjerg F. et al . IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS.  Neurology. 2004;  63 2028-2033
  • 44 Roed H G, Langkilde A, Sellebjerg F T. et al . A double-blind, randomized trial of IV immunoglobulin treatment in acute optic neuritis.  Neurology. 2005;  64 804-810
  • 45 Hommes O R, Sorensen P S, Fazekas F. et al . Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial.  Lancet. 2004;  364 1149-1156
  • 46 Sorensen P S, Fazekas F, Lee M. Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis.  Eur J Neurol. 2002;  9 557-563
  • 47 Achiron A, Kishner I, Dolev M. et al . Effect of intravenous immunoglobulin treatment on pregnancy and post-partum related relapses in multiple sclerosis.  J Neurol. 2004;  251 1133-1137
  • 48 Dalakas M, Fujii M, Li M. et al . High-dose intravenous immune globulin for stiff person syndrome.  N Engl J Med. 2001;  345 1870-1876
  • 49 Bain P G, Motomura M, Newsom-Davis J. et al . Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome.  Neurology. 1996;  47 678-683
  • 50 Stangel M, Gold R. Use of i. v. immunoglobulins in neurology - evidence-based consensus.  Nervenarzt. 2004;  75 801-815
  • 51 Dodel R, Hampel H, Depboylu C. et al . Human antibodies against amyloid β peptide: A potential treatment for Alzheimer's disease.  Ann Neurol. 2002;  52 256
  • 52 Dodel R, Du Y, Depboylu C. et al . Intravenous immunoglobulins containing antibodies against β-amyloid for the treatment of Alzheimer's disease.  J Neurol Neurosurg Psychiatry. 2004;  75 1472-1474
  • 53 Bard F, Cannon C, Barbour R. et al . Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.  Nat Med. 2000;  6 916-919
  • 54 Istrin G, Bosis E, Solomon B. Intravenous immunoglobulin enhances the clearance of fibrillar amyloid-β peptide.  J Neurosci Res. 2006;  84 434-443
  • 55 Gonzalez H, Khademi M, Andersson M. et al . Prior poliomyelitis-IvIg treatment reduces proinflammatory cytokine production.  J Neuroimmunol. 2004;  150 139-144
  • 56 Gonzalez H, Sunnerhagen K S, Sjöberg I. et al . Intravenous immunoglobulin for post-polio syndrome: a randomised controlled trial.  Lancet Neurol. 2006;  5 493-500
  • 57 Farbu E, Rekand T, Vik-Mo E. et al . Post-polio syndrome patients treated with intravenous immunoglobulin: a double-blind randomized controlled pilot study.  Eur J Neurol. 2007;  14 60-65
  • 58 Siegel J M, Boehmer L N. Narcolepsy and the hypocretin system - where motion meets emotion.  Nat Clin Pract Neurol. 2006;  2 548-556
  • 59 Dauvilliers Y, Carlander B, Rivier F. et al . Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset.  Ann Neurol. 2002;  56 905-908
  • 60 Dauvilliers Y. Follow-up of four narcolepsy patients treated with intravenous immunoglobulins.  Ann Neurol. 2006;  60 153
  • 61 Goebel A, Netal S, Schedel R, Sprotte G. Human pooled immunoglobulin in the treatment of chronic pain syndromes.  Pain Med. 2002;  3 119-127
  • 62 Bayry J, Kazatchkine M D, Kaveri S V. Shortage of human intravenous immunoglobulin - reasons and possible solutions.  Nat Clin Pract Neurol. 2007;  3 120-121
  • 63 McCrone P, Chisholm D, Knapp M. et al . Cost-utility analysis of intravenous immunoglobulin and prednisolone for chronic inflammatory demyelinating neuropathy.  Eur J Neurol. 2003;  10 687-694
  • 64 Pul R, Nguyen D, Schmitz U. et al . Comparison of intravenous immunoglobulin preparations on microglial function in vitro: More potent immunomodulatory capacity of an IgM/IgA-enriched preparation.  Clin Neuropharmacol. 2002;  25 254-259
  • 65 Zhang G, Lopez P HH, Sheikh K A. Comparison of different brands of IVIg in an in vitro model of immune neuropathy.  J Neuroimmunol. 2006;  173 200-203
  • 66 Ahsan N, Wiegand L A, Abendroth C S, Manning E C. Acute renal failure following immunoglobulin therapy.  Am J Nephrol. 1996;  16 532-536
  • 67 Levy J B, Pusey C D. Nephrotoxicity of intravenous immunoglobulin.  Q J Med. 2000;  93 751-755
  • 68 Kittner J M, Grimbacher B, Wulff W. et al . Patients' attitude to subcutaneous immunoglobulin substitution as home therapy.  J Clin Immunol. 2006;  26 400-405
  • 69 Köller H, Schroeter M, Feischen H. et al . Subcutaneous self-infusions of immunoglobulins as a potential therapeutic regimen in immune-mediated neuropathies.  J Neurol. 2006;  253 1505-1506
  • 70 Maier E, Reipert B M, Novy-Weiland T. et al . Induction of immune tolerance by oral IVIG.  Int Immunopharmacol. 2007;  7 351-359

Prof. Dr. Martin Stangel

Neurologische Klinik, Medizinische Hochschule Hannover

Carl-Neuberg-Straße 1

30625 Hannover

Email: stangel.martin@mh-hannover.de