Intravenous Immune Globulin in Autoimmune and Inflammatory Disease

NEW ENGLAND JOURNAL OF MEDICINEMECHANISMS OF DISEASE

Speaker: Pharmacist Ting-wei WuDepartment of Pharmacy

Jan. 23rd, 2013

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Outline

What is IVIG?FDA-approved indicationAdditional approved indication with criteriaNational Health Insurance (in Taiwan) Criteria for IVIGHow do Immunoglobulins been produced?How does Immunoglobulin looks like?How does Immunoglobulin work?IVIG for Primary ImmunodeficiencyIVIG for Bone Marrow TransplantationIVIG for Kawasaki’s DiseaseIVIG for Idiopathic Thrombocytopenic PurpuraIVIG for Guillain–Barré SyndromeIVIG preparation in our hospitalSummaryReference

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What is IVIG?

IVIG is stands for Intravenous Immune Globulin.

IVIG is prepared from plasma pooled from thousands of healthy donors.

More than a dozen preparations suitable for intravenous administration have been approved by the FDA for the treatment of primary immunodeficiency disease.

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FDA-approved indication

Primary immunodeficiency disease

Chronic lymphocytic leukemia

Pediatric HIV infection

Kawasaki’s disease

Allogeneic bone marrow transplantation

Chronic inflammatory demyelinating polyneuropathy

Multifocal motor neuropathy

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Additional approved indication with criteria

Neuromuscular disorders

Guillain–Barré syndrome

Myasthenia gravis

Hematologic disorders

Autoimmune hemolytic anemia

Neonatal alloimmune thrombocytopenia

Dermatologic disorders

Ref: N Engl J Med 2012;367:2015-25.DOI: 10.1056/NEJMra10094335

National Health Insurance (in Taiwan)Criteria for IVIG

1.先天或後天性免疫球蛋白低下症併發嚴重感染時(須附六個月內免疫球蛋白檢查報告)

2.免疫血小板缺乏性紫斑症(ITP)病例經傳統治療無效且血小板嚴重低下(< 20,000/cumm)合併有嚴重出血危及生命者。

3.免疫血小板缺乏性紫斑(ITP)病例合併血小板嚴重低下(< 20,000/cumm)或合併有嚴重出血而又必須接受緊急手術治療者。

4.先天性免疫不全症之預防性使用,但需有醫學中心之診斷証明。

5.川崎病合乎美國疾病管制中心所訂之診斷標準,限由區域醫院(含)以上教學醫院實施,並填寫「全民健康保險使用Intravenous Immune Globulin (IVIG) 治療川崎病」申請表併當月份醫療費用申報。

6.因感染誘發過度免疫機轉反應,而致維生重要器官衰竭,有危及生命之慮者,限由區域醫院(含)以上有加護病房⼄乙等級以上之教學醫院實施。(93/2/1)

7. 腸病毒感染嚴重患者,且符合行政院衛生署疾病管制局於97年1月修訂之『腸病毒感染嚴重患者靜脈注射免疫球蛋白之適應症』。(97/5/9)

Ref: Bureau of National Health Iinsurance, Department of Health, Executive Yuan6

How do Immunoglobulins been produced?Ref: Vander's Human Physiology: The Mechanisms of Body Function, 11e, FIGURE 18-14

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How does Immunoglobulin look like?Ref: N Engl J Med 2012;367:2015-25.DOI: 10.1056/NEJMra1009433

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How does Immunoglobulin work?Ref: N Engl J Med 2012;367:2015-25.DOI: 10.1056/NEJMra1009433

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How does Immunoglobulin work?Ref: N Engl J Med 2012;367:2015-25.DOI: 10.1056/NEJMra1009433

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IVIG for Primary Immunodeficiency

Dosage of IVIG for Primary immunodeficiency disease:

0.2-0.6g /kg each month

ReF: National Taiwan University Hospital Hsin-Chu Branch Formulary, 101 1st ED, p174

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IVIG for Bone Marrow Transplantation

Dosage of IVIG for allogeneic bone marrow transplantation:

Initial dose: 0.5g /kg /week

ReF: National Taiwan University Hospital Hsin-Chu Branch Formulary, 101 1st ED, p174

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IVIG for Kawasaki’s disease

Underlying pathophysiological characteristics of the disease remain to be clearly defined.

The anti-inflammatory potential of IVIG in patients with Kawasaki’s disease has been well described.

After a single intravenous infusion of immune globulin, fever often abates, with concomitant reductions in several inflammatory markers.

Ref: N Engl J Med 2012;367:2015-25.DOI: 10.1056/NEJMra1009433

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IVIG for Kawasaki’s disease

Decreases in the production of pro-inflammatory cytokines (e.g., tumor necrosis factor α [TNF-α], interleukin-1α, and interleukin-6)

Down-regulation of adhesion molecule and chemokine and chemokine-receptor expression

Neutralization of super-antigens

Ref: N Engl J Med 2012;367:2015-25.DOI: 10.1056/NEJMra1009433

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IVIG for Kawasaki disease

Dosage of IVIG for Kawasaki’s disease:

1.6-2g /kg in two to five days

2g /kg for single dose

ReF: National Taiwan University Hospital Hsin-Chu Branch Formulary, 101 1st ED, p174

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IVIG for ITP

ITP stands for idiopathic thrombocytopenic purpura.

ITP is primarily a disease of increased peripheral platelet destruction.

Most patients have immunoglobulin G autoantibodies to specific membrane glycoproteins on the platelet surface.

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IVIG for ITP

Dosage of IVIG for ITP:

2g /kg in two to five days

ReF: National Taiwan University Hospital Hsin-Chu Branch Formulary, 101 1st ED, p174

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IVIG for GBS

GBS stands for Guillain–Barré Syndrome which is a post-infectious, immune-mediated disease.

The pathophysiologic mechanism of GBS can be typified by C jejuni infections.

Immune responses against lipopolysaccharide antigens in the capsule of C jejuni.

Antibodies cross-react with ganglioside GM1 in myelin, resulting in the immunologic damage to the peripheral nervous system.

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Ref: Vander's Human Physiology: The Mechanisms of Body Function, 11e, FIGURE 6-2

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IVIG for GBS

Dosage of IVIG for Guillain–Barré syndrome:

2g /kg in five days

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IVIG preparation in our hospital

Human Immunoglobulin (TBSF) injection (6% 3g/50mL/btl)

Cost: $6750 NTD/btl

How supply:IVIG dilutes with 50mL D5W or NSIntravenous infusion; infusion rate:1 mL/min for first 15 min3-4 mL/min for max speed

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SummaryThe use of IVIG has been firmly established for the treatment of a wide variety of autoimmune and inflammatory diseases, either as adjunctive therapy or as first-line therapy in some conditions, such as Kawasaki’s disease.

Results in animal models have not been entirely consistent and easy to translate to human disease. Double-blind, placebo-controlled trials remain essential to establish the efficacy of this intervention a variety of disease states.

IVIG therapy, especially at doses of 2 g per kilogram per month, is expensive, and with expanding use there are concerns about present and future supplies, especially if the donor pool decreases or is limited by safety issues and increased pathogen screening of donors of the source plasma.

Attempts to bioengineer a protein with immunomodulatory activities similar to those of native IgG should be a priority if we are to sustain this approach to disease modification.

The successes with IVIG witnessed over the past few decades are just the beginning. Now the real work needs to begin.

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Reference:

N Engl J Med 2012;367:2015-25.DOI: 10.1056/NEJMra1009433

Vander's Human Physiology: The Mechanisms of Body Function, 11e; ISBN 978-986-157-640-4

National Taiwan University Hospital Hsin-Chu Branch Formulary, 101 1st ED

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Thanks For Your Attention.

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