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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). Overview. Understanding Immunoglobulins in the Immune System IgG Other Immunoglobulins

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A Review of Immune Globulin Therapy for Autism Treatment

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  1. 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

  2. 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

  3. 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

  4. Overview • Criteria for Immune Globulin to Treat Autism • Side Effects • Other Considerations • Conclusions • References • Questions/Discussion Immune Globulin Therapy and Autism Treatment

  5. 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

  6. 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

  7. 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

  8. Prevalence of IgG Subclasses in the total IgG serum in the bloodstream Immune Globulin Therapy and Autism Treatment

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. Present Day Realities:Administration • Administration Routes of Immune Globulin Therapy • Intramuscular (IMIG) • Intravenous (IVIG) • Subcutaneous (SCIG) Immune Globulin Therapy and Autism Treatment

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. Research Gupta et al (1996) Immune Globulin Therapy and Autism Treatment

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. ResearchNiederhofer et al (2003) Immune Globulin Therapy and Autism Treatment

  49. 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

  50. 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

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