Intravenous immunoglobulin (IVIG)

Intravenous immunoglobulin (IVIG) therapy
History
Applications
Indications
Safe practice

1. Usama Ragab Youssif Assistant Lecturer of Medicine Clinical Immunology IVIG Sunday, 6 January 2019 Sharkia Medical Syndicate Clinical Immunology 1 st Announcement

2. Outlines Definitions & Nomenclatures Structure of immunoglobulins Immunoglobulins in our bodies Physiologic actions of immunoglobulins The Idea behind use of immunoglobulins Uses: indications, mechanisms, preparation, posology, administration Adverse effects Safe practice Final bottom-line 2

3. Immunoglobulins Also called antibodies . Group of glycoprotiens present in the serum and tissue fluid of all mammals. They are found mainly in the gamma globulin fraction of the serum. They bind specifically to the antigen that induced their production. Produced by differentiated B cells termed plasma cells 3 Abla M. El- Mishad : Manual of Microbiology & Immunology. Vol I 8 th Edition. 2010 El- Ahram press Egypt

4. IVIG or IVIg IVIG is an abbreviation for Intravenous Immunoglobulin Administered intravenously in case of IVIG IG therapy has other route. 4 Spickett , Gavin. Oxford handbook of clinical immunology and allergy. Oxford University Press, 2013.

5. Structure of immunoglobulin 5 https://www.nobelprize.org/prizes/medicine/1972/porter/facts/ Rodney R. Porter Gerald M. Edelman

6. Structure of immunoglobulin (cont.) 6 Gorczynski , R., and J. Stanley. "Clinical immunology–An introductory text."  Immunology, T lympho-cytes . Texas: Landes Bioscience  (1999): 2-185.

7. Structure of immunoglobulin (cont.) 7 Abla M. El- Mishad : Manual of Microbiology & Immunology. Vol I 8 th Edition. 2010 El- Ahram press Egypt

8. Structure of immunoglobulin (cont.) Diversity Specificity Cellular Biologic 8 Gorczynski , R., and J. Stanley. "Clinical immunology–An introductory text."  Immunology, T lympho-cytes . Texas: Landes Bioscience  (1999): 2-185.

9. Structure of immunoglobulin (cont.) 9 Gorczynski , R., and J. Stanley. "Clinical immunology–An introductory text."  Immunology, T lympho-cytes . Texas: Landes Bioscience  (1999): 2-185.

10. Physiologic Effects of IgG Fab fragment activity = antigen binding site Agglutination Neutralization Opsonization 10 Abla M. El- Mishad : Manual of Microbiology & Immunology. Vol I 8 th Edition. 2010 El- Ahram press Egypt

11. Physiologic Effects of IgG (cont.) Fc fragment activity = Crystallization Fragment Complement activation ADCC Inflammation 11 Abla M. El- Mishad : Manual of Microbiology & Immunology. Vol I 8 th Edition. 2010 El- Ahram press Egypt

12. How B-cell produces Igs Initial signal = Ag- Ab on surface of B-cell after leaving BM to be processed and presented in association with MHC-II to T-cell (TCR) Co-stimulatory signals = - B7 on B-cell with CD28 on T-cell. - CD40 to be associated with CD40L on T-cell. Cytokine release : IL-2,4,5,6 Memory cell production 12 Abla M. El- Mishad : Manual of Microbiology & Immunology. Vol I 8 th Edition. 2010 El- Ahram press Egypt

13. How B-cell produces Igs (cont.) 13 CD40/CD40L Abla M. El- Mishad : Manual of Microbiology & Immunology. Vol I 8 th Edition. 2010 El- Ahram press Egypt

14. How B-cell produces Igs (cont.) 14 Abla M. El- Mishad : Manual of Microbiology & Immunology. Vol I 8 th Edition. 2010 El- Ahram press Egypt

15. Uses of IVIG Replacement therapy. Immunomodulatory effect. 15 Jessica Katz, and Kinjal Parikh. "Intravenous immunoglobulin."  Medscape  (2018).

16. Uses of IVIG (cont.) Replacement therapy (Low dose therapy) Immunomodulatory effect (High dose therapy) Licensed Off-label Primary immunodeficiency HIV infection BMT B-cell lymphocytic leukemia Multiple myeloma Immune thrombocytopenic purpura GBS CIDP Kawasaki disease Multifocal motor neuropathy Autoimmune neutropenia Autoimmune hemolysis Anti Factor VIII inhibitor Multiple sclerosis Myasthenia gravis Stiff person syndrome ANCA associated vasculitis Polymyositis / Dermatomyositis RA SLE – APS GVHD Sepsis syndrome TEN Graves opthalmopathy 16 Jessica Katz, and Kinjal Parikh. "Intravenous immunoglobulin."  Medscape  (2018).

17. Mechansim of IVIG as Replacement 17 Peter, J. G., J. M. Heckmann , and N. Novitzky . "Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement."  South African Medical Journal  104.11 (2014): 796.

18. Mechansim of IVIG as Immunomodulatory 18 Gelfand , Erwin W. "Intravenous immune globulin in autoimmune and inflammatory diseases."  New England Journal of Medicine  367.21 (2012): 2015-2025.

19. Example for IVIG role in ITP Fc receptor blockade of reticuloendothelial system Fc γ receptor downregulation Idiotype–antiidiotype interaction between antiplatelet GPIIb / IIa autoantibodies and the antiidiotypic antibodies in IVIG Activation of inhibitory receptor Fc γ RIIB Saturation of FcRn receptor to accelerate the catabolism of antiplatelet autoantibodies 19 Hsia, Cyrus C et al. “Intravenous Immunoglobulin ( IVIg ) Utilization in Immune Thrombocytopenia (ITP): A Multi-Center, Retrospective Review”  Drugs - real world outcomes  vol. 2,1 (2015): 35-42.

20. Preparation of IVIG 20 Rich, Robert R., et al.  Clinical Immunology, Principles and Practice (Expert Consult-Online and Print), 5: Clinical Immunology . Elsevier Health Sciences, 2019.

21. Preparation of IVIG (cont.) 21 Rich, Robert R., et al.  Clinical Immunology, Principles and Practice (Expert Consult-Online and Print), 5: Clinical Immunology . Elsevier Health Sciences, 2019. It contains pooled Ig (mainly IgG ) Donor pool usually >1000 donors to ensure broad spectrum of antibody specificities (esp. as replacement therapy) IVIg / SCIg is stabilized with sugars (e.g. maltose)

22. Forms available 22 Dosage Forms & Strengths injectable solution 10% (100mg/mL) 5% (50mg/mL) https://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138

23. Routes of adminstration IV; IVIG: the main route of treatment inpatient, and if patient refuse inhome treatment via oter routes. (5-10% preparations) IM: rarely used nowadays, doses are too low to be effective in preventing infection. Preferred by elderly patients who was initiated on this old fashioned route SC; SCIG: For those with poor venous access, high-dose SCIg replacement is at least equivalent to IVIg in terms of maintaining adequate trough IgG levels and preventing infection (16-20% preparations) 23 Spickett , Gavin. Oxford handbook of clinical immunology and allergy. Oxford University Press, 2013.

24. Routes of administration (cont.) IVIG SCIG Advantages Achieve rapid plasma levels Can use this route in patients with bleeding disorders 3–4 week intervals IV access not needed Achieve stable serum levels Less systemic AE More flexibility for parents and patients Disadvantages Need IV access Interrupt patient’s schedule for 3–5-hour period Often needs to come to a hospital or infusion center System side effects may be more frequent in some patients Minor local reactions at the site of infusion Patient reliability Need for a pump 24 Rich, Robert R., et al.  Clinical Immunology, Principles and Practice (Expert Consult-Online and Print), 5: Clinical Immunology . Elsevier Health Sciences, 2019.

25. Home therapy Criteria for home therapy Comment 4-6 month of hospital treatment Must be reaction free Good venous access for IVIg Consider SCIg if venous access poor Patient must be motivated Patient must have a trainable long-term partner Never infuse while patient alone Hotline with treating physician or hospital Regular follow up Patient must agree to keep infusion logs with batch records 25 Spickett , Gavin. Oxford handbook of clinical immunology and allergy. Oxford University Press, 2013.

26. Example for IVIG posology in different scenarios Primary Immunodeficiency Syndrome: - 300-600 mg/kg q3-4Week - Initial infusion rate: 0.5 mg/kg/min for the first 30 min Immune Thrombocytopenic Purpura - 1 g/kg IV x 2 days or 400 mg/kg IV x 5 days Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) - Load: 2 g/kg IV in divided doses for 2-4 days - Maintenance: 1000 mg/kg/day IV for 1 day q3Week or 500 mg/kg/day for 2 days q3Week Bone Marrow Transplant - 500 mg/kg IV beginning on days 7 & 2 pretransplantation , THEN qWk through 90 days post-transplantation Guillain-Barre ; LEMS; Stiff Person Syndrome (Off-label): - 400 mg/kg IV qDay x5 days or 1 g/kg qDay x 2 days 26 https://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138

27. IVIG adverse effects 27 Peter, J. G., J. M. Heckmann , and N. Novitzky . "Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement."  South African Medical Journal  104.11 (2014): 796.

28. Risk Factors for Adverse Events Infusion issues Prior history of an infusion reaction with an immunoglobulin ( Ig ) product First infusion in a patient with active infection or inflammation Changing immunoglobulin products Rapid infusion and/or large dose 28 Rich, Robert R., et al.  Clinical Immunology, Principles and Practice (Expert Consult-Online and Print), 5: Clinical Immunology . Elsevier Health Sciences, 2019.

29. Risk Factors for Adverse Events (cont) Patient factors Preexisting renal impairment Prior history of thrombotic event Autoimmune disorder Diabetes mellitus Age—older age Dyslipidemia Dehydration with volume depletion Hypercoagulable state Indwelling catheters Paraproteinemia or other causes of hyperviscosity Cardiac or peripheral vascular disorders Estrogen use Smoking 29 Rich, Robert R., et al.  Clinical Immunology, Principles and Practice (Expert Consult-Online and Print), 5: Clinical Immunology . Elsevier Health Sciences, 2019.

30. Black Box Warnings Acute renal dysfunction and renal failure Related to sucrose content Highly osmotic load Associated with renal dysfunction, acute renal failure, osmotic nephrosis , and death Slow initial rates of infusion in high risk patients. Thrombosis: May relate to underlying condition, hyperviscosity , poor fluid balance. 30 https://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138

31. Contraindications Hypersensitivity to gamma globulin Isolated IgA deficiency Hyperprolinemia (with some products) 31 https://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138

32. Other cautions Prion transmitted disease. Serum sickness like reaction. Aseptic meningitis syndrome. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. Postpone live virus vaccines for at least 3 months False high blood glucose due to high maltose content Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing 32 https://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138

33. Pregnancy & Lactation Pregnancy Category : C Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. Lactation : not known if excreted in breast milk 33 https://reference.medscape.com/drug/gammagard-s-d-carimune-nf-immune-globulin-iv-igiv-343138

34. IVIG good practice points At initiation of therapy: 1. Check baseline renal and liver function, full blood count, and infection screen for hepatitis B/C and HIV 2. Anticipate potential side-effects 3. Store sample of serum for later testing if any questions about infectious agent transmission is raised 4. Consider the planned duration of therapy and product availability to avoid unnecessary future product changes 5. Complete documentation 6. Record brand, lot number, dose and reactions with each set 7. Adequate pre-hydration; slow first infusion, incremental increase 34 Peter, J. G., J. M. Heckmann , and N. Novitzky . "Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement."  South African Medical Journal  104.11 (2014): 796.

35. IVIG good practice points (cont.) For long-term treatment: 1. Plan further treatment routes IVIG to SCIG. 2. Review every 2 months then 6 monthly for AE, trough levels, infection rebound if used as replacement therapy. 3. Backup plan for uneventful travelling, pregnancy, insurance interruption. 35 Peter, J. G., J. M. Heckmann , and N. Novitzky . "Recommendations for the use of immunoglobulin therapy for immunomodulation and antibody replacement."  South African Medical Journal  104.11 (2014): 796.

36. IVIG good practice points (cont.) Technical issues during preparation: Dilution is dependent upon manufacturer & brand; do not shake, avoid foaming; discard unused portion Administer in separate infusion line from other medications; flush line with NS. Prepare epinephrine; keep it near you. Start low go slow First thing to do if reaction occurs, stop infusion 36 Spickett , Gavin. Oxford handbook of clinical immunology and allergy. Oxford University Press, 2013.

37. Final Bottom-line Igs has diverse immunologic actions. IVIG therapy has been the last resort in many autoimmune diseases. IVIG replacement therapy is life saving in many immunodeficiency disorders. There are other route for IG therapy, however in replacement therapy only. IVIG has many side effects, though it can be avoided by proper selection of patients, and to expect them when risk factors apply. 37