SLIT: Review and Update

SLIT: Review and Update

Disclosure Speaker: ISTA Pharmaceuticals Speaker: GlaxoSmithKline

Allergen IT - Evidence Based Evaluation: Rescue Medications Meta-analysis Disease IT # of Patients Rescue Medication SMD (95% CI) Abramson 2003 Asthma SCIT 3506-0.80 (-1.13 to -0.48), p < 0.0003 Calamita 2006 Asthma SLIT 303-0.82 (-1.25 to 0.39), p = 0.002 Penagos 2008 * Asthma SLIT 366-1.63 (-2.83 to -0.44), p = 0.0007 Durham Rhinitis SCIT -0.84 (-1.31 to -0.37), p < 0.002 Wilson 2005 Rhinitis SLIT 979-0.43 (-0.63 to -0.23), p = 0.0003 Penagos 2006 Rhinitis SLIT 279-0.76 (-1.46 to -0.06), p = 0.03 Calderon 2007 Rhinitis SLIT 1063-0.57 (-0.82 to -0.33), p < 0.001 * Ages 3-18 years

SLIT in Asthma: Meta-analysis Penagos M et al. Chest 2008;133-599-609

Valovirta E et al. Allergy 2006;61:1177-83 SLIT in Children Efficacy in children Symptoms improved in high and low dose groups Medication: improved ONLY in high dose group

Alvarez-Cuesta et al. Allergy 2007;62:810-7 Sublingual Immunotherapy with Cat Dander Extract

Kägi and Wüthrich. Allergologie Jahrgang 2007. Multiallergen SLIT

Development of Asthma in Children with Allergic Rhinitis After 3 Years of SCIT or SLIT Moller et al. JACI 2002;109:251-6 Novembre et al. JACI 2004;114:851-7

Long-term SLIT in Mite-allergic Children with Asthma 3 year prospective, open, parallel-group, controlled study Asthmatics aged 4-16 yr, sensitive to house dust mite (HDM), 1- year run-in period SLIT + pharmacotherapy (n=62); pharmacotherapy alone (n=28) SLIT + pharmacotherapy: significantly lower mean daily dose and annual duration of inhaled corticosteroid (ICS) usage versus controls At the end of 3 years, significant decreases in the dose and duration of ICS only in the SLIT group 52.4% of subjects in the SLIT + pharmacotherapy group were able to discontinue ICS treatment for at least 6 months versus 9.1% for the pharmacotherapy group Ozdemir C et al. Ped Allergy Immunol 2007;18:508-15

Ozdemir C et al. Ped Allergy Immunol 2007;18:508-15 Long-term SLIT in Mite-allergic Children with Asthma

SLIT Versus Pharmacotherapy 65 patients allergic to mite and positive to methacholine challenge 12 control patients treated for 4 years with standard pharmacotherapy (SPT); 53 received SLIT and SPT 15 patients treated for 1 year (SLIT 1); 10 patients treated for 2 years (SLIT 2); 14 patients treated for 3 years (SLIT 3); 14 patients treated for 4 years (SLIT 4) Results At 2 to 3 years after end of treatment, symptoms improved in the SLIT groups versus placebo, but not methacholine challenge and FEV1 An effect on methacholine challenge also seen in SLIT 3 After 7-8 years a significant difference was seen for symptoms; significantly better in SLIT 4 than in the other groups Bronchial reactivity still improved in SLIT 1, 3 and 4 only after 5-6 years Marogna et al. Int Arch Allergy Immunol 2007;142:70-8

Dose, Efficacy, Treatment Schedules Definite dose versus efficacy range for SLIT Evidence that multiple allergens should be effective in a similar manner to SCIT No specific guidelines for treatment schedules

Proposed Mechanism of Action of SLIT Allergens Th2 Suppression B cell IgG Oral mucosal dendritic cell Th0 T REG Interleukin-10 TGF- IgA Frew. NEJM 2008;358:2259-64

SLIT with Grass Allergen Tablet: Immunological Changes Dahl et al. JACI 2008;121:512-8

Biological Changes Induced by SLIT Burastero et al. Ann Allergy Asthma Immunol 2008;100:343 350

Immunologic Changes with SLIT Early increase in IgG1, with a decline after 2 years of treatment Slow initial increase in IgG4, rapid increase between 18 and 24 months Decrease in antigen-specific IgE Reduced post seasonal increase in IgE Reduction in T cell proliferation, neutrophils, eosinophils Increased IL-10 production Decrease in urinary leukotriene levels Decreases in serum ECP, serum IL-13, serum prolactin Decrease in nasal tryptase and specific IgE Decrease in nasal tryptase during allergen challenge Leatherman. Otolaryngol Clin N Am 2008;41:359-374

Biological Changes Induced by SLIT Design 2-month study, no up-dosing, 2 tablets, equivalent to 2.2 micrograms of Phl p 1 daily Cumulative dose approximately 60,000 AU, equivalent to 132 micrograms of Phl p 1 major allergen monomeric allergoid) derived from a 3-grass pollen extract Results Allergen-specific proliferation decreased (P=0.002) IL-10 transcription increased (P<0.001) TGBeta-transcription increased but not statistically significantly (P=0.06) Conclusion SLIT can induce a decrease in allergen-specific T-cell proliferation associated with an increase in cytokines capable of impairing Th2 responses Burastero et al. Ann Allergy Asthma Immunol 2008;100:343 350

Possible Mechanism of Action of SLIT Allergens Th2 Suppression B cell IgG Oral mucosal dendritic cell Th0 T REG Interleukin-10 TGF- IgA Frew. NEJM 2008;358:2259-64

Acute Systemic Reactions in Patients Treated with SLIT Number of patients: 43 Doses given: 23,154 16 patients (37%): oral and sublingual itching 5 patients (11.6%): 7 systemic reactions (0.3 per 1000 doses), all dust mite 4 patients by 30 minutes, 3 were grade 2, 1 was grade 3 1 patient 60 minutes later No hospitalizations Rodríguez-Pérez et al. Ann Allergy Asthma Immunology 2008;101:304-10

SLIT Adverse Events Treatment-emergent Adverse Events Reported by 5% of Subjects Grass Allergen Tablet Placebo Category N % N % Number of subjects 316 318 Oral pruritus 145 46 13 4 Nasopharyngitis 47 15 60 19 Edema mouth 58 18 2 1 Influenza 23 7 24 8 Ear pruritus 38 12 3 1 Throat irritation 30 9 3 1 Headache 9 3 19 6 Orodispersible grass allergen tablet 75,000 SQ-T (approximately 15 mg major allergen Phl p 5), or a placebo Efficacy demonstrated against placebo Adverse events: 5/316 patients withdrawn due to angioedema of tongue, lips, pharynx, throat Dahl et al. JACI 2006;118:434-40 E = number of events

USA SLIT Safety Trial: Types of Adverse Effects Reported During 8-week Treatment of 91 Patients Category Number % Nose 12,515 50.5 Mouth and throat 4,478 18.1 Eye 4,099 16.5 Lung 2,066 8.3 Ear 1,052 4.2 Gut 420 1.7 Skin 142 0.6 Headache 4 0.02 12 patients- 34 severe reactions, 3 patients withdrawn Esch et al. Ann Allergy Asthma Immunol 2008;100:475-481

Summary: Safety Considerations Evidence is that SLIT is safer than SCIT No reported fatalities from SLIT Systemic reactions can occur

SLIT for Other Disorders Atopic Dermatitis Insect Sting Reactions Pajno et al. JACI 2007;120:164-70 Severino et al. JACI 2008;122:44-8

SLIT: Food Allergy Mempel et al. JACI 2003;111:1406-9. Severe anaphylaxis to kiwi? Desensitization or tolerance? Enrique et al. JACI 2005;116:1073. Effective for hazelnut allergy. De Boissieu. Allergy 2006; 61:1238-9. Cow s milk allergy tolerance improved.

SLIT: Conclusions Effective for allergic rhinitis, asthma; possibly atopic dermatitis, foods; US studies are ongoing Safer than SCIT but not totally safe; systemic reactions may occur Administered at home, but administration under allergist supervision seems best Still lacks FDA approval and CPT coding An additional tool for the allergist