Abstracts
During recent years, an increasing number of neuromuscular diseases have been recognized either to be caused primarily by autoimmune mechanisms, or to have important autoimmune components. The involved pathophysiological mechanisms and clinical manifestations have been better recognized and many of these disorders are potentially treatable by immunosuppression or by immunomodulation with intravenous immunoglobulin (IVIg). IVIg has been tried in a variety of immune-mediated neurological diseases, being target of widespread use in central and peripheral nervous systems diseases.
Objective
To give an overview of the main topics regarding the mechanism of action and different therapeutic uses of IVIg in neurological practice, mainly in neuromuscular diseases.
immunoglobulin; neuromuscular diseases; autoimmunity; inflammatory myopathy
Nos últimos anos, um número progressivo de doenças neuromusculares passaram a ser reconhecidas tanto por ser causadas por mecanismos autoimunes ou por envolver importantes componentes autoimunes. Os mecanismos fisiopatológicos e as manifestações clínicas envolvidos têm sido mais bem reconhecidos e muitas de tais doenças são potencialmente tratáveis por imunossupressão ou imunomodulação com imunoglobulina intravenosa (IVIg). IVIg vem sendo utilizada em uma variedade de doenças neurológicas imunomediadas, sendo alvo de amplo uso em doenças dos sistemas nervosos central e periférico.
Objetivo
Oferecer uma visão global sobre os principais tópicos relacionados aos mecanismos de ação e aos diferentes usos terapêuticos da IVIg na prática neurológica, principalmente em doenças neuromusculares.
imunoglobulina; doenças neuromusculares; autoimunidade; miopatia inflamatória
The number of inflammatory neurological diseases has significantly increased in the last
decades. The involved pathophysiological mechanisms and clinical manifestations have
been better recognized and in proportion has been increasing the number of different
therapeutic proposals, notably in the field of immune-mediated neurological diseases.
Old neurological disorders essentially credited as primarily degenerative and infectious
diseases evinced the importance of its inflammatory and immune-mediated components in
its pathophysiology. Treatments formely used for autoimmune inflammatory diseases and
primary immunodeficiencies have become frequently used in various neurological diseases
and in a wide different group of contexts, highlighting the immunomodulatory drugs,
corticosteroids, plasmapheresis and intravenous immunoglobulin (IVIg)11 Elovaara I, Hietaharju A. Can we face the challenge of expanding use
of intravenous immunoglobulin in neurology? Acta Neurol Scand.
2010;122(5):309-15.
http://dx.doi.org/10.1111/j.1600-0404.2009.01317.x
https://doi.org/10.1111/j.1600-0404.2009...
. In this perspective, the use of IVIg
represents an important therapeutic perspective in large amounts of immune-mediated
neurological diseases, being target of widespread use in central and peripheral nervous
systems diseases. The main focus of this review is to highlight the main mechanisms of
action and current uses of IVIg in neurological practice.
Mechanisms of action and basis of current use of immunoglobulin
IVIg preparation offers a mix of concentrated formulations of human IgG prepared by
industrial fractionation of different pools of plasma donations with functionally
and structurally intact immunoglobulin and its associated antibody profiles. More
than 30 different preparations of intravenous immunoglobulin are currently available
for use in different settings and clinical conditions. In primary and secondary
antibody immunodeficiencies, immunoglobulin replacement therapy originally required
monthly intravenous applications of 400 to 600 mg/kg associated with serum IgG level
controls. Nowadays anti-inflammatory and immunomodulatory actions are commonly
observed at higher doses (400 mg/kg per day, most commonly for 5 days, or 1 g/kg per
day for 2 days). This total dose of 2 g/kg is the most common applied therapeutic
strategy to treat different immunomediated neurological disorders22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
, since the first clinical attempts
with refractory chronic polymyositis33 Roifman CM, Schaffer FM, Wachsmuth SE, Murphy G, Gelfand EW.
Reversal of chronic polymyositis following intravenous immune serum globulin
therapy. JAMA. 1987;258(4):513-5.
http://dx.doi.org/10.1001/jama.1987.03400040111034
https://doi.org/10.1001/jama.1987.034000...
. Subcutaneous administration has been also previously used,
temporarily abandoned due to complications from sterile abscesses in the past, and
currently used safely as an alternative for prophylaxis in primary
immunodeficiencies22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
. It is not
well-established for use in neurological autoimmune diseases.
Drug adverse effects are commonly described affecting up to 15% of patients with
intravenous infusion of immunoglobulin, generally in a mild early-onset
non-anaphylactoid fashion with nonspecific systemic clinical complaints, including
headache, drowsiness, tachycardia and hypotension. Some of theses cases are
self-limiting and require the stop or prompt slowing of immunoglobulin infusion rate
or even stoppage and the use of symptomatic therapy, mainly represented by
corticosteroids, nonsteroidal antiinflammatory drugs and intravenous hydration.
There is also the description of early-onset severe anaphylaxis commonly associated
with IgA deficiency in serum levels lesser than 0.05 g/L. Acute renal failure (not
related to sorbitol-based formulations), sepsis, transient neutropenia, disseminated
intravascular coagulation, hepatitis C viral and parvovirus B19 infection,
Transfusion-associated Acute Lung Injury (TRALI), aseptic meningitis, thrombotic
events (deep venous thrombosis, pulmonary embolism, acute myocardial infarction,
stroke), pseudohyponatremia and late-onset arthritis, aseptic meningitis and
neurodegeneration have also been described in related to the use of IVIg22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,44 Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin:
adverse effects and safe administration. Clin Rev Allergy Immunol.
2005;29(3):173-84. http://dx.doi.org/10.1385/criai:29:3:173
https://doi.org/10.1385/criai:29:3:173...
.
Although initially applied for patients with specific primary immunodeficiency
diseases, IVIg is widely used nowadays for different groups of clinical conditions
(Table 1), mainly hematological,
dermatological and autoimmune diseases55 Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does
IgG modulate the immune system? Nat Rev Immunol. 2013;13(3):176-89.
http://dx.doi.org/10.1038/nri3401
https://doi.org/10.1038/nri3401...
,66 Lemieux R, Bazin R, Néron S. Therapeutic intravenous
immunoglobulins. Mol Immunol. 2005;42(7):839-48.
http://dx.doi.org/10.1016/j.molimm.2004.07.046
https://doi.org/10.1016/j.molimm.2004.07...
,77 Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA et
al. Use of intravenous immunoglobulin in human disease: a review of evidence by
members of the Primary Immunodeficiency Committee of the American Academy of
Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117(4
Suppl):S525-53. http://dx.doi.org/10.1016/j.jaci.2006.01.015
https://doi.org/10.1016/j.jaci.2006.01.0...
,88 Gürcan HM, Ahmed AR. Efficacy of various intravenous
immunoglobulin therapy protocols in autoimmune and chronic inflammatory
disorders. Ann Pharmacother. 2007;41(5):812-23.
http://dx.doi.org/10.1345/aph.1k037
https://doi.org/10.1345/aph.1k037...
,99 Gelfand EW. Intravenous immune globulin in autoimmune and
inflammatory diseases. N Engl J Med. 2012;367(21):2015-25.
http://dx.doi.org/10.1056/nejmra1009433
https://doi.org/10.1056/nejmra1009433...
. Despite the seemingly supplementation and prophylatic
mechanism involved with its classical use in some immunodeficiencies, the clinical
response observed in different contexts of diverse pathophysiological autoimmunity
enabled the development of different hypotheses regarding the drug’s
mechanism of action. This review covers some of the key mechanisms previously
described.
Major non-neurological diseases for which intravenous immunoglobulin has been previously used55 Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol. 2013;13(3):176-89. http://dx.doi.org/10.1038/nri3401
https://doi.org/10.1038/nri3401... ,66 Lemieux R, Bazin R, Néron S. Therapeutic intravenous immunoglobulins. Mol Immunol. 2005;42(7):839-48. http://dx.doi.org/10.1016/j.molimm.2004.07.046
https://doi.org/10.1016/j.molimm.2004.07... ,77 Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117(4 Suppl):S525-53. http://dx.doi.org/10.1016/j.jaci.2006.01.015
https://doi.org/10.1016/j.jaci.2006.01.0... ,88 Gürcan HM, Ahmed AR. Efficacy of various intravenous immunoglobulin therapy protocols in autoimmune and chronic inflammatory disorders. Ann Pharmacother. 2007;41(5):812-23. http://dx.doi.org/10.1345/aph.1k037
https://doi.org/10.1345/aph.1k037... ,99 Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012;367(21):2015-25. http://dx.doi.org/10.1056/nejmra1009433
https://doi.org/10.1056/nejmra1009433... .
The set of immunomodulatory mechanisms related to the action of IVIg is variable,
complex and not well established, and there is still controversial points between
clinical practice and experimental studies66 Lemieux R, Bazin R, Néron S. Therapeutic intravenous
immunoglobulins. Mol Immunol. 2005;42(7):839-48.
http://dx.doi.org/10.1016/j.molimm.2004.07.046
https://doi.org/10.1016/j.molimm.2004.07...
. It is also important to emphasize that the
inflammatory activities of immunoglobulin depend mainly on its concentration,
producing paradoxical responses of pro- and anti-inflammatory actions1010 Durandy A, Kaveri SV, Kuijpers TW, Basta M, Miescher S, Ravetch JV
et al. Intravenous immunoglobulins: understanding properties and mechanisms.
Clin Exp Immunol. 2009;158:2-13.
http://dx.doi.org/10.1111/j.1365-2249.2009.04022.x
https://doi.org/10.1111/j.1365-2249.2009...
. Its uses comprise different
groups of actions mediated via the variable regions Fab (fragment, antigen-binding
region in the arms of the Y arm) and the direct effect of Fc region (fragment,
crystallizable region in the base of the Y arm), by complement binding in the Fc
region, and by other immunomodulatory substances present in the preparations of
intravenous immunoglobulin66 Lemieux R, Bazin R, Néron S. Therapeutic intravenous
immunoglobulins. Mol Immunol. 2005;42(7):839-48.
http://dx.doi.org/10.1016/j.molimm.2004.07.046
https://doi.org/10.1016/j.molimm.2004.07...
,1111 Baerenwaldt A, Biburger M, Nimmerjahn F. Mechanisms of action of
intravenous immunoglobulins. Expert Rev Clin Immunol. 2010;6(3):425-34.
http://dx.doi.org/10.1586/eci.10.9
https://doi.org/10.1586/eci.10.9...
. There is direct interaction between the Fc portion of
immunoglobulins with their receptors yielding the well-known immunoregulatory
effects. It also occurs in modulating effector functions and activation of B and T
lymphocytes, neutralization of pathogenic autoantibodies, interference with the
process of antigen presentation and the complement and cytokine-dependent overall
anti-inflammatory effect1212 Bayry J, Misra N, Latry V, Prost F, Delignat S, Lacroix-Desmazes S
et al. Mechanisms of action of intravenous immunoglobulin in autoimmune and
inflammatory diseases. Transfus Clin Biol. 2003;10(3):165-9.
http://dx.doi.org/10.1016/s1246-7820(03)00035-1
https://doi.org/10.1016/s1246-7820(03)00...
.
Inhibitory Fc-gamma receptor FcgammaRIIB, expressed on myeloid cells and B cells, is
required for the anti-inflammatory activity of intravenous immunoglobulin1313 Tackenberg B, Nimmerjahn F, Lünemann JD. Mechanisms of IVIG
efficacy in chronic inflammatory demyelinating polyneuropathy. J Clin Immunol.
2010;30(1 Suppl):S65-9.
http://dx.doi.org/10.1007/s10875-010-9398-1
https://doi.org/10.1007/s10875-010-9398-...
. For example, impaired expression
of the inhibitory FcgammaR in chronic inflammatory demyelinating polyneuropathy
(CIDP) can be partially restored by immunoglobulin treatment and changing the
impaired late B cell differentiation step checkpoint. In the context of
immunoglobulin’s V-region dependent mechanisms of action, in the case of
medium-sized vessel vasculitis, an important reduction in serum cytokines levels has
been established1414 Pyne D, Ehrenstein M, Morris V. The therapeutic uses of intravenous
immunoglobulins in autoimmune rheumatic diseases. Rheumatology (Oxford).
2002;41(4):367-74. 10.1093/rheumatology/41.4.367
https://doi.org/10.1093/rheumatology/41....
.
In the context of the overall anti-inflammatory effect, for example, it has also been
proved that immunoglobulin use in polymyositis inhibits TNF-alpha, interleucin-1 and
the uptake of C3 for deposition of complement membrane attack complex on the
endomysial capillaries, and also blocks the process of macrophageal Fc
receptor-mediated phagocytosis1515 Dalakas MC. Clinical benefits and immunopathological correlates of
intravenous immune globulin in the treatment of inflammatory myopathies. Clin
Exp Immunol. 1996;104 Suppl:55-60..
Other mechanism proposed involving the immunoglobulin Fc region in dermatomyositis
involves also the binding of C4b1414 Pyne D, Ehrenstein M, Morris V. The therapeutic uses of intravenous
immunoglobulins in autoimmune rheumatic diseases. Rheumatology (Oxford).
2002;41(4):367-74. 10.1093/rheumatology/41.4.367
https://doi.org/10.1093/rheumatology/41....
. It is also established new anti-inflammatory properties of
the minor fraction of sialylated immunoglobulin molecules1010 Durandy A, Kaveri SV, Kuijpers TW, Basta M, Miescher S, Ravetch JV
et al. Intravenous immunoglobulins: understanding properties and mechanisms.
Clin Exp Immunol. 2009;158:2-13.
http://dx.doi.org/10.1111/j.1365-2249.2009.04022.x
https://doi.org/10.1111/j.1365-2249.2009...
.
Furthermore, in addition to the more classical mechanisms, recent studies also showed
that immunoglobulin products contains specific anti-Tau antibodies, suggesting the
possibility of applying this drug for patients with mild to moderate
Alzheimer’s disease1616 Smith LM, Coffey MP, Klaver AC, Loeffler DA. Intravenous
immunoglobulin products contain specific antibodies to recombinant human tau
protein. Int Immunopharmacol. 2013;16(4):424-8.
http://dx.doi.org/10.1016/j.intimp.2013.04.034
https://doi.org/10.1016/j.intimp.2013.04...
,
although no clinical evidence was obtained from former clinical trials and
experimental studies from over a decade1717 Loeffler DA. Intravenous immunoglobulin and Alzheimer’s
disease: what now? J Neuroinflammation. 2013;10(1):70.
http://dx.doi.org/10.1186/1742-2094-10-70
https://doi.org/10.1186/1742-2094-10-70...
. It is believed, though mainly hypothetical, that human
anti-amyloid-beta antibodies may also play an important role in the clearance of
aggregates of amyloid proteins in the elderly with Alzheimer’s disease1818 Hughes RAC, Dalakas MC, Cornblath DR, Latov N, Weksler ME, Relkin N.
Clinical applications of intravenous immunoglobulins in neurology. Clin Exp
Immunol. 2009;158(Suppl):34-42.
http://dx.doi.org/10.1111/j.1365-2249.2009.04025.x
https://doi.org/10.1111/j.1365-2249.2009...
. Other proposed associated
mechanism of action involves target-site integrins on extracellular matrix and cell
surfaces1919 Blank M, Nur I, Toub O, Maor A, Shoenfeld Y. Toward molecular
targeting with specific intravenous immunoglobulin preparation. Clin Rev Allergy
Immunol. 2005;29(3):213-7.
http://dx.doi.org/10.1385/criai:29:3:213
https://doi.org/10.1385/criai:29:3:213...
, lymphocyte and
monocyte apoptosis induction22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,
modulation of regulatory T cells, inhibition of differentiation and maturation of
dendritic cells, and apoptosis of B and T cells using Fas receptor-related
pathways2020 Novaretti MC, Dinardo CL. Immunoglobulin: production, mechanisms of
action and formulations. Rev Bras Hematol Hemoter. 2011;33(5):377-82.
http://dx.doi.org/10.5581/1516-8484.20110102
https://doi.org/10.5581/1516-8484.201101...
.
IVIg – PREPARATIONS
There are different preparations of IVIg available for use in clinical practice (Table 2).
Different preparations of immunoglobulin available and their biochemical and pharmacokinetic properties.
Classical and current neurological indications
Its use has been widespread in other specialties than Neurology (Table 1)55 Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does
IgG modulate the immune system? Nat Rev Immunol. 2013;13(3):176-89.
http://dx.doi.org/10.1038/nri3401
https://doi.org/10.1038/nri3401...
,66 Lemieux R, Bazin R, Néron S. Therapeutic intravenous
immunoglobulins. Mol Immunol. 2005;42(7):839-48.
http://dx.doi.org/10.1016/j.molimm.2004.07.046
https://doi.org/10.1016/j.molimm.2004.07...
,77 Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA et
al. Use of intravenous immunoglobulin in human disease: a review of evidence by
members of the Primary Immunodeficiency Committee of the American Academy of
Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117(4
Suppl):S525-53. http://dx.doi.org/10.1016/j.jaci.2006.01.015
https://doi.org/10.1016/j.jaci.2006.01.0...
,88 Gürcan HM, Ahmed AR. Efficacy of various intravenous
immunoglobulin therapy protocols in autoimmune and chronic inflammatory
disorders. Ann Pharmacother. 2007;41(5):812-23.
http://dx.doi.org/10.1345/aph.1k037
https://doi.org/10.1345/aph.1k037...
,99 Gelfand EW. Intravenous immune globulin in autoimmune and
inflammatory diseases. N Engl J Med. 2012;367(21):2015-25.
http://dx.doi.org/10.1056/nejmra1009433
https://doi.org/10.1056/nejmra1009433...
, although US Food and Drug Administration approved
the use of IVIg in few conditions, including Allogeneic bone marrow
transplantation, chronic lymphocytic leukemia, common variable immunodeficiency,
pediatric HIV type I infection, Kawasaki disease, immune-mediated
thrombocytopenia, kidney transplantation (with high antibody recipiente or with
an ABO incompatible donor), primary immunodeficiency disorders with defects in
humoral immunity and hematopoietic stem cell transplantation (patients older
than 20 years). In Brazil, regarding the autoimmune neurological conditions, the
Agência Nacional de Vigilância Sanitária
(ANVISA) approved the use of IVIg in only five conditions (ANVISA Public
Consultation, number 36, 20/05/2004; and Ministry of Health of Brazil, Ordinance
number 3,439, 11/11/2010): Guillain-Barré syndrome, myasthenia gravis,
juvenil dermatomyositis, other dermatomyositis, and polymyositis. Although
commonly used among different neurological contexts (Table 3), immunoglobulin use has been studied in a proper
manner in neuromuscular disorders22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,1818 Hughes RAC, Dalakas MC, Cornblath DR, Latov N, Weksler ME, Relkin N.
Clinical applications of intravenous immunoglobulins in neurology. Clin Exp
Immunol. 2009;158(Suppl):34-42.
http://dx.doi.org/10.1111/j.1365-2249.2009.04025.x
https://doi.org/10.1111/j.1365-2249.2009...
,2121 Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular
diseases. JAMA. 2004;291(19):2367-75.
http://dx.doi.org/10.1001/jama.291.19.2367
https://doi.org/10.1001/jama.291.19.2367...
,2222 Stangel M. New advances in the treatment of neurological diseases
using high dose intravenous immunoglobulins. Ther Adv Neurol Disord.
2008;1(2):52-61. http://dx.doi.org/10.1177/1756285608095747
https://doi.org/10.1177/1756285608095747...
,2323 Gold R, Stangel M, Dalakas MC. Drug Insight: the use of intravenous
immunoglobulin in neurology--therapeutic considerations and practical issues.
Nat Clin Pract Neurol. 2007;3(1):36-44.
http://dx.doi.org/10.1038/ncpneuro0376
https://doi.org/10.1038/ncpneuro0376...
,2424 Wiles C, Brown P, Chapel H, Guerrini R, Hughes RA, Martin TD et al.
Intravenous immunoglobulin in neurological disease: a specialist review. J
Neurol Neurosurg Psychiatry. 2002;72(4):440-8.
http://dx.doi.org/10.1136/jnnp.72.4.440
https://doi.org/10.1136/jnnp.72.4.440...
,2525 Cursiefen S, Mäurer M. Current use of immunoglobulins in
neurology. Nervenarzt. 2008;79(2 Suppl):67-74.
10.1007/s00115-008-2461-y
https://doi.org/10.1007/s00115-008-2461-...
,2626 Winkelmann A, Zettl UK. Use of intravenous immunoglobulin in the
treatment of immune-mediated demyelinating diseases of the nervous system. Curr
Pharm Des. 2012;18(29):4570-82.
http://dx.doi.org/10.2174/138161212802502314
https://doi.org/10.2174/1381612128025023...
. Neuromuscular junction diseases have been target
of studies with different immunomodulatory therapies, including the isolated and
combined use of immunoglobulin. In myasthenia gravis, IVIg has its use approved
in cases of rapidly progressive disease (severe clinical manifestation or in
severe exacerbation), myasthenic crisis (similarly to the plasma exchange),
preparation of patients with weakness for surgeries (including therapeutic
thymectomy) and as adjuvant in cases of chronic oral immunossupressive therapy
aiming the reduction of cumulative dose and minimizing its long-term side
effects22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,2727 Skeie GO, Apostolski S, Evoli A, Gilhus N/e, Illa I, Harms L et al.
Guidelines for the treatment of autoimmune neuromuscular transmission disorders.
Eur J Neurol. 2010;17(7):893-902.
http://dx.doi.org/10.1111/j.1468-1331.2010.03019.x
https://doi.org/10.1111/j.1468-1331.2010...
. There is no formal
indication for chronic maintenance therapy alone. In other neuromuscular
junction disorders, like Lambert-Eaton myasthenic syndrome, case reports and
small placebo-controlled study indicate the possibility of mild to moderate
improvement in clinical and electroneuromyographic parameters (mainly the
amplitude of the resting CMAP) in patients refractory to immunossupressive
drugs2828 Dalakas MC, Stein DP, Otero C, Sekul E, Cuple EJ, McCrosky S. Effect
of high-dose intravenous immunoglobulin on amyotrophic lateral sclerosis and
multifocal motor neuropathy. Arch Neurol. 1994;51(9):861-4.
http://dx.doi.org/10.1001/archneur.1994.00540210031010
https://doi.org/10.1001/archneur.1994.00...
.
Major groups of neurological diseases for which intravenous immunoglobulin has been studied in clinical trials, case reports and currently used in practice22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A, Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol. 2008;15(9):893-908. http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008... ,1818 Hughes RAC, Dalakas MC, Cornblath DR, Latov N, Weksler ME, Relkin N. Clinical applications of intravenous immunoglobulins in neurology. Clin Exp Immunol. 2009;158(Suppl):34-42. http://dx.doi.org/10.1111/j.1365-2249.2009.04025.x
https://doi.org/10.1111/j.1365-2249.2009... ,2121 Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-75. http://dx.doi.org/10.1001/jama.291.19.2367
https://doi.org/10.1001/jama.291.19.2367... ,2222 Stangel M. New advances in the treatment of neurological diseases using high dose intravenous immunoglobulins. Ther Adv Neurol Disord. 2008;1(2):52-61. http://dx.doi.org/10.1177/1756285608095747
https://doi.org/10.1177/1756285608095747... ,2323 Gold R, Stangel M, Dalakas MC. Drug Insight: the use of intravenous immunoglobulin in neurology--therapeutic considerations and practical issues. Nat Clin Pract Neurol. 2007;3(1):36-44. http://dx.doi.org/10.1038/ncpneuro0376
https://doi.org/10.1038/ncpneuro0376... ,2424 Wiles C, Brown P, Chapel H, Guerrini R, Hughes RA, Martin TD et al. Intravenous immunoglobulin in neurological disease: a specialist review. J Neurol Neurosurg Psychiatry. 2002;72(4):440-8. http://dx.doi.org/10.1136/jnnp.72.4.440
https://doi.org/10.1136/jnnp.72.4.440... ,2525 Cursiefen S, Mäurer M. Current use of immunoglobulins in neurology. Nervenarzt. 2008;79(2 Suppl):67-74. 10.1007/s00115-008-2461-y
https://doi.org/10.1007/s00115-008-2461-... ,2626 Winkelmann A, Zettl UK. Use of intravenous immunoglobulin in the treatment of immune-mediated demyelinating diseases of the nervous system. Curr Pharm Des. 2012;18(29):4570-82. http://dx.doi.org/10.2174/138161212802502314
https://doi.org/10.2174/1381612128025023... .
Among all peripheral neuropathy and polyradiculoneuropathy, most studies with
promising and positive results with immunoglobulin involved patients with
multifocal motor neuropathy (MMN), Guillain-Barré syndrome (GBS) and
variants, and CIDP. In CIDP with moderate to severe motor disability, IVIg is
proven as the first-line immunotherapy, including for maintenance treatment
associated with immunomodulatory drugs22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,1313 Tackenberg B, Nimmerjahn F, Lünemann JD. Mechanisms of IVIG
efficacy in chronic inflammatory demyelinating polyneuropathy. J Clin Immunol.
2010;30(1 Suppl):S65-9.
http://dx.doi.org/10.1007/s10875-010-9398-1
https://doi.org/10.1007/s10875-010-9398-...
,2222 Stangel M. New advances in the treatment of neurological diseases
using high dose intravenous immunoglobulins. Ther Adv Neurol Disord.
2008;1(2):52-61. http://dx.doi.org/10.1177/1756285608095747
https://doi.org/10.1177/1756285608095747...
. In GBS, similarly to the observed effect of
plasma exchange therapy, equal responses and effects are observed with IVIg in
the standard classical dose of 400 mg/kg per day for 5 days. Its use as
immunotherapy in GBS remits to 1988. However, it is not established the
advantage of one method instead of the other in cases of recurrence or no
response if another course should be given or plasma exchange performed22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,2222 Stangel M. New advances in the treatment of neurological diseases
using high dose intravenous immunoglobulins. Ther Adv Neurol Disord.
2008;1(2):52-61. http://dx.doi.org/10.1177/1756285608095747
https://doi.org/10.1177/1756285608095747...
. In MMN, it is established in
different randomized controlled trials the first-line treatment function of
IVIg, using the same initial dose of GBS, irrespective of the presence of
positivity for anti-GM1 ganglioside antibody or conduction block22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,2222 Stangel M. New advances in the treatment of neurological diseases
using high dose intravenous immunoglobulins. Ther Adv Neurol Disord.
2008;1(2):52-61. http://dx.doi.org/10.1177/1756285608095747
https://doi.org/10.1177/1756285608095747...
. Refractory cases or partial
responses are indicative of the possible use of immunomodulatory drugs. In
paraproteinaemic demyelinating neuropathies, especially in cases of IgM
monoclonal gammopathy of undetermined significance, immunoglobulin use
represents the initial first-line treatment22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
.
In the case of motor neuron disease, there is no therapeutic improvement after
high-dose intravenous immunoglobulin use in amyotrophic lateral sclerosis2828 Dalakas MC, Stein DP, Otero C, Sekul E, Cuple EJ, McCrosky S. Effect
of high-dose intravenous immunoglobulin on amyotrophic lateral sclerosis and
multifocal motor neuropathy. Arch Neurol. 1994;51(9):861-4.
http://dx.doi.org/10.1001/archneur.1994.00540210031010
https://doi.org/10.1001/archneur.1994.00...
, although moderate motor
effects have been evinced in individual cases of post-polio syndrome with rapid
weakness and amyotrophy progression22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
. Following the text the use of immunoglobulin for
inflammatory myopathies is discussed in detail.
Clinical applications of immunoglobulin in inflammatory myopathies
Inflammatory myopathies represent a wide group of heterogeneous neuromuscular
diseases, including mainly acquired immune and infectious myopathies. The most
important clinical conditions include polymyositis, inclusion body myositis and
dermatomyositis. Several clinical and pathological acquired variants, including
paraneoplastic and other myopathies related to autoimmune diseases, have been
described, however hereditary conditions are also found. Specific pathological,
clinical and currently radiological criteria and findings are described in each
of this condition. In general, in summary, the treatment of most autoimmune
inflammatory forms depends on the use of oral corticosteroids or maintenance
pulse, in addition to any combination with immunomodulators such as
cyclosporine, methotrexate and azathioprine2929 Dalakas MC. Review: an update on inflammatory and autoimmune
myopathies. Neuropathol Appl Neurobiol. 2011;37(3):226-42.
http://dx.doi.org/10.1111/j.1365-2990.2010.01153.x
https://doi.org/10.1111/j.1365-2990.2010...
. It is exactly for cases in which there is
prolonged use of these therapies, in cases of serious adverse events or in
clinical refractory or partially responsive disease that IVIg has been studied
and applied.
The treatment of inflammatory myopathies with IVIg has been mostly empirical. In
recente years several open studies have indicated a favorable effect mainly for
dermatomyositis, in which it has proved to increase clinical improvement and
muscle strength in cases of resistance to immunossupressive and immunomodulatory
drugs and in severe presentations, generally in association with prednisone22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
. The same results were less
pronounced and evinced for polymyositis, in which few studies showed the
importance for reduction of corticosteroid dosage in chronic refractory disease,
especially in cases without response to steroid immunosupressive treatment22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
. In sporadic inclusion body
myositis, it has been proved that cases with severe dysphagia could benefit from
intravenous immunoglobulin, even though a formal recommendation is still
needed22 Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A,
Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in
treatment of neurological diseases: EFNS task force on the use of intravenous
immunoglobulin in treatment of neurological diseases. Eur J Neurol.
2008;15(9):893-908.
http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
https://doi.org/10.1111/j.1468-1331.2008...
,2222 Stangel M. New advances in the treatment of neurological diseases
using high dose intravenous immunoglobulins. Ther Adv Neurol Disord.
2008;1(2):52-61. http://dx.doi.org/10.1177/1756285608095747
https://doi.org/10.1177/1756285608095747...
,3030 Illa I. IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome
and inflammatory myopathies: current status. J Neurol. 2005;252(1 Suppl):i14-8.
http://dx.doi.org/10.1007/s00415-005-1104-5
https://doi.org/10.1007/s00415-005-1104-...
,3131 Pul R, Stangel M. Using immunoglobulins in muscular disease
treatment. Expert Opin Biol Ther. 2008;8(8):1143-50.
10.1517/14712598.8.8.1143
https://doi.org/10.1517/14712598.8.8.114...
,3232 Dalakas MC. High-dose intravenous immunoglobulin in inflammatory
myopathies: experience based on controlled clinical trials. Neurol Sc. 2003;24(4
Suppl):S256-9. http://dx.doi.org/10.1007/s10072-003-0090-6
https://doi.org/10.1007/s10072-003-0090-...
. Although clinical response
was noticed in the cases described, molecular immune mechanisms, activated
immune cells and hystopathological muscle changes were still equally represented
before and after immunoglobulin therapy3333 Helmers SB, Dastmalchi M, Alexanderson H, Nennesmo I,
Esbjörnsson M, Lindvall B et al. Limited effects of high-dose intravenous
immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of
patients with inflammatory myopathies. Ann Rheum Dis. 2007;66(10):1276-83.
http://dx.doi.org/10.1136/ard.2006.058644
https://doi.org/10.1136/ard.2006.058644...
.
FINAL REMARKS
The use of intravenous immunoglobulin has been proven effective in various situations within the neurological practice, notably in neuromuscular diseases. Few randomized multicenter clinical trials to study the effectiveness of the drug in larger samples of patients have been made for most diseases. Positive effects are demonstrated in open studies in dermato- and polymyositis, myasthenia gravis, and inflammatory neuropathies. Properly conducted randomized clinical trials demonstrating the effect of IVIg are available in GBS, CIDP, dermatomyositis, and smaller ones in multifocal motor neuropathy. There is no doubt as to the necessity to enhance the therapeutic role of this medication in neurological diseases, especially in cases of severe disease or refractoriness to the usual therapeutic modalities. It is also outstanding the restricted indicators for use of IVIg in neurological disorders in Brazil, limited to SGB, myasthenia gravis, juvenile dermatomyositis, other dermatomyositis and polymyositis.
References
-
1Elovaara I, Hietaharju A. Can we face the challenge of expanding use of intravenous immunoglobulin in neurology? Acta Neurol Scand. 2010;122(5):309-15. http://dx.doi.org/10.1111/j.1600-0404.2009.01317.x
» https://doi.org/10.1111/j.1600-0404.2009.01317.x -
2Elovaara I, Apostolski S, Doorn P, Gilhus NE, Hietaharju A, Honkaniemi J et al. EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurol. 2008;15(9):893-908. http://dx.doi.org/10.1111/j.1468-1331.2008.02246.x
» https://doi.org/10.1111/j.1468-1331.2008.02246.x -
3Roifman CM, Schaffer FM, Wachsmuth SE, Murphy G, Gelfand EW. Reversal of chronic polymyositis following intravenous immune serum globulin therapy. JAMA. 1987;258(4):513-5. http://dx.doi.org/10.1001/jama.1987.03400040111034
» https://doi.org/10.1001/jama.1987.03400040111034 -
4Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005;29(3):173-84. http://dx.doi.org/10.1385/criai:29:3:173
» https://doi.org/10.1385/criai:29:3:173 -
5Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol. 2013;13(3):176-89. http://dx.doi.org/10.1038/nri3401
» https://doi.org/10.1038/nri3401 -
6Lemieux R, Bazin R, Néron S. Therapeutic intravenous immunoglobulins. Mol Immunol. 2005;42(7):839-48. http://dx.doi.org/10.1016/j.molimm.2004.07.046
» https://doi.org/10.1016/j.molimm.2004.07.046 -
7Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117(4 Suppl):S525-53. http://dx.doi.org/10.1016/j.jaci.2006.01.015
» https://doi.org/10.1016/j.jaci.2006.01.015 -
8Gürcan HM, Ahmed AR. Efficacy of various intravenous immunoglobulin therapy protocols in autoimmune and chronic inflammatory disorders. Ann Pharmacother. 2007;41(5):812-23. http://dx.doi.org/10.1345/aph.1k037
» https://doi.org/10.1345/aph.1k037 -
9Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012;367(21):2015-25. http://dx.doi.org/10.1056/nejmra1009433
» https://doi.org/10.1056/nejmra1009433 -
10Durandy A, Kaveri SV, Kuijpers TW, Basta M, Miescher S, Ravetch JV et al. Intravenous immunoglobulins: understanding properties and mechanisms. Clin Exp Immunol. 2009;158:2-13. http://dx.doi.org/10.1111/j.1365-2249.2009.04022.x
» https://doi.org/10.1111/j.1365-2249.2009.04022.x -
11Baerenwaldt A, Biburger M, Nimmerjahn F. Mechanisms of action of intravenous immunoglobulins. Expert Rev Clin Immunol. 2010;6(3):425-34. http://dx.doi.org/10.1586/eci.10.9
» https://doi.org/10.1586/eci.10.9 -
12Bayry J, Misra N, Latry V, Prost F, Delignat S, Lacroix-Desmazes S et al. Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Transfus Clin Biol. 2003;10(3):165-9. http://dx.doi.org/10.1016/s1246-7820(03)00035-1
» https://doi.org/10.1016/s1246-7820(03)00035-1 -
13Tackenberg B, Nimmerjahn F, Lünemann JD. Mechanisms of IVIG efficacy in chronic inflammatory demyelinating polyneuropathy. J Clin Immunol. 2010;30(1 Suppl):S65-9. http://dx.doi.org/10.1007/s10875-010-9398-1
» https://doi.org/10.1007/s10875-010-9398-1 -
14Pyne D, Ehrenstein M, Morris V. The therapeutic uses of intravenous immunoglobulins in autoimmune rheumatic diseases. Rheumatology (Oxford). 2002;41(4):367-74. 10.1093/rheumatology/41.4.367
» https://doi.org/10.1093/rheumatology/41.4.367 -
15Dalakas MC. Clinical benefits and immunopathological correlates of intravenous immune globulin in the treatment of inflammatory myopathies. Clin Exp Immunol. 1996;104 Suppl:55-60.
-
16Smith LM, Coffey MP, Klaver AC, Loeffler DA. Intravenous immunoglobulin products contain specific antibodies to recombinant human tau protein. Int Immunopharmacol. 2013;16(4):424-8. http://dx.doi.org/10.1016/j.intimp.2013.04.034
» https://doi.org/10.1016/j.intimp.2013.04.034 -
17Loeffler DA. Intravenous immunoglobulin and Alzheimer’s disease: what now? J Neuroinflammation. 2013;10(1):70. http://dx.doi.org/10.1186/1742-2094-10-70
» https://doi.org/10.1186/1742-2094-10-70 -
18Hughes RAC, Dalakas MC, Cornblath DR, Latov N, Weksler ME, Relkin N. Clinical applications of intravenous immunoglobulins in neurology. Clin Exp Immunol. 2009;158(Suppl):34-42. http://dx.doi.org/10.1111/j.1365-2249.2009.04025.x
» https://doi.org/10.1111/j.1365-2249.2009.04025.x -
19Blank M, Nur I, Toub O, Maor A, Shoenfeld Y. Toward molecular targeting with specific intravenous immunoglobulin preparation. Clin Rev Allergy Immunol. 2005;29(3):213-7. http://dx.doi.org/10.1385/criai:29:3:213
» https://doi.org/10.1385/criai:29:3:213 -
20Novaretti MC, Dinardo CL. Immunoglobulin: production, mechanisms of action and formulations. Rev Bras Hematol Hemoter. 2011;33(5):377-82. http://dx.doi.org/10.5581/1516-8484.20110102
» https://doi.org/10.5581/1516-8484.20110102 -
21Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-75. http://dx.doi.org/10.1001/jama.291.19.2367
» https://doi.org/10.1001/jama.291.19.2367 -
22Stangel M. New advances in the treatment of neurological diseases using high dose intravenous immunoglobulins. Ther Adv Neurol Disord. 2008;1(2):52-61. http://dx.doi.org/10.1177/1756285608095747
» https://doi.org/10.1177/1756285608095747 -
23Gold R, Stangel M, Dalakas MC. Drug Insight: the use of intravenous immunoglobulin in neurology--therapeutic considerations and practical issues. Nat Clin Pract Neurol. 2007;3(1):36-44. http://dx.doi.org/10.1038/ncpneuro0376
» https://doi.org/10.1038/ncpneuro0376 -
24Wiles C, Brown P, Chapel H, Guerrini R, Hughes RA, Martin TD et al. Intravenous immunoglobulin in neurological disease: a specialist review. J Neurol Neurosurg Psychiatry. 2002;72(4):440-8. http://dx.doi.org/10.1136/jnnp.72.4.440
» https://doi.org/10.1136/jnnp.72.4.440 -
25Cursiefen S, Mäurer M. Current use of immunoglobulins in neurology. Nervenarzt. 2008;79(2 Suppl):67-74. 10.1007/s00115-008-2461-y
» https://doi.org/10.1007/s00115-008-2461-y -
26Winkelmann A, Zettl UK. Use of intravenous immunoglobulin in the treatment of immune-mediated demyelinating diseases of the nervous system. Curr Pharm Des. 2012;18(29):4570-82. http://dx.doi.org/10.2174/138161212802502314
» https://doi.org/10.2174/138161212802502314 -
27Skeie GO, Apostolski S, Evoli A, Gilhus N/e, Illa I, Harms L et al. Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17(7):893-902. http://dx.doi.org/10.1111/j.1468-1331.2010.03019.x
» https://doi.org/10.1111/j.1468-1331.2010.03019.x -
28Dalakas MC, Stein DP, Otero C, Sekul E, Cuple EJ, McCrosky S. Effect of high-dose intravenous immunoglobulin on amyotrophic lateral sclerosis and multifocal motor neuropathy. Arch Neurol. 1994;51(9):861-4. http://dx.doi.org/10.1001/archneur.1994.00540210031010
» https://doi.org/10.1001/archneur.1994.00540210031010 -
29Dalakas MC. Review: an update on inflammatory and autoimmune myopathies. Neuropathol Appl Neurobiol. 2011;37(3):226-42. http://dx.doi.org/10.1111/j.1365-2990.2010.01153.x
» https://doi.org/10.1111/j.1365-2990.2010.01153.x -
30Illa I. IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol. 2005;252(1 Suppl):i14-8. http://dx.doi.org/10.1007/s00415-005-1104-5
» https://doi.org/10.1007/s00415-005-1104-5 -
31Pul R, Stangel M. Using immunoglobulins in muscular disease treatment. Expert Opin Biol Ther. 2008;8(8):1143-50. 10.1517/14712598.8.8.1143
» https://doi.org/10.1517/14712598.8.8.1143 -
32Dalakas MC. High-dose intravenous immunoglobulin in inflammatory myopathies: experience based on controlled clinical trials. Neurol Sc. 2003;24(4 Suppl):S256-9. http://dx.doi.org/10.1007/s10072-003-0090-6
» https://doi.org/10.1007/s10072-003-0090-6 -
33Helmers SB, Dastmalchi M, Alexanderson H, Nennesmo I, Esbjörnsson M, Lindvall B et al. Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies. Ann Rheum Dis. 2007;66(10):1276-83. http://dx.doi.org/10.1136/ard.2006.058644
» https://doi.org/10.1136/ard.2006.058644
Publication Dates
-
Publication in this collection
02 Dec 2014 -
Date of issue
Dec 2014
History
-
Received
27 June 2014 -
Reviewed
13 Aug 2014 -
Accepted
01 Sept 2014