Allergen Immunotherapy and Asthma. Linda Cox, MD, FAAAI ASCIA 2013 Meeting

Transcription

1 Allergen Immunotherapy and Asthma Linda Cox, MD, FAAAI ASCIA 2013 Meeting

2 Allergen Immunotherapy and Asthma Overview: burden/prevalence of asthma and allergic disease Allergen immunotherapy and asthma: is it effective? SCIT and SLIT efficacy AIT and asthma safety AIT as a disease modifying treatment; prevention, duration

3 The Burden & Prevalence of Allergic disease: Key Points Allergic rhinitis is one of the most common pediatric & adult chronic diseases Allergic rhinitis is a risk factor for asthma Up to 40% of allergic rhinitis patients will develop asthma Asthma is one of the most common and costly chronic pediatric illnesses Asthma and allergy medications only control symptoms Allergen immunotherapy is currently the only disease modifying treatment for allergic disease Disease modification may translate into significant cost-savings 2º to reduced medication use, co-morbidillnesses, progression of disease, etc.

4 World Health Organization survey regarding asthma Doctor diagnosed asthma 4.5% Current World Population Of 7 Billion Translates To 315 Million Individuals With Asthma. The prevalence of clinical asthma varied widely amongst the 70 participating countries, ranging from 1.0% in Vietnam to 21.5% in Australia, who reported the highest rate of doctor diagnosed, clinical/treated asthma, and wheezing To et al Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC public health. 2012;12:204.

5 Prevalence % Perennial allergen sensitization early in life and chronic asthma in children: a birth cohort study 80 Prevalence of current wheeze from birth to age 13 years in children with any wheezing episode at school age (5 7 years), Atopic n= Growing out of asthma Non-atopic n= Age (years) Sensitisztion to perennial allergens developing in the fi rst 3 years of life was associated with a loss of lung function at school age. 90% non-atopic wheeze Illi S, et al. Lancet 2006

6 A Longitudinal, Population-Based, Cohort Study of Childhood Asthma Followed to Adulthood Purpose: To identify risk factors for persistence and relapse of asthma Design: Assessed 1139 children from age 9 to 26 yrs with questionnaires, PFT, bronchial challenge and allergy testing Seen every 2 yrs, PFT at 9,11,13,15,21 years Skin test 13 & 21years 613 with complete respiratory data included in analysis Seare et al, NEJM 2003; 349:

7 613 Children Followed From Age 9 To 26 Yrs 75% Reported Wheezing On At Least One Occasion And 51% Wheezed > One Occasion Sensitization to house dust mites predicted the persistence of wheezing (OR,2.41; P=0.001) and relapse (OR, 2.18; P=0.01), Seare, M et al NEJM 2003; 349:

8 Asthma burden of disease economic reality US: Asthma rates and associated costs have increased dramatically over the last thirty years. 1 Asthma prevalence increased from 7.3% in 2001 to 8.4% in 2010, ~25.7 million 2 Estimated total direct and indirect costs to society was $56 billion in 2007 ED and hospitalization ~58% and 64% of total direct costs Florida: : hospital costs more than tripled-$210.8 million to $748.5 million which was a 255% increase, Akinbami et al Trends in asthma prevalence, health care use, and mortality in the US, NCHS data brief, no 94.

9 Florida Asthma Stats From 2000 to 2005 ED costs doubled $102.3 million to $204.1 million represents a 99.6% increase Largest increase in total charges (and total visits) occurred among those paid for by Medicare or Medicaid (i.e., government insurer.)

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11 Florida Asthma Coalition 36 Measures Only One Addresses Triggers and this does not specify allergen trigger

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13 Where Does AIT Fit in the Guidelines for Allergen Immunotherapy for Asthma? ARIA recommendations 2010: SCIT: conditional recommendation in allergic asthma (moderate quality evidence) SLIT: conditional recommendation in allergic asthma (low quality evidence) GINA report 2012: Immunotherapy should be considered only after strict environmental avoidance and pharmacological intervention, including ICS Immunotherapy is not listed in GINA treatment steps for achieving control Brożek et al. ARIA revision JACI 2010;126: GINA global strategy for asthma management and prevention: updated 2012

14 3415 adults with asthma in 11 countries prescribed regular maintenance therapy, 74% of patients used shortacting β2-agonists daily and 51% were classified by ACT as having uncontrolled asthma. Even patients with wellcontrolled asthma reported an average of 6worsenings/year Compliance in Asthma is a major concern 70% of patients adjust themselves their medication Partridge et al BMC pulmonary medicine. 2006;6:13. 16

15 EARLY TREATMENT DOES NOT PREVENT PROGRESSION OR HAVE SUSTAINED EFFECT: PHARMACOTHERAPY IS NOT DISEASE MODIFYING In preschool children at high risk for asthma, 2 years of ICS did not change the development of asthma symptoms or lung function during a third, treatment-free year. 1 CAMP at 4.8 year posttrial f/u no difference in lung function or asthma control seen in ICS vs placebo but still significant decreased mean height (1.1 cm) 2 1.Guilbert N Engl J Med 2006; Strunk J Pediatr. 2009;154(5):682-7.

16 PATIENTS PERSPECTIVE ON ALLERGY MEDICATIONS PHARMACOTHERAPY NOT DISEASE MODIFYING OR SATIFACTORY= UNMET NEED According to Allergies in America, a Survey of 2500 Nasal Allergy Sufferers 66% of patients who requested an allergy medication change due to dissatisfaction did so because of lack of efficacy The majority of patients reported that the effects of their medication wore off over time Nearly a third of patients stopped taking their nasal allergy medication because it did not provide 24-hour relief Allergies in America Web site. Accessed September 3, 2007.

17 Patient Concern/Lack of Commitment on the Need for Frequent Office Visits "Needle Phobia" Cost of Therapy Limited Efficacy Side Effects Allergists (n=46) Risk of Anaphylaxis PCPs (n=46)

18 Allergen Immunotherapy and Asthma: the controversy Allergen specific immunotherapy has long been a controversial treatment for asthma. The recommendations of professional bodies have ranged from cautious acceptance to outright dismissal. 1 It is difficult to compare results from the various studies of IT because of the large number of variations in the clinical trial protocols. Given the heterogeneity of IT clinical trials as a group, it is not surprising that variable results occur. The use of multiple studies in a meta-analysis with its underlying assumption of homogeneity is problematic Abramson,Allergen immunotherapy for asthma. Cochrane Database Syst Rev Portnoy Ann Allergy Asthma Immunol 2001;87

19 Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials A meta-analysis of all 20 published prospective, randomized, PC trials of immunotherapy for asthma between These were statistically significant improvement in symptoms, medication use, and BHR. Mean improvement in FEV1 of 0.71 (CI ) corresponding to an average FEV1 increase of 7.1%. Symptomatic improvement Medication reduction Odds ratio 3.2 Odds ratio 4.2 Odds ratio 6.8 Confidence interval ( ) Confidence interval ( ) Decrease in Bronchial Hyperresponsiveness Confidence interval (3.8-12) Abramson et al. Am J Respir Crit Care Med; (4):969-74

20 The Many AIT Meta-analyses: Symptoms SMD=Standardized Mean Difference is the difference of the means of both treatment arms divided by the pooled standard deviation. Burks, et al. Update on allergy immunotherapyaaaai/eaaci /PRACTALL consensus report. J Allergy Clin Immunol Mar 13

21 Allergen Immunotherapy For Asthma Cochrane Database Systemic Review: trials between with a total of 3,459 with asthma, 13 new trials) 42 trials of immunotherapy for house mite allergy 27 pollen allergy trials 10 animal dander allergy trials* 2 Cladosporium mould allergy* 1 latex* 6 trials of multiple allergens* Concealment of allocation was assessed as clearly adequate in only 16 of these trials. Significant heterogeneity was present in a number of comparisons.* *no change from update Abramson et al.,. Allergen immunotherapy for asthma Cochrane Database Syst Rev. 2010;8:CD

22 Allergen Immunotherapy For Asthma Cochrane Database Systemic Review: 2010 Significant improvement in asthma symptom scores (SMD -0.59, CI-0.83 to -0.35) Immunotherapy significantly reduced allergen specific BHR, with some reduction in non-specific BHR as well. No consistent effect on lung function Necessary to treat (NNT) 3 (CI 3 to 5) patients with SIT to avoid one deterioration in asthma symptoms. 4 (CI 34 to 6) patients with SCIT to avoid one requiring increased medication. One systemic reaction for every 9 treated

23 Meta-analysis: plotting the data Forest plot: trying to see the wood and the trees Forest plots show the information from the individual studies used in meta-analysis at a glance which are shown as squares centred on the point estimate of the result of each study. Horizontal line runs through the square to show its 95% confidence interval. Show the amount of variation between the studies and an estimate of the overall result The diamond point at the bottom represents the pooled point estimate, and its horizontal tips represent the confidence interval. Significance is achieved if the diamond is clear of the line of no effect. Lewis, Forest plots: trying to see the wood and the trees BMJ 2001;322:

24 Outcome: Asthma Medication Score. Outcome: Asthma medication score Standardised Mean Difference (SMD) Heterogeneity I 2 > 50% significant Size effect Poor > Medium = 0.50 High < -0.80

25 SCIT versus placebo Lung Function FEV Non specific BHR Specific BHR SLIT Placebo

26 SCIT Allergen Specific Bronchial Hyperresponsiveness Dust mite All allergens: 5 pollen, 6 animal, 2 other Heterogeneity: I 2 =0.0%

27 Efficacy of SLIT systematic review of randomized-clinical trials using the Cochrane Collaboration method in asthma: Using the above selection method, 25 studies with 1706 patients were included in this meta-analysis (10 specifically on children) HDM : 8 studies, Pollen : 14, Mixture : 2, Latex : 1 Calamita et al, Efficacy of SLIT in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy. 2006;61(10):

28 SLIT Meta-Analysis of Asthmatic Symptom Scores I 2 = 63.9% [-0.79, 0.03]

29 SLIT: Meta-analysis of Allergic Symptoms Group (Asthma, Rhinitis, Conjunctivitis, Etc ) I 2 =89.4% [-1.93, -0.43]

30 SLIT and Asthma Meta-Analysis Conclusions: SLIT is beneficial for asthma treatment albeit the magnitude of the effect is not very large. Moreover, it is a safe alternative to the subcutaneous route. More RCT with standardization of symptom scores and medications are needed in order to contribute further to this subject. Calamitra et al., Allergy 2006;61:

31 SCIT and SLIT for Asthma Systematic Reviews Comparison of the systematic reviews of sublingual and subcutaneous immunotherapy Asthma symptoms Immunotherapy Asthma medication scores scores Route SMD (95% CI) SMD (95% CI) Subcutaneous [-0.99, -0.33] [-1.13,-0.40] Sublingual [-0.79, 0.03] [-1.94, 0.12] SMD=standardized mean difference, CI= confidence interval 1. Abramson et al. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003:CD Calamita et.al,. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. 2006:

32 Effectiveness of SLIT vs. SCIT for ARC and Asthma: A Systematic Review MEDLINE, Embase, and Cochrane databases were searched through December 21, 2012 Evidence report commissioned by the US Agency for Healthcare Research and Quality, GRADE methodology 8 RCT comparing SLIT & SCIT in managing allergic asthma and ARC were reported in 4 and 6 clinical trials, respectively. Chelladurai et al, Journal of Allergy and Clinical Immunology: In Practice. 2013;1(4):

33 Effectiveness of Subcutaneous SLIT vs. SCIT for the Treatment of ARC and Asthma: A Systematic Review Low-grade evidence supports greater effectiveness of SCIT than SLIT: asthma symptom reduction reducing a combined measure of rhinitis symptoms and medication use. Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction. Safety: All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT. Chelladurai et al, Journal of Allergy and Clinical Immunology: In Practice. 2013;1(4):

34 Subjects: Prospective controlled study of 210 children with asthma referred to the pediatric allergy clinic of between Tested to multiple inhalants: pollens, cat, horse, dust, molds, etc. Randomly assigned to one of 4 groups: saline, or extract mixtures at: 10-7, 1/5,000 or highest tolerated up to 1/250 w/v concentration of each allergen to which they had a positive skin test. Assessed for presence asthma at age 16 years (N=131). Diagnosis determined by mothers diary and clinic assessment of a blinded allergist Johnstone DE, Dutton A, Pediatrics 1968l42:

35 Dose-response Effect On Persistence of Asthma Dose-dependent response in terms of presence of asthma Authors conclusions: Allergen immunotherapy is clinically effective in children with asthma when administered as a multiple allergen mix to multiply sensitized patients. It is dose-dependent with the highest tolerated dose resulting in maximum efficacy Free of Asthma Dose group After 4 years of SIT Age 16 year end of SIT Placebo and 18% 22% lowest dose 1/5,000 w/v 58% 66% 1/250 w/v or highest tolerated 81% 78% Johnstone DE, Dutton A, Pediatrics 1968l42:

36 Multiallergen Immunotherapy for Asthma In Allergic Children. Methods: DBPC multiple-allergen immunotherapy in 121 allergic children with moderate-to-severe, perennial asthma randomized after 1 year of observation and stabilization to SCIT with up to 7 allergens or placebo injections. Medications were adjusted every 2-3 weeks on the basis of PEFR and symptoms the previous 14 days. Principal outcome was the daily medication scores. Study was essentially asking at least 2 questions: Is multiallergen SCIT effective? & Is effective as add-on to optimal pharmocotherapy & environmental control measures? Adkinson F, et al., N Engl J Med 1997; 336

37 Efficacy of Multiallergen SCIT in Asthmatic Children Not Demonstrated BUT Results: No difference between groups in medication score (1 outcome), use of medical care, symptoms, median PC20 or PEFR- but a trend toward favoring SCIT in 8/10 outcomes Subgroup analysis - approached statistical significance in favor of SCIT in Younger age (8.5 years; p =0.02) Mild asthma (medication score, 5; p= 0.19 and no ICS use) Authors suggested future investigations should focus on the potential prophylactic use of immunotherapy in children with allergic rhinitis, who are at high risk for asthma, or in highly allergic children with the recent onset of mild asthma. Adkinson et al., N Engl J Med 1997; 336

38 Effect of SCIT added to pharmacologic treatment and allergen avoidance in HDM asthmatic patients Method: DBPC study of 72 HDM randomized to SCIT or placebo after an observational year of pharmacotherapy & allergen avoidance. Maintenance 6 mcg (Der 1 + Der 2) Q 3 weeks. Results: SCIT was associated with Significant decrease in # of subjects needing rescue β- agonist Increase in AM & PM PEFR Reduced dust mite skin test reactivity No significant effects on the cumulative dose of ICS, asthma symptoms, lung volumes, or methacholine BHR Maestrelli et al, J Allergy Clin Immunol 2004;113:643-9.

39 SLIT HDM Allergic Asthma in Children Method: 97 mild to moderate asthmatic children aged 6-12 years monosensitized to DM randomized to placebo or SLIT for 24 weeks Cumulative dose: 1.7 mg of Der.p. and 3.0 mg of Der.f. ~26 mcg daily or 783 mcg monthly of mixed mites Results: Statistically significant difference between 2 groups: Daily, nighttime, and daytime asthmatic scores Improved FVC, FEV1, and PEF as compared to baseline No differences were found in SPT, total IgE and specific IgE Tolerance with was good with few minor adverse events reported Niu et al., Respir Med 2006; 100:

40 SLIT for HDM-allergic Asthma Comparison of asthma scores (mean ± SD) before and after 24- week treatment between SLIT and placebo group. daily nighttime There was statistically significant difference between the two groups in the analysis of daily and nighttime asthmatic scores after 24 weeks of treatment Niu et al., Respir Med 2006; 100:

41 SLIT for HDM-allergic Asthma in Children Changes of daily asthma scores (mean ± SD) in SLIT and placebo groups throughout the study period Improvement of asthma symptoms gradually over time in the SLIT group. Placebo group had almost the same asthma score at the endpoint as baseline Niu et al., Respir Med 2006; 100:

42 SLIT for Seasonal Asthma in Children Method: 39 children aged 3-16 years with seasonal allergic asthma randomized to placebo or SLIT over 2 successive grass-pollen season Requiring at least 200 μg of inhaled beclomethasone (or Results: equivalent) daily Substantial reduction in the asthma symptom-medication score (p =.04) in the SLIT compared with placebo group. After the first and second pollen seasons, there were statistically significant differences between the 2 treatment groups for bronchial allergen reactivity No difference in highest FE NO value Roberts et al. J Allergy Clin Immunol. 2006;117(2):263-8.

43 Fig 3 Seasonal Asthma in Children Grass-pollenBHR Allergen concentration producing a 20% FEV1 decrease Immunotherapy was shown to lead to substantial reductions in reactivity to grass pollen in the lungs Roberts et al. J Allergy Clin Immunol. 2006;117(2):263-8

44 Allergy Immunotherapy Safety

45 If 9 patients were treated with SCIT, expect 1 to develop a SR of any severity

46 No. of Systemic Reactions AAAAI/ACAAI Surveillance Study of SCIT Safety: 10.2 SRs per 10,000 injection visits (0.1% for all 3 years) About 8 million injections visits per year Per injection SR rate & number (%) practices reporting 1 Grade 1 mild SR: 1 per 1,287 (.07% injection visits) 613 (76%) practices Grade 2 moderate SR: 1 per 4,166 (.02% injection visits) 436 (54%) practices Grade 3 severe SR: 1 per 30,566 (.003%) 144 (18%) practices Grade 1 Mild 6,293 74% 1,944 Grade 2 Moderate 23% 265 Grade 3 Severe 3% Epstein et al Annals of Allergy, Asthma & Immunology. 2013;110(4):274-8.

47 Worse Case Scenario Subcutaneous Immunotherapy Fatalities 3 surveys of AAAAI members on immunotherapy fatalities spanning time period between

48 SLIT Safety in Published Literature SLIT appears to be better tolerated than SCIT. No reports of SLIT-related fatalities to date in an estimated one billion doses Majority of SLIT AEs are local reactions in the mouth and throat are common at the beginning of treatment, but resolve within a few days or weeks without any medication intervention Dose-response relationship with AEs in some studies No apparent relationship with updosing schedule and AEs Several large (N>300 patients) grass-pollen tablet studies demonstrate good safety profile with no updosing Few reported cases of anaphylaxis (at least 11)* Calderon et al. Allergy Mar;67(3):

49 Sublingual Immunotherapy Safety Summary SLIT should only be prescribed by physicians with appropriate allergy training and expertise. Specific instructions should be provided to patients regarding the management of adverse reactions, unplanned interruptions in treatment and situations when SLIT should be withheld. Risk factors for the occurrence of SLIT severe adverse events have not yet been established. Although there is some suggestion that there may be increased risk in patients who have had prior SCIT systemic reactions. A uniform classification system for grading for AIT systemic reactions 2 and SLIT LR has been developed by WAO 3 1. Canonica et al, Sublingual Immunotherapy: WAO Position Paper Update in progress 2. Cox L, et al, J Allergy Clin Immunol Mar;125(3):569-74, 74 e1-74 e7 3. Passalacqua. Grading local side effects of sublingual immunotherapy: speaking the same language. Submitted for publication

50 Characteristics Of The Slit-induced Anaphylaxis Reported In Literature Author, year De 2009 De 2009 Groot, Groot, Blazowski, 2008 Sex (age) Allergen (producer) M (13) Grass (Grazax, ALK-Abellò) F (27) Grass (Grazax, ALK-Abellò) F (16) HDM (Staloral, Stallergenes) Eifan, 2008 F (11) dust mite + grass pollen mix (Stallergenes) Dunski, 2006 F (31) Alternaria, cat, dog 2 nd day of grass, ragweed, updosing (Greer) Antico, 2006 F (36) Latex End of rush buildup Phase Onset Description Epinephrine First dose 15 min Generalized urticaria, swelling of tongue First dose 5 min Abdominal cramps, asthma, generalized itching, hypotension Maintenance 10 min Hypotension-collapse, overdose (60 flushing, urticaria drops) Maintenance. 3 min Abdominal pain, chest pain, fever, nausea 5 min Angioedema, dizziness, dyspnea, generalized itching 10 min Asthma, generalized urticaria NO YES YES Not specified NO Not specified

51 1. Cox et al, J Allergy Clin Immunol 2010;125: Passalacqua et al, J Allergy Clin Immunol. 2013: in press Speaking the Same Language in Terms of AIT Safety Reporting 1 2

52 Measures to Improve Safety Premedication Antihistamines Studies with RIT & cluster suggest decreased incidence of local and SRs. Conventional IT: One DBPC study found premedication with fexofenadine reduced # of severe SRs, number of pts who reached TMD & time to TMD 1 Leukotriene receptor antagonist Anecdotal reports of reductions in SR rates. One DBPC study demonstrated LLR during venom RIT with moneleukast 2 1.Ohashi et al, Ann Allergy Asthma Immunol 2006; Wohrl et al., Int Arch Allergy Immunol 2007;144:137-42

53 Number of Patients Effect of 16 week pretreatment with omalizumab on the tolerability of AIT in moderate persistent allergic asthma inadequately controlled with ICS Severity of First Systemic Allergic Reaction Patients who experienced SR: omalizumab 13.5%, placebo 26.2% P= Grade 1 (Skin) Grade 2 (GI) Grade 3 (Resp) 2 2 Grade 4 (CV) Omalizumab N=17 Placebo N=32 Massanari et al, J Allergy Clin Immunol. 2010;125(2):383-9

54 AIT and Asthma Safety SCIT incidence of SR ~ 0.1% of injections Poorly controlled/symptomatic asthma identified risk factor for SCIT severe AE SLIT appears to have safer profile Majority of studies have been done in AR ± mild-to-moderate asthma and no studies in severe asthma Risk factors for SLIT severe AE have not yet been established but? increased risk in prior SCIT SR patients Unmet need per WAO SLIT PPU The safety of SLIT in moderate to severe asthmatics. Are there are specific precautions/instructions for asthma patients before taking SLIT

55 Duration of Allergy Immunotherapy Efficacy AIT

56 Duration of allergen immunotherapy in respiratory allergy: when is enough, enough? OBJECTIVES: To investigate the duration of effective SCIT reported in the published literature. RESULTS: The rate of relapse after discontinuing SCIT ranges from 0% to 55% of patients. The length of the SCIT and allergen type (ie, perennial vs seasonal) may be variables that affect the duration of clinical remission after cessation of SCIT. CONCLUSION: Until specific tests or clinical markers are identified that will clearly distinguish between patients who will relapse from those who will remain in long-term clinical remission after discontinuing effective allergen immunotherapy, the decision to continue or stop immunotherapy must be individualized. Cox L,Cohn J, Ann Allergy Asthma Immunol 2007; 98:

57 Long-term follow-up of patients treated with a three-year course of cat or dog immunotherapy A 5-year follow-up study was conducted to investigate the duration of the effects of a 3-year course of immunotherapy with standardized cat or dog extracts in 32 children and adults with asthma caused by animal dander. Clinical Allergen-BHR NS-BHR Hedlin et al J Allergy Clin Immunol. 1995;96(6 Pt 1): Table from Cox L,Cohn J, Ann Allergy Asthma Immunol 2007; 98:

58 ACS (adjusted means) Long-term Clinical Efficacy 300 IR grass SLIT tablets Discontinuous Treatment 2 vs. 4 months Before Season Average Combined Score (ACS): Worst Pollen Period - years 1 to 4 End of treatment 1-23% - 15% Placebo % - 29% - 34% - 32% - 27% - 26% 300IR 2M 300IR 4M p value <.0001 <.0001 <.0001 < ANCOVA (FAS) The Average Combined Score results are consistent with the Average Adjusted Symptom Score throughout the 4 years at worst pollen period. EAACI 2011 Annual Congress presentation Professor Sabina Rak-provided with permission Robert Zeldin, MD Didier et al, J Allergy Clin Immunol Sep;128(3):

59 Immunotherapy with a standardized dust mite Duration of the efficacy of immunotherapy after cessation. Study design: 40 asthmatic received SIT with DPT for 12 to 96 months followed for 3 years after discontinuation 55% of pts relapsed. Relapse defined as return of asthma ± rhinitis or impaired PFT Duration of efficacy related to Duration of immunotherapy (P<0.04) 52% of pts treated >36 months no relapse vs. 38% no relapse in <35 month treatment group Decrease in skin test reactivity (P<0.003) Most pts who did not relapse had ed STR vs. most who relapsed had no change Des Roches et al. Allergy 1996; 51: 430-4

60 Optimal Duration for Sublingual Immunotherapy Methods: In this prospective open controlled study we followed up patients with respiratory allergy who were monosensitized to mites for 15 years. 4 groups receiving drug therapy alone or SLIT for 3, 4, or 5 years. Clinical scores, skin sensitizations, MCH, and nasal eosinophila evaluated yearly during the winter months. Clinical effect was considered to persist until clinical scores remained at less than 50% of the baseline value, and then patients underwent another course of SLIT. Marogna et al. J Allergy Clin Immunol. 2010;126(5):969-75

61 4-year duration of SLIT is the optimal choice New sensitizations in all control subjects Less than 25% SLIT patients: 21%-3yr, 12%-4yr, 11%-5 yr SLIT for 4 or 5 years= 8 years of control. CONCLUSION:.. it can be suggested that a 4-year duration of SLIT is the optimal choice because it induces a long-lasting clinical improvement similar to that seen with a 5-year course and greater than that of a 3-year vaccination. Marogna et al. J Allergy Clin Immunol. 2010;126(5):969-75

62 Preventing the progression of the allergic disease i.e. the allergic march

63 Preventive Allergy Treatment (PAT) Study: Multi-center prospective European study Objective: to determine if SCIT can prevent the development of asthma in 205 children, ages 6-14, with mod-severe allergic rhinitis: randomized to either SIT (birch and/grass) or an open control group for 3 yrs. asthma was diagnosed as recurrence of at least 2 of the following 3 symptoms within the previous 12 months Cough Wheeze Shortness of breath

64 SCIT Reduces Risk of Developing Asthma End of treatment 1 and 5-year 2 & 10-year 3 follow-up two (n=142) 2 & seven yrs (n=117) 2 after SCIT discontinuation at the beginning of the study, ) 3y 5y 10y 3y 5y 10y Odds-ratio: 3 years= 2.52 ( ) 5 year= 2.68 ( ) 10 years = 3.19 ( ) 1. Moller et al: JACI 2002;109: Niggemann et al, Allergy 2006; 61: Jacobson et al., Allergy 2007; 62:943-8

65 Coseasonal SLIT Reduces The Development Of Asthma In Children With ARC Methods: Open study of 113 children aged 5 to 14 years with grass-pollen AR were randomized to receive co-seasonal SLIT for 3 years or standard symptomatic therapy. None with asthma at baseline. Active treatment: Feb-June for 3 yrs, build-up 15 days, Maintenance dose: 0.5 mcg major grass allergen grp 5 given 5 days a week (11 mcg major grass CMD=low dose) Novembre J Allergy Clin Immunol 2004;114:851-7.)

66 % of patients SLIT Reduces Risk of Developing Asthma Three years of coseasonal SLIT reduces the development of seasonal asthma in children with hay fever 100% Odds ratio 3.80 ( ) 80% n=37 60% 40% 20% n=8 80% n=26 n=18 40% 60% w asthma w/o asthma 0% 20% SLIT Control Novembre E et al. J Allergy Clin Immunol 2004; 114: 851-7

67 Effects of SCIT with Parietaria on Symptoms and Progression to Asthma 30 with SAR patients randomly assigned to SCIT or placebo for 3 year. Monthly maintenance 4.8 mcg of the major allergen Par j 1 Changes in symptom scores at the peak season for allergic rhinitis in adult patients Polosa et al. Allergy 2004;59: Rhinitis patients developing asthmatic symptoms

68 Polasa et al. Respir Res ;6:153 Greater risk of incident asthma cases in adults with allergic rhinitis and effect of allergen immunotherapy: a retrospective cohort study.. Objective: investigate history of allergic rhinitis as a risk factor for asthma and the potential effect of SIT Method: cohort of non-asthmatic adults ± AR, aged yr in , were retrospectively followed up until asthma diagnosis, history of SIT, second-hand smoking and the presence of pets in the household A total of 436 of the 1104 non-asthmatic adults were available for final analyses

69 AIT Lowers the risk of the development of new asthma cases in adults with allergic rhinitis. Highest odds ratio: associated with asthma development was AR (10.26) Lowest odds ratio: SCIT treatment was significantly and inversely related to the development of new onset asthma (OR, 0.63) Polasa Respir Res ;6:153.

70 To determine whether SCIT can prevent the development of new sensitizations over a 3-years follow-up survey in children suffering from asthma due House Dust Mite 44 children (4 to 6 years) with asthma, monosensitized to HDM. - Clinical history of asthma clearly established, - Positive skin prick test response to D. pteronyssinus. and DM sige SCIT treatment: 2 µg of Der p 1) every 2 weeks for 1 year, and then every month over the next 2 years. Des Roches A. et al. J Allergy Clin Immunol, 1997;99(4): /5

71 SIT in children monosensitized to HDM alters the natural course of allergy in preventing the development of new sensitizations. New sensitizations was significantly less in monosensitized children who received SIT than in children in the control group (p < 0.001). Ten of 22 (45%) who received SIT did not develop new sensitivities Zero in the control group. did not develop new sensitivities New sensitivities (number of patients) Initial sensitivity No. of patients None Cat Dog Alt Grass SIT group Control group Des Roches A. et al. J Allergy Clin Immunol, 1997;99(4):

72 AIT is it Cost-effectiveness? Although, the primary means for assessing outcome A/I clinical trials and practice has been clinical.., other outcomes, such as cost-effectiveness, will likely become increasingly more important to health care decision makers. Famed "Show Me the Money!" scene *Cox L, et al. Allergen immunotherapy practice in the United States: guidelines, measures, and outcomes. Ann Allergy Asthma Immunol. 2011;107(4):289-99

73 YR/AUTHOR Health Economics of SIT (15 Studies from 1995 to 2011) C T SOURCE SUBJECTS ILLNESS COMPARATORS RESULTS 95 Buchner D E Lit Rev Unspecified AR; Asthma SIT vs SDT AR $7,335/10 Years; Asthma $14,137/10 Years 97 Le Pen F R Survey Unspecified Various 1-2 Years SIT vs <1 Year SIT Not Provided 00 Schadlich D E 05 Berto I T 05 Peterson D K Clin Trial Unspecified AR 3 Years SIT vs SDT $960/10 Years Mite; $1,109/10 Years Pollen MR Children AR ± Asthma Year Prior vs Year of SLIT $363/Year Survey Years AR ± Asthma 4 Years SIT vs SDT $1,447/4 Years 06 Ariano I T Diary Adults AR + Asthma 3 Years SIT v SDT; 3 Years FU $932/Year in Year 6 (3 rd Year FU) 06 Berto I T RC Years AR ± Asthma 3 Years SLIT+ SDT vs SDT $632/6 Years (3 rd Year FU) 07 Bachert E u r 07 Keiding U K Clin Trial Adults AR ± Asthma 3 Years SLIT+SDT vs SDT; 6 Years FU Clin Trial Years AR 3 Years SLIT+SDT vs SDT; 6 Years FU $19,345 to $27,324 cost per QALY gained $14,536 to $38,695 cost per QALY gained 07 Omnes F R Delphi Adults/ Children AR ± Asthma 3 Years SIT Adults; 4 Years SIT Children; 3 Years FU ICER (add l improved pt): SCIT vs SDT $517 to $1,964; SLIT vs SDT $933 to $5,829 Poor outcomes for SIT are shown in red font. 82

74 Sustained significant reductions in cost beginning in the 3 rd year subcutaneous allergen immunotherapy Results: In additional to reduced symptom/medication scores there was a significant difference in costs favor of SIT vs control 15% the second year 48% the third year (80% reduction ) 80% reduction maintained up to 6 th year, 3 years after stopping immunotherapy Net saving per patient: $830/year. Conclusion: SCIT has significant economic advantages over pharmocotherapy alone Ariano et al Allergy Asthma Proc 2006;27

75 Study: Retrospective ( ) Florida Medicaid claims analysis compared mean 18-month health care costs of patients with newly diagnosed AR who received de novo AIT more versus matched controls who did not receive AIT Results: Significant 18-month total health care cost reduction in AIT group compared with control 42% children 30% adults Significant savings seen beginning at 3 months Hankin J Allergy Clin Immunol 2013;131:

76 Reductions include: inpatient, outpatient and pharmacy costs Hankin et al, J Allergy Clin Immunol 2013;131:

77 SLIT versus SCIT For Asthma Are they both effective? Yes, several meta-analyses have demonstrated efficacy of both symptoms & medication and secondary outcomes If so, are they equally effective? Magnitude may be greater for SCIT What determines efficacy for each method? Quality of extract, duration, other exposures for both Dose for SCIT range 5-20mcg, but SLIT effect may vary with allergen extract formulation Are they safe and how does safety compare between the two methods? SLIT appears to be safer but anaphylaxis has been reported & risk factors for SLIT not clearly identified

78 SLIT AND SCIT for Asthma Can they both prevent the progression of allergic disease? Yes, both in terms of asthma and new allergen sensitizations Pharmacotherapy only treats the tip of the allergy iceberg with Allergen immunotherapy is the only immune modifying treatment. Sustained benefits after discontinuation and possible prevention of allergic disease progression

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