A review of immune globulin therapy for autism treatment
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A Review of Immune Globulin Therapy for Autism Treatment. Elizabeth Cohen Amanda Davis Jane Sondern (Caldwell College Graduate Programs in Applied Behavior Analysis). Overview. Understanding Immunoglobulins in the Immune System IgG Other Immunoglobulins

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A review of immune globulin therapy for autism treatment

A Review of Immune Globulin Therapy for Autism Treatment

Elizabeth Cohen

Amanda Davis

Jane Sondern

(Caldwell College Graduate

Programs in Applied Behavior Analysis)

Immune Globulin Therapy and Autism Treatment


Overview

Overview

  • Understanding Immunoglobulins in the Immune System

  • IgG

  • Other Immunoglobulins

  • What is Immune Globulin Therapy?

  • History of Immune Globulin Therapy

  • Present day realities

    • Indications

    • Routes of Administration

    • Contraindications

    • Off-label Utilization

  • What does Immune Globulin Therapy have to do with autism?

  • Autism and IVIG: Claims

Immune Globulin Therapy and Autism Treatment


Overview1

Overview

  • Research

    • Gupta et al (1996)

    • Gupta (1997)

    • Singh (1997)

    • Plioplys (1998)

    • Singh (1999)

    • DelGiudice-Asch et al (1999)

    • Niederhofer et al (2003)

    • Schneider et al (2006)

    • Adams (2007)

Immune Globulin Therapy and Autism Treatment


Overview2

Overview

  • Criteria for Immune Globulin to Treat Autism

  • Side Effects

  • Other Considerations

  • Conclusions

  • References

  • Questions/Discussion

Immune Globulin Therapy and Autism Treatment


Understanding immuno globulins in the immune system

Understanding Immuno-globulins in the Immune System

  • Immune globulins are produced by B cells and are also known as antibodies.

  • Immune globulins are naturally occurring in the blood plasma serum of healthy individuals.

Immune Globulin Therapy and Autism Treatment


Understanding immuno globulins in the immune system1

Understanding Immuno-globulins in the Immune System

  • The purpose of immune globulins is to neutralize and opsonize pathogens.

  • There are 5 classes of immunoglobulins

    • IgG

    • IgM

    • IgA

    • IgE

    • IgD

Immune Globulin Therapy and Autism Treatment


A review of immune globulin therapy for autism treatment

IgG

  • IgG is the most prevalent immunoglobulin found in the bloodstream at about 80%. IgG is formed in large quantities, easily travels from the bloodstream to tissues, and lasts for approximately 1 month.

  • IgG is produced upon second exposure to an antigen at which time it binds to the antigen.

  • IgG is the only immunoglobulin that crosses the placenta and passes immunity from the mother to the newborn.

  • IgG is broken into four subclasses:

    • IgG1- IgG3

    • IgG2- IgG4

Immune Globulin Therapy and Autism Treatment


Prevalence of igg subclasses in the total igg serum in the bloodstream

Prevalence of IgG Subclasses in the total IgG serum in the bloodstream

Immune Globulin Therapy and Autism Treatment


Igg subclasses

IgG Subclasses

  • Functions of the IgG Subclasses

    • IgG1 and IgG3

      • rich in antibodies against proteins

    • IgG2

      • predominantly antibodies against the polysaccharide (complex sugar/carbohydrate) coating or capsule of certain disease producing bacteria

    • IgG4

      • function is largely unknown possibly due to it’s limited prevalence in the total IgG serum

      • generally accepted that IgG4 works with IgG2 to bind to carbohydrate antigens

Immune Globulin Therapy and Autism Treatment


Other classes of immunoglobulins

IgA antibodies

produced near mucous membranes and found in secretions

IgE antibodies

responsible for allergic reations and antibodies binding to antigens produce inflammatory sustances (histamine)

IgM antibodies

first antibodies to be formed in response to an infection to provide important protection during the early days of an infection

IgD antibodies

role not fully understood, found on the surface of B cells and may be involved in cell differentiation

Other Classes of Immunoglobulins

Immune Globulin Therapy and Autism Treatment


What is immune globulin therapy

What is Immune Globulin Therapy?

  • Immune globulin therapy is a treatment to provide high doses of IgG.

  • Immune globulin therapy is usually used as a replacement therapy.

  • Immune globulin therapy products are derived from pooled human blood plasma.

Immune Globulin Therapy and Autism Treatment


History

History

  • Immune globulin was first used to prevent infectious diseases in World War II.

  • Processes for large-scale fractionization of human plasmawere initially developed by Edwin Cohn and his colleagues at Harvard to provide albumin as a treatment for shock in World War II.

  • Plasma cooled to 0°C, ethanol and buffer added, and four protein fractions were precipitated out of solution

  • Cohn fraction II contained most antibodies

Immune Globulin Therapy and Autism Treatment


History1

History

  • 1952

    • Immune globulin therapy was first given to treat primary immune deficiencies following Bruton’s description of agammaglobulinemia.

  • 1960’s

    • Barundun and others from the Swiss Red Cross Laboratories prepared IgG for intravenous use, however it was not FDA approved until the 1980’s.

Immune Globulin Therapy and Autism Treatment


History2

History

  • 1980’s

    • Early in the decade, new manufacturing processes were developed to make immunoglobulin preparations that could be administered intravenously (IVIG). Prior to this, the only form of immune globulin therapy available was intramuscular injection (IM).

  • 1992 to 2003

    • IVIG production tripled from 19.4 tons to 52.6 tons annually.

  • 2006

    • The FDA approved preparations of immunoglobulin for subcutaneous administration (SCIG).

Immune Globulin Therapy and Autism Treatment


Additional history

Additional History

  • Procedures for further purification of gamma globulins and other proteins precipitating at lower concentrations of ethanol were then developed by Oncley et al. Gamma globulin rapidly replaced convalescent and animal sera for the prevention and treatment of infectious diseases such as measles, hepatitis, and polio, then came into widespread use as replacement therapy in the primary immune deficiencies, which emerged in the antibiotic era of the early 1950s. http://www.ncbi.nlm.nih.gov/pubmed/12165202

Immune Globulin Therapy and Autism Treatment


Present day realities

Present Day Realities

  • Although it took 40 years to develop preparations of gamma globulin that could be safely given intravenously, the eventual accomplishment of that goal has led to better treatment of antibody deficiency syndromes and also the wide use of high-dose intravenous immunoglobulin in autoimmune and inflammatory diseases. Those uses continue to expand even as monoclonal antibodies are being introduced for specific infectious diseases in high-risk populations.http://www.ncbi.nlm.nih.gov/pubmed/12165202

Immune Globulin Therapy and Autism Treatment


Present day realities indications

Present Day Realities:Indications

  • FDA Approved Indications

    • Primary Immune Deficiency

    • Idiopathic Thrombocytopenic Purpura

    • Kawasaki Disease

    • B-Cell Chronic Lymphocytic Leukemia

    • HIV Infection (pediatric)

    • Bone Marrow Transplantation

Immune Globulin Therapy and Autism Treatment


Present day realities administration

Present Day Realities:Administration

  • Administration Routes of Immune Globulin Therapy

    • Intramuscular (IMIG)

    • Intravenous (IVIG)

    • Subcutaneous (SCIG)

Immune Globulin Therapy and Autism Treatment


A review of immune globulin therapy for autism treatment

kidney disease

diabetes

sepsis

plasma cell disease

volume depletion

those taking medications that can cause kidney damage

Present Day Realities:ContraindicationsImmune globulin therapy is contraindicated in anyone with a history of:

Immune Globulin Therapy and Autism Treatment


Present day realities off label utilization

Autism

Chronic fatigue syndrome

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Clostridium difficile colitis

Dermatomyositis and polymyositis

Graves' ophthalmopathy

Guillain-Barré syndrome

Kawasaki disease

Muscular Dystrophy

Inclusion body myositis

Lambert-Eaton syndrome

Lupus erythematosus

Multifocal motor neuropathy

Multiple sclerosis

Myasthenia gravis

Neonatal alloimmune thrombocytopenia

Present Day Realities:Off Label Utilization

Immune Globulin Therapy and Autism Treatment


Present day realities off label utilization cont d

Parvovirus B19

Pemphigus

Post-transfusion purpura

Renal transplant rejection

Spontaneous Abortion/Miscarriage

Stiff person syndrome

Severe sepsis and septic shock in critically ill adults[7]

Toxic epidermal necrolysis

In chronic lymphocytic leukemia and multiple myeloma, as well as various rare deficiencies of immunoglobulin synthesis (e.g. X-linked agammaglobulinemia, hypogammaglobulinemia), IVIG is administered to maintain adequate immunoglobulin levels to prevent infections.

Present Day Realities:Off Label Utilization (cont’d)

Immune Globulin Therapy and Autism Treatment


What does immune globulin therapy have to do with autism

What does immune globulin therapy have to do with autism?

  • Some people believe that people with autistic spectrum disorders are susceptible to immune deficiencies and that these deficiencies may produce some of the symptoms of autism.

  • By injecting or swallowing immune globulin, an antibody used by the immune system to identify and neutralize foreign objects like bacteria and viruses, it is believed those abnormalities can be overcome and the symptoms of autism reduced.

    http://www.researchautism.net/interventionitem.ikml?print&ra=19&infolevel=4

Immune Globulin Therapy and Autism Treatment


What does immune globulin therapy have to do with autism1

What does immune globulin therapy have to do with autism?

  • Vijendra K. Singh, Ph.D. (neuroimmunologist)

    • Up to eighty percent (and possibly all) cases of autism are caused by an abnormal immune reaction, commonly known as autoimmunity (http://www.crossroadsinstitute.org/newsletter/nlarticles/aug05/singhautism.html)

    • 1992 study linked autism to heightened autoimmunity, finding autistic children have about an eight times greater incidence of antibodies to myelin basic protein (MBP) than control children

    • 2002 study suggested that MMR-vaccinated children have abnormally high levels of measles virus antibodies, indicating autism may be a neuro-immune response to the vaccine

Immune Globulin Therapy and Autism Treatment


What does immune globulin therapy have to do with autism2

What does immune globulin therapy have to do with autism?

  • Sudhir Gupta, M.D.

    • Increased evidence in immunological abnormalities including T cells, B cells, NK cells, and complement system

    • Data shows markedly dysregulated immune system in children with autism

  • Marinos C. Dalakas, M.D.

    • High-dose intravenous immune globulin (IVIg) has emerged asan important therapy for various neurologic diseases(http://www.annals.org/cgi/content/full/126/9/721)

Immune Globulin Therapy and Autism Treatment


Autism and ivig claims researchers suggest they will demonstrate improvement in the following areas

Eye Contact

Speech

Behavior

Echolalia

GI signs and symptoms

Hyperactivity

Inappropriate stims

Social Interactions

Aberrant behaviors

Other autistic behaviors

Autism and IVIGClaimsResearchers suggest they will demonstrate improvement in the following areas:

Immune Globulin Therapy and Autism Treatment


Research gupta aggarwal heads 1996

ResearchGupta, Aggarwal, Heads (1996)

  • Claims

    • Autism is syndrome of neuro-development associated with impairments in communication, social interaction, learning and thinking skills, repetitive and self-injurious behaviors

    • Factors

      • Genetic

      • Infectious

      • Immunological

    • Increased evidence in immunological abnormalities including T cells, B cells, NK cells, and complement system

    • Data shows markedly dysregulated immune system in children with autism

Immune Globulin Therapy and Autism Treatment


Research gupta et al 1996

ResearchGupta et al (1996)

  • Participants

    • 25 children (ages 3-12, 17 male, 8 female)

    • All diagnosis of autism according to the DSM III-R

    • Immune system abnormalities were shown in participants

      • 56% increased IgM & IgE

      • 20% IgA Deficiency

      • 20% IgG Subclass Deficiency

Immune Globulin Therapy and Autism Treatment


Research gupta et al 19961

ResearchGupta et al (1996)

  • Methods

    • 10 children given IVIG at 400mg/kg at 4 week intervals for 6 months

    • Parents were instructed to pre-medicate with oral benadryl prior to arrival for infusion

    • Information was obtained from speech and behavior therapists as well as psychiatrists for behavioral, cognitive, and developmental characteristics

    • Psychiatrists were blind to type of treatment

Immune Globulin Therapy and Autism Treatment


Research gupta et al 19962

Research Gupta et al (1996)

Immune Globulin Therapy and Autism Treatment


Research gupta et al 19963

ResearchGupta et al (1996)

  • Results

    • 6 months of IVIG infusion resulted in marked improvement in a number of autistic characteristics including eye contact, calmer behavior, speech, echolalia, and so forth.

    • Earliest observable effects were calmer behavior and improved eye contact

    • Speech is slow to improve and spontaneous speech develops last

Immune Globulin Therapy and Autism Treatment


Research gupta et al 19964

ResearchGupta et al (1996)

  • Results (cont’d)

    • Discontinuation after the 6 months resulted in re-appearance of autism characteristics for few patients

      • When re-started on IVIG, improvement was shown

    • 2 patients were followed for 5 months prior and following the IVIG infusions

      • Prior to IVIG: no significant changes were observed (positive or negative)

      • Post-IVIG: significant changes with regard to spontaneous conversational speech, thinking and processing, oral reading and attention span

Immune Globulin Therapy and Autism Treatment


Research gupta et al 19965

ResearchGupta et al (1996)

  • Results (cont’d)

    • Unclear how long IVIG is indicated in autism

    • Effect of age and gender on the response to IVIG cannot be determined based on small sample size and presence of only 1 female in the study

    • Appears that younger children respond earlier (within 2-3 infusions) as compared to older children (within 4-5 infusions)

Immune Globulin Therapy and Autism Treatment


Research gupta et al 19966

ResearchGupta et al (1996)

  • Future research

    • Planning a controlled double-blind placebo multicenter study to extend the observations and develop a profile of patient most likely to respond and examine the effect of IVIG on dysregulated immune functions in autism

Immune Globulin Therapy and Autism Treatment


Research gupta 1997

ResearchGupta (1997)

  • Grant funded by Cure Autism Now (CAN)

  • Claims

    • Improved eye contact, speech, behavior, echolalia, and other autistic behaviors

  • Participants

    • 20 children enrolled

      • 12 children randomly assigned placebo (Group 1)

      • 12 obtained IVIG (Group 2)

Immune Globulin Therapy and Autism Treatment


Research gupta 19971

ResearchGupta (1997)

  • Methods

    • Double-blind placebo controlled study

    • Study divided into 2 phases (6 treatments in each phase)

      • Phase I: 4 week interval of IVIG for Group1 and a placebo for Group 2

      • Phase II: 4 week interval of IVIG for Group 2 and a placebo for Group 1

Immune Globulin Therapy and Autism Treatment


Research gupta 19972

ResearchGupta (1997)

  • Results

    • As a group, there was no significant different between placebo and IVIG

    • Some children did show improvement but significance could not be determined based on study size

Immune Globulin Therapy and Autism Treatment


Research singh 1997

ResearchSingh (1997)

  • Vijendra Singh has been studying autism as an autoimmune disorder for 15 years

  • Unpublished data

    • double-blind study shows that IVIG was found to decrease brain auto-antibody titers in 5 patients however, they were positive pre-therapy but negative post-therapy

Immune Globulin Therapy and Autism Treatment


Research plioplys 1998

ResearchPlioplys (1998)

  • Participants

    • 10 children with immunological abnormalities

      • 8 males

      • 2 females

      • Age range: 4 years 3 months to 15 years 7 months

  • Methods

    • Intent of treatment program was to use 200mg/kg to 400mg/kg of IVIG per treatment every 6 weeks for a total of 4 administrations

    • Actual dose administered ranged from 154 mg/kg to 375 mg/kg (mean dosage 270 mg/kg) per administration.

Immune Globulin Therapy and Autism Treatment


Research plioplys 19981

ResearchPlioplys (1998)

  • Methods (cont’d)

    • 6 children had the planned 4 infusions and one child each had 1, 3, 5, and 6 infusions

    • 7 children needed to be sedated prior to infusions (4 with rectal pentobarbital and 3 with oral chloral hydrate)

    • In the child who received 6 infusions, two were administered by the author and 4 by local physicians

    • In the child who received 5 infusions, the 5th infusion was given at the request of the parents

    • The children who received 1 and 3 infusions were withdrawn from the treatment program by the parents due to apparent lack of effectiveness

Immune Globulin Therapy and Autism Treatment


Research plioplys 19982

ResearchPlioplys (1998)

  • Results (cont’d)

    • 4 made mild improvements with IVIG

    • 5 made no clinical changes

    • 1 progressed and “normalized” during the treatment

    • The 1 dramatic response that was demonstrated indicated that there may but a subset of children with autism whose disorder is due to an autoimmune abnormality

    • Following the study, none of the parents elected to continue intravenous immune globulin therapy. The parents felt that the costs and inconvenience involved with IVIG outweighed the slight improvements seen.

Immune Globulin Therapy and Autism Treatment


Research singh 1999

ResearchSingh (1999)

  • Open-label trials of low and high dose IVIG have shown most (but not all) children have responded favorably with a better response seen in children receiving a high dose

  • Clinical results demonstrate improvement in language, communication, social interaction, and attention span

Immune Globulin Therapy and Autism Treatment


Research delgiudice asch simon schmeidler cunningham rundles hollander 1999

ResearchDelGiudice-Asch, Simon, Schmeidler, Cunningham-Rundles, Hollander (1999)

  • Participants

    • Seven children, ages 3½-6 years (6 male, 1 female)

    • The diagnosis of autism was established using the Autism Diagnostic Interview (ADI; Le Couteur, Rutter, Lord, & Rios, 1989) and DSM IV criteria (APA, 1994)

    • All children were enrolled in full day educational program in addition to receiving IVIG

    • Immunologic testing was not performed and past histories of the children were not notable for an increased frequency of infections or seizure disorder.

Immune Globulin Therapy and Autism Treatment


Research delguidice et al 1999

ResearchDelGuidice et al (1999)

  • Methods

    • Five children ages 3M-6 years (4 male, 1 female) completed 6 months of IVIG clinical treatment in a highly monitored outpatient setting

    • One child withdrew from the study after receiving 2 months of IVIG (considered diagnosis of Laudau-Kleffner syndrome)

    • Another child opted to receive the final 2 IVIG infusions through a private home care company

Immune Globulin Therapy and Autism Treatment


Research delguidice et al 19991

ResearchDelGuidice et al (1999)

  • Methods (cont’d)

    • Bimonthly behavioral assessments were performed by an experienced educator who was not blind to the treatment using the following scales:

      • The Ritvo-Freeman Real Life Rating Scale

      • The Children Yale-Brown Obsessive-Compulsive Scale

      • The Clinical Global Impression Scale for Autistic Disorder

      • The Autism Modification of the NIMH Global Obsessive-Compulsive Scale

Immune Globulin Therapy and Autism Treatment


Research delguidice et al 19992

ResearchDelGuidice et al (1999)

  • Results

    • Study suggests that IVIG does not appear to be beneficial

  • Future Research

    • Further systematic research on therapeutic interventions is needed

Immune Globulin Therapy and Autism Treatment


Research niederhofer staffin and mair 2003

ResearchNiederhofer, Staffin, and Mair (2003)

  • Participants

    • 12 patients (4.2-14.9 yrs.)

    • No immunological abnormalities

    • Patients received no medication 1 month before procedure

  • Methods

    • Double-blind crossover design

    • Participants continued to receive educational and behavioral interventions

    • Checked at 6 & 12 weeks

Immune Globulin Therapy and Autism Treatment


Research niederhofer et al 2003

Research Niederhofer et al (2003)

  • Results

    • The study demonstrated mixed results:

      • Showed improvement on Abberant Behavior (ABC) and symptom checklist

      • No significant difference between placebo and IVIG treatment group

      • Doubtful statistical difference of outcome

Immune Globulin Therapy and Autism Treatment


Research niederhofer et al 20031

ResearchNiederhofer et al (2003)

Immune Globulin Therapy and Autism Treatment


Research schneider melmed enriquez barstow ranger moore ostrem 2006

ResearchSchneider, Melmed, Enriquez, Barstow, Ranger-Moore, Ostrem (2006)

  • Hypothesis

    • Gastrointestinal disturbances associated with autistic disorder (AD) may be due to an underlying deficiency in mucosal immunity, and that orally administered immunoglobulin would be effective in alleviating chronic GI dysfunction in these individuals.

  • Claims

    • Improved GI signs and symptoms, significant behavioral improvements

Immune Globulin Therapy and Autism Treatment


Research schneider et al 2006

ResearchSchneider et al (2006)

  • Participants

    • 12 male subjects diagnosed with AD

    • evaluated using a GI severity index (GSI) while receiving daily dosing with encapsulated human immunoglobulin

  • Methods

    • 8-week, open label, fixed dose evaluation of the safety and efficacy of oral immunoglobulin (Panglobulin) taken at a dose of 420 mg (IgG) prior to bedtime

Immune Globulin Therapy and Autism Treatment


Research schneider et al 20061

ResearchSchneider et al (2006)

  • Methods (cont’d)

    • A follow-up visit was conducted at week 12, 4 weeks after discontinuation of study medication

  • Results

    • Thirty four adverse events were recorded during the study

      • 28 categorized as mild

      • 6 categorized as moderate

      • No serious adverse events were recorded during the study

Immune Globulin Therapy and Autism Treatment


Research schneider et al 20062

ResearchSchneider et al (2006)

  • Results (cont’d)

    • Oral human immunoglobulin administered for eight weeks at daily doses of 420 mg were shown to be well tolerated and effective in improving the clinical course of the GI signs and symptoms experienced by subjects

  • Future research

    • Larger, controlled trials will be necessary to answer the most important questions regarding the relationship, if any, between GI symptoms and core behavioral aspects of AD

Immune Globulin Therapy and Autism Treatment


Research adams 2007

ResearchAdams (2007)

  • Claims

    • Improved aberrant behaviors, speech, hyperactivity, inappropriate stims, and social interactions

  • Participants

    • 26 autistic children

  • Methods

    • received IVIG every 4 weeks for 6 months (dosage 400mg/kg)

  • Results

    • 22 of the 26 children regressed within 4 months after IVIG was discontinued

Immune Globulin Therapy and Autism Treatment


Criteria for ivig for the treatment of autism

Criteria for IVIG for the Treatment of Autism

  • In order to be considered for IVIG, the patient must meet:

    • All 5 absolute criteria

    • 2 contributing major criteria

    • 1 contributing minor factor

      (http://www.webpediatrics.com/ivig.html)

Immune Globulin Therapy and Autism Treatment


Criteria for ivig for the treatment of autism1

Criteria for IVIG for the Treatment of Autism

Immune Globulin Therapy and Autism Treatment


Side effects

pain at the injection site

allergic/anaphylactic reactions

acute renal failure

venous thrombosis

aseptic meningitis

hives or rash

dermatitis - usually peeling of the skin of the palms and soles

redness of the face

chills

fever

sweating

unusual tiredness or weakness

Side Effects

Immune Globulin Therapy and Autism Treatment


Side effects cont d

dizziness

headache

backache

leg cramps

joint or muscle pain

general feeling of discomfort

chest tightness

pulmonary edema from fluid overload, due to the high colloid oncotic pressure of IVIG

upset stomach

vomiting

Side Effects (cont’d)

Immune Globulin Therapy and Autism Treatment


Other considerations

Other Considerations

  • Hazards

    • IVIg treatment is usually well tolerated. Most adverse effects are mild and are usually related to the rate of infusion. However, according to MedlinePlus, IVIG can cause a number of significant, life-threatening hazards.

    • It can cause kidney failure, especially in those with a history of kidney disease, diabetes, sepsis, plasma cell disease, or volume depletion, or in those taking medications that can cause kidney damage

Immune Globulin Therapy and Autism Treatment


Other considerations1

Other Considerations

  • Hazards (cont’d)

    • Immune globulin therapy carries the risk of potentially fatal transmission of blood-borne pathogens (i.e. HIV, hepatitis, etc). Pharmaceutical grade immune globulin is prepared commercially by separating immunoglobulin fractions from pooled human blood specimens. Several steps in the process are added to ensure that any live viruses or bacteria in the specimens are inactive – but there is still a risk.

    • There is potentially an unknown risk of contracting variant Creutzfeldt-Jakob disease (vCJD).

Immune Globulin Therapy and Autism Treatment


Other considerations2

Other Considerations

  • Insurance

    • Many patients receiving immune globlin therapy for FDA approved indications have difficulty with insurance approval

    • Most private health insurance carriers as well as public health assistance (i.e. MediCare and MediCaid) will not cover the expense of any medication or treatment for off label uses.

Immune Globulin Therapy and Autism Treatment


Other considerations3

Other Considerations

  • Expense

    • Approximate wholesale price paid by hospitals or retail pharmacies is approximately $18.00 to $25.00 per gram of IVIG.

    • Health Health insurers are charged$46.00 to $80.00 per gram by hospitals, home infusion companies, andphysicians who administer the drug.

Immune Globulin Therapy and Autism Treatment


Other considerations4

Other Considerations

  • Expense (cont’d)

    • Combined total retail cost amounts to $6,400 to $11,200 per month for the drug alone to treat a patient of average weight (154lbs)

    • The cost of treatment also dependson whether the drug is administered in a hospital, an outpatientclinic, or a home-infusion program and on whether it is givenin 2 days or 5 days

    • Total monthly charges for immune globulin therapy can range from $8,500to $20,000.

Immune Globulin Therapy and Autism Treatment


Other considerations5

Availability

Availability is directly connected to the number of blood plasma donors donating at plasma donation centers

Though a national shortage has not been declared, in the last few years, many patients receiving immune globulin therapy for FDA approved indications have had their treatment impacted due to limited availability including:

Change in brand

Decrease in dosage

Missed infusions

Change in infusion location

Decreased frequency of infusions

Other Considerations

Immune Globulin Therapy and Autism Treatment


Other considerations6

Other Considerations

  • Availability (cont’d)

    • There may be ethical considerations with using IVIG for off-label/experimental uses when availability is limited and there is a potential for shortage. Life saving dosages could be withheld from patients receiving IVIG for FDA Approved Indications and given to patients when the effectiveness is minimal or unknown.

    • IVIG effectiveness is heavily contingent upon maintaining consistent levels of IgG in the blood. Determining effectiveness for off-label uses may be difficult if dosages or infusions are missed due to limited availability.

Immune Globulin Therapy and Autism Treatment


Conclusions

Conclusions

  • There is strong evidence that immune globulin is ineffective in the treatment of the majority of people with autistic spectrum disorders.

  • It is also expensive, inconvenient to use, and potentially harmful.

  • It is strongly recommended that immune globulin therapy is not used as a treatment for autism in children because of the substantial risks and the lack of proven benefit associated with this intervention.

    • The FDA has not approved immune globulin therapy as an intervention for autism

  • If it is used, it should only be undertaken with great caution and only as part of formal research studies.

    http://www.researchautism.net/interventionitem.ikml?print&ra=19&infolevel=4

Immune Globulin Therapy and Autism Treatment


Conclusions1

Conclusions

  • Pseudoscience

    • Definition: A procedure, method or therapy that is adopted rapidly in the presence of little validating research

  • Immune Globulin andPseudoscience

    • The research on immune globulin as a treatment for autism has not shown any significant clinical improvements in any of the claims stated. The studies have also shown that few of the changes were long-lasting.

Immune Globulin Therapy and Autism Treatment


Conclusions2

Conclusions

  • Gupta

    • 2 studies 1996 and 2000.

    • His research showed children with autism treated with IVIG improve in several areas.

    • However…….

Immune Globulin Therapy and Autism Treatment


Conclusions3

Conclusions

  • Gupta’s research is flawed

    • No control group

    • Group was too small

    • Research cannot be replicated

    • Anecdotal observations

    • Research published in Journal of Autism and Dev. Disability

Immune Globulin Therapy and Autism Treatment


Conclusions4

Conclusions

  • No Control Group

    • In 1996 study, Gupta had treated Group1 with IVIG, and gave Group 2 placebo. After 4 weeks, he administered Group 1 with placebo and gave Group 2 IVIG.

  • Group Size was too small

    • The sample size was too small and one female. The effect of age and gender on the responsiveness of IVIG cannot be ascertained.

Immune Globulin Therapy and Autism Treatment


Conclusions5

Conclusions

  • Research cannot be replicated.

    • Plioplys, Adams, Schneider, Neideholfer,Staffen and Mair, andDelgiudice- Asch

    • All tried to replicate the research

    • All have mixed results.

Immune Globulin Therapy and Autism Treatment


Conclusions6

Conclusions

  • DelGuidice et al (1999)

    • Not a double-blind, placebo-controlled study resulting in a unclear answers as to whether a subgroup of patients may be responders or if a longer treatment is needed.

    • Small sample, large number of measures, and high variance of the measures limits the generalization it of the findings.

    • No effects

  • Plioplys (1998)

    • Limited results

Immune Globulin Therapy and Autism Treatment


Conclusions7

Conclusions

  • Niederhofer et al (2003)

    • Limited results

    • Non Scientific - continue to receive other interventions

    • ABC ratings by teacher and parents – subjective and anecdotal.

    • Clinician - insignificant differences between placebo and immune globulin

  • “For that reason, our results should be understood as a strong cautionary word against the growing indiscriminate use of intravenous immunoglobulin in treating autistic children.”

  • Schneider et al (2006)

    • Limited results

Immune Globulin Therapy and Autism Treatment


Conclusions8

Conclusions

  • Research published in Journal of Developmental Disabilities

    • In instructions for authors, under checklist states, “A brief report may not meet the demands of scientific rigor required of an article can be preliminary findings.”

Immune Globulin Therapy and Autism Treatment


Conclusions9

Conclusions

  • Singh

    • In a study in 1997, Singh found IVIG decrease symptoms of autism. The data on this study is not published. In a paper presented in 1999, high dose of IVIG was found to produce better results than low dose in reducing autism symptoms.

Immune Globulin Therapy and Autism Treatment


Conclusions10

Conclusions

  • Singh’s research is flawed

    • Data not published

    • Speaking out of his profession

    • Observations anecdotal

    • Group too small

Immune Globulin Therapy and Autism Treatment


Conclusions11

Conclusions

  • NY State Dept of Health and Clinical Practice

    • “It is strongly recommended that intravenous immune globulin therapy not be used as a treatment for autism for children in autism in children because of substantial risk and lack of proven benefit associated with this intervention.”

  • The evidence that has been presented has not proven to be reliable so far. It is in our opinion that IVIG not be used as a treatment for children with autism.

Immune Globulin Therapy and Autism Treatment


References

References

  • Adams, J. A. (2007). Summary of biomedical treatments for autism. Autism Research Institute Publication 40,1-28.

  • Blaese, R. M. & Winkelstein, J. A. (Eds.). (2007). Patient & Family Handbook for Primary Immunodeficiency Diseases. Towson, Maryland: Immune Deficiency Foundation.

  • DelGiudice-Asch, G., Simon, L., Schmeidler, J., Cunningham-Rundles, C., Hollander, E. (1999). Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. Journal of Autism and Developmental Disorders, 29(2), 157-160.

  • Gupta, S., Aggerwal, S., & Heads, C. (1996). Brief report: Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. Journal of Autism and Developmental Disorders, 26(4), 439-452.

Immune Globulin Therapy and Autism Treatment


References1

References

  • Gupta, S. (1997). A double-blind placebo-controlled crossover study of the effects of intravenous immunoglobulin (IVIG) in autism. Retrieved June 6, 2008, from http://www.autismspeaks.org/science/ research/grants/funded_1997_can.php

  • Niederhofer, H., Staffen, W., & Mair, A. (2003). Immunoglobulins as an alternative strategy of psychopharmacological treatment of children with autistic disorder. Neuropsychopharmacology, 28(5), 1014-1015.

  • Plioplys, A., V. (1998). Intravenous immuneglobulin treatment of children with autism. Journal of Child Neurology, 13(2), 79-82.

  • Schneider, C. K., Melmed, R. D., Enriquez, F. J., Barstow, L. E., Ranger-Moore, J., & Ostrem, J. A. (2006). Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study. Journal of Autism and Developmental Disorders, 36(8), 1053-1064.

Immune Globulin Therapy and Autism Treatment


A review of immune globulin therapy for autism treatment

Immune Globulin Therapy and Autism Treatment


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