REVIEWS
Intravenous immunoglobulin therapy
in rheumatic diseases
Jagadeesh Bayry, Vir Singh Negi and Srini V. Kaveri
Abstract | Prepared from the collective plasma of several thousand people, therapeutic intravenous
immunoglobulin (IVIg) consists mostly of human polyspecific IgG. In addition to its use in primary and secondary
immune deficiencies, IVIg is used in the treatment of several rheumatic conditions, including Kawasaki disease,
dermatomyositis and antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. In these diseases, IVIg
therapy generally involves the use of 2 g/kg administered over either 2 or 5 consecutive days. However, dosage
regimens have not been thoroughly explored, and indications for IVIg in most rheumatic diseases, such as
systemic lupus erythematosus, polymyositis and catastrophic antiphospholipid syndrome, derive from its
off-label usage. Randomized clinical trials are warranted to support the evidence-based use of IVIg, and to
identify the ideal administration protocols to maximize the benefits of what is a limited resource. Further
research to improve the therapeutic application of IVIg relies essentially on the conception of next-generation
immunoglobulin preparations and optimization of combined therapies with immunomodulatory drugs and
biologic agents.
Bayry, J. et al. Nat. Rev. Rheumatol. 7, 349–359 (2011); published online 10 May 2011; doi:10.1038/nrrheum.2011.61
Introduction
Therapeutic preparations of intravenous immuno­globulin
(IVIg)—which are derived from the plasma of several
thousand healthy individuals—consist mostly of IgG and
have a wide range of specificities (owing to the diversity
of donors) and an immunoglobulin subclass distribution
comparable to that in normal plasma. Small amounts of
IgM, IgA and traces of soluble mo­lecules including HLA
and certain cytokines are also present.1 Initially used as a
replacement therapy for patients with immuno­deficiencies,
IVIg is now used in the treatment of a broad spectrum of
autoimmune and systemic inflammatory diseases, including a number of rheumatic conditions. Nevertheless, many
of these uses are off-label, and many clinicians are unsure of
the role of IVIg in the rheumatology clinic, especially in the
era of biologic therapies. Although data about speci­fic IVIg
dose regimens are scant for most rheumatic diseases, and
in some cases entirely lacking, 2 g/kg in total over either
2 or 5 consecutive days is the most common treatment.
The studies we discuss in relation to individual diseases
used this dose unless stated otherwise.
In this Review, we discuss the rheumatic diseases for
which IVIg therapy has been considered, focusing on the
evidence available to support its use and the underlying
immunoregulatory mechanisms thought to be respon­
sible for its beneficial effects. We also summarize recent
advances in the routes of IVIg administration and in the
Competing interests:
J. Bayry and S. V. Kaveri declare associations with the following
organizations: Laboratoire Français du Fractionnement et des
Biotechnologies, Octapharma, Talecris and CSL Behring. See
the article online for full details of the relationships. V. S. Negi
declares no competing interests.
understanding of IVIg pharmacokinetics and adverse events.
Finally, we outline the prospects for combination therapies
and next-generation immunoglobulin preparations.
Indications for IVIg in rheumatology
Pediatric rheumatic diseases
Kawasaki disease
Kawasaki disease is a systemic vasculitis of young children.2 Aneurysms or distensions of the coronary artery
develop in up to a quarter of untreated children, potentially
causing ischemic heart disease, heart attack and death.3
The main causes of such lesions are immune activation
and the subsequent secretion of cytokines, in particular of
tumor necrosis factor (TNF). A direct corre­lation between
disease progression and elevated serum levels of IL‑6,
IL‑8, CC-chemokine ligand (CCL)2, vascular endothelial
growth factor and neutrophil expression of integrin αM
(also known as CD11b) has been demonstrated.2 Providing
further evidence of a pathogenic role for cytokines, genetic
studies have implicated interactions of CCR5 (encoding
CC-chemokine receptor [CCR] 5) and CCL3L1 (encoding the most potent CCR5 ligand, CCL3‑like 1) genes in
Kawasaki disease susceptibility.4
IVIg has been successfully used in Kawasaki disease as
a first-line therapy.5 A Cochrane review 6 confirmed a significant reduction in new coronary artery aneurysms with
IVIg therapy, as compared with placebo. A single 2 g/kg
dose of IVIg administered within 10 days of the onset of
fever was found to be more beneficial than multiple doses
administered over consecutive days.6
Reduced levels of circulating IL‑1β, IL‑6, granulocyte
c­olony-stimulating factor and acute-phase C‑reactive
NATURE REVIEWS | RHEUMATOLOGY Institut National de la
Santé et de la
Recherche Médicale
Unité 872 (INSERM
U872), Université
Pierre et Marie Curie
and Université René
Descartes, 15 rue de
l’Ecole de Médicine,
Paris, F‑75006, France
(J. Bayry, S. V. Kaveri).
Department of Clinical
Immunology, Jawaharlal
Institute Postgraduate
Medical Education &
Research, Puducherry,
605006, India
(V. S. Negi).
Correspondence to:
S. V. Kaveri
srini.kaveri@
crc.jussieu.fr
VOLUME 7 | JUNE 2011 | 349
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
■■ Intravenous immunoglobulin (IVIg)—polyspecific IgG extracted from the plasma
of >1,000 healthy blood donors—is used to treat autoimmune and systemic
inflammatory diseases including several rheumatic conditions
■■ At present, 2 g/kg IVIg administered over either 2 or 5 consecutive days is
the commonly practiced regimen, but a proper evidence base for this dosage
is lacking
■■ Randomized clinical trials are warranted for identifying the optimum dose
regimen, frequency of administration and window of treatment, and to support
the evidence-based use of IVIg in off-label indications
■■ Preliminary studies suggest that a subcutaneous route of administration of
immunoglobulin (SCIg) presents with practical advantages compared with IVIg
■■ More information about the mechanisms of action of IVIg might enable the
rational use of particular IVIg (or SCIg) preparations in rheumatic diseases
protein have been reported following IVIg therapy in
Kawasaki disease.7 Further, by downregulating the expres­
sion of CD40 ligand (CD40L), IVIg reduces CD40Lmediated vascular damage. 8 IVIg inhibited CCR2, a
receptor for CCL2, and downregulated activating Fcγ receptors FcγR1 and FcγRIII on monocytes and macrophages
from patients with Kawasaki disease.9 Interestingly, the
beneficial effect of IVIg in Kawasaki disease might also
implicate neutralization of staphylococcal toxin, a super­
antigen that stimulates T cells due to its dual affinity for
the antigen-presenting molecule HLA-DR, and the variable
region of the β chain of the T‑cell receptor.1
CD4+CD25+FOXP3+ T regulatory (TREG) cells are critical in maintaining immune tolerance and in preventing
autoimmunity and inflammation.10–13 A dysregulated TREG
cell compartment accompanied by enhanced acti­vity of
type 17 T helper (TH17) cells has been reported in patients
with Kawasaki disease.14–16 Of particular in­terest, ex vivo
and in vivo studies in various models have demonstrated
that IVIg induces TREG cell expansion, and reciprocally
downregulates the number of TH17 cells and levels of
cytokines including IL‑17.15–19
Current guidelines provided by the Department of
Health in the UK, the European Medical Agency, and
other health agencies recommend that all patients with
Kawasaki disease should receive a single 2 g/kg dose of
IVIg soon after diagnosis, in conjunction with high-dose
aspirin. This recommendation in Kawasaki disease is
currently the strongest indication for IVIg in a rheumatic
disease; rated grade A, its high level of evidence reflects
its basis in randomized, prospective, controlled trials in
which primary outcomes were clearly defined.20 In the
absence of response, or in the event of relapse within
48 h, a further 2 g/kg dose of IVIg is recommended.20 Risk
factors for a poor response to IVIg therapy in Kawasaki
disease include high erythrocyte sedimentation rate,
elevated levels of C‑reactive protein or alanine amino
transferase 1, elevated white blood cell count, and high
transcript abundance for genes encoding IL‑1 pathway
components, granulocyte colony-stimulating factor, and/
or matrix m
­ etalloproteinase‑8.21–23 Furthermore, the efficacy of the treatment is also lowered by delayed initiation
of therapy (that is, starting it >10 days after the onset of
fever). For those patients in whom the two IVIg doses both
350 | JUNE 2011 | VOLUME 7
fail to elicit a response, the recommended second-line
therapy is high-dose pulsed corticosteroids.20 Pilot studies
have suggested that in IVIg-refractory Kawasaki disease,
anti-TNF therapy could be considered as an alternative
treatment, but larger studies are needed.24
Juvenile dermatomyositis
Juvenile dermatomyositis (JDM) is an uncommon
multi­system disease of children characterized by non­suppurative inflammation of striated muscles, skin and
the gastrointestinal tract.25 Immune-complex-mediated
vasculitis occurs early in the disease course and is followed by calcinosis. Shared epitopes between human
skeletal muscle proteins and a key virulence protein, M5,
from Streptococcus pyogenes have been proposed to be
triggeri­ng factors.26
No randomized trials have evaluated IVIg treatment
for JDM, but the therapy has been tried in several small
studies. In a 4‑year follow-up of nine patients with steroidresistant JDM, IVIg therapy (initially administered at 2 g/kg
over 3 days, followed by the same dose spread over 5 consecutive days) produced modest clinical improvement
as analyzed by myometry scores.27 IVIg therapy was also
associated with a reduced requirement for steroids.27
Similarly, in a retrospective study, IVIg therapy markedly
reduced the requirement for steroids in 12 of 18 children with steroid-dependent or steroid-resistant JDM.28
Current guidelines support the use of IVIg (at 2 g/kg over
2 days) in JDM refractory to conventional treatment, but
no generalized conclusions or recommendations can be
provided based on currently available data.20,29
Systemic-onset juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) occurs in young children and is characterized by arthritis of unknown
eti­ology. Systemic-onset JIA (sJIA) accounts for approxi­
mately 10% of cases and can cause life-long physical impairment in children refractory to conventional
therapy (with steroids), prompting some clinicians to
try off-label IVIg therapy. Nevertheless, the use of IVIg
in sJIA is controversial. Although open-label studies
have shown remission in some of the patients treated
with IVIg (2 g/kg per month),30,31 the only randomized,
double-blind, placebo-controlled trial conducted to date
(involving 31 patients and a dose regimen of 1.5 g/kg
of IVIg every 2 weeks for 2 months, then monthly for
4 months) failed to show any significant difference
between IVIg and placebo.32 Now that anti-TNF agents
have emerged as major therapeutics in the management
of arthritis in adults,33 it is unlikely that IVIg will have a
major role in the treatment of sJIA.
Adult rheumatic diseases
Idiopathic inflammatory myopathies
The idiopathic inflammatory myopathies (referred to
collectively as ‘myositis’) include dermatomyositis, poly­
myositis and inclusion body myositis (IBM). The implication of immune cells and molecules such as complement
in the pathogenesis of these diseases has prompted clinicians to explore the therapeutic utility of IVIg. However,
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as discussed below, the response to IVIg therapy is not
uniform in the various types of myositis.
In dermatomyositis, which presents with charac­teristic
skin manifestations, immune cells (CD4+ T cells, B cells and
macrophages) infiltrate muscle tissue, with accompany­ing
perimysial and perivascular inflammation.34,35 The presence of TH1 and TH17 cells in muscle biopsy specimens
suggests the involvement of activated CD4+ T cells in the
disease process.36 Endothelial cell destruction is thought
to result from the deposition of the C5b–C9 membrane
attack complex in intramuscular capillaries, leading
to microinfarction of muscle fibers and perifascicular
atrophy.37 A double-blind, randomized, placebo-controlled
crossover trial in 15 patients, investigating the efficacy of
IVIg at 2 g/kg per month for 3 months, showed significant improvements in muscle strength and skin rash with
IVIg therapy, in comparison with placebo.38 Data from two
studies (involving eight patients in total) indicate that the
use of IVIg early after dermatomyositis diagnosis is associated with ameliora­tion of muscle cyto-architecture and
resolution of aberrant immunopathological parameters,
accompanied (accordingly) by modification of the expression of a number of genes involved in immune regulation
or that encode structural proteins.39,40 In a double-blind,
placebo-controlled crossover study, IVIg administration
in patients with steroid-resistant dermatomyositis was
associated with the inhibition of serum C3 uptake and a
reduction in serum levels of the C5b–9 complex, according to serum samples from 13 patients. Biopsy samples
taken from 5 of the 13 patients showed depletion of C3b
NEO (a neoantigen expressed on the surface of activated
C3 component upon its incorporation into immune complexes) in muscle tissue, and the prevention of membrane
attack complex deposits from entering endomysial capillaries.41 Collectively, these effects resulted in restoration of
the capillary network, thus preventing muscle damage.41
IVIg therapy also limited the migration of activated T cells
into muscle fibers, by downregulating the expression of
intercellular adhesion molecule 1 on capillaries and
muscle cells.40 Despite these reported effects, however, a
more recent study failed to correlate the aforementioned
immunological parameters with clinical improvements.42
This study was, however, relatively small: it involved four
patients. The discrepancies between the reported effects
of IVIg on immune parameters and on clinical improvements might also be related to differences in sampling
time points (3 months after IVIg therapy versus within
24–48 h of the first IVIg infusion). Alternative mechanisms
that have been proposed to explain the clinical benefit
of IVIg in dermatomyositis include direct in­hibition of
TH17 cells.19,43
Currently, IVIg is recommended as a second-line
therapy in patients with steroid-resistant dermato­
myositis.20,29,44 This approach may be used in aggressive
disease (when involvement of respiratory and throat
muscles necessitates hospitalization), or when other
treatments fail or are inappropriate. Furthermore, a
recent study has highlighted the successful use of IVIg
in steroid-resistant poly­myositis or dermatomyositis with
life-threatening esophageal manifestations.45
Polymyositis—a subacute inflammatory myopathy
that often occurs in association with infection, connective tissue disease or systemic autoimmune disease—is
less common than dermatomyositis.46 The underlying
mecha­nisms, similar to dermatomyositis, involve immune
cell infiltration of muscle tissue. Muscle fiber necrosis,
mediated by the perforin pathway, is precipitated (in
fibers expressing HLA class I) by the invasion of clonal­ly
expanded CD8+ T cells.37 Cells producing IL‑17 and interferon γ contribute to CD4+ T‑cell-mediated muscle tissue
damage in polymyositis.36
There are no controlled trials for IVIg therapy in
polymyositis, but open-label, uncontrolled studies
in ­polymyositis in adults refractory to traditional therapies such as steroids and methotrexate have reported
benefi­c ial effects. 47 In an open-label study, 25 of 35
patients treated with a combination of IVIg and other
immuno­suppressive agents for 6 months reported significant improvements in their symptoms. Furthermore,
after a follow-up of 51 months, 12 of the responding
patients remained in full remission without medication.48
Nevertheless, given the dearth of large-scale controlled
studies, current evidence is insufficient for IVIg to be
recom­mended as a first-line therapy in polymyositis,20,29,44
although it can be considered for patients who do not
respond to first-line immunosuppressive treatment.44
IBM predominately affects the forearm flexors and
quadriceps femoris muscles, primarily in middle-aged
men.35 Placebo-controlled studies of high-dose IVIg (2 g/kg
over 2 days per month for 3 months), with a primary endpoint of improved muscle strength, have shown thera­
peutic benefits in some of the few patients included in the
studies.49,50 Due to the modest scale of such benefits, and
the small sample sizes, these trials are, however, insufficient to provide advice about the routine use of IVIg
in IBM.29
ANCA-associated vasculitis
Antineutrophil cytoplasmic antibody (ANCA)-associated
vasculitis (AAV) is a group of systemic small-vessel vasculitic disorders associated with circulating ANCA, and
comprise granulomatosis with polyangiitis (Wegener
granulo­matosis), microscopic polyangiitis and Churg–
Strauss syndrome. The universal pathological lesion of
AAV is a necrotizing vasculitis affecting arteries, ar­terioles,
capillaries or venules; endothelial damage is caused by
ANCA-mediated activation of neutrophils.51
Several small prospective clinical studies of IVIg treatment for AAV have reported conflicting results. In an
uncontrolled study, 15 patients with AAV were treated
with single (10 patients) or multiple courses (2 patients
received two courses, 3 patients received three courses)
of IVIg at 30 g per day over 5 days. No patient experienced complete remission despite the repeated cycles
of IVIg infusion.52 By contrast, a randomized, placebocontrolled single-course trial of IVIg (total dose 2 g/kg)
in patients with AAV previously treated with prednisolone and cyclophosphamide or azathioprine but with
persistent disease activity, showed improvement in 14
of 17 patients, but this effect was not maintained beyond
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3 months.53 Interestingly, a recent open-label study of IVIg
(0.5 g/kg per day for 4 days per month, for 6 months) in
relapsed AAV reported complete remission in 13 of 24
patients at 9 months. Furthermore, at 24 months, 8 of
the patients were in complete remission without additional therapy, whereas 10 were in remission with the
help of other treatment.54 The discrepancies in the results
of IVIg therapy for AAV might be attributable to the wide
variations between the dose regimens used in the studies;
indeed, longer duration of therapy seems to be more effective. Further randomized, controlled trials are necessary,
there­fore, to demonstrate the efficacy (and ideal dose) of
IVIg in AAV.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is characterized by the
production of autoantibodies to nuclear antigens, diverse
clinical manifestations that encompass almost all organ
systems, a variable clinical course, and a prognosis associated with remissions and flares of disease activity. Studies
have demonstrated the involvement of TH1, TH2 and TH17
cells in the pathogenesis of SLE.55–59 Evidence supporting
the efficacy of IVIg in SLE comes mostly from small clinical trials, case series, and case reports.60,61 The only small
randomized trial in lupus nephritis, involving 14 patients,
indicated a beneficial effect of IVIg (at 400 mg/kg
monthly for 18 months) similar to that of cyclophosphamide, and remission was maintained for more than
18 months.62 Despite these encouraging reports, the value
of IVIg treatment needs to be established through placebocontrolled and dose-comparison clinical trials. Currently,
IVIg is indicated either in patients with severe SLE who are
nonresponsive to conventional immunosuppressive drugs,
or for use as a steroid-sparing agent.20
The beneficial effect of IVIg in SLE might involve either
the neutralization of pathogenic autoantibodies by antiidiotypic antibodies within the IVIg preparation, and/or
suppression of the function of B lymphocytes, the producers of pathogenic autoantibodies.63–66 Furthermore,
IVIg inhibits type I interferon-mediated differentiation
of dendritic cells, and suppresses the endocytosis of
nucleosomes; both of these activities could counteract
the SLE disease process.67
Antiphospholipid syndrome
Antiphospholipid syndrome (APS) is associated with
ar­terial and venous thrombosis, thromboembolic phenomena, thrombocytopenia, pregnancy-related complications and antibodies against cardiolipin and β 2
glycoprotein I.68 IVIg (at a dose of 1 g/kg per day for 2
consecutive days every month until the end of pregnancy)
has been used in pregnant women with both primary APS
and APS secondary to SLE, although the benefits associated with IVIg therapy are similar to those of combination
therapy with heparin and low-dose aspirin.69,70 Results
from patients and from experimental models (the fetal
loss and passive transfer mouse models of APS) suggest
that the benefits of IVIg in APS might be elicited by blockade of the neonatal Fc receptor for IgG (FcRn), leading
to enhanced catabolism of pathogenic antibodies and
352 | JUNE 2011 | VOLUME 7
neutralization of anti­cardiolipin and anti‑β2 glycoprotein I
auto­antibodies by anti-idiotypic antibodies.71–73
IVIg is not a first-line therapy in treating women with
APS. Conventional treatment with aspirin and lowmolecular-weight heparin during pregnancy seems to be
superior to IVIg and is recommended by health authorities.69,70 Alternatively, a combination therapy of IVIg with
heparin and low-dose aspirin might be considered as a
treatment option, and has been effective in the management of women positive for antiphospholipid antibodies
undergoing in vitro fertilization.74
Catastrophic antiphospholipid syndrome
A rare complication of APS is catastrophic APS, in which
multiple, life-threatening thromboses of medium and
small arteries can cause stroke, peripheral gangrene,
and infarction of any or all of the major internal organs.75
As compared with historical outcomes, the mortality rate
in catastrophic APS dropped from approximately 50% to
roughly 20% after the introduction of a combined therapy
consisting of anticoagulation agents, corticosteroids,
plasma exchange and IVIg. In a total of 280 patients with
catastrophic APS, those treated with the combination of
anticoagulation plus cortico­steroids alongside attempts
to achieve a prompt reduction of antiphospholipid antibody titer (using plasma exchange and/or IVIg) had the
highest survival rate (around 70%), in comparison with
those treated with anticoagulants, corticosteroids, plasma
exchange, cyclophosphamide, and anti-aggregants.76
Unfortunately, the dose of IVIg used in this study was not
made clear. Nevertheless, although the individual contribution of IVIg in this combination therapy is unclear, its
use in this life-threatening condition might be justified
when conventional treatment options fail.20,76
Systemic sclerosis
Systemic sclerosis (SSc) is a multi-system connective tissue
disorder involving immune system activation, vascular
damage, fibroblast proliferation and production of collagen, and is characterized by skin fibrosis and internal organ
dysfunction.77 Patients treated with IVIg (2 g/kg over a
4‑day78 or 5-day79 period) are reported to show a significant
decrease in skin sclerosis, reduced joint pain and tenderness, significant recovery of joint function and improved
quality of life.78–81 The use of IVIg in SSc is, however,
limited, owing to a lack of randomized trials. Consequently,
no guidelines support the use of IVIg in SSc.
Other rheumatic diseases
Several other rheumatic conditions, such as stiff-person
syndrome and neurological complications associated
with Sjögren’s syndrome, are reported to benefit from
IVIg therapy, but further studies are required to support
its routine use.82,83 Similarly, IVIg therapy in anti-Ro­p ositive pregnant women with fetal congenital heart
block also needs further exploration, to delineate whether
benefits observed in a small study are attributable to IVIg
(1 g/kg at the fourteenth and eighteenth weeks of gestation) alone, or attributable to the steroids that were used
in combination.84
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Mechanisms of action of IVIg
Several mutually nonexclusive mechanisms have been des­
cribed for IVIg therapy in autoimmune and inflammatory
diseases,1,65,66,85–88 and have been reviewed in detail else­
where.1,65,88–89 The precise basis of the therapeutic benefit
of IVIg in rheumatic diseases will depend on the immune
cells and signaling pathways that are activated in the disease
process. Indeed, IVIg can target every compart­ment of the
immune system, including cellular compartments (innate
and adaptive immune cells, endothelial cells and natural
killer cells) and soluble factors (cytokines, chemokines,
complement and pathogenic antibodies). IVIg inhibits
the activation of innate cells, suppressing their production
of inflammatory cytokines while enhancing production of
anti-­inflammatory mediators, and blocks the capacity
of antigen-presenting cells to stimulate T cells. IVIg also
targets T cells directly by inducing apoptosis and inhibiting pathogenic TH1 and TH17 cell responses while enhancing TREG cell expansion.15–19,43 Furthermore, IVIg regulates
B‑cell functions, including suppression of the production
of pathogenic autoantibodies. Although some of the
reported mechanisms involve F(ab’)2 fragments of the IgG
molecule, whereas others are essentially Fc-dependent, we
believe that an intact IgG molecule is necessary for exerting the maximum immunoregulatory function in a wide
range of pathologies.
Properties of therapeutic IVIg
Quality control
The first large-scale production of human IgG was
achieved by a process of cold ethanol precipitation, and
the product was called immune serum globulin. Many
of the patients treated with this preparation experienced adverse events such as anaphylactoid reactions
and hypotension, owing to aggregate formation during
storage. The effort to develop safer IVIg preparations led
to a refinement in the manufacturing process, involving isolation of intact IgG. However, with the reports of
hepatitis C transmission in 1993, and the potential risk
of prion diseases, third-­generation IVIg (an intact IgG
isolation prepared with intentional viral inactivation and/
or elimination steps such as low pH treatment, pasteurization, treatment with caprylic acid or solvent detergent,
and nanofiltration) were developed to ensure safety.90
No reports of transmission of any infectious diseases by
IVIg have been reported since these steps were implemented. Current quality control mea­sures applied in the
ma­nufacture of IVIg are summariz­ed in Table 1.90
Adverse effects
IVIg therapy is relatively safe. Mild adverse events occur
in 24–36% patients after high-dose IVIg (1–2 g/kg), and
most reported adverse events are attributable to high
levels of IgG attained in blood and the subsequent mechanisms that ensue (Table 2). Systemic effects are considerably lower in the case of subcutaneous immuno­globulin
infusions (<1%, in comparison with 5% for IVIg), possibly owing to the absence of the sudden and rapid
increase of serum IgG that is observed upon intravenous
infusion.91–94 Although the assessment of the frequency
Table 1 | Current quality control measures for therapeutic IVIg90
Characteristics
Quality control measure
Specifications
Physical properties
Appearance
pH
Clear, no particles
4–6, as specified by the
manufacturer
≥240 mosmol/kg
Should be mentioned in the
product label
Osmolality
Excipients
Chemical
properties
Total protein concentration
γ-globulin content
Immune aggregates
Human origin identity test
≥30 g/l
≥95%
≤3%
Positive
Viral inactivation
components
Tri‑n-butyl phosphate
Polysorbate‑80
Permissible level 10 μg/ml
Permissible level 100 μg/ml
Protein
contaminants
Anti‑A and anti‑B*
Negative at HA titer of 1:64
(3% protein preparation)
≤3.5 IU/ml (3% protein preparation)
≤1 CH50 per mg of IgG
Prekallikrein activator
Total hemolytic complement
levels
Viral marker tests
HBsAg, HIV p24 antigen,
anti-HIV‑1 antibodies,
anti-HIV‑2 antibodies
and anti-HCV antibodies
All negative
Safety tests
Bacterial sterility test
Endotoxin assay
Sterile
<0.5 IU/ml (5% protein preparation)
*Anti‑A & anti‑B are IgG antibodies directed against human blood group antigens. Abbreviations: CH 50,
the dose of complement that lyses 50% of a red cell suspension; HA, hemagglutinin; HBsAg, hepatitis B
surface antigen; HCV, hepatitis C virus; IU, international units; IVIg, intravenous immunoglobulin.
of adverse effects is somewhat subjective, owing to the
lack of rigorous studies, local reactions are frequently
associat­ed with subcutaneous injection.
Pharmacokinetics
Initial studies on the pharmacokinetics of IVIg showed
that the catabolism of IgG is concentration-dependent.95
It is now established that the principal mechanism of
regula­tion of the serum level of IgG involves FcRn, which
prevents FcγR-mediated catabolism of IgG.96 After intravenous administration, the serum concentration of IVIg
exhibits an initial sharp rise followed by a rapid waning
for 1–4 days, and then a gradual decline (Figure 1).97,98 The
initial elimination phase, called α phase, is attributable to
catabolism of immunoglobulin in combination with its
distribution to extravascular spaces, whereas the terminal or β phase represents immunoglobulin ca­tabolism
alone (Figure 1).97
Subcutaneously-administered immunoglobulin (SCIg)
is absorbed and redistributed slowly. Although the total
monthly subcutaneous dose is equivalent to the intra­
venous dose, the fluctuations in blood IgG level are
much smaller with SCIg than with IVIg, due to smaller
and more frequent dosing, and to relatively slow absorption of immunoglobulin from the subcutaneous infusion
sites.99 The fluctuations of serum IgG levels are negli­
gible in weekly subcutaneous infusion as compared with
biweekly infusion.92,99
Knowledge of population-specific and patient-­specific
pharmacokinetic parameters of IVIg preparations equips
clinicians with tools to design rational therapeutic regimens for maximum clinical benefit. Increased availability of pharmacokinetic information might aid in
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Table 2 | Adverse events associated with IVIg and SCIg therapies
Adverse events
Risk factors
Manifestations
Mechanisms
Prevention and
treatment strategies
Inflammatory
reactions115
Fast infusion rate
Allergic or anaphylactic
reactions
IgA deficiency
Mild reactions*
Moderate reactions‡
Severe reactions§
Anaphylactoid reactions
Immune complex formation
Anti-complement activity
Fc receptor-mediated release of
prostaglandins, platelet-activating factor, and
cytokines from macrophages and leukocytes
Vasoactive contaminants
Development of anti-IgA antibodies that react
with the IgA molecules in the IVIg preparation
Slow infusion rate as per
body weight
Product substitution
Prophylactic steroids
Antihistamines, or
anti-inflammatory agents
(not very useful)
Cautious use of IVIg
containing low levels of IgA
Thromboembolic
events116,117
Age >60 years
High dose
Fast infusion rate
Hypertension
Coronary heart disease
Type 1 diabetes mellitus
Dyslipidemia
Coronary artery disease
Transient ischemic attack
Infarct
Stroke
Peripheral
thromboembolism
Hyperviscosity
Contamination with clotting factors
Vasospasm
Formation of platelet–leukocyte aggregates
Slower infusion rate
Prophylaxis
Early treatment of high-risk
patients
Renal
complications117
Age >60 years
Type 1 diabetes mellitus
Renal disease
Sepsis
Paraproteinemia
Nephrotoxic agents
Stabilizers in IVIg preparation
(sucrose, maltose, glucose)
Acute renal failure
Mild alteration
in renal function
Osmotic injury
Adequate hydration
Use of correct dose
Periodic monitoring
of renal function
Use of sugar-free stabilizers
Hemolysis90,118
High dose
Blood group other than O
Multiparous women
Intravascular hemolysis
Passive transfer of ABO isohemagglutinins to
non‑O blood group patients
Underlying inflammatory state
Blood type cross-matching
Determination of anti‑A
and anti‑B antibody titer
before infusion
Post-transfusion testing
for hemolysis within 36 h
Acute meningeal
inflammation119
Fast infusion rate
History of migraine
Single high dose of IVIg
Aseptic meningitis
Release of inflammatory cytokines
Presence of ANCA-like immunoglobulins
Anti-inflammatory agents
Initiation of SCIg therapy
Swelling, redness,
and itching or burning
sensation
Headache, vomiting,
pain, and fatigue
Local irritant effect
Symptomatic management
Monitoring to ensure no
long-term changes such as
fat necrosis or fibrosis
IVIg
SCIg
Local
reactions92,120
*Mild reactions include headache, fever, chills, nausea, emesis, hypotension and muscle cramps. ‡Moderate reactions include worsening of mild reactions necessitating discontinuation of the
infusion. §Severe reactions include persistence or worsening of moderate reactions or appearance of new symptoms such as tightness of the throat or chest (anaphylaxis), severe chills and
rigor, breathlessness, dizziness, fainting or collapse. Abbreviations: ANCA, antineutrophil cytoplasmic antibody; IVIg, intravenous immunoglobulin; SCIg, subcutaneous immunoglobulin.
reducing the frequency and severity of adverse effects of
IVIg therapy.
Immunoglobulin dosage regimens
Dosage
Following the first description of successful treatment
of individuals with immune thrombocytopenic purpura
(ITP) with IVIg by Imbach in 1981,100 the dose of 400 mg/kg
per day for 5 days (total 2 g/kg) had been a standard
regimen for the management of autoimmune and inflammatory disorders. However, Newburger et al.5 observed
that a single 2 g/kg infusion in patients with Kawasaki
disease achieved a rapid increase in the therapeutic levels
of IgG as compared with a 4‑day regimen using doses of
354 | JUNE 2011 | VOLUME 7
400 mg/kg.5 Patients displayed an accelerated resolution of
systemic inflammation with lower prevalence of coronary
artery abnormalities, and without any increase in adverse
events. The authors concluded that a single infusion of
IVIg was more effective than the 4‑day regimen for the
treatment of acute Kawasaki disease.
At present, given that data supporting a single dose are
even more scarce than for multiple-dose schedules, 2 g/kg
administered over either 2 or 5 consecutive days is the
commonly practiced dose regimen in auto­immune diseases. Although no dose-comparison studies have been
conducted in many autoimmune diseases, evidence from
randomized controlled studies in ITP and in chronic
inflammatory demyelinating polyneuropathy suggest that
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Routes of administration
Currently, intravenous is the preferred route of IVIg
admini­stration for the treatment of immune-mediated
inflam­matory disorders, as it ensures rapid attainment of
high concentrations of IgG in blood and tissues, and is
associated with rapid amelioration of clinical symptoms
and reversal of disease pathology. However, such benefits
can be accompanied by a number of adverse events, as
described above and in Table 2.
SCIg might be the preferred choice in patients with
difficult venous access. For patients receiving long-term
therapy, the subcutaneous route allows self-­administration
at home, which leads to cost savings linked to hospitalization and transportation to hospital, and reduces productivity loss due to absence from work. Better quality of life
with significant improvement in treatment satisfaction is
reported by patients who receive SCIg instead of IVIg.94
Although the subcutaneous route has not been much
explored for specific autoimmune and inflammatory diseases, preliminary observations suggest that it is effective
for these conditions.94
α phase
β phase
Serum IgG
IVIg at doses as low as 0.8 g/kg 101 and 1 g/kg,102 respectively, are also therapeutically effective. These data highlight the need for randomized clinical trials to identify
optimum dose regimens, frequencies of administration
and windows of treatment for individual rheumatic and
autoimmune diseases.
Basal
level
IVIg
administration
Time
α phase
Degradation of excess IgG
Lysosome
Vascular endothelial cell
Blood
β phase
Future perspectives
Despite substantial progress in the understanding of the
mechanisms of action of IVIg in autoimmune and inflammatory conditions, several issues regarding its prescription in rheumatic diseases remain unanswered, as we
have discussed. Furthermore, the demand for IVIg is everincreasing, accompanied, unfortunately, by a simulta­neous
(and incompletely understood) reduction in the number
of willing plasma donors, and by more stringent procedures for blood collection, leading to an inevitable shortage.103 Priority, therefore, should be given to those diseases
where the benefit of IVIg has been confirmed through randomized clinical trials, or where there are strong indications that IVIg might be beneficial (Box 1). Mean­while,
randomized clinical trials should be initiated to support
the ­evidence-based use of IVIg in off-label indications.
Promoting research into new-generation immunoglobulin
preparations and studies of the efficacy of IVIg in combination therapies might provide additional information about
how to appropriately apportion this valuable therapy.
Figure 1 | Pharmacokinetics of IVIg. Upon intravenous administration, IgG enters
the vascular compartment at high concentration, redistributes rapidly into tissue
compartments, and then is more slowly catabolized. The early redistribution phase
is sometimes called the α phase, and involves rapid lysomal degradation of IVIg
resulting from the saturation of FcRn on endothelial surfaces. In the β phase, FcRn
is not saturated and recycles most of the IgG it binds back to the cell surface,
where it is released back into the bloodstream.98 Abbreviations: IVIg, intravenous
immunoglobulin; FcγR, Fc receptor for IgG; FcRn, neonatal Fc receptor. Adapted
with permission from Elsevier © Bonilla, A. Immunol. Allergy Clin. North Am. 28,
803–819 (2008).98
Combination therapies
In most pathologies, IVIg is used as a second-line therapy
in patients whose disease is refractory to the conventional treatments, or who have experienced relapse,20,29,44
and in combination with other agents in aggressive, life­threatening diseases.45 Combination therapies using IVIg
are a promising strategy for increasing the number of
first-line therapeutic options for some rheumatic diseases,
owing to favorable safety profiles in studies to date, and to
synergistic immune-modulatory effects.
IVIg with biologic agents
Few data yet exist for IVIg in combination with biologic
agents, but combination therapy with rituximab (an antiCD20 antibody) has been found to be efficacious in transplant recipients (IVIg 2 g/kg on day 0 and day 30; plus 1 g
rituximab twice, on day 7 and day 22) and in patients with
refractory pemphigus vulgaris (rituximab at 375 mg/m2
of body surface area once weekly for 3 weeks and IVIg at a
single dose of 2 g/kg in the 4th week).104,105 Rituximab and
IVIg share some mechanisms of action, such as induction
Vascular endothelial cell
Blood
IgG
FcRn
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REVIEWS
Box 1 | Indications for IVIg therapy in rheumatic diseases
Definite indications
■■ Kawasaki disease
■■ Dermatomyositis (steroid-resistant or aggressive)
■■ ANCA-positive vasculitis
■■ Stiff-person syndrome
Possible indications
■■ Systemic-onset juvenile idiopathic arthritis
■■ Juvenile dermatomyositis
■■ Systemic vasculitides
■■ Polymyositis
■■ Systemic lupus erythematosus (for remission)
■■ Catastrophic antiphospholipid syndrome
■■ Neurological complications associated with Sjögren’s
syndrome
Not indicated
■■ Inclusion body myositis
■■ Systemic sclerosis
■■ Antiphospholipid syndrome
■■ Rheumatoid arthritis
Abbreviations: ANCA, antineutrophil cytoplasmic antibody; IVIg,
intravenous immunoglobulin.
of B‑cell apoptosis and antibody-dependent cell-mediated
cytotoxicity, and reduction of B‑cell activation; hence, the
two drugs can act in synergy.106 How­ever, unlike rituxi­mab,
IVIg can also act on other compartments of the immune
system. Currently, the available data do not support the
superi­ority of rituximab monotherapy in rheumatic
dis­e ases wherein the efficacy of IVIg alone has been
confirmed through randomized clinical trials (Box 1).
Similarly, combination therapy comprising the TNF inhi­
bitor etaner­cept (50 mg/week), plasma­pheresis and highdose IVIg (200 mg/kg per week) was safe and effective in a
pregnant woman with severe lupus nephrit­is,107 but more
widely-applicable data are lacking.
IVIg with conventional immunosuppressants
Combining IVIg with cyclophosphamide might be an
appropriate strategy for inducing rapid remission of dis­
ease symptoms, without the risks of immuno­suppression
that accompany cyclophosphamide when used as a monotherapy (which necessitates a higher dose of this immuno­
suppressive drug). A strategy of combining IVIg (400 mg/kg
per day for 5 consecutive days) with cyclophosphamide
(2.2 mg/kg) and oral prednisolone (70 mg per day) 4 days
after a second course of IVIg therapy was effective in controlling refractory manifestations associated with dermato­
myositis, such as refractory Evans syndrome, in one case
study.108Also in myositis, the long-term efficacy of combining IVIg therapy (2 g/kg over 2 days) with ciclosporin
has been demonstrated in two case studies in patients with
myositis, with steroid-­refractory or relapsed disease.109
Further­more, the two patients remained relatively free
of the infections that result from immuno­suppression.
Finally, IVIg as an add-on treatment at 1 g/kg (5 g/h) on
356 | JUNE 2011 | VOLUME 7
2 days per month for 6 months, followed by three more
cycles every other month, with mycophenolate mofetil
(started at 500 mg and then titrated to 30 mg/kg per day)
was effective and had steroid-sparing properties in severe
and refractory myositis.110 This therapeutic combination
also has an additive antiproliferative effect on T cells and
B cells.111
Next-generation immunoglobulin
We have discussed the processes that are currently used to
generate IVIg preparations (in the section on properties of
therapeutic IVIg) and existing quality control measures are
summarized in Table 1. Nevertheless, as knowledge of the
roles of individual immunoglobulin classes and subclasses
(and of particular portions of the molecules) in inflammatory and autoimmune processes develops, new, more
specific preparations are being considered.
Recombinant sialylated Fc
Recent observations have revealed that the anti-­inflam­
matory properties of IVIg are essentially mediated by the
Fc portion of immunoglobulin with terminal 2,6 sialic
acid residues, which are expressed on a fraction of IgG.85
These results were successfully recapitulated using recombinant Fc.86 In diseases where a therapeutic benefit of IVIg
implicates specific action by the Fc fraction (for example,
in ITP), such novel preparations could potentially be
superior to the standard formulation.87,112 However, considering the heterogeneity of autoimmune diseases in
terms of pathogenesis and clinical presentation, and the
beneficial effect of ‘whole’ IVIg in these diverse pathologies, recombinant sialylated IgG Fc alone is unlikely to
be consistently effective in all subgroups of patients.
Also, these sialylated IgG Fc preparations are unlikely to
change the modality of IVIg therapy in immunodeficient
patients, because immune functions in these patients are
maintained by the complete repertoire of antibodies with
their anti-microbial specificities imparted by the variable
region of IgG.87,112
IgM and IgA
Natural IgM antibodies form the first line of defense
against pathogens and have a regulatory role in preventing autoimmune and inflammatory processes. In vitro
and in vivo studies in experimental models have identified the therapeutic potential of pooled IVIgM (preparations of IgM derived from plasma pooled from >2,500
healthy donors) for immune-mediated inflammatory
diseases such as experimental autoimmune uveitis,
experimental multiple sclerosis and experimental myasthenia gravis.113 Anti-idiotypic antibodies against IgG
autoantibodies have been identified in pooled IgM, and
in vitro studies provide evidence that IgM blocks the
pathogenic action of IgG autoantibodies from patients
with autoimmune diseases.113
Data on therapeutic IgA are more preliminary than for
IgM, and derive only from experimental and analytical
preparations. Serum IgA exerts several immunoregulatory properties and is able to both induce and suppress
immune responses. IgA-mediated inhibitory functions
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have been successfully used to prevent inflammatory
diseases such as asthma and glomerulonephritis in
experimental animal models.114 Despite these preliminary
hints that specific immunoglobulin preparations such as
IVIgM and IVIgA might improve outcomes in particular
diseases, more study is needed before any of them can be
recommended for the treatment of rheumatic diseases.
Conclusions
IVIg has consolidated its place among the choices of treatment in a number of rheumatological diseases in recent
years. Although IVIg is considered as definitely indicated
only in Kawasaki disease, steroid-resistant or aggressive
dermatomyositis, ANCA-positive vasculitis and stiff­p erson syndrome, the possibility of using IVIg as an
alternative therapeutic option remains for other conditions, such as sJIA, juvenile dermatomyositis, polymyositis, SLE and catastrophic APS. Issues such as diagnostic
complexity, the small number of patients with some diseases, inade­quate outcome parameters, unclear levels of
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Acknowledgments
The authors’ research activities are supported by
grants from the Indian Council of Medical Research
(VSN), Institut National de la Santé et de la Recherche
Médicale (INSERM), Center National de la Recherche
Scientifique (CNRS), Université Pierre et Marie Curie
and Université Paris Descartes (J. B. and S. V. K.) and
the European Community’s 7th Framework Program
[FP7‑2007‑2013] under Grant Agreement N°
HEALTH‑F2‑2010‑260338-ALLFUN (J. B.). Due to
space limitations, we could not cite all relevant
published work; we do not mean to undermine the
value of uncited studies.
Author contributions
All authors contributed equally to researching data,
discussing content and writing the article, and
reviewing/editing of the manuscript before submission.
VOLUME 7 | JUNE 2011 | 359
© 2011 Macmillan Publishers Limited. All rights reserved