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Yada Sirisa, M.D.
Division of Allergy, Immunology and Rheumatology Unit
Department of Pediatrics
King Chulalongkorn Memorial Hospital
Immunoglobulin
Therapy
Outline
● Structure of immunoglobulin
● Mechanisms of action
● Manufacturing Process
● Pharmacokinetics
● Indication
● Dose and administration
● Adverse effects
● Differences among immunoglobulin products
Introduction
● Intravenous immunoglobulin (IVIG) preparations comprise the pooled fraction of serum IgG from
~3,000-60,000 blood donors, which is generated in principle by a cold ethanol precipitation
● Besides IgG, varying amounts of other immunoglobulin isotypes, most notably IgA, can be found
in the IVIG preparation
● Very much reflect the hierarchy present in the serum, consisting mainly of IgG1 and IgG2 and
containing much smaller amounts of the other IgG subclasses
Schwab I, et al.Nat Rev Immunol. 2013 Mar;13(3):176-89.
Structure of immunoglobulin
● Immunoglobulin (Ig) = antibody
● Gamma globulin: the third fastest migrating
group of globulin in electrophoretic separation
of serum or plasma
● Immunoglobulin: immunity-conferring portion
of globulin fraction of serum or plasma
Abbas 10th edition
Structure of immunoglobulin
● Two identical heavy chains (HC)
● Two identical light chains (LC)
● Linked by disulfide bonds
● Variable region (V): Antigen-binding site
● Constant region (C): Mediate effector function
by interacting with other molecule and cells
● Determined class of antibody
Abbas 10th edition and Middleton's’ Allergy: Principle and Practice, 9th edition
Structure of immunoglobulin
● Immunoglobulins (Ig) are glycoproteins
● Fab fragments
○ Able to bind antigen
○ Variable domains of LCs and HCs combine
● Fc fragments
○ Bind to complement or Fc receptors (FcRs)
○ Composed of the C-terminal portion of the
HCs bound to each orhter
Abbas 10th edition and Middleton's’ Allergy: Principle and Practice, 9th edition
Middleton's’ Allergy: Principle and Practice, 9th edition
Fc portion: bind to complement, FcRs and determine class of antibody and effector functions
IgG Receptors
Schwab I, et al.Nat Rev Immunol. 2013 Mar;13(3):176-89.
• Consists of several activating
receptors and one inhibitory receptor
in both mice and humans
• These receptors are broadly
expressed by most cells of the innate
immune system, including basophils,
eosinophils. neutrophils, mast cells,
monocytes and macrophages
Fc receptor expression patterns on human cells and biologic activity
Middleton's’ Allergy: Principle and Practice, 9th edition
Neonatal Fc receptor for IgG (FcRn)
Middleton's’ Allergy: Principle and Practice, 9th edition
• Endothelial cells and monocytes express the
neonatal Fc receptor for IgG (FcRn) that
internalizes serum IgG in an acidic endosomal
compartment
• FcRn then recycles IgG molecules back into
circulation, effectively prolonging their half-life
• Serum proteins without a recycling receptor
are internalized in lysosomes and degraded
Gelfand
EW.
et
al.
N
Engl
J
Med.
2012
Nov
22;367(21):2015-25.
Mechanisms of action
Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
Antibody-mediated opsonization and phagocytosis
Abbas Cellular and Molecular Immunology, 10th edition
Neutralization of microbes and microbial toxins
Complement activation
Abbas Cellular and Molecular Immunology, 10th edition
3 major pathway of complement activation
• Classical pathway: activated by certain isotypes of
antibodies bound to antigens
• Alternative pathway: activated on microbial cells
surfaces in absence of antibody
• Lectin pathway: activated by mannose-binding
protein bound to surface carbohydrates on microbes
Mechanisms of immunoglobulin activity
Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Abbas Cellular and Molecular Immunology, 10th edition
Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5.
Suppression of cytokine production
• Inhibits production of cytokines by mononuclear cells (IL-1, TNF-𝛼, TNF-𝑩, and IFN-𝜸 by PBMCs)
• Increasing production of IL-1 receptor antagonist
• Inhibits endothelial cell proliferation
• Downregulates mRNA expression of adhesion molecule (ICAM1, VCAM1), chemokine
• Inhibit T-cell activation by these staphylococcal and streptococcal superantigens
Ballow
M.
et
al.
J
Allergy
Clin
Immunol.
2011
Feb;127(2):315-23;
quiz
324-5.
Cytokine and autoantibody neutralization
• Decrease levels of autoreactive IgG antibodies that recognize a wide array of self antigens:
Cytokines, Antigen-specific autoantibody, CD95 (FAS) or CD95 ligand (FASL), Sialic acid-binding
immunoglobulin-like lectin 9 (SIGLEC9) expressed on neutrophils, SIGLEC8 expressed on
eosinophils, T cell-expressed antigens, B cell-activating factor (BAFF), A proliferation-inducing
ligand (APRIL), Adhesion molecules involved in leukocyte trafficking
Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5.
Modulation of apoptosis
• TEN: death of the keratinocytes leads to large
sections of the epidermis sloughing off
• Keratinocytes express Fas, and sera contain high
circulating levels of Fas ligand
Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5.
Modulation of apoptosis
• IVIG contains anti-Fas antibodies prevent keratinocyte cell death by blocking the effects of Fas
ligand on Fas receptor on keratinocytes
• The anti-Fas antibodies in IVIG can enhance the apoptosis of human lymphocytes and monocytes
• Immunomodulating effects of anti-Fas antibodies might depend on the dose of IVIG and the clinical
disease state
> Low conc, (1-10 mg/mL) blocked anti-CD95-mediated neutrophil apoptosis
> High conc. (20-50 mg/mL) induced neutrophil death
Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5.
Restoration of idiotypic-anti-idiotypic network
• Anti-idiotypic antibodies: Antibodies that are specific for the antigen-specific binding site of an
immunoglobulin or a T cell receptor and therefore may compete with the antigen for binding
• Benefit in circulating autoantibody inhibitors to Factor VIll coagulant activity, SLE, Anti-neutrophil
cytoplasmic antibody-associated vasculitis, Guillain-Barre syndrome (GBS), Chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP), Myasthenia gravis
Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5.
Inhibition of complement deposition on target tissue
• In vitro study: high levels of IgG could inhibit the uptake of C3 on erythrocytes and inhibition of
binding of C3b to antibodies on platelets reduce C3b dependent opsonization of antibody-coated
platelets by macrophages of the RE system
• Decrease C3 and MAC deposition on endomysial capillaries and decrease ICAM1 expression in
muscle tissue
• Prevent complement mediated neuronal cell death
Benefit in Dermatomyositis, GBS,
CIDP, Myasthenia gravis
Dalakas
MC.,
et
al..
J
Clin
Immunol
2014;34:Suppl
1:
S120-S126.
Mechanisms of immunoglobulin activity
Blocking of
activating Fc𝜸R
Decreased
autoantibody half-life
Modulation of inhibitory Fc𝜸 R
expression on innate immune
effector cells and B cells
Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5.
Fc receptor blockade
• Fc receptor blockade of the reticuloendothelial system platelet counts rapidly increase after
administration of IVIG (dose 1-2 g/kg)
• Autoantibody-opsonized platelets are destroyed in spleen and liver by means of Fc𝜸R-mediated
phagocytic clearance.
• Fc receptor blockade on macrophages in spleen and in other parts of the reticuloendothelial system
using an mAb directed against the Fc𝜸RIIIa receptor
Benefit in ITP
Anti-inflammatory activity of sialylated Fc
• Sialylated Fc, present in low quantities in intravenous
immune globulin, binds to SIGN-R1 on macrophages,
resulting in the release of soluble mediators
• These mediators bind to effector macrophages and
increase expression of the inhibitory FcγRIIB
receptors, which compete with antigen–antibody
complex binding to activating FcγRs
The net result is an increase in the
concentration of the complexes required to
initiate an inflammatory response
Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
Ballow
M.
et
al.
J
Allergy
Clin
Immunol.
2011
Feb;127(2):315-23;
quiz
324-5.
Saturation of FcRn
• Benefit in Bullous pemphigoid, Arthritis, ITP
• FcRn: specialized receptor binds serum IgG, protects IgG from degradation inside the lysosomes,
• and returns IgG intact to plasma circulation
• Shorten the half-life of the autoantibody, more rapidly eliminating it from the circulation
Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5.
Modulation of B cell
• Long term effects in ITP
• Inhibited both B cell receptor-dependent and independent antigen presentation (not mediated
through the FcyRllb receptor but was mediated by intracellular events)
• Under conditions such as CD40 activation: IVIG promote differentiation into IgG secreting B cells
• Contains other specific antibodies that react with number of cell-surface determinants that could
potentially modulate the immune response, such as the 𝛼𝑩-TCR, cytokine receptors, HLA
determinants, CD5, CCR5, CD40, and sialic acid-binding immunoglobulin-like lectins 8 and 9
Modulation of T cell immunoregulatory function
• Benefit in Kawasaki disease, GBS, autoimmune encephalomyelitis
• Suppress T-cell proliferative responses to mitogens by IVIG and F(ab')2 fragments to CD3 and
CD28 stimulations
• Expanding and enhancing the function of FOXP3-positive Treg cells increase production of IL-10,
TGF-B, or effects on DC cells
• Inhibited maturation of monocytes into immature dendritic cells
Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
Bayry
J,
et
al.
Nat
Clin
Pract
Rheumatol.
2007
May;3(5):262-72.
Ballow
M.
et
al.
J
Allergy
Clin
Immunol.
2011
Feb;127(2):315-23;
quiz
324-5.
History of production of IVIG
Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
Manufacturing Process
• At present, there are more than 20 different IgG products commercially available worldwide
• Despite having similar biological properties and efficacy, commercial IgG products are manufactured using
different methods resulting in variations in their physicochemical properties including pH, sodium
concentration, osmolality, sodium content, and IgA content
• These characteristics may lead to differences in tolerability and adverse events (AEs)
Bonilla FA, et al. Immunol Allergy Clin N Am 2008;28:803-819.
Manufacturing Process
• Exogenous concentrated
immunoglobulins, mostly are “IgG”
• Purified from pooled plasma obtained
from thousand of donors
• Same distribution of IgG subclasses,
same half-life as normal plasma
• Very small amount of IgA (varies among
different products)
• Only trace amounts of IgM
Sriaroon
P,
et
al.
Immunol
Allergy
Clin
North
Am.
2015
Nov;35(4):713-30.
Manufacturing Process
Three dedicated virus reduction steps
Poelsler G, et al. Vox Sang. 2008 Apr;94(3):184-192.
Bayry
J,
et
al.
Nat
Rev
Rheumatol.
2011
Jun;7(6):349-59.
Pharmacokinetics of Immunoglobulin
Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19
Two-compartment model of IgG pharmacokinetics
Pharmacokinetics of Immunoglobulin
Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19
Saturation of the FcRn
Pharmacokinetics of Immunoglobulin
Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19
Indications of IVIG
• Replacement therapy
• Prevent infections
• Primary and secondary immunodeficiency
• Immunomodulatory mechanisms
• Treatment of autoimmune pathology
• Higher dose of immunoglobulin
Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
Indications of IVIG: Immunodeficiency
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
IVIG in Primary immunodeficiency
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
A framework of 6 distinct phenotypes of PI disease for which Ig replacement is or may be indicated:
1. Agammaglobulinemia due to absence of B cells
2. Hypogammaglobulinemia with poor antibody function
3. Normal immunoglobulins with poor antibody function
4. Hypogammaglobulinemia with normal antibody function
5. Isolated IgG subclass deficiency with recurrent infections
6. Recurrent infections due to a complex immune mechanism related to genetically defined PI disease
Agammaglobulinemia due to the absence of B cells
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• Evaluation of IVIG usage in patients lacking immunoglobulin has demonstrated a clear benefit in
terms of reducing both acute and chronic infections
• In severe combined immunodeficiency (SCID), the T-cell defect is often accompanied by an absence
of B cells or B-cell function
• Immunoglobulin replacement is warranted at diagnosis, post-transplantation period, during gene
therapy or enzyme replacement (for adenosine deaminase deficiency), until B-cell function is restore
• In case of B-cell function is never restored, and continual immunoglobulin replacement remains
necessary
Hypogammaglobulinemia with
impaired specific antibody production
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• In patients with recurrent bacterial infections, reduced levels of serum immunoglobulin, coupled with a
lack of response to protein and/or polysaccharide vaccine challenge (ie, in patients who cannot make
IgG antibody against diphtheria and tetanus toxoids and/or pneumococcal polysaccharide vaccine),
are a clear indication of immunoglobulin replacement
The prototype of this category is CVID
Normal levels of immunoglobulins with impaired specific-
antibody production (selective antibody deficiency)
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• Patients with normal total IgG levels but impaired production of specific antibodies, including those
with isolated deficient responses to numerous polysaccharide antigens following vaccination
• Severity of infection and/or the efficacy of antibiotic prophylaxis should be the driving force behind any
decision to provide immunoglobulin replacement therapy
• IVIG replacement therapy should be provided when there is well-documented severe polysaccharide
non-responsiveness and evidence of recurrent infections
Normal levels of immunoglobulins with impaired specific-
antibody production (selective antibody deficiency)
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• The treatment may be stopped after a period of time (preferably in the spring in temperate regions) and
that the immune response will be reevaluated at least 3-5 months after the discontinuation of IVIG
• While some patients, usually children, show improved responses to antigen challenge (typically with
pneumococcal polysaccharide vaccine) after treatment with immunoglobulin for 6-24 months and improve
clinically, others require restarting the immunoglobulin therapy because of a recurrence of infections
• Cessations of therapy are likely to identify whether a patient's defect in antibody specificity was transient
Hypogammaglobulinemia with normal-quality antibody response
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
Transient hypogammaglobulinemia (THI)
• IgG levels normalize with age and antibody function is initially partially impaired but typically intact
• In select cases, treatment with replacement immunoglobulin may be considered temporarily
• Age-specific normal ranges of IgG vary, and 2.5% of healthy individuals have 'lower-than-normal" IgG
(below the lower limit of the 95% confidence interval for age), which may not be clinically significant, in
the absence of recurrent infections
Hypogammaglobulinemia with
normal-quality antibody response
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
Isolated hypogammaglobulinemia (other than THI) can be a feature of many immune function
defects, and must be differentiated from secondary causes
• Increased loss of IgG, such as chylothorax, lymphangiectasia, or protein-losing enteropathy
• Medication, especially corticosteroids, some seizure medications, and biologics such as rituximab
Hypogammaglobulinemia with
normal-quality antibody response
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• A subset of patients also present with very low IgG and no history of infection
• Severe hypogammaglobulinemia should be considered a risk for infection
• IgG level <150 mg/dL is widely accepted as severe hypogammaglobulinemia, for which additional testing
apart from verification of the low level is not required prior to starting replacement therapy
• Levels between 150 and 250 mg/dL are also considered severely low but warrant consideration of
additional testing for specific antibody against vaccines to assess function, depending on the clinical history
Normal immunoglobulin levels and normal
quality with deficient IgG subclass
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• Isolated subclass deficiency is often asymptomatic, but a minority of patients may have poor antibody
responses to specific antigens and recurrent infections
• Prophylactic antibiotics and the treatment of other underly conditions, such as allergies or asthma, that may
contribute to recurrent sinopulmonary infections are the usual management
• Immunoglobulin replacement should remain a therapeutic option in patients in whom other ameliorative
interventions have failed
Recurrent infections due to
an unknown immune mechanism
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• The need for immunoglobulin therapy may arise as the only viable option for therapy in PIs in which the
mechanism underlying the susceptibility to recurrent infection is not yet characterized, the patient
presents with recurrent infections and an otherwise normal or near-normal immune function evaluation
• Hyper-IgE syndrome who usually have normal serum IgG, IgM and IgA levels, but who may have defects
in antibody responses
Recurrent infections due to
an unknown immune mechanism
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• Wiskott-Aldrich syndrome (WAS) is another immunodeficiency typically characterized by normal total IgG,
but with impaired specific-antibody responses against both protein and polysaccharide antigens:
immunoglobulin therapy should always be a consideration in this disease
• The same considerations as for WAS apply to ataxia telangiectasia (AT) as well as others of these types
of combined immunodeficiencies, including, but not limited to, deficiencies in STAT-3, nuclear factor-kB
essential modulator (NEMO), and STAT-1
IVIG in Secondary immunodeficiency
Otani
IM,
et
al.
J
Allergy
Clin
Immunol.
2022
May;149(5):1525-1560.
IVIG in Secondary immunodeficiency
Otani
IM,
et
al.
J
Allergy
Clin
Immunol.
2022
May;149(5):1525-1560.
IVIG in Secondary immunodeficiency
Otani
IM,
et
al.
J
Allergy
Clin
Immunol.
2022
May;149(5):1525-1560.
Indications of IVIG: Autoimmune diseases
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
Indications of IVIG: Infectious diseases
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
Indications of IVIG: Miscellaneous uses
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
Practical use of IVIG therapy
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
MIMS
Thailand
2/2023
บัญชียาหลักแห่งชาติ พ.ศ. 4566
IVIG therapy in Immunodeficiency
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
Route of Ig administration
Patel NC, et al. Pediatr Allergy Immunol. 2018 Sep;29(6):583-588.
Berger M, et al. Clin Immunol. 2004 Jul;112(1):1-7.
IVIG vs SCIG
Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19
Serum IgG levels during SCIG
(A) Weekly infusions
• The lgG levels vary, on average, less than 10%
over the week in between infusions
(B) Biweekly infusions
• The lgG level varies more than it does with weekly
infusions, but not as much as with IVIG
• The absorption is still blunted in comparison to IVIG
Dose is absorbed slowly and redistributed
slowly, whereas concentration dependent
catabolism is ongoing
Dosages of intravenous immunoglobulin
Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
Primary immunodeficiency disease
• Recommended starting dosages
• 400-600 mg/kg every 3-4 weeks
• Equilibration takes up to 3 months
• Dose must be individualized to achieve
clinical benefit for each patients
Autoimmune/inflammatory disease
• Doses are generally 4-5 times higher than
those used for replacement therapy
• 1-2 gm/kg in 1-2 days
• 2 gm/kg in 2-5days
Target trough level
o > 500 mg/dl: prevent serious bacterial infections
o > 800 mg/dl: recurrent pneumonia, structural lung damage
o PID without chronic lung disease: 600-800 mg/dl
o PID with chronic lung disease: >800 mg/dl
Dosages of intravenous immunoglobulin
Orange JS, et al. Clin Immunol. 2010 Oct;137(1):21-30.
For each 100 mg/kg of IVIG à Trough
levels increased by ~100 mg/dl
Dosages of subcutaneous immunoglobulin
Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
• The usual dose for SCIG is also 300 to 500
mg/kg/month, similar to the IVIG dose
• Infusions are usually given weekly at 25% of
the monthly dose
• Thus a weekly dose of 100 mg/kg (400
mg/kg/month requires a subcutaneous infusion
of 1.0 mL/kg of a 10% IG product or 0.5 mL/kg
of a 20% IG product.)
Dosages of subcutaneous immunoglobulin
Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
• This is given slowly using a portable infusion pump
• Multiple sites on the abdominal wall, thighs or arms can
be used so that no more than 5 to 30 mL is given at a
single site, depending on the patient's weight
• Because of the lessened risk of systemic side effects,
SCIG can be given at home, often by self-infusion, and
without premedication
Skoda-Smith S, et al. Ther Clin Risk Manag. 2010 Feb 2;6:1-10.
Side effect of IVIG
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
• Most reactions are mild and non-anaphylaxis
• 1/3 of patients receiving IVIG experience systemic adverse effects during or within 72 hours after infusions
Side effect of IVIG
Infusion-related reactions
• IgG aggregates form oligomeric or polymeric IgG
• Interact with Fc receptors on phagocytes or
monocytes
• Complement activation
Serious adverse effects
• Anaphylaxis
• Thromboembolic events
May be due to increased viscosity/osmolality
• Renal failure
Sucrose containing products
• Aseptic meningitis
• Hemolysis
Anti-A and anti-B antibodies isoagglutinin
To prevent IVIG infusions-related reactions
• Starting the infusion slowly
• Currently marketed IVIG products contain
stabilizers to reduce IgG aggregation
Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
Side effect of IVIG: Risk factors
Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
Infusion related
• First infusion
• Larger dose
• Rapid infusion rate
Product related
• Type of stabilizer
• Sodium content
• Osmolarity
• pH
• IgA content
Patient related
• Advanced age
• Active infection or fever
• Hypercoagulable state
• Cardiovascular risk
• Preexisting renal disease
Bayry
J,
et
al.
Nat
Rev
Rheumatol.
2011
Jun;7(6):349-59.
Side effect of IVIG
Side effect of IVIG
Bayry
J,
et
al.
Nat
Rev
Rheumatol.
2011
Jun;7(6):349-59.
Management of adverse reactions
Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
• Slow or half the rate
• Subsequent infusions
• Administer more slowly. • Administer smaller doses, more frequently
• Medication and premedication
• Acetaminophen, ibuprofen, H1-antihistamine • Severe reactions: systemic steroid
• If pre- and post-infusion medications and manipulations of IVIG dosing regimen do not control
adverse reactions à changing IVIG product or switch to SCIG
Guo Y, et al. Front Immunol. 2018 Jun 8;9:1299.
Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66.
Differences among products
• Formulation (liquid, Iyophilized)
• Volume load
• Sodium content
• Type of stabilizer
• Osmolality
• IgA content
• pH
Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66.
Differences among products
Stabilizers
• To minimize IgG aggregates
• Type of stabilizers:
Amino acids: proline, glycine
Sugars: sorbitol, maltose, glucose, sucrose
ㆍSugar contents associate with adverse events
Osmotic nephrosis
Sucrose: renal toxicity, renal failure/insufficiency
Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66.
Differences among products
Volume load
• An important consideration in very young, elderly, cardiac impairment
Sodium content
• Varies widely in currently available preparations
• High salt contents à higher incidence of AEs & thromboembolic complications
Osmolality
• Sodium & sugar content
• Physiologic osmolality: 280-296 mOsm/kg of water
• Hyperosmotic state à thromboembolic complications
Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66.
Differences among products
pH
• Optimum pH: 4.0-4.5 to remain IgG in unaggregated state
• Low pH may be associated with phlebitis
IgA Content
• IgG or IgE anti-IgA antibodies in patients with hypogammaglobulinemia and absent serum IgA who are
receiving IgA-containing IVIG can cause severe reactions including anaphylaxis.
• To minimize risk of severe reactions/anaphylaxis
- Use products with the lowest concentration of IgA
- Starting initial IVIG infusion slowly and gradually increase the rate with subsequent infusions
CVID patient with serum IgA level <7 mg/dL are at highest risk
Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66.
IVIG characteristics corresponding to patient risk factors
Perez
EE,
et
al..
J
Allergy
Clin
Immunol.
2017
Mar;139(3S):S1-S46.
IV form
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
SC form
IV/SC form
Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
IM form
Saeedian
M,
et
al.
Int
Arch
Allergy
Immunol.
2014;164(2):151-66.
Specific considerations of IVIG dosage and administration
Differences among products: available at KCMH
Product
Dosage
formulation
Osmolality
(mOsm/L)
Sodium pH IgA (μg/ml) Stabilizer
TRCS 5% liquid 240-350 Trace 4-7.4 <100 Maltose
Flebogamma 5% liquid 240-370 Trace 5-6 <50 D-sorbitol
Liv-Gamma 5% liquid N/A N/A N/A N/A Maltose
Gamunex 10% liquid 258 None added 4-4.5 46 Glycine
Privigen 10% liquid 240-440 Trace 4.6-5 <25 L-proline
Kiovig 10% liquid 240-300 None added 4.6-5.1 37 Glycine
Hizentra (SC) 20% liquid 380
Trace <10
mmol/L
4.6-5.2 <50 Proline
IVIG products: available at KCMH
Available at KCMH Amount (gram) Volume (ml) Price (THB)
5% LIV-Gamma 5g 100 7,211
5% Flebogamma DIF 2.5 g 50 6,111
5% Flebogamma DIF 10g 200 24,261
5% TRCS 2.5 g 50 2,790
5% TRCS 5g 100 5,150
10% Kiovig 10g 100 22,983
10% Gamunex-C 10g 100 22,071
10% Privigen 5g 50 11,501
5% LIV-Gamma
10% Kiovig
5% TRCS
10% Gamunex-C
10% Privigen
5% Flebogamma DIF
Lived vaccines
and IVIG
IVIG dosages
Lived vaccine
interval
400 mg/kg 8 months
1 g/kg 10 months
2 g/kg 11 months
ตําราวัคซีนและการสร้างเสริมภูมิคุ้มกันโรคปี ;<=>
Thank You

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Immunoglobulin therapy

  • 1. Yada Sirisa, M.D. Division of Allergy, Immunology and Rheumatology Unit Department of Pediatrics King Chulalongkorn Memorial Hospital Immunoglobulin Therapy
  • 2. Outline ● Structure of immunoglobulin ● Mechanisms of action ● Manufacturing Process ● Pharmacokinetics ● Indication ● Dose and administration ● Adverse effects ● Differences among immunoglobulin products
  • 3. Introduction ● Intravenous immunoglobulin (IVIG) preparations comprise the pooled fraction of serum IgG from ~3,000-60,000 blood donors, which is generated in principle by a cold ethanol precipitation ● Besides IgG, varying amounts of other immunoglobulin isotypes, most notably IgA, can be found in the IVIG preparation ● Very much reflect the hierarchy present in the serum, consisting mainly of IgG1 and IgG2 and containing much smaller amounts of the other IgG subclasses Schwab I, et al.Nat Rev Immunol. 2013 Mar;13(3):176-89.
  • 4. Structure of immunoglobulin ● Immunoglobulin (Ig) = antibody ● Gamma globulin: the third fastest migrating group of globulin in electrophoretic separation of serum or plasma ● Immunoglobulin: immunity-conferring portion of globulin fraction of serum or plasma Abbas 10th edition
  • 5. Structure of immunoglobulin ● Two identical heavy chains (HC) ● Two identical light chains (LC) ● Linked by disulfide bonds ● Variable region (V): Antigen-binding site ● Constant region (C): Mediate effector function by interacting with other molecule and cells ● Determined class of antibody Abbas 10th edition and Middleton's’ Allergy: Principle and Practice, 9th edition
  • 6. Structure of immunoglobulin ● Immunoglobulins (Ig) are glycoproteins ● Fab fragments ○ Able to bind antigen ○ Variable domains of LCs and HCs combine ● Fc fragments ○ Bind to complement or Fc receptors (FcRs) ○ Composed of the C-terminal portion of the HCs bound to each orhter Abbas 10th edition and Middleton's’ Allergy: Principle and Practice, 9th edition
  • 7. Middleton's’ Allergy: Principle and Practice, 9th edition Fc portion: bind to complement, FcRs and determine class of antibody and effector functions
  • 8. IgG Receptors Schwab I, et al.Nat Rev Immunol. 2013 Mar;13(3):176-89. • Consists of several activating receptors and one inhibitory receptor in both mice and humans • These receptors are broadly expressed by most cells of the innate immune system, including basophils, eosinophils. neutrophils, mast cells, monocytes and macrophages
  • 9. Fc receptor expression patterns on human cells and biologic activity Middleton's’ Allergy: Principle and Practice, 9th edition
  • 10. Neonatal Fc receptor for IgG (FcRn) Middleton's’ Allergy: Principle and Practice, 9th edition • Endothelial cells and monocytes express the neonatal Fc receptor for IgG (FcRn) that internalizes serum IgG in an acidic endosomal compartment • FcRn then recycles IgG molecules back into circulation, effectively prolonging their half-life • Serum proteins without a recycling receptor are internalized in lysosomes and degraded
  • 12. Mechanisms of action Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
  • 13. Antibody-mediated opsonization and phagocytosis Abbas Cellular and Molecular Immunology, 10th edition
  • 14. Neutralization of microbes and microbial toxins
  • 15. Complement activation Abbas Cellular and Molecular Immunology, 10th edition 3 major pathway of complement activation • Classical pathway: activated by certain isotypes of antibodies bound to antigens • Alternative pathway: activated on microbial cells surfaces in absence of antibody • Lectin pathway: activated by mannose-binding protein bound to surface carbohydrates on microbes
  • 16. Mechanisms of immunoglobulin activity Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
  • 17. Antibody-dependent cell-mediated cytotoxicity (ADCC) Abbas Cellular and Molecular Immunology, 10th edition
  • 18. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Suppression of cytokine production • Inhibits production of cytokines by mononuclear cells (IL-1, TNF-𝛼, TNF-𝑩, and IFN-𝜸 by PBMCs) • Increasing production of IL-1 receptor antagonist • Inhibits endothelial cell proliferation • Downregulates mRNA expression of adhesion molecule (ICAM1, VCAM1), chemokine • Inhibit T-cell activation by these staphylococcal and streptococcal superantigens
  • 19. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Cytokine and autoantibody neutralization • Decrease levels of autoreactive IgG antibodies that recognize a wide array of self antigens: Cytokines, Antigen-specific autoantibody, CD95 (FAS) or CD95 ligand (FASL), Sialic acid-binding immunoglobulin-like lectin 9 (SIGLEC9) expressed on neutrophils, SIGLEC8 expressed on eosinophils, T cell-expressed antigens, B cell-activating factor (BAFF), A proliferation-inducing ligand (APRIL), Adhesion molecules involved in leukocyte trafficking
  • 20. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Modulation of apoptosis • TEN: death of the keratinocytes leads to large sections of the epidermis sloughing off • Keratinocytes express Fas, and sera contain high circulating levels of Fas ligand
  • 21. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Modulation of apoptosis • IVIG contains anti-Fas antibodies prevent keratinocyte cell death by blocking the effects of Fas ligand on Fas receptor on keratinocytes • The anti-Fas antibodies in IVIG can enhance the apoptosis of human lymphocytes and monocytes • Immunomodulating effects of anti-Fas antibodies might depend on the dose of IVIG and the clinical disease state > Low conc, (1-10 mg/mL) blocked anti-CD95-mediated neutrophil apoptosis > High conc. (20-50 mg/mL) induced neutrophil death
  • 22. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Restoration of idiotypic-anti-idiotypic network • Anti-idiotypic antibodies: Antibodies that are specific for the antigen-specific binding site of an immunoglobulin or a T cell receptor and therefore may compete with the antigen for binding • Benefit in circulating autoantibody inhibitors to Factor VIll coagulant activity, SLE, Anti-neutrophil cytoplasmic antibody-associated vasculitis, Guillain-Barre syndrome (GBS), Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Myasthenia gravis
  • 23. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Inhibition of complement deposition on target tissue • In vitro study: high levels of IgG could inhibit the uptake of C3 on erythrocytes and inhibition of binding of C3b to antibodies on platelets reduce C3b dependent opsonization of antibody-coated platelets by macrophages of the RE system • Decrease C3 and MAC deposition on endomysial capillaries and decrease ICAM1 expression in muscle tissue • Prevent complement mediated neuronal cell death Benefit in Dermatomyositis, GBS, CIDP, Myasthenia gravis
  • 25. Mechanisms of immunoglobulin activity Blocking of activating Fc𝜸R Decreased autoantibody half-life Modulation of inhibitory Fc𝜸 R expression on innate immune effector cells and B cells Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
  • 26. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Fc receptor blockade • Fc receptor blockade of the reticuloendothelial system platelet counts rapidly increase after administration of IVIG (dose 1-2 g/kg) • Autoantibody-opsonized platelets are destroyed in spleen and liver by means of Fc𝜸R-mediated phagocytic clearance. • Fc receptor blockade on macrophages in spleen and in other parts of the reticuloendothelial system using an mAb directed against the Fc𝜸RIIIa receptor Benefit in ITP
  • 27. Anti-inflammatory activity of sialylated Fc • Sialylated Fc, present in low quantities in intravenous immune globulin, binds to SIGN-R1 on macrophages, resulting in the release of soluble mediators • These mediators bind to effector macrophages and increase expression of the inhibitory FcγRIIB receptors, which compete with antigen–antibody complex binding to activating FcγRs The net result is an increase in the concentration of the complexes required to initiate an inflammatory response Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
  • 28. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Saturation of FcRn • Benefit in Bullous pemphigoid, Arthritis, ITP • FcRn: specialized receptor binds serum IgG, protects IgG from degradation inside the lysosomes, • and returns IgG intact to plasma circulation • Shorten the half-life of the autoantibody, more rapidly eliminating it from the circulation
  • 29. Ballow M. et al. J Allergy Clin Immunol. 2011 Feb;127(2):315-23; quiz 324-5. Modulation of B cell • Long term effects in ITP • Inhibited both B cell receptor-dependent and independent antigen presentation (not mediated through the FcyRllb receptor but was mediated by intracellular events) • Under conditions such as CD40 activation: IVIG promote differentiation into IgG secreting B cells • Contains other specific antibodies that react with number of cell-surface determinants that could potentially modulate the immune response, such as the 𝛼𝑩-TCR, cytokine receptors, HLA determinants, CD5, CCR5, CD40, and sialic acid-binding immunoglobulin-like lectins 8 and 9
  • 30. Modulation of T cell immunoregulatory function • Benefit in Kawasaki disease, GBS, autoimmune encephalomyelitis • Suppress T-cell proliferative responses to mitogens by IVIG and F(ab')2 fragments to CD3 and CD28 stimulations • Expanding and enhancing the function of FOXP3-positive Treg cells increase production of IL-10, TGF-B, or effects on DC cells • Inhibited maturation of monocytes into immature dendritic cells Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
  • 34. Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30. Manufacturing Process • At present, there are more than 20 different IgG products commercially available worldwide • Despite having similar biological properties and efficacy, commercial IgG products are manufactured using different methods resulting in variations in their physicochemical properties including pH, sodium concentration, osmolality, sodium content, and IgA content • These characteristics may lead to differences in tolerability and adverse events (AEs)
  • 35. Bonilla FA, et al. Immunol Allergy Clin N Am 2008;28:803-819. Manufacturing Process • Exogenous concentrated immunoglobulins, mostly are “IgG” • Purified from pooled plasma obtained from thousand of donors • Same distribution of IgG subclasses, same half-life as normal plasma • Very small amount of IgA (varies among different products) • Only trace amounts of IgM
  • 37.
  • 38.
  • 39. Three dedicated virus reduction steps Poelsler G, et al. Vox Sang. 2008 Apr;94(3):184-192.
  • 41. Pharmacokinetics of Immunoglobulin Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19 Two-compartment model of IgG pharmacokinetics
  • 42. Pharmacokinetics of Immunoglobulin Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19 Saturation of the FcRn
  • 43. Pharmacokinetics of Immunoglobulin Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19
  • 44. Indications of IVIG • Replacement therapy • Prevent infections • Primary and secondary immunodeficiency • Immunomodulatory mechanisms • Treatment of autoimmune pathology • Higher dose of immunoglobulin Gelfand EW. et al. N Engl J Med. 2012 Nov 22;367(21):2015-25.
  • 45. Indications of IVIG: Immunodeficiency Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
  • 46. IVIG in Primary immunodeficiency Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. A framework of 6 distinct phenotypes of PI disease for which Ig replacement is or may be indicated: 1. Agammaglobulinemia due to absence of B cells 2. Hypogammaglobulinemia with poor antibody function 3. Normal immunoglobulins with poor antibody function 4. Hypogammaglobulinemia with normal antibody function 5. Isolated IgG subclass deficiency with recurrent infections 6. Recurrent infections due to a complex immune mechanism related to genetically defined PI disease
  • 47. Agammaglobulinemia due to the absence of B cells Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • Evaluation of IVIG usage in patients lacking immunoglobulin has demonstrated a clear benefit in terms of reducing both acute and chronic infections • In severe combined immunodeficiency (SCID), the T-cell defect is often accompanied by an absence of B cells or B-cell function • Immunoglobulin replacement is warranted at diagnosis, post-transplantation period, during gene therapy or enzyme replacement (for adenosine deaminase deficiency), until B-cell function is restore • In case of B-cell function is never restored, and continual immunoglobulin replacement remains necessary
  • 48. Hypogammaglobulinemia with impaired specific antibody production Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • In patients with recurrent bacterial infections, reduced levels of serum immunoglobulin, coupled with a lack of response to protein and/or polysaccharide vaccine challenge (ie, in patients who cannot make IgG antibody against diphtheria and tetanus toxoids and/or pneumococcal polysaccharide vaccine), are a clear indication of immunoglobulin replacement The prototype of this category is CVID
  • 49. Normal levels of immunoglobulins with impaired specific- antibody production (selective antibody deficiency) Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • Patients with normal total IgG levels but impaired production of specific antibodies, including those with isolated deficient responses to numerous polysaccharide antigens following vaccination • Severity of infection and/or the efficacy of antibiotic prophylaxis should be the driving force behind any decision to provide immunoglobulin replacement therapy • IVIG replacement therapy should be provided when there is well-documented severe polysaccharide non-responsiveness and evidence of recurrent infections
  • 50. Normal levels of immunoglobulins with impaired specific- antibody production (selective antibody deficiency) Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • The treatment may be stopped after a period of time (preferably in the spring in temperate regions) and that the immune response will be reevaluated at least 3-5 months after the discontinuation of IVIG • While some patients, usually children, show improved responses to antigen challenge (typically with pneumococcal polysaccharide vaccine) after treatment with immunoglobulin for 6-24 months and improve clinically, others require restarting the immunoglobulin therapy because of a recurrence of infections • Cessations of therapy are likely to identify whether a patient's defect in antibody specificity was transient
  • 51. Hypogammaglobulinemia with normal-quality antibody response Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. Transient hypogammaglobulinemia (THI) • IgG levels normalize with age and antibody function is initially partially impaired but typically intact • In select cases, treatment with replacement immunoglobulin may be considered temporarily • Age-specific normal ranges of IgG vary, and 2.5% of healthy individuals have 'lower-than-normal" IgG (below the lower limit of the 95% confidence interval for age), which may not be clinically significant, in the absence of recurrent infections
  • 52. Hypogammaglobulinemia with normal-quality antibody response Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. Isolated hypogammaglobulinemia (other than THI) can be a feature of many immune function defects, and must be differentiated from secondary causes • Increased loss of IgG, such as chylothorax, lymphangiectasia, or protein-losing enteropathy • Medication, especially corticosteroids, some seizure medications, and biologics such as rituximab
  • 53. Hypogammaglobulinemia with normal-quality antibody response Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • A subset of patients also present with very low IgG and no history of infection • Severe hypogammaglobulinemia should be considered a risk for infection • IgG level <150 mg/dL is widely accepted as severe hypogammaglobulinemia, for which additional testing apart from verification of the low level is not required prior to starting replacement therapy • Levels between 150 and 250 mg/dL are also considered severely low but warrant consideration of additional testing for specific antibody against vaccines to assess function, depending on the clinical history
  • 54. Normal immunoglobulin levels and normal quality with deficient IgG subclass Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • Isolated subclass deficiency is often asymptomatic, but a minority of patients may have poor antibody responses to specific antigens and recurrent infections • Prophylactic antibiotics and the treatment of other underly conditions, such as allergies or asthma, that may contribute to recurrent sinopulmonary infections are the usual management • Immunoglobulin replacement should remain a therapeutic option in patients in whom other ameliorative interventions have failed
  • 55. Recurrent infections due to an unknown immune mechanism Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • The need for immunoglobulin therapy may arise as the only viable option for therapy in PIs in which the mechanism underlying the susceptibility to recurrent infection is not yet characterized, the patient presents with recurrent infections and an otherwise normal or near-normal immune function evaluation • Hyper-IgE syndrome who usually have normal serum IgG, IgM and IgA levels, but who may have defects in antibody responses
  • 56. Recurrent infections due to an unknown immune mechanism Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • Wiskott-Aldrich syndrome (WAS) is another immunodeficiency typically characterized by normal total IgG, but with impaired specific-antibody responses against both protein and polysaccharide antigens: immunoglobulin therapy should always be a consideration in this disease • The same considerations as for WAS apply to ataxia telangiectasia (AT) as well as others of these types of combined immunodeficiencies, including, but not limited to, deficiencies in STAT-3, nuclear factor-kB essential modulator (NEMO), and STAT-1
  • 57. IVIG in Secondary immunodeficiency Otani IM, et al. J Allergy Clin Immunol. 2022 May;149(5):1525-1560.
  • 58. IVIG in Secondary immunodeficiency Otani IM, et al. J Allergy Clin Immunol. 2022 May;149(5):1525-1560.
  • 59. IVIG in Secondary immunodeficiency Otani IM, et al. J Allergy Clin Immunol. 2022 May;149(5):1525-1560.
  • 60. Indications of IVIG: Autoimmune diseases Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
  • 61. Indications of IVIG: Infectious diseases Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
  • 62. Indications of IVIG: Miscellaneous uses Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
  • 63. Practical use of IVIG therapy Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
  • 65. IVIG therapy in Immunodeficiency Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46.
  • 66. Route of Ig administration Patel NC, et al. Pediatr Allergy Immunol. 2018 Sep;29(6):583-588.
  • 67. Berger M, et al. Clin Immunol. 2004 Jul;112(1):1-7. IVIG vs SCIG
  • 68. Bonilla FA, et al. Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19 Serum IgG levels during SCIG (A) Weekly infusions • The lgG levels vary, on average, less than 10% over the week in between infusions (B) Biweekly infusions • The lgG level varies more than it does with weekly infusions, but not as much as with IVIG • The absorption is still blunted in comparison to IVIG Dose is absorbed slowly and redistributed slowly, whereas concentration dependent catabolism is ongoing
  • 69. Dosages of intravenous immunoglobulin Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30. Primary immunodeficiency disease • Recommended starting dosages • 400-600 mg/kg every 3-4 weeks • Equilibration takes up to 3 months • Dose must be individualized to achieve clinical benefit for each patients Autoimmune/inflammatory disease • Doses are generally 4-5 times higher than those used for replacement therapy • 1-2 gm/kg in 1-2 days • 2 gm/kg in 2-5days Target trough level o > 500 mg/dl: prevent serious bacterial infections o > 800 mg/dl: recurrent pneumonia, structural lung damage o PID without chronic lung disease: 600-800 mg/dl o PID with chronic lung disease: >800 mg/dl
  • 70. Dosages of intravenous immunoglobulin Orange JS, et al. Clin Immunol. 2010 Oct;137(1):21-30. For each 100 mg/kg of IVIG à Trough levels increased by ~100 mg/dl
  • 71. Dosages of subcutaneous immunoglobulin Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30. • The usual dose for SCIG is also 300 to 500 mg/kg/month, similar to the IVIG dose • Infusions are usually given weekly at 25% of the monthly dose • Thus a weekly dose of 100 mg/kg (400 mg/kg/month requires a subcutaneous infusion of 1.0 mL/kg of a 10% IG product or 0.5 mL/kg of a 20% IG product.)
  • 72. Dosages of subcutaneous immunoglobulin Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30. • This is given slowly using a portable infusion pump • Multiple sites on the abdominal wall, thighs or arms can be used so that no more than 5 to 30 mL is given at a single site, depending on the patient's weight • Because of the lessened risk of systemic side effects, SCIG can be given at home, often by self-infusion, and without premedication
  • 73. Skoda-Smith S, et al. Ther Clin Risk Manag. 2010 Feb 2;6:1-10.
  • 74. Side effect of IVIG Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. • Most reactions are mild and non-anaphylaxis • 1/3 of patients receiving IVIG experience systemic adverse effects during or within 72 hours after infusions
  • 75. Side effect of IVIG Infusion-related reactions • IgG aggregates form oligomeric or polymeric IgG • Interact with Fc receptors on phagocytes or monocytes • Complement activation Serious adverse effects • Anaphylaxis • Thromboembolic events May be due to increased viscosity/osmolality • Renal failure Sucrose containing products • Aseptic meningitis • Hemolysis Anti-A and anti-B antibodies isoagglutinin To prevent IVIG infusions-related reactions • Starting the infusion slowly • Currently marketed IVIG products contain stabilizers to reduce IgG aggregation Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.
  • 76. Side effect of IVIG: Risk factors Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30. Infusion related • First infusion • Larger dose • Rapid infusion rate Product related • Type of stabilizer • Sodium content • Osmolarity • pH • IgA content Patient related • Advanced age • Active infection or fever • Hypercoagulable state • Cardiovascular risk • Preexisting renal disease
  • 78. Side effect of IVIG Bayry J, et al. Nat Rev Rheumatol. 2011 Jun;7(6):349-59.
  • 79. Management of adverse reactions Sriaroon P, et al. Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30. • Slow or half the rate • Subsequent infusions • Administer more slowly. • Administer smaller doses, more frequently • Medication and premedication • Acetaminophen, ibuprofen, H1-antihistamine • Severe reactions: systemic steroid • If pre- and post-infusion medications and manipulations of IVIG dosing regimen do not control adverse reactions à changing IVIG product or switch to SCIG
  • 80. Guo Y, et al. Front Immunol. 2018 Jun 8;9:1299.
  • 81. Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66. Differences among products • Formulation (liquid, Iyophilized) • Volume load • Sodium content • Type of stabilizer • Osmolality • IgA content • pH
  • 82. Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66. Differences among products Stabilizers • To minimize IgG aggregates • Type of stabilizers: Amino acids: proline, glycine Sugars: sorbitol, maltose, glucose, sucrose ㆍSugar contents associate with adverse events Osmotic nephrosis Sucrose: renal toxicity, renal failure/insufficiency
  • 83. Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66. Differences among products Volume load • An important consideration in very young, elderly, cardiac impairment Sodium content • Varies widely in currently available preparations • High salt contents à higher incidence of AEs & thromboembolic complications Osmolality • Sodium & sugar content • Physiologic osmolality: 280-296 mOsm/kg of water • Hyperosmotic state à thromboembolic complications
  • 84. Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66. Differences among products pH • Optimum pH: 4.0-4.5 to remain IgG in unaggregated state • Low pH may be associated with phlebitis IgA Content • IgG or IgE anti-IgA antibodies in patients with hypogammaglobulinemia and absent serum IgA who are receiving IgA-containing IVIG can cause severe reactions including anaphylaxis. • To minimize risk of severe reactions/anaphylaxis - Use products with the lowest concentration of IgA - Starting initial IVIG infusion slowly and gradually increase the rate with subsequent infusions CVID patient with serum IgA level <7 mg/dL are at highest risk
  • 85. Saeedian M, et al. International Archives of Allergy and Immunology. 2014;164(2):151-66. IVIG characteristics corresponding to patient risk factors
  • 87. Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. SC form IV/SC form
  • 88. Perez EE, et al.. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. IM form
  • 90. Differences among products: available at KCMH Product Dosage formulation Osmolality (mOsm/L) Sodium pH IgA (μg/ml) Stabilizer TRCS 5% liquid 240-350 Trace 4-7.4 <100 Maltose Flebogamma 5% liquid 240-370 Trace 5-6 <50 D-sorbitol Liv-Gamma 5% liquid N/A N/A N/A N/A Maltose Gamunex 10% liquid 258 None added 4-4.5 46 Glycine Privigen 10% liquid 240-440 Trace 4.6-5 <25 L-proline Kiovig 10% liquid 240-300 None added 4.6-5.1 37 Glycine Hizentra (SC) 20% liquid 380 Trace <10 mmol/L 4.6-5.2 <50 Proline
  • 91. IVIG products: available at KCMH Available at KCMH Amount (gram) Volume (ml) Price (THB) 5% LIV-Gamma 5g 100 7,211 5% Flebogamma DIF 2.5 g 50 6,111 5% Flebogamma DIF 10g 200 24,261 5% TRCS 2.5 g 50 2,790 5% TRCS 5g 100 5,150 10% Kiovig 10g 100 22,983 10% Gamunex-C 10g 100 22,071 10% Privigen 5g 50 11,501
  • 92. 5% LIV-Gamma 10% Kiovig 5% TRCS 10% Gamunex-C 10% Privigen 5% Flebogamma DIF
  • 93. Lived vaccines and IVIG IVIG dosages Lived vaccine interval 400 mg/kg 8 months 1 g/kg 10 months 2 g/kg 11 months ตําราวัคซีนและการสร้างเสริมภูมิคุ้มกันโรคปี ;<=>