The clinical
use of intravenous immunoglobulin (IVIg) has expanded beyond its
traditional place in the treatment of patients with primary
immunodeficiencies. Due to its multiple anti-inflammatory and
immunomodulatory properties, IVIg is used successfully in a wide range
of autoimmune and inflammatory conditions. Recognized autoimmune
indications include idiopathic thrombocytopenic purpura (ITP), Kawasaki
disease, Guillain–Barré syndrome and other autoimmune neuropathies,
myasthenia gravis, dermatomyositis and several rare diseases. Several
other indications are currently under investigation and require
additional studies to establish firmly the benefit of IVIg treatment.
Increasing attention is being turned to the use of IVIg in combination
with other agents, such as immunosuppressive agents or monoclonal
antibodies. For example, recent studies suggest that combination therapy
with IVIg and rituximab (an anti-CD20 monoclonal antibody) may be
effective for treatment of autoimmune mucocutaneous blistering diseases
(AMBDs), with sustained clinical remission. The combination of IVIg and
rituximab has also been used in the setting of organ transplantation.
Firstly, IVIg ± rituximab has been administered to highly human
leucocyte antigen (HLA)-sensitized patients to reduce anti-HLA antibody
levels, thereby allowing transplantation in these patients. Secondly,
IVIg in combination with rituximab is effective in the treatment of
antibody-mediated rejection following transplantation. Treatment with
polyclonal IVIg is a promising adjunctive therapy for severe sepsis and
septic shock, but its use remains controversial and further study is
needed before it can be recommended routinely. This review covers new
developments in these fields and highlights the broad range of potential
therapeutic areas in which IVIg may have a clinical impact.
Keywords: autoimmunity, immunoglobulin, vasculitis, sepsis, transplantation
Introduction
Intravenous
immunoglobulins (IVIgs) are therapeutic preparations of pooled
polyspecific IgG obtained from the plasma of a large number of healthy
individuals. These preparations were commercialized in the early 1980s
to replace intramuscular preparations of polyspecific IgG, which were
the only available substitutive therapy at that time for patients with
primary or secondary immunodeficiencies. For patients with primary
immunodeficiencies, IVIg (or subcutaneous immunoglobulin – SCIg) remains
the treatment option of choice.
In 1981, Imbach and
colleagues reported that, in patients with Wiskott–Aldrich syndrome who
presented with thrombocytopenia and hypogammaglobulinaemia, high-dose
IVIg infusion was followed by an increase in the platelet count [
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Since then, IVIg has been demonstrated to be effective in idiopathic
thrombocytopenic purpura (ITP) and a large number of autoimmune and/or
systemic inflammatory diseases, notably Kawasaki disease, and in
immune-mediated neurological disorders such as Guillain–Barré syndrome
(GBS), chronic idiopathic demyelinating polyneuropathy (CIDP),
multi-focal neuropathy with conduction block (MNCB) and acute myasthenia
gravis [
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For
other diseases, IVIg is not always used as a first-line therapy. It may
be administered as a steroid-sparing agent and in certain conditions
may represent an alternative to other available therapeutic approaches,
such as immunosuppressants, plasma exchange or monoclonal antibodies.
IVIg is also often employed to treat diseases that are refractory to
other treatments or where conventional therapies result in unacceptable
side effects. Combination therapy of IVIg with immunosuppressants has
been applied successfully in several conditions, including autoimmune
vasculitis, dermato- and polymyositis, transplantation and sepsis [
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When
considering the emerging uses of IVIg, it is important to consider the
evidence base. In some patient populations the therapeutic value of IVIg
has been proven in large controlled trials, while in other patient
populations only small, uncontrolled studies or case reports are
available, often due to the small numbers of patients with these rare
diseases.
IVIg for the treatment of autoimmune and inflammatory disorders
Despite
the large number of autoimmune diseases being treated with IVIg,
guidance on the clinical usage is limited to only three conditions: ITP,
GBS and Kawasaki disease. Because of the costs, finite supply and time
for the patient receiving IVIg therapy, there is a need to rationalize
and prioritize the disorders for which, based on currently available
evidence, IVIg is adopted. In France, the Comité d'Evaluation et de
Diffusion des Innovations Technologiques (CEDIT) IVIg expert group,
chaired by Professor Loïc Guillevin, aims to identify scientifically
validated uses and issue recommendations regarding the usage of IVIg [
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Guidelines for the use of immunoglobulin have also been developed in the United Kingdom [
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Canada [
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Australia [
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and elsewhere.
Indications
have been divided into those patients for whom the benefit of IVIg
treatment is recognized, those under evaluation and those where benefit
is not documented. Recognized indications include ITP, Kawasaki disease,
myasthenia gravis, dermatomyositis (DM), as well as autoimmune
neuropathies such as GBS, chronic inflammatory demyelinating
polyradiculoneuropathy, multi-focal motor neuropathy (MMN) and stiff
person syndrome. IVIg efficacy is also recognized in rare diseases, such
as parvovirus B19 infection, autoimmune erythroblastopenia and
neutropenia, acquired hypocoagulability and birdshot
retinochoroidopathy; however, no prospective randomized studies in these
indications exist, due mainly to the rarity of these conditions.
Indications
that are currently under evaluation by CEDIT include inclusion body
myositis (IBM), demyelinating central nervous system diseases (but not
multiple sclerosis or Devic syndrome), corticoresistant polymyositis,
autoimmune encephalitis and refractory epilepsy. The efficacy of IVIg in
the treatment of select populations of transplant patients, haemolytic
anaemia, adult-onset Still's disease, anti-phospholipid syndrome,
anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated
vasculitides and pemphigus vulgaris is also under evaluation.
IVIg for the treatment of autoimmune vasculitides
Systemic
vasculitides are classified based on the diameter of the vessels
involved. Large vessel involvement is found in giant cell arteritis and
Takayasu's arteritis, while medium vessels are affected in diseases such
as polyarteritis nodosa and Kawasaki disease. Small vessels are
involved in necrotizing glomerulonephritis and ANCA-associated systemic
vasculitides.
Kawasaki disease is characterized by a
systemic inflammation of the blood vessels and affects predominantly
children under the age of 5 years [
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the next button to revert the control to an accessible version. It is one of the first vasculitides reported to be treated with IVIg, with or without acetyl salicylic acid (aspirin) [
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Since then, IVIg in combination with aspirin has become the standard of care for patients with Kawasaki disease [
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the next button to revert the control to an accessible version. A meta-analysis of 16 prospective randomized trials was conducted in
2003, showing that there is a significant decrease in new coronary
abnormalities at day 30 in patients treated with IVIg compared with
placebo and demonstrated that infusion of a single dose of 2 g/kg body
weight induces a significant reduction in coronary aneurysms at day 30
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.
The analysis concluded that children fulfilling the diagnostic criteria
for Kawasaki disease should be treated with 2 g/kg of IVIg within 10
days of the first symptoms in order to gain the maximum benefit [
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Wegener's
granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strauss
syndrome (CSS) are small-sized vessel vasculitides that are associated
frequently with anti-neutrophil cytoplasmic autoantibodies [
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ANCA-associated vasculitides are characterized by vascular necrosis
either in the glomerular visceral epithelial cells or in other visceral
tissues. Renal and lung involvement is often observed. The major target
of anti-neutrophil antibodies in WG is proteinase 3, whereas in MPA and
CSS the antibodies target myeloperoxidase (MPO). Treatment of
ANCA-associated vasculitides is initiated commonly with induction
therapy of corticosteroids, cyclophosphamide and sometimes plasma
exchanges. Maintenance therapy usually involves azathioprine,
methotrexate or mycophenolate mofetil (MMF). Relapses of ANCA-associated
vasculitides are often treated with immunosuppressants, such as
cyclophosphamide or methotrexate or with biologicals such as IVIg,
anti-TNF or anti-CD20 therapy. Plasma exchanges can also be used in this
setting.
Several small prospective clinical studies of IVIg treatment of ANCA-associated vasculitides have been conducted
The first open prospective study of seven patients with WG, MPA or
rheumatoid vasculitis was performed in 1991 and showed promising
results, with six patients in complete remission and one with transient
response to IVIg therapy (total dose 2 g/kg) [
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This study was followed by an extensive report on 26 patients, showing
that 8 weeks after IVIg treatment 13 patients were in full and 13 in
partial remission [
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The clinical benefit was maintained in 18 patients for up to 1 year
after IVIg therapy. Conflicting results were obtained in another study
of 15 patients with ANCA-associated vasculitis who responded poorly to
conventional therapy. These patients were treated with single or
multiple courses of IVIg, to a total dose of 30 g/day over 5 days [
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Six of 15 patients experienced significant clinical benefit; however,
no patient experienced complete remission. Another study with patients
resistant to conventional treatment similarly showed that IVIg treatment
was effective in six of 10 patients [
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Only one randomized, placebo-controlled trial of IVIg in ANCA-associated vasculitis has been conducted to date.
The study investigated the efficacy of a single course of IVIg (total
dose 2 g/kg) in previously treated patients with persistent disease. At
the 3-month time-point (primary end-point), 14 of 17 patients showed
improvement in response to IVIg treatment, compared with six of 17 in
the placebo group (
P = 0·035). However, this was a short trial of only 3 months, so there is still need for additional data in this setting [
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Clinical
studies of the use of intravenous immunoglobulin (IVIg) for the
treatment of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated
vasculitis.
A recent open,
prospective non-randomized study evaluated the efficacy and safety of
IVIg administered for 6 months for the treatment of relapses of WG, MPA
or CSS that occurred during or within 1 year following the withdrawal of
corticosteroids and/or immunosuppressants [
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The study evaluated 22 patients (21 with ANCA-specific antibodies).
Twenty-one patients experienced partial initial responses and, at 9
months, 13 patients experienced complete remission. At 24 months, eight
patients were in complete remission in the absence of any other
treatment, while another 10 were in remission with the help of treatment
modification.
Although studies in a number of
ANCA-associated vasculitides have shown some benefit of IVIg treatment,
proven efficacy is observed in only a handful of conditions. For
example, the benefits of IVIg in the treatment of Kawasaki disease are
well documented, and the data suggest that children meeting the
diagnostic criteria for this disease must be treated within 10 days of
the onset of symptoms. IVIg may also represent an option in patients
with relapsing ANCA-associated vasculitides, but additional randomized
controlled trials are needed in this field.
Combination therapy with IVIg in autoimmune mucocutaneous blistering diseases
Autoimmune
mucocutaneous blistering diseases (AMBDs) are rare but potentially
fatal diseases. Since the introduction of corticosteroids, the annual
mortality rate due to blistering diseases has fallen; nonetheless
patients suffering from these conditions continue to experience high
morbidity and mortality.
There are currently two
approaches to the pharmacological management of AMBDs. One approach
targets the production of the autoantibody in the bone marrow, spleen
and lymph nodes, and involves the use of immunosuppressive drugs such as
azathioprine, MMF, cyclophosphamide and methotrexate. The other
approach targets the sites at which the autoantibodies exert their
effects, namely in the skin or mucosal surfaces. This approach uses
anti-inflammatory drugs, such as prednisone and dapsone, to ameliorate
the effects of the autoantibodies [
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].
Conventional
immunosuppressive therapy for the treatment of AMBDs involves high-dose
corticosteroids (80–240 mg/day) for prolonged periods of time. However,
this therapy is not always effective and usually results in a poor
quality of life. Conventional immunosuppression has a variety of
reversible and non-reversible side effects, including prolonged
vulnerability to infection and increased risk of cancer. Indeed, the
side effects of such therapies are often the ultimate cause of death in
these patients.
IVIg is usually employed when
conventional therapy fails, causes side effects or is contraindicated.
Beneficial clinical effects of IVIg have been demonstrated in the
treatment of a number of AMBDs, including pemphigus vulgaris, pemphigus
foliaceus, bullous pemphigoid, mucous membrane pemphigoid and
epidermolysis bullosa aquisita (EBA). A ‘Consensus Statement’ on the use
of IVIg in these diseases recommends a dose of 2 g/kg/cycle, given
monthly until clinical control, with a progressive increase of the
intervals between the cycles thereafter to 6, 8, 10, 12 and 14 weeks [
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. The last cycle is given after a 16-week interval, and is considered as the end of therapy.
In a recent study, 156 patients with AMBD treated with IVIg using this protocol demonstrated successful clinical outcomes [
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In these patients IVIg could be used as monotherapy, once concomitant
prednisone and immunosuppressive agents were gradually discontinued.
These included 42 patients with pemphigus vulgaris, 26 with pemphigus
foliaceus, 32 with bullous pemphigoid, 68 with mucous membrane
(cicatricial) pemphigoid and nine with epidermolysis bullosa acquisita.
IVIg produced long-term, sustained remission for at least 2 years of
follow-up, after discontinuing IVIg therapy. The patients were in
serological remission and enjoyed a high quality of life. It could be
speculated that, compared to previous therapies, IVIg changed the
clinical course of these diseases [
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Destroy user interface control21].
As
a therapeutic option, the costs associated with IVIg use are often
perceived to be high. However, when the true costs of conventional
therapy are calculated, including the costs of the treatment of side
effects and hospitalizations, they are approximately two- to threefold
higher than the costs of IVIg therapy. According to one US analysis, the
true cost of conventional therapy for pemphigus vulgaris was $US 123
133 per patient per year, while the mean annual cost of IVIg was $US 76
249 [
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Destroy user interface control22].
A
large study analysed 275 patients who had been treated according to the
Consensus Statement protocol and who remained in clinical remission for
a minimum of 2 years after discontinuing IVIg (unpublished data). About
70% of the patients responded to IVIg monotherapy and were considered
high responders. The remaining 30% were partial responders or
non-responders. Partial responders, in whom the dose of prednisone and
immunosuppressive agent was reduced by 50% or less, were subclassified
as mild (clinical response of 50% or less) or moderate (clinical
response between 50% and 100%) responders. Moderate responders were
treated subsequently with 50–150 mg dapsone daily. Clinical improvement
was achieved in less than 4 months (mean 3·8, range 2·1–7·5). Mild
responders were treated with oral methotrexate (5–20 mg/weekly) and
dapsone (50–150 mg daily). These patients responded to therapy within 6
months (mean 5·7, range 4–8·6). Thereafter, the clinical response of
each group of patients was the same as that observed in the high
responder group. Non-responders were patients whose disease, in spite of
adjunctive therapy, flared if the interval between cycles was increased
by more than 4 weeks, or who continued to have active disease after 1
year of IVIg therapy. These patients were treated with rituximab and
IVIg, and all showed clinical improvement.
It has been
demonstrated previously that the combination of IVIg and rituximab is
effective in patients with refractory pemphigus vulgaris who had
inadequate responses to conventional therapy and IVIg. Patients were
treated with two cycles of rituximab (375 mg/m2 of
body-surface area) once weekly for 3 weeks and IVIg (2 g/kg) in the
fourth week, followed by a monthly infusion of rituximab and IVIg for 4
months [
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In this study, nine of 11 patients showed rapid resolution of lesions
and a clinical remission lasting 22–37 months (mean 31·1 months).
All immunosuppressive therapy, including prednisone, could be
discontinued. Two patients were treated with rituximab only during
recurrences and had sustained remission. None of the patients in this
study had serious side effects, although the long-term consequences of
rituximab and IVIg combination therapy in such patients with autoimmune
diseases are unknown and need to be investigated.
