Immunoglobulin replacement therapy

16th February 2018
Thansinee Saetae, MD.
Pediatric Allergy and Immunology unit
King ChulalongkornMemorial Hospital

• Immunoglobulin G
• Structure
• Effectors function of antibodies
• Immunoglobulin replacement Therapy
• Mechanism
• Route of administration
• Catabolism
• Pharmacokinetic
• Indication for IgG replacement
therapy
• US-FDA approved indication
• IgG replacement therapy in PIDs
• ข ้อบ่งใช ้ตามบัญชียาหลักแห่งชาติ
• IVIg replacement therapy
• Properties of IVIG
• Products
• Manufacturing process
• QC and specifications of IgG preparations
• Dosage & Trough level
• Adverse events
• SCIg replacement Therapy
• Products
• Adverse events
• IVIg VS SCIg
• Switching IVIg to SCIg
• Immunoglobulin available products
• IVIg products available in KCMH

• Structure
• Effectors functions of antibodies

Abbas et al. Cellular and Molecular Immunology. 8th edition

• Mechanism of action
• Route of administration
• Catabolism
• Pharmacokinetic

J G Peter et al. S Afr Med J 2014;104(11):796

Tha-In T et al. Trends Immunol 2008;29:608-14.

• IVIG replacement therapy has been used for many years.
• SCIG is now widely available in Europe, the United States and a
steadily growing number of other countries.
• slower rate at which IgG reaches the bloodstream
• reduce incidence of systemic and severe adverse events
• more frequent administration
• IMIg is no longer considered appropriate for routine replacement
therapy.
• appropriatefor administration of specific Ig for infection prophylaxis
• tetanus, rabies, hepatitis B, varicella
S. Jolles et al. Clinical and Experimental Immunology 2014;179: 146–160
Bonilla. Immunol Allergy Clin N Am 2008;28:803–819

The fractional catabolic rate
of IgG increases as the
serum concentration rises
and vice versa

• slower than all other Ig classes
• saturable protection receptor system for IgG Fc

The mechanism of the concentration dependence of
IgG catabolism mediated by FcRn

Longer infusion intervals
(weeks) are more likely to
deviate from the observed
decay curve in the early
phase, as opposed to the
late phase.

More physiologic IgG levels
• the peaks and nadirs between
infusions are blunted
• slow absorption and
maintenance of closer
equilibrium between intra- and
extravascular compartments.

S. Jolles et al. Clinical and Experimental Immunology 2014;179: 146–160

• US-FDA approved indication
• IG replacement therapy in PIDs
• ข ้อบ่งใช ้ตามบัญชียาหลักแห่งชาติ

Perez et al. J Allergy Clin Immunol 2017;139:S1-46

• Immunoglobulin therapy is vital for minimizing potentially fatal
infections and improving quality of life and overall clinical outcomes.
• Clinical trials of immunoglobulin replacement are not feasible in the
more rare disorders
• Only lower evidence-based recommendation scores are available for some.
(1) Agammaglobulinemia due to absence of B cells: XLA, SCID
(2) Hypogammaglobulinemiawith poor antibody function: CVID, HIGM
(3) Normal immunoglobulins with poor antibody function
(4) Hypogammaglobulinemiawith normal antibody function: THI
(5) Isolated IgG subclass deficiency with recurrent infections
(6) Recurrent infections due to a complex immune mechanism related to a genetically defined PI
disease: HIES, WAS, AT, deficiencies in STAT-3, NEMO, STAT-1

• Acute phase of Kawasaki disease
• Primary immunodeficiency diseases
• Immune thrombocytopenia ชนิดรุนแรง
• Autoimmune hemolytic anemia (AIHA) ที7ไม่ตอบสนองต่อการรักษา ตามขัDนตอนของมาตรฐานการ
รักษาและมีอาการรุนแรงที7อาจเป็นอันตรายถึงแก่ชีวิต
• Guillain–Barre syndrome ที7มีอาการรุนแรง
• Myasthenia gravis, acute exacerbation หรือ Myasthenic crisis
• Pemphigus vulgaris ที7มีอาการรุนแรง และไม่ตอบสนองต่อการรักษาด้วยยามาตรฐาน
• Hemophagocytic lymphohistiocytosis (HLH)
• Dermatomyositis ทีHมีอาการรุนแรง
บัญชียาหลักแห่งชาติ พ.ศ.2561
ข้อบ่งใช้ตามบัญชียาหลักแห่งชาติ บัญชี จ(2) ปี 2561

รายชืHอโรคภูมิคุ้มกันบกพร่องปฐมภูมิ
แต่ละชนิดที7ต้องได้รับการระบุในแบบฟอร์มขออนุมัติการใช้ยา
• Common Variable immunodeficiency (CVID)
• Severe combined immunodeficiency (SCID)
• DiGeorge anomaly
• X-linked agammaglobulinemia(XLA or Bruton's
agammaglobulinemia)
• Autosomal recessive agammaglobulinemia
• X-linked hyper-IgM syndrome
• Autosomal recessive hyper-IgM syndrome
• Ataxia-telangiectasia and diseases of DNA repair
defects
• Wiskott-Aldrich syndrome
• X-linked lymphoproliferative syndrome (XLP)
• Isolated IgG subclass deficiency
• IgA with IgG subclass deficiency
• Specific antibody deficiency with normal Ig
concentrations and numbers of B cells
• Reticular dysgenesis
• Omenn syndrome
• Thymoma with immunodeficiency (Good
syndrome)
• Transient hypogammaglobulinemiaof infancy
• Cartilage hair hypoplasia
• Hyper- IgE syndrome
• WHIM syndrome

• ต้องไม่เป็นผู้ป่วยระยะสุดท้าย (terminally ill)
• ต้องไม่เป็นผู้ป่วยที7ได้รับการวินิจฉัยว่าเป็น dermatomyositis associated with malignancy
• ผู้ป่วยได้รับการวินิ จฉัยว่าเป็ นโรค dermatomyositis โดยมีผื7นที7เป็นลักษณะจาเพาะสําหรับโรคนีD
ได้แก่ Heliotrope หรือ Gottron’s papule หรือ Gottron’s sign หรือ V-sign หรือ Shawl’s sign หรือ
Mechanic’s hands ร่วมกับ มีลักษณะทางคลินิกอย่างน้อย 2 ใน 4 ข้อ ดังต่อไปนีD
• มีกล้ามเนืDอส่วนต้นแขนและต้นขาอ่อนแรงแบบสมมาตร (symmetrical proximal muscle weakness)
• มีระดับเอนไซม์ของกล้ามเนืDอชนิดใดชนิดหนึ7งสูงขึDน ได้แก่ creatinine kinase (CK) หรือ aspartate transaminase
(AST) หรือ alanine transaminase (ALT) หรือ lactate dehydrogenase(LDH)
• ผลตรวจทางพยาธิวิทยาของกล้ามเนืDอเข้าได้กับภาวะกล้ามเนืDออักเสบ (inflammatory myopathy)
• ผลการตรวจคลื7นไฟฟ้ากล้ามเนืDอเข้าได้กับภาวะกล้ามเนืDออักเสบ (inflammatory myopathy)
เกณฑ์อนุมัติการใช้ยาในผู้ป่วย Dermatomyositis ทีHมีอาการรุนแรง

• ผู้ป่วยต้องมีอาการรุนแรงจนอาจถึงแก่ชีวิต (life-threatening condition) ซึ7งหมายถึง กล้ามเนืDอที7เกี7ยวข้อง กับ
การหายใจ (respiratory muscle) หรือการกลืน (esophageal involvement) อ่อนแรงขัDนรุนแรง ได้แก่ มี
ภาวะการหายใจล้มเหลวชนิดเฉียบพลัน (acute respiratory failure) หรือมีประวัติสาลักอาหารจนเกิดปอด
อักเสบเฉียบพลัน (aspiration pneumonia)
• ผู้ป่วยไม่ตอบสนองต่อการรักษาด้วยยากลุ่มสเตียรอยด์ (steroids) ในขนาดสูงหรือยากดภูมิคุ้มกัน
(immunosuppressive agents) หรือเกิดผลข้างเคียงอย่างรุนแรงจากการรักษาดังกล่าว หรือไม่สามารถให้
ยากลุ่มสเตียรอยด์หรือยากดภูมิคุ้มกันในการรักษาเบืDองต้นได้ตามคําจํากัดความข้อใดข้อหนึ7งดังต่อไปนีD
• ไม่ตอบสนองต่อการรักษาด้วยยากลุ่มสเตียรอยด์ในขนาดสูงหรือยากดภูมิคุ้มกัน หมายถึง ได้รับยา ดังกล่าวมาแล้วอย่างน้อย
2-4 สัปดาห์ แล้วอาการไม่ดีขึDน หรือ
• เกิดผลข้างเคียงอย่างรุนแรงจากการรักษาด้วยยากลุ่มสเตียรอยด์ในขนาดสูงหรือยากดภูมิคุ้มกัน หมายถึง การเกิดผลข้างเคียง
จนอาจเป็นอันตรายถึงแก่ชีวิต เช่น เม็ดเลือดขาวต่าอย่างรุนแรง (agranulocytosis) เป็นต้น หรือ
• ไม่สามารถให้การรักษาด้วยยากลุ่มสเตียรอยด์หรือหรือยากดภูมิคุ้มกัน เช่น มีการติดเชืDออย่างรุนแรงและยังไม่สามารถควบคุม
ได้ด้วยยาปฏิชีวนะ (antibiotics) เป็นต้น
เกณฑ์อนุมัติการใช้ยาในผู้ป่วย Dermatomyositis ทีHมีอาการรุนแรง

• Properties of IVIG
• Products
• Manufacturing process
• QC and specifications of IgG preparations
• Adverse events

Robert R Rich. Clinical immunology principle and practice 3rd edition 2008;1265-1280

• The number of donors contributing to a pool that will be processed
to yield IVIG has been recommended by the FDA and Plasma Protein
Therapeutics Association: 15,000-60,000 donors.
• Donor screening: Hx, PE, CBC, LFT
• Donor testing for viral pathogens:
• HBsAg
• HIV-p24 antigen
• HIV-1, HIV-2 antibodies
• HCV antibodies
• Antibodies to syphilis
• Pooled plasma testing: sensitive nucleotide testing

Sriaroon & Ballow. Immunol Allergy Clin N Am 2015;35:713–730
Remove both non–lipid-coated viruses and prions
Prevent aggregation of purified IgG
Precipitate the immunoglobulin-
containing fraction
Inactivate any residual pathogens
Removal of IgG aggregates

M. Radosevich & T. Burnouf. Vox Sanguinis 2010;98:12–28

• An acceptable starting point for maintenance dosing is 400-600
mg/kg every 3-4 weeks
• Be aware of weight changes in growing children and adjust doses accordingly.
• When initiating therapy, patients with extremely low IgG levels may
benefit from a larger loading dose before the initiation of regular
maintenance dosing.
• 1 g/kg administered slowly
• Half dose every 2 weeks to a full dose to minimize adverse event.

• After the fifth infusion, a steady state will have been achieved.
• steady-state IgG levels of approximately 600 to 800 mg/dL
• Variability in the pharmacokinetics of IgG between patients,
• different trough levels in different patients
• For each 100 mg/kg of IVIG infused
• Peak levels generally increase by 250 mg/dL.
• Trough levels increase by approximately 100 mg/dL.

• Trough level > 500 mg/dL
• prevent serious bacterial infections
• Trough level > 800 mg/dL
• very low IgG levels
• recurrent pneumonia
• severe infection
• structural lung damage (eg bronchiectasis)
• The biological trough level should be the serum IgG trough level that best
improves a patient’s clinical course and infection rate.
• The trough or steady-state IgG levels can be measured after 3 months.
• Once infection rates have improved and IgG levels are in the desirable range, the IgG
trough level can be measured every 6 to 12 months.

Data from meta-analysis in PID patients with
hypogammaglobulinemia receiving IVIG
J.S. Orange et al. Clin Immunol 2010;137:21-30

Infection outcomes in CVID patients
during Ig therapy over 22 years
• 3 different thresholds of breakthrough infections
• Similar results
• Doses of replacement Ig required to keep a
particular patient free of bacterial infections are
individual to that patient.
• The goal of therapy should be to reduce
breakthrough infections rather than to achieve a
particular IgG trough level.
Lucas et al. J Allergy Clin Immunol 2010;125:1354-60

Biologic IgG level in PID patients
The biologic IgG level
• minimal serum IgG level that renders a patient as disease free as possible
• unique for each patient
Bonagura VR et al. J Allergy Clin Immunol 2008 Jul;122(1):210-2

• Rapid physical changes
• weight gain, pregnancy, or growth spurts after entering puberty.
• Obese individuals
• exclude from clinical trials
• Fixed dosing or dose adjustment according to ideal body weight
• Significant infections, or IgG trough or steady-state levels remain low
• the therapy should be titrated up
• by increasing the dosage or shortening the infusion interval
• Wear-off effects
• Eg.malaiseor upper respiratory symptoms during the week prior to the next infusion
• shortening the infusion interval
• switching to SCIG

• Immune Deficiency Foundation 44% report experiencing adverse reactions
• Most IVIG reactions are rate-related, are mild, and occur in only 5-15% of
infusions.
• Back or abdominal pain, nausea, breathing difficulties, chills, flushing, rash, anxiety,
low-grade fever, arthralgia, myalgias, and/or headache
• Slowing or stopping the infusion for 15-30 minutes will reverse many reactions.
• Pretreatment : 1 hour before the infusion
• NSAIDs, acetaminophen (15 mg/kg/dose)
• Diphenhydramine (1 mg/kg/dose)
• Nonsedating antihistamine
• Hydrocortisone (6 mg/kg/dose; maximum, 100 mg)
• Oral hydration prior to the infusion is often helpful.
If side effects continue,
changing the IVIG product or
switching to SCIG should be
considered.

• More common AEs
• newer received IVIG, new IVIg product
• recently bacterial infection
• underlying chronic inflammation
• Possible mechanisms
• Complement activity
• infused antibodies + antigens of infectious agents in the patient à immune complexes
• Formation of IgG complexes that interact with Fc receptors
• release of inflammatory mediators.
• Newer liquid IVIG preparations are generally better tolerated.
• liquid formulation
• stabilizers to prevent IgG complex formation
The result of components
• IgG products
• rapid infusion rate
• patient’s risk factors
• combinations

Anaphylaxis VS Anaphylactoid Reactions
• True IgE-mediated anaphylactic reactions are uncommon.
• Anaphylactoid reactions may occur as a result of IgG aggregates.
• decrease in severity over time with repeated use of the same IVIG product
• usually associate with hypertension
• activation of the complement and the kallikrein-kinin systems
àcytokines and lipid mediators.
• patients with active infections

Reactions Due to Anti-immunoglobulin A Antibodies
• preformed IgE or IgG antibodies to IgA
• True anaphylaxis due to IgE anti-IgA is extremely rare.
• CVID and undetectable levels of serum IgA are at highest risk.
• Profound hypogammaglobulinemia, agammaglobulinemiaand low serum
IgA levels are presumably not at risk .
• IVIG infusion should be initiated slowly at 0.001 mL/kg/min.
• Anti-IgA antibody levels are not routinely measured.
• All currently available IVIG preparations have at least trace amounts of IgA.
• If anaphylaxis occurs
• change to one with the lowest IgA content
• SCIG

Aseptic Meningitis
• The cause remains unclear.
• Symptoms often begin within 24 hours after infusion and may last several days.
• Risk factors
• High dose IVIG (1–2 g/kg)
• Rapid infusion
• History of migraine
• Rarelyseen in patients with PID.
• Treatment
• Corticosteroids such as prednisone or hydrocortisone for a few days may be effective.
Treatment of autoimmune or inflammatory conditions

Renal Complications
• Acute renal insufficiency is a rare but serious AE.
• Osmotic injury to the proximal renal tubular cells.
• sucrose as the stabilizer à infusion rate should not exceed 3 mg/kg/min
• Respond well to conservative treatment
• Permanent renal failure and mortality have been described.
• preexisting renal disease, diabetes, advanced age (>65 years), paraproteinemia,
dehydration, sepsis, and concomitant use of nephrotoxic agents.
• use a non-sucrose-containing product
• IVIG solutions more concentrated than 5% should be avoided.
• Prehydrating IV fluid
• Fractionating doses into smaller ones given on different days

Acute Hemolysis and Hemolytic Anemia
• Anti-A or anti-B IgG isohemagglutinins in IVIg
• Rarely in PID patients
• The major risk factors
• large doses, active systemic inflammatory state and non-O blood group.
• There are case reports of reactions in patients with blood type O
• other non-A/B antibodies might also contribute.
• The presentations
• absence of symptoms
• clinically significant or even severe intravascular hemolysis
• acute renal failure à deaths

Thromboembolic Events
• Local thromboses, DVT, MI, PE, TIA, stroke, and TRALI
• Potential risk factors
• advanced age, smoking, cardiovascular risk, DM, dyslipidemia, anemia, polycythemia,
hypercoagulable state, hyperviscosity, supplemental estrogens, indwelling vascular
catheters
• Increase serum viscosity from the IgG itself and/or hypertonic state (caused
by sugars or other stabilizers) that may induce platelet activation.
• First infusions, large dose, and rapid infusion rate are also associated with TEEs.
• The increase in FXIa in IVIg likely correlates with the rates of TEEs
• Management
• slow infusion rate (0.05 g/kg/ h for the first hour and 0.1 g/kg/h thereafter)
• preinfusion/postinfusion hydration
• limiting IVIG administration to 0.4 to 0.5 g/kg/d
• prophylaxis with aspirin, antiplatelet medication, or low-molecular-weight heparin

E.W. Gelfand. Int Immunopharmacol 2006;6:592-599

• Products
• Adverse events
• IVIg VS SCIg
• Switching IVIg to SCIg

• SCIG therapy was FDA-approved for use in the treatment of PIDs only.
• Popularity during the past decade for several reasons
• similar efficacy to IVIG
• significantly fewer systemic AEs
• shorter infusion time
• almost no wear-off effects
• more flexibility in scheduling, a feeling of independence, and improved quality of life.
• SCIG might not be a suitable option for elderly patients.
• who lack assistance at home or patients with poor compliance.
• Safety profile
• well tolerated in vulnerable patients: children, pregnant women and the elderly
population.
• well tolerated in patients who have IgA deficiency.

• SCIG administration should be individualized for each patient.
• Starting dose of 100-200 mg/kg each week.
• Frequency
• Products available for daily to weekly, biweekly or monthly --> 20% SCIG formulation
• Monthly SCIG: hyaluronidase, increase tissue permeability and facilitates the slow
absorption of IgG
• Infusion rate
• 10 to 35 mL/hr/site by pump à 30 to 90 minutes or 5 to 20 minutes via rapid push
• Lower volumes and rates: 20% SCIG formulation

• Site
• abdomen, outer thigh, upper arm and buttock.
• The number of sites
• 1 to 6 sites
• depend on total volume à volumes of 15-40 mL/site.
• Steady state
• levels should be monitored periodically after approximately 3 months
• half-life of SCIG can vary significantly (ranging from 18 to 46 days)
• Absorption
• particularly erratic in the first 24 hours
• Total serum IgG levels
• can be used for monitoring patient adherence.

• Rare of systemic AEs (< 5% of patients)
• smaller doses at each administration
• gradual systemic absorption
• Local site reactions are common. (upto 75%)
• itchiness, swelling, warmth, redness, induration, soreness, or bruising
• Symptoms generally last for less than 24 to 48 hours and do not require treatment.
• do not usually lead to treatment discontinuation.
• decrease with repeated infusions.
• minimized by
• carefully cleaning the skin
• length of the infusion needle reaching the SC compartment
• Long-term sequelae at the infusion sites have not been described.
• fibrosis, atrophy, lipodystrophy, or SC nodules

• The 1st SCIG infusion is usually given 1 to 2 weeks after the last IVIg.
• Without active infection: SCIG treatment without transitioning from IVIG.
• New steady state5 to 12 weeks
• Serum IgG level is generally higher than the serum IgG trough levels of IVIg cycle
• The bioavailability of SCIG is approximately 66.7% +/-1.8% of IVIG.
• Adjust dose
• USA: base on area-under-the-curve calculation
• 1.37 for the 16% preparations
• 1.53 for the 20% formulation
• Europe:
• not adjusted dose

All Intravenous Immunoglobulin Products are not created equal.

Trade name
Dosage
form
Strength/package size ราคาขาย
บ ัญชียาหลัก
แห่งชาติ
KIOVIG inj 5 gm, 50 mL 12,125 จ(2)
LIV-GAMMA (G) inj 5 gm, 100 mL 8,200 จ(2)
FLEBOGAMMA DIF5% inj 2.5 gm, 50 mL 6,111 จ(2)
FLEBOGAMMA DIF5% inj 10 gm, 200 mL 24,261 จ(2)

LIV-GAMMA KIOVIG FLEBBOGAMMA
Formulation 5% liquid 10% liquid 5% liquid
Sodium content NA NA <0.032
Stabilizer Maltose Glycine D-sorbitol
Osmolality (mOSm/kg) >240 240-300 240-350
IgG (g/L) >95% >98% >99%
IgM (g/L) NA NA Trace
IgA (mcq/mL) NA <140 <50
pH 4.0-7.4 4.4-4.9 5-6
Refrigeration 2-8 C 2-25 C 2-25 C
HIV ELISA ELISA, PCR NAT, PCR
HAV - PCR NAT
HBV ELISA ELISA, PCR NAT, PCR
HCV PCR ELISA, PCR NAT, PCR
Parvovirus B NA PCR (<105 IU/mL) NAT (<104 IU/mL)
Viral
inactivation/removal
S/D S/D, low pH incubate,
Nanofiltration (35nm)
Pasteurization, PEG, S/D, Low pH
incubation, Nanofiltration (35nm)
Manufacturer SK chemicals, Korea Baxter, Belgium Grifols, Spain

Immunoglobulin replacement therapy

Immunoglobulin replacement therapy

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Immunoglobulin replacement therapy

Similar to Immunoglobulin replacement therapy (20)

More from Chulalongkorn Allergy and Clinical Immunology Research Group

More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Recently uploaded

Recently uploaded (20)

Immunoglobulin replacement therapy