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Intravenous immunoglobulin in neurology—mode of action and clinical efficacy

Key Points

  • Intravenous immunoglobulin (IVIg) is established for the treatment of several inflammatory neurological diseases, including Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy, either as adjunctive or first-line therapy

  • IVIg was shown to be largely ineffective in Alzheimer disease, but was superior to placebo in apolipoprotein E ε4 carriers, suggesting possible benefits in this subgroup of patients

  • Subcutaneous IgG is currently being tested in controlled trials for neuromuscular diseases, owing to its effectiveness in primary immunodeficiency, ease of home administration relative to IVIg, and promising preliminary results

  • It has been difficult to develop a common mechanistic understanding of IVIg's mode of action, as different mechanisms may be involved depending on the pathology of IVIg-responsive diseases

  • A subset of patients do not benefit from IVIg therapy, and well-validated surrogate parameters that predict the response to therapy from the outset are needed

  • Modification of the Fc-glycosylation site might improve efficacy of IVIg, as fragments enriched for terminal sialic acid residues have a higher anti-inflammatory activity than conventional IVIg in animal models

Abstract

Intravenous immunoglobulin (IVIg)—a preparation of polyclonal serum IgG pooled from thousands of blood donors—has been used for nearly three decades, and is proving to be an efficient anti-inflammatory and immunomodulatory treatment for a growing number of neurological diseases. Evidence from controlled clinical trials has established IVIg as a first-line therapy for Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. IVIg is also an effective rescue therapy in some patients with worsening myasthenia gravis, and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. IVIg has been tested in some neurodegenerative disorders, but a controlled study in Alzheimer disease yielded disappointing results. Despite its widespread use and therapeutic success, the mechanisms of action of IVIg are poorly understood. Several hypotheses, based on the function of either the variable or constant IgG fragments, have been proposed to explain IVIg's immunomodulatory activity. This Review highlights emerging data on the mechanisms of action of IVIg related to its anti-inflammatory activity, especially that involving the cellular Fcγ receptors and Fc glycosylation. We also summarize recent trials in neurological diseases, discuss potential biomarkers of efficacy, offer practical guidelines on administration, and provide a rationale for experimental trials in neuroinflammatory disorders.

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Figure 1: Potential mechanisms of intravenous immunoglobulin activity mediated by F(ab′)2-dependent and Fc-dependent pathways.
Figure 2: The family of Fc receptors for mouse and human IgG.

References

  1. 1

    Casadevall, A., Dadachova, E. & Pirofski, L. A. Passive antibody therapy for infectious diseases. Nat. Rev. Microbiol. 2, 695–703 (2004).

    CAS  PubMed  Google Scholar 

  2. 2

    Viard, I. et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282, 490–493 (1998).

    CAS  PubMed  Google Scholar 

  3. 3

    Le Pottier, L. et al. Intravenous immunoglobulin and cytokines: focus on tumor necrosis factor family members BAFF and APRIL. Ann. N. Y. Acad. Sci. 1110, 426–432 (2007).

    CAS  PubMed  Google Scholar 

  4. 4

    Prins, C., Gelfand, E. W. & French, L. E. Intravenous immunoglobulin: properties, mode of action and practical use in dermatology. Acta Derm. Venereol. 87, 206–218 (2007).

    CAS  PubMed  Google Scholar 

  5. 5

    Rossi, F. & Kazatchkine, M. D. Antiidiotypes against autoantibodies in pooled normal human polyspecific Ig. J. Immunol. 143, 4104–4109 (1989).

    CAS  PubMed  Google Scholar 

  6. 6

    Schwab, I. & Nimmerjahn, F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat. Rev. Immunol. 13, 176–189 (2013).

    CAS  PubMed  Google Scholar 

  7. 7

    Vassilev, T. et al. Antibodies to the CD5 molecule in normal human immunoglobulins for therapeutic use (intravenous immunoglobulins, IVIg). Clin. Exp. Immunol. 92, 369–372 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Vassilev, T. L. et al. Inhibition of cell adhesion by antibodies to Arg–Gly–Asp (RGD) in normal immunoglobulin for therapeutic use (intravenous immunoglobulin, IVIg). Blood 93, 3624–3631 (1999).

    CAS  PubMed  Google Scholar 

  9. 9

    von Gunten, S. et al. Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations. Blood 108, 4255–4259 (2006).

    CAS  PubMed  Google Scholar 

  10. 10

    von Gunten, S. & Simon, H. U. Natural anti-Siglec autoantibodies mediate potential immunoregulatory mechanisms: implications for the clinical use of intravenous immunoglobulins (IVIg). Autoimmun. Rev. 7, 453–456 (2008).

    CAS  PubMed  Google Scholar 

  11. 11

    von Gunten, S. et al. Intravenous immunoglobulin contains a broad repertoire of anti-carbohydrate antibodies that is not restricted to the IgG2 subclass. J. Allergy Clin. Immunol. 123, 1268–1276.e15 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    von Gunten, S. et al. Intravenous immunoglobulin preparations contain anti-Siglec-8 autoantibodies. J. Allergy Clin. Immunol. 119, 1005–1011 (2007).

    CAS  PubMed  Google Scholar 

  13. 13

    Basta, M., Langlois, P. F., Marques, M., Frank, M. M. & Fries, L. F. High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance. Blood 74, 326–333 (1989).

    CAS  PubMed  Google Scholar 

  14. 14

    Debre, M. et al. Infusion of Fcγ fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342, 945–949 (1993).

    CAS  PubMed  Google Scholar 

  15. 15

    Anthony, R. M. et al. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320, 373–376 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    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 18, 573–581 (2003).

    CAS  PubMed  Google Scholar 

  17. 17

    Kaneko, Y., Nimmerjahn, F., Madaio, M. P. & Ravetch, J. V. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J. Exp. Med. 203, 789–797 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Kaneko, Y., Nimmerjahn, F. & Ravetch, J. V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313, 670–673 (2006).

    CAS  PubMed  Google Scholar 

  19. 19

    Samuelsson, A., Towers, T. L. & Ravetch, J. V. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291, 484–486 (2001).

    CAS  PubMed  Google Scholar 

  20. 20

    Hansen, R. J. & Balthasar, J. P. Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor. Thromb. Haemost. 88, 898–899 (2002).

    CAS  PubMed  Google Scholar 

  21. 21

    Li, N. et al. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J. Clin. Invest. 115, 3440–3450 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Tackenberg, B. et al. Impaired inhibitory Fcγ receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc. Natl Acad. Sci. USA 106, 4788–4792 (2009).

    CAS  PubMed  Google Scholar 

  23. 23

    Mackay, M. et al. Selective dysregulation of the FcγIIB receptor on memory B cells in SLE. J. Exp. Med. 203, 2157–2164 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Anthony, R. M., Kobayashi, T., Wermeling, F. & Ravetch, J. V. Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway. Nature 475, 110–113 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Kaneko, Y., Nimmerjahn, F., Madaio, M. P. & Ravetch, J. V. Pathology and protection in nephrotoxic nephritis is determined by selective engagement of specific Fc receptors. J. Exp. Med. 203, 789–797 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M. & Dwek, R. A. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu. Rev. Immunol. 25, 21–50 (2007).

    CAS  PubMed  Google Scholar 

  27. 27

    Schwab, I., Biburger, M., Kronke, G., Schett, G. & Nimmerjahn, F. IVIg-mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1. Eur. J. Immunol. 42, 826–830 (2012).

    CAS  PubMed  Google Scholar 

  28. 28

    Campbell, I. K. et al. Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils. J. Immunol. 192, 5031–5038 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Othy, S. et al. Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin. Eur. J. Immunol. 44, 2059–2063 (2014).

    CAS  PubMed  Google Scholar 

  30. 30

    Dalakas, M. C. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 22, 1479–1497 (1999).

    CAS  PubMed  Google Scholar 

  31. 31

    Dalakas, M. C. Advances in the diagnosis, pathogenesis and treatment of CIDP. Nat. Rev. Neurol. 7, 507–517 (2011).

    PubMed  Google Scholar 

  32. 32

    van der Meche, F. G. & Schmitz, P. I. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain–Barré syndrome. Dutch Guillain–Barré Study Group. N. Engl. J. Med. 326, 1123–1129 (1992).

    CAS  PubMed  Google Scholar 

  33. 33

    [No authors listed]. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain–Barré syndrome. Plasma Exchange/Sandoglobulin Guillain–Barré Syndrome Trial Group. Lancet 349, 225–230 (1997).

  34. 34

    Hughes, R. A. et al. Clinical applications of intravenous immunoglobulins in neurology. Clin. Exp. Immunol. 158 (Suppl. 1), 34–42 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Kuitwaard, K. et al. Pharmacokinetics of intravenous immunoglobulin and outcome in Guillain–Barré syndrome. Ann. Neurol. 66, 597–603 (2009).

    CAS  PubMed  Google Scholar 

  36. 36

    Dyck, P. J. et al. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann. Neurol. 36, 838–845 (1994).

    CAS  PubMed  Google Scholar 

  37. 37

    Hughes, R. et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann. Neurol. 50, 195–201 (2001).

    CAS  PubMed  Google Scholar 

  38. 38

    Mendell, J. R. et al. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 56, 445–449 (2001).

    CAS  PubMed  Google Scholar 

  39. 39

    Hughes, R. A. et al. 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, 136–144 (2008).

    CAS  PubMed  Google Scholar 

  40. 40

    Merkies, I. S. et al. Health-related quality-of-life improvements in CIDP with immune globulin IV 10%: the ICE Study. Neurology 72, 1337–1344 (2009).

    CAS  PubMed  Google Scholar 

  41. 41

    Bril, V. et al. Electrophysiology in chronic inflammatory demyelinating polyneuropathy with IGIV. Muscle Nerve 39, 448–455 (2009).

    CAS  PubMed  Google Scholar 

  42. 42

    Latov, N. et al. Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. Arch. Neurol. 67, 802–807 (2010).

    PubMed  Google Scholar 

  43. 43

    Vermeulen, M. et al. Intravenous immunoglobulin treatment in patients with chronic inflammatory demyelinating polyneuropathy: a double blind, placebo controlled study. J. Neurol. Neurosurg. Psychiatry 56, 36–39 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    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 119, 1067–1077 (1996).

    PubMed  Google Scholar 

  45. 45

    Iijima, M. et al. Single nucleotide polymorphism of TAG-1 influences IVIg responsiveness of Japanese patients with CIDP. Neurology 73, 1348–1352 (2009).

    CAS  PubMed  Google Scholar 

  46. 46

    Klehmet, J. et al. Effective treatment with intravenous immunoglobulins reduces autoreactive T-cell response in patients with CIDP. J. Neurol. Neurosurg. Psychiatry http://dx.doi.org/10.1136/jnnp-2014-307708.

  47. 47

    Dalakas, M. C. Pathogenesis of immune-mediated neuropathies. Biochim. Biophys. Acta http://dx.doi.org/10.1016/j.bbadis.2014.06.013.

  48. 48

    Hahn, A. F. et al. A controlled trial of intravenous immunoglobulin in multifocal motor neuropathy. J. Peripher. Nerv. Syst. 18, 321–330 (2013).

    CAS  PubMed  Google Scholar 

  49. 49

    Federico, P., Zochodne, D. W., Hahn, A. F., Brown, W. F. & Feasby, T. E. Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Neurology 55, 1256–1262 (2000).

    CAS  PubMed  Google Scholar 

  50. 50

    Dalakas, M. C. et al. A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy. Ann. Neurol. 40, 792–795 (1996).

    CAS  PubMed  Google Scholar 

  51. 51

    Comi, G. et al. A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy. J. Neurol. 249, 1370–1377 (2002).

    CAS  PubMed  Google Scholar 

  52. 52

    Vaccaro, C., Zhou, J., Ober, R. J. & Ward, E. S. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat. Biotechnol. 23, 1283–1288 (2005).

    CAS  PubMed  Google Scholar 

  53. 53

    Barbosa, D. et al. Polyomavirus BK viremia in kidney transplant recipients after desensitization with IVIg and rituximab. Transplantation 97, 755–761 (2013).

    Google Scholar 

  54. 54

    Jordan, S. C., Vo, A., Lai, C. H. & Reinsmoen, N. Defining the benefits of desensitization therapy. Transplantation 95, e31–e32 (2013).

    PubMed  Google Scholar 

  55. 55

    Hung, I. F. et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A (H1N1) infection. Chest 144, 464–473 (2013).

    PubMed  Google Scholar 

  56. 56

    Gajdos, P., Chevret, S., Clair, B., Tranchant, C. & Chastang, C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann. Neurol. 41, 789–796 (1997).

    CAS  PubMed  Google Scholar 

  57. 57

    Gajdos, P. et al. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch. Neurol. 62, 1689–1693 (2005).

    PubMed  Google Scholar 

  58. 58

    Zinman, L., Ng, E. & Bril, V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology 68, 837–841 (2007).

    CAS  PubMed  Google Scholar 

  59. 59

    Gajdos, P., Chevret, S. & Toyka, K. V. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database of Systematic Reviews, Issue 12. Art. No.: CD002277. http://dx.doi.org/10.1002/14651858.CD002277.pub4.

  60. 60

    Dalakas, M. C. IVIg in the chronic management of myasthenia gravis: is it enough for your money? J. Neurol. Sci. 338, 1–2 (2014).

    PubMed  Google Scholar 

  61. 61

    Dalakas, M. C. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA 291, 2367–2375 (2004).

    CAS  PubMed  Google Scholar 

  62. 62

    Bain, P. G. et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert–Eaton myasthenic syndrome. Neurology 47, 678–683 (1996).

    CAS  PubMed  Google Scholar 

  63. 63

    Dalakas, M. C. et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N. Engl. J. Med. 329, 1993–2000 (1993).

    CAS  PubMed  Google Scholar 

  64. 64

    Basta, M. & Dalakas, M. C. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J. Clin. Invest. 94, 1729–1735 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Raju, R. & Dalakas, M. C. Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes. Brain 128, 1887–1896 (2005).

    PubMed  Google Scholar 

  66. 66

    Chalela, J. A. Guillain–Barre variant in the deployed setting. Mil. Med. 178, e1156–e1158 (2013).

    PubMed  Google Scholar 

  67. 67

    Nagelkerke, S. Q. et al. Inhibition of FcγR-mediated phagocytosis by IVIg is independent of IgG-Fc sialylation and FcγRIIb in human macrophages. Blood 124, 3709–3718 (2014).

    CAS  PubMed  Google Scholar 

  68. 68

    Dalakas, M. C. et al. Treatment of inclusion-body myositis with IVIg: a double-blind, placebo-controlled study. Neurology 48, 712–716 (1997).

    CAS  PubMed  Google Scholar 

  69. 69

    Dalakas, M. C. Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis. Neurology 51, S37–S45 (1998).

    CAS  PubMed  Google Scholar 

  70. 70

    Walter, M. C. et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J. Neurol. 247, 22–28 (2000).

    CAS  PubMed  Google Scholar 

  71. 71

    Dalakas, M. C. et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 56, 323–327 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    Dalakas, M. C. et al. High-dose intravenous immune globulin for stiff-person syndrome. N. Engl. J. Med. 345, 1870–1876 (2001).

    CAS  PubMed  Google Scholar 

  73. 73

    Sorensen, P. S., Haas, J., Sellebjerg, F., Olsson, T. & Ravnborg, M. IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS. Neurology 63, 2028–2033 (2004).

    CAS  PubMed  Google Scholar 

  74. 74

    Visser, L. H. et al. A randomized, double-blind, placebo-controlled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS. Mult. Scler. 10, 89–91 (2004).

    CAS  PubMed  Google Scholar 

  75. 75

    Fazekas, F. et al. Intravenous immunoglobulin in relapsing–remitting multiple sclerosis: a dose-finding trial. Neurology 71, 265–271 (2008).

    CAS  PubMed  Google Scholar 

  76. 76

    Hommes, O. R. et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 364, 1149–1156 (2004).

    CAS  PubMed  Google Scholar 

  77. 77

    Achiron, A. et al. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-related relapses in multiple sclerosis. J. Neurol. 251, 1133–1137 (2004).

    CAS  PubMed  Google Scholar 

  78. 78

    Dodel, R. C. et al. Intravenous immunoglobulins containing antibodies against β-amyloid for the treatment of Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 75, 1472–1474 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    DeMattos, R. B. et al. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 8850–8855 (2001).

    CAS  PubMed  Google Scholar 

  80. 80

    Leoyklang, P. et al. Sialylation of Thomsen–Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy. Biomark. Med. 8, 641–652 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Ahmed, A. A. et al. Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. J. Mol. Biol. 426, 3166–3179 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Gonzalez, H. et al. Intravenous immunoglobulin for post-polio syndrome: a randomised controlled trial. Lancet Neurol. 5, 493–500 (2006).

    CAS  PubMed  Google Scholar 

  83. 83

    Juji, T., Satake, M., Honda, Y. & Doi, Y. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens 24, 316–319 (1984).

    CAS  PubMed  Google Scholar 

  84. 84

    Mignot, E. & Thorsby, E. Narcolepsy and the HLA system. N. Engl. J. Med. 344, 692 (2001).

    CAS  PubMed  Google Scholar 

  85. 85

    Plazzi, G. et al. Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy. J. Neurol. 255, 1549–1554 (2008).

    PubMed  Google Scholar 

  86. 86

    von Gunten, S. et al. IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. Nat. Rev. Immunol. 14, 349 (2014).

    CAS  PubMed  Google Scholar 

  87. 87

    Goebel, A. et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann. Intern. Med. 152, 152–158 (2010).

    PubMed  Google Scholar 

  88. 88

    Elsone, L. et al. Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. Mult. Scler. 20, 501–504 (2014).

    CAS  PubMed  Google Scholar 

  89. 89

    Fokkink, W. J. et al. IgG Fc N-glycosylation in Guillain–Barré syndrome treated with immunoglobulins. J. Proteome Res. 13, 1722–1730 (2014).

    CAS  PubMed  Google Scholar 

  90. 90

    Donofrio, P. D. et al. Consensus statement: the use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the AANEM ad hoc committee. Muscle Nerve 40, 890–900 (2009).

    CAS  PubMed  Google Scholar 

  91. 91

    Woodruff, R. K., Grigg, A. P., Firkin, F. C. & Smith, I. L. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 2, 217–218 (1986).

    CAS  PubMed  Google Scholar 

  92. 92

    Dalakas, M. C. & Clark, W. M. Strokes, thromboembolic events, and IVIg: rare incidents blemish an excellent safety record. Neurology 60, 1736–1737 (2003).

    PubMed  Google Scholar 

  93. 93

    Dalakas, M. C. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 44, 223–226 (1994).

    CAS  PubMed  Google Scholar 

  94. 94

    Voltz, R., Rosen, F. V., Yousry, T., Beck, J. & Hohlfeld, R. Reversible encephalopathy with cerebral vasospasm in a Guillain–Barré syndrome patient treated with intravenous immunoglobulin. Neurology 46, 250–251 (1996).

    CAS  PubMed  Google Scholar 

  95. 95

    Germishuizen, W. A., Gyure, D. C., Stubbings, D. & Burnouf, T. Quantifying the thrombogenic potential of human plasma-derived immunoglobulin products. Biologicals 42, 260–270 (2014).

    CAS  PubMed  Google Scholar 

  96. 96

    Dalakas, M. C. Intravenous immune globulin therapy for neurologic diseases. Ann. Intern. Med. 126, 721–730 (1997).

    CAS  PubMed  Google Scholar 

  97. 97

    Dalakas, M. C. Update on the use of intravenous immune globulin in the treatment of patients with inflammatory muscle disease. J. Clin. Immunol. 15 (Suppl. 6), 70S–75S (1995).

    CAS  PubMed  Google Scholar 

  98. 98

    Sekul, E. A., Cupler, E. J. & Dalakas, M. C. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann. Intern. Med. 121, 259–262 (1994).

    CAS  PubMed  Google Scholar 

  99. 99

    Bjorkander, J. et al. Immunoglobulin prophylaxis in patients with antibody deficiency syndromes and anti-IgA antibodies. J. Clin. Immunol. 7, 8–15 (1987).

    CAS  PubMed  Google Scholar 

  100. 100

    Horn, J. et al. Anti-IgA antibodies in common variable immunodeficiency (CVID): diagnostic workup and therapeutic strategy. Clin. Immunol. 122, 156–162 (2007).

    CAS  PubMed  Google Scholar 

  101. 101

    Burks, A. W., Sampson, H. A. & Buckley, R. H. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia. N. Engl. J. Med. 314, 560–564 (1986).

    CAS  PubMed  Google Scholar 

  102. 102

    Ahsan, N. Intravenous immunoglobulin induced-nephropathy: a complication of IVIG therapy. J. Nephrol. 11, 157–161 (1998).

    CAS  PubMed  Google Scholar 

  103. 103

    Ahsan, N., Palmer, B. F., Wheeler, D., Greenlee, R. G. Jr & Toto, R. D. Intravenous immunoglobulin-induced osmotic nephrosis. Arch. Intern. Med. 154, 1985–1987 (1994).

    CAS  PubMed  Google Scholar 

  104. 104

    Gelfand, E. W. Intravenous immune globulin in autoimmune and inflammatory diseases. N. Engl. J. Med. 368, 777 (2013).

    CAS  PubMed  Google Scholar 

  105. 105

    McCrone, P. et al. Cost-utility analysis of intravenous immunoglobulin and prednisolone for chronic inflammatory demyelinating polyradiculoneuropathy. Eur. J. Neurol. 10, 687–694 (2003).

    PubMed  Google Scholar 

  106. 106

    Koffman, B. M. & Dalakas, M. C. Effect of high-dose intravenous immunoglobulin on serum chemistry, hematology, and lymphocyte subpopulations: assessments based on controlled treatment trials in patients with neurological diseases. Muscle Nerve 20, 1102–1107 (1997).

    CAS  PubMed  Google Scholar 

  107. 107

    Markvardsen, L. H. et al. Subcutaneous immunoglobulin preserves muscle strength in chronic inflammatory demyelinating polyneuropathy. Eur. J. Neurol. 21, 1465–1470 (2014).

    CAS  PubMed  Google Scholar 

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Lünemann, J., Nimmerjahn, F. & Dalakas, M. Intravenous immunoglobulin in neurology—mode of action and clinical efficacy. Nat Rev Neurol 11, 80–89 (2015). https://doi.org/10.1038/nrneurol.2014.253

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