Bret Haymore, MD FAAAAI, FACAAI Food Oral Desensitization: Potential & Pitfalls Bret Haymore, MD FAAAAI, FACAAI

OBJECTIVES Understand prevalence and evaluation of patients with suspected food allergy - Understand management of food allergy Understand role of food desensitization in management of food allergy

DISCLOSURES NONE

Background: Food Allergy • Prevalence: • – 3 million school age children (3.9%) 18% increase since 1997 Branum 2009 Pediatrics. 124:1549-55 • 7 most common food allergens in U.S. – Milk, egg, peanut, tree nuts, shellfish, soy, wheat • Peanut allergy Prevalence ~1% Most common cause of anaphylaxis in children presenting to ED Most common cause of fatal food anaphylaxis • Standard of care – Self-injectable epinephrine/antihistamines Avoidance of only foods appropriately diagnosed Bock, J Allergy Clin Immunol 2007 Vander Leek, J Peds 2000

Background: Food Allergy • Accidental exposures – Incidence ~33% per year Peanut IgE can’t predict severity Vast majority of fatalities in patients with known allergy ~20% of Children with peanut allergy outgrow the disease • – Generally by school age • Significant adverse effect on quality of life – Cummings 2010 Allergy 65(8):933-945 Greater than some other chronic diseases (i.e., type 1 diabetes) • No proactive therapy available Fleischer 2007 Curr.Allergy Asthma Rep. 7:175-181 Skripak 2007 J Allergy Clin.Immunol. 120:1172-1177

Peanut Sensitization Burks AW. Lancet 2008;371,9623:1538-1546

Peanut Sensitization Burks AW. Lancet 2008;371,9623:1538-1546

Development of Treatment Options Allergen non-specific Anti-IgE – not stand alone treatment Leung, Sampson, et al. NEJM 2003; 348:986-93 Li, X 2003 J.Allergy Clin.Immunol. 112:159-167 • Chinese herbal medicine – in trials now • Allergen-specific • Engineered recombinant protein – reduced Oral immunotherapy (OIT) Sublingual immunotherapy (SLIT) IgE binding Skripak Current Opinion In Immunology 2008,20:690-696

Initial Food Allergy Study Goals • Goals of treatment are two-fold – Clinical desensitization • tolerate more food before an accidental reaction – Eventual clinical tolerance • off treatment • Goals of research on food allergy treatment Identify the mechanisms of the changes brought on by the treatment – Identify immunologic markers associated with the treatment

Methods of Immunotherapy • Oral IT (OIT) • Sublingual IT (SLIT) • – swallowed with food • Sublingual IT (SLIT) – sublingually then swallowed • Differences – possibility of causing tolerance? amount of protein, route?, digestion?, OIT SLIT

Peanut OIT Blinded Study Design 4000 mg Jones et al. ‐AAAAI 2010 Maintenance 4000 mg Dose Escalation Food Challenge #1 (OFC 1) Desensitization Initial escalation day – 6 mg 1 peanut = 300 mg Jones et al. ‐AAAAI 2010

Meet criteria for assessing tolerance Peanut OIT Blinded Study Design Meet criteria for assessing tolerance Maintenance Off OIT 4000 mg 1 mo Dose Escalation Food Challenge #1 (OFC 1) Food Challenge #2 (OFC 2) Desensitization Food Challenge #3 (OFC3) Initial escalation day – 6 mg Tolerance 1 peanut = 300 mg Jones et al. ‐AAAAI 2010

Peanut OIT – Blinded Study •Any peanut-allergic subject – unless accompanied by significant hypotension •25 subjects – 16 - active treatment; 9 - placebo •All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up * * * P=.008 Jones et al. -AAAAI 2010

Peanut OIT – Blinded Study •Any peanut-allergic subject – unless accompanied by significant hypotension •25 subjects – 16 - active treatment; 9 - placebo •All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up * * * * * P=.008 * P=.001 Jones et al. -AAAAI 2010

Levels of Peanut-Specific IgE and IgG4 Serum Levels of Peanut-Specific IgE and IgG4 Change with Treatment Jones et al. -AAAAI 2010 ImmunoCAP-FEIA (Phadia)

Levels of Peanut-Specific IgE and IgG4 Serum Levels of Peanut-Specific IgE and IgG4 Change with Treatment Jones et al. -AAAAI 2010 ImmunoCAP-FEIA (Phadia)

Allergen-Specific T cells Peanut OIT • Basophil markers - %CD63 – Significant change over first few months of OIT • Peanut-specific CD4+CD25+Foxp3+ – T-Regulatory cells T cells • decreased thereafter increased at 12 months • Peanut-specific cytokines – Decreased – pro-allergic cytokines - IL-4, IL-5, IL-13 – Increased – regulatory cytokines - IL-10, TGF-ß Breslin et al. AAAAI - 2010 Jones, Burks et al. – J Allergy Clin Immunol – August 2009

Permanent Tolerance Develops after 3 Years of OIT Permanent Tolerance Develops after • 27 subjects - on OIT >36 months • 13/27 (48%) passed food challenges • Off treatment • These subjects remain off OIT and ingest peanut in their diet to peanuts Varshney, Jones, Burks et al. AAAAI 2010

Methods of Immunotherapy • Oral IT (OIT) • Sublingual IT (SLIT) • – swallowed with food • Sublingual IT (SLIT) – sublingually then swallowed • Differences – possibility of causing tolerance? amount of protein, route?, digestion?, SLIT OIT

- Adolescents and adults Sublingual Immunotherapy (SLIT) SLIT – Peanut allergic adults and children 5% (1) Initial pilot study (Duke) - Adolescents and adults Laubach, Burks, et al. J Allergy Clin Immunol 2008;121:S96 Bird et al. J Allergy Clin Immunol 2009 4.6% Total home doses (n=4737) 0.6% oropharyngeal non-oropharyngeal 0.7% 4% (2) 2nd blinded study (Duke) – children Bird et al. AAAAI 2010, Kim et al. AAAAI 2010 3% percent of home doses 2% 1% (3) 3rd study (CoFAR-NIH) 0% 3 year study - Adolescents and adults – 0% Skin Upper Resp Chest Abdomen Symptom

SLIT Causes Clinical and Mast Cell Desensitization SLIT – peanut allergic children and adults 2nd blinded study (Duke) – children Bird et al. AAAAI 2010, Kim et al. AAAAI 2010 • Peanut extract – given sublingually • 8 gtts (2 mg) maintenance dose Updosing period – 6 months; Maintenance dosing – 6 months Double-blind, placebo-controlled food challenge (DBPCFC) at 12 months DBPCFC

SLIT Causes Clinical and Mast Cell Desensitization SLIT – peanut allergic children and adults 2nd blinded study (Duke) – children Bird et al. AAAAI 2010, Kim et al. AAAAI 2010 • Peanut extract – given sublingually • 8 gtts (2 mg) maintenance dose Updosing period – 6 months; Maintenance dosing – 6 months Double-blind, placebo-controlled food challenge (DBPCFC) at 12 months DBPCFC Peanut prick skin test

Johns Hopkins/Duke Study – Milk Allergy • Combined SLIT/OIT for milk – ~5 months • Pre-study milk Oral Food Challenge – Dose at reaction ~40 mg – then • Initial SLIT in all groups 1. 2. 3. Continued SLIT A (low) OIT B (higher) OIT Keet, Burks, Wood et al JACI 2010

Immunotherapy Comparison Type of Therapy OIT SLIT Daily dose 300-4000 mg 2-7 mg Side effects GI, systemic, fever, Oral-pharyngeal, exercise Desensitization Large effect Smaller effect Long term tolerance Unknown Unknown

Immunotherapy for Food Allergy - Future • OIT/SLIT – still investigational Studies needed to understand possible clinical benefit and mechanism RCTs are in process Optimizing pharmacokinetics, targeting correct populations • Determine mechanism of action of OIT/SLIT – Basophils/mast cells, humoral, cellular • Determine if food IT induces – Desensitization without/and clinical tolerance Is desensitization only worthwhile? • Goal: development of active treatment for food allergy

Food Allergy Immunotherapy Questions?

Contact Dr. Bret Haymore 405.896.2268; 918.856.6077 drbhaymore@gmail.com www.allergyasthmacarecenters.com NW OKC, Midwest City, Broken Arrow

What does an Allergist-Immunologist Treat Environmental allergy (hay fever) Immunotherapy (allergy shots/drops) Asthma, chronic cough Chronic sinusitis Food allergy / Food desensitization Atopic dermatitis/eczema Contact dermatitis Hives/angioedema Stinging insect allergy Immunotherapy Medication allergy / oral challenge / desensitization Penicillin skin testing Aspirin desensitization Eosinophilic Esophagitis Immune deficiencies / recurrent infections