INTRAVENOUS IMMUNOGLOBULIN by dr Seema.pptx

Excellent pptx for md dermatologist for seminar presentation

1. INTRAVENOUS IMMUNOGLOBULIN Presented By- Dr Vijay Kumar Sharma Moderator- Dr Devendra Kumar Yadav

2. INTRODUCTION IVIG is a blood product prepared from the serum of 1000 to 100000 healthy donors per batch depending upon the manufacture. IVIG products are prepared using the Cohn- Oncley procedure. It contains Ig G in supraphysiologic levels with small amount of other Ig ( IgA, IgE , IgM) ,albumin, sugars, salts and solvents.

3. Mechanism of action- 1.Reduced Antibody Production- One of the mechanisms first postulated was the suppression of Ab production by IgG binding via its Fc fragment to corresponding cellular surface receptors on B lymphocytes. This may result in the downregulation of pathogenic autoantibody production. Moreover, application of IVIg leads to a reduced half-life of circulating immunoglobulins, probably by saturating the protective neonatal Fc receptor ( FcRn ), and in this way causing an accelerated Ab catabolism.

4. 2.Effects on complement system- IVIg also appears to function via the neutralization of complement-mediated effects. Accordingly, antibodies in IVIg preparations are capable of binding to complement components such as C3 and C5 convertases, and thereby block complement activation at an early stage. In addition, IVIg seems to interfere with the formation of the terminal membrane attack complex C5b–C9 (MAC).

5. 3. Effects on Circulating Antibodies and Receptors- Because IVIg preparations contain a diversity of immunoglobulins, there are ‘anti-idiotypic’ antibodies that can bind and neutralize pathogenic antibodies. After infusions of IVIg, a marked reduction or even disappearance of these antibodies could be demonstrated. Furthermore, there is evidence that IVIg binds to Fc receptors on macrophages, subsequently saturating, altering, or downregulating these receptors. This may lead to an inhibition of the auto antibody-mediated cellular activation and therefore suppresses cytokine production.

6. 4. Effects on T-Cell Activation- IVIg preparations contain amounts of soluble CD4, CD8, MHC-I, and MHC-II molecules, which may have the ability to inhibit autoreactive T lymphocytes. IVIg has been reported to downregulate the expression of co-stimulatory molecules such as lymphocyte function-associated antigen 1 (LFA-1) on activated T cells, interfering with T-cell activation. Another possible mechanism of action of IVIg is the restoration of a T helper (Th)1/Th2 cytokine balance by supplying neutralizing antibodies.

7. 5.Effects on Immune Cell Trafficking- IVIg may affect the migration of immunocompetent cells from blood to the target tissue. Antibodies against the extracellular matrix protein Arg-Gly-Asp may inhibit the cellular adhesion and subsequent cellular migration, and thereby modify the local inflammatory response. 6.Effects on Fas / Fas Ligand- IVIg also contains anti- Fas -receptor Ab, which is able to block molecular Fas ligand/ Fas receptor interactions and consequently keratinocyte apoptosis. This mechanism seems to play a vital role in the therapy of Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with IVIg.

8. 7.Synergistic Effect with Corticosteroids- In a wide range of dermatologic diseases, the adjunctive use of IVIg has led to reduced dose requirements for systemic corticosteroid (CS). This was because of the increased glucocorticoid receptor sensitivity, and because IVIg and CS can synergistically suppress the lymphocyte activation.

9. The Indications for IVIG can be classified informally into a few broad categories based on the mechanism of action and the type of conditions they treat. They are as follow:- As a replacement therapy in immunodeficiencies. For immunomodulatory and anti-inflammatory therapy- Immunomodulation in hematological and organ specific autoimmune disorders. Anti-inflammatory in rheumatic inflammatory conditions, infectious and neurological disorders. 3. As a hyperimmune therapy against specific infectious agents

10. FDA approved indications Immune thrombocytopenic purpura Primary immunodeficiency Kawasaki disease Pediatric HIV inf. GVHD Chronic inflammatory demyelinating polyneuropathy Dermatomyositis Multifocal motor neuropathy Hypogammaglobulinemia B cell CLL

11. IVIGs Dermatological Indications 1.Vascular Diseases Kawasaki disease Antineutrophil cytoplasmic antibody- associated vasculitis Livedoid vasculopathy 2.Autoimmune Connective Tissue Disorders Dermatomyositis Scleroderma Scleromyxedema Systemic lupus erythematosus

12. 3.Autoimmune Bullous Dermatoses Pemphigus vulgaris and foliaceus Bullous pemphigoid Mucous membrane pemphigoid Epidermolysis bullosa acquisita Pemphigoid gestationis (herpes gestationis ) Linear immunoglobulin A bullous dermatosis

13. 4.Other Inflammatory Dermatoses Chronic autoimmune urticaria Atopic dermatitis Graft-versus-host disease Psoriasis Pyoderma gangrenosum 5.Other Dermatoses Toxic epidermal necrolysis/ Stevens-Johnson syndrome DRESS syndrome Pretibial myxedema Necrobiotic xanthogranuloma

14. NOTE- Based on published reports, the following general guidelines are useful to determine whether IVIg therapy is appropriate for autoimmune diseases: There is progressive, uncontrolled, or rapidly debilitating disease activity despite conventional immunosuppressive therapy. There are significant AE from conventional immunosuppressive therapy that are potentially life-threatening, or that cause significant morbidity or inability to carry out activities of daily living.

15. 3. There are contraindications (relative or absolute) to the use of high-dose, long-term systemic CS therapy or immunosuppressive agents. 4. The patient’s age and pregnancy status do not contraindicate the use of IVIg therapy.

16. Pharmacology- Peak serum concentrations occur immediately after intravenous injection and are dose related. Within 24 hours, up to 30% of the dose may be removed by catabolism and distribution. IVIg distributes itself throughout the intravascular (60%) and extravascular (40%) spaces, crosses the placenta, and may be excreted into milk. The serum half-life is 2 to 5 weeks.

17. Administration Available either as 5% (50mg/dl) or 10% (100mg/ml) liquid or as lyophilized preparations. The most common dosage regimen used in dermatology to produce desired or expected results is 2 g/kg per cycle, divided into three equal doses, given on each of three consecutive days. The infusion is given slowly over 4 to 4.5 hours (a stepwise increase of the infusion rate is encouraged), and vital signs are monitored frequently.

18. Low dose replacement therapy:- in primary immunodeficiencies ,IVIG is usually administered at replacement doses of 400 to 600 mg/kg per month, achieving plasma levels of 1200 to 1400 mg/dl. IgG trough levels of 500 to 800 mg/dl are achievable with this dosing and are considered tb be protective from infectious consequences in immunodeficient patients.

19. 2. High-dose immunomodulatory and anti-inflammatory therapy:- For immunomodulation ,higher doses of IVIG are necessary ,ranging from 1000 to 3000mg/kg of body weight to achieve peak plasma concentration of 2500 to 3500 mg/dl. In general, a protocol of 2g/kg/course divided into 400mg/day for 5 days and is a universally employed administration strategy for autoimmune diseases.

20. 3. Hyperimmue therapy:- The dosage of this varies with every indication. The most comman means of administration is as a single intramuscular dose after the suspected exposure to a particular pathogen.

21. Infusion rate In patients new to IVIG therapy, infusion started at a rate of 0.5 to 1 ml/kg/hour for the first 15 to 30 minutes, and if no adverse reaction occurs, than the rate can be increased subsequently every 15 to 30 min. to maximum of 3 to 6 ml/kg/hr. SCIG is usually administered at a lower dose of 100 to 200 mg/kg and is administered much more frequently , i.e every week or two weeks.

22. Adverse effects Infusion-related general effects- Headache, myalgia, chills, flushing, fever, nausea or vomiting, low back pain, wheezing, chest pain, BP changes and tachycardia. These AE are generally mild and often occur 30 to 60 min. after the onset of the infusion and easily be managed by slowing down the infusion rate or temporarily discontinuing the infusion. In addition ,pretreatment with analgesics, NSAID, antihistamines or low dose IV corticosteroid may be needed.

23. 2. Anaphylaxis and other Hypersensitivity Reactions Particularly in patients with IgA deficiency having anti-IgA Ab. Therefore IVIG products with a very low IgA concentration should be used in patients with undetectable IgA levels. In addition dermatitis, erythema multiforme, purpura and alopecia have been reported. 3. Haematologic Effects Transient neutropenia and rarely hemolysis have been noted in individuals with auto AB against blood group antigens of the ABO and Rh system.

24. 4. Neurologic effects Headache , Aseptic meningitis 5. Thromboembolic Events Both cerebral infarct and MI have been reported in patients Cardiovascular risk factors, hyperviscocity ( dehydration, monoclonal gammapathies , cryoglobulinemia), older age, previous thrombosis and immobilization. Risk of these AE seems to be greater in patients receiving higher doses or rapid infusion rates. By lowering the IVIG dose, slowing the rate of infusion and administration of IV fluid before IVIG risk of AE may be minimized. 6. Infection Risk

25. Toxicity Though IVIG is generally considered to be safe, well tolerated and efficacious therapeutic modality, reports exist in the literature of reported toxicities- 1.There are reports of renal toxicity with sucrose-containing products in patients – greater than or equal to 65 years patients receiving concomitant nephrotoxic agents patients with diabetes mellitus pre-existing renal disease, hypovolemia, and sepsis.

26. These patients are all at increased risk for acute renal failure and renal insufficiency. Urine output, blood urea nitrogen, and creatinine require assessment in patients with an increased risk of developing acute renal failure.

27. 2.There is also a report of cardiac toxicity after IVIG therapy in a patient with scleromyxedema , which resulted in myocardial infarction. 3. Hematological toxicities , including various cytopenias and thrombotic complications, have also been reported and should be considered in patients with an increased risk of thrombosis.

28. Monitoring guidelines- Baseline History and Physical Examination Complete history and physical with emphasis on cardiopulmonary and renal status (at risk for fluid overload) Weigh patient before treatment for comparison if at risk of fluid overload

29. Laboratory Complete blood count (CBC) Assess liver function and renal function Immunoglobulin levels (in particular to exclude immunoglobulin A (IgA)deficiency increases risk of anaphylaxis) Screen for rheumatoid factor and cryoglobulins (these patients are at Increased risk for renal failure from IVIg) Consider screening for hepatitis B and C, along with human Immunodeficiency virus (HIV) (medicolegal considerations) Patients with blood types A, B, or AB should be monitored carefully for hemolytic transfusion reaction during high- dose therapy as they may contain anti-A or anti-B blood group antibodies. These patients should be followed up with a hemoglobin workup two days after the therapy.

30. Follow-Up History and Physical Examination During Infusion During infusions monitor blood pressure and heart rate frequently Assess for signs of fluid overload-auscultate lungs and heart, weight patient

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