Sublingual Immunotherapy From Efficacy, Safety to Practical Considerations

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Presentation by Dr. Linda Cox
Kentucky Society of Allergy, Asthma & Clinical Immunology Annual Meeting-September 2011

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  • dear doctor
    greetings
    can you kindly send me the full text of your PPT
    Adel M. Alwahadneh MD MSc. FRCPCH (London)
    Senior Consultant Pediatric Immunologist, Allergist &Rheumatologist
    Head, Pediatric Immunology, Allergy &Rheumatology Section
    Head, Bone Marrow transplantation group for primary Immunodeficiency
    Queen Rania Children Hospital
    King Hussein Medical Center
    E. Mail: adelwahadneh@yahoo.com
    00962799018432
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  • I would be grateful if you can kindly give me an access to full text of your appreciated PPT
    Adel M. Alwahadneh MD MSc. FRCPCH (London)
    Senior Consultant Pediatric Immunologist, Allergist &Rheumatologist
    Head, Pediatric Immunology, Allergy &Rheumatology Section
    Head, Bone Marrow transplantation group for primary Immunodeficiency
    Queen Rania Children Hospital
    King Hussein Medical Center
    E. Mail: adelwahadneh@yahoo.com
    00962799018432
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • Dear Dr
    I am interested in your presentation I am teaching medical student and pediatricians under graduate and post graduate and I ask your permission to download your presentation for teaching purpose
    appreciate your help
    Dr Hussni Qari
    pediatric allergist immunologist
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  • BACKGROUND: Allergic ocular symptoms, although frequently trivialised, are common and represent an important comorbidity of allergic rhinitis. Sublingual Immunotherapy (SLIT) is an effective and well-tolerated treatment for allergic rhinitis, but its effects on symptoms of ocular allergy have not been well established. OBJECTIVES: To evaluate the efficacy of SLIT compared with placebo for reductions in ocular symptoms, topical ocular medication requirements and conjunctival immediate allergen sensitivity. SEARCH STRATEGY: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1950 to January 2011), EMBASE (January 1980 to January 2011), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2011), Web of Science (January 1970 to January 2011), Biosis Previews, (January 1979 to January 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (January 2011), ClinicalTrials.gov (www.clinicaltrials.gov) (January 2011), the Australian New Zealand Clinical Trials Registry (ANZCTR) (www.actr.org.au) (July 2010), SCOPUS (November 2008) and the UK Clinical Trials Gateway (January 2010). There were no language or date restrictions in the search for trials. All electronic databases except for SCOPUS, the UK Clinical Trials Gateway and ANZCTR were last searched on 19 January 2011. SELECTION CRITERIA: Randomised controlled trials (RCTs), double-masked and placebo controlled, which evaluated the efficacy of SLIT in patients with symptoms of allergic rhinoconjunctivitis (ARC) or allergic conjunctivitis (AC). DATA COLLECTION AND ANALYSIS: The primary outcome was the total ocular symptom scores. Secondary endpoints included individual ocular symptom scores (such as itchy eyes, red eyes, watery eyes, swollen eyes), ocular medication scores (eye drops) and conjunctival immediate allergen sensitivity (CIAS). Data were analysed and reported as standardised mean differences (SMDs) using Review Manager software. MAIN RESULTS: Forty-two trials (n = 3958 total participants; n= 2011 SLIT and n = 1947 placebo) had available data to evaluate the efficacy of SLIT on AC and were included in the meta-analyses. Heterogeneity among studies (I(2) statistic) was around 50% or below for all endpoints. Sublingual immunotherapy induced a significant reduction in both total ocular symptom scores (SMD -0.41; 95% confidence interval (CI) -0.53 to -0.28; P < 0.00001; I(2) = 59%) and individual ocular symptom scores for red eyes (SMD -0.33; 95% CI -0.45 to -0.22; P < 0.00001; I(2) = 27%), itchy eyes (SMD -0.31; 95% CI -0.42 to -0.20; P < 0.00001; I(2) = 46%) and watery eyes (SMD -0.23; 95% CI -0.34 to -0.11; P < 0.0001; I(2) = 42%) compared to placebo. Those participants having active treatment showed an increase in the threshold dose for the conjunctival allergen provocation test (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05; I(2) = 43%). No significant reduction was observed in ocular eye drops use (SMD -0.10; 95% CI -0.22 to 0.03; P = 0.13; I(2) = 34%). AUTHORS' CONCLUSIONS: Overall, SLIT is moderately effective in reducing total and individual ocular symptom scores in participants with ARC and AC. There were however some concerns about the overall quality of the evidence-base, this relating to inadequate descriptions of allocation concealment in some studies, statistical heterogeneity and the possibility of publication bias. There is a need for further large rigorously designed studies that study long-term effectiveness after discontinuation of treatment and establish the cost-effectiveness of SLIT.
  • Sublingual immunotherapy for allergic respiratory diseases:An evaluation of meta-analysesAntonio Nieto, MD, PhD, Angel Mazon, MD, PhD, Rafael Pamies, MD, Laura Bruno, MD, Mariola Navarro, MD,and Ana Montanes, MD Valencia, SpainBackground: Five published meta-analyses (MAs) seem to provethe efficacy of sublingual immunotherapy in allergic asthma andrhinoconjunctivitis.Objective: We aimed to assess the consistency, magnitude, androbustness of the results of these MAs.Methods: The data reported in the MAs were checked with thedata reported in the original studies. Funnel plots wereperformed to test for potential publication bias, and the trimand-fill method was used to assess and correct the estimate ofthe effects if asymmetry was present.Results: The 5 MAs included 43 studies; 17 were used in morethan one MA. There were discrepancies among the MAs in thedata reported from the same original studies: the MAs reporteddifferent estimates for the same outcome or the same estimatesfor different outcomes in 16 of those 17 studies. The MAsevaluated 15 main outcomes, 10 of which showed benefits thatreached statistical significance. Funnel plots showed asymmetryin 7 outcomes, and correction by using the trim-and-fill methodled to a decrease in their effect estimates and even to a loss ofstatistical significance in 4 of the previously significantoutcomes. There was inconsistency among the MAs in thebenefits when considering age, disease, allergen, or symptomsand medication use.Conclusion: Because of discrepancies, inconsistencies, and lackof robustness, the MAs on sublingual immunotherapy do notprovide enough evidence to support its current routinemanagement in patients with allergic asthma orrhinoconjunctivitis. Sensitivity to potential publication biasshould be tested and reported in all MAs
  • L10 Efficacy and Safety of Grass Allergy Immunotherapy Tablet(AIT) in a North American Pediatric PopulationM. Blaiss1, J. Maloney2, H. Nolte2, S. Gawchik3, D. Skoner4; 1Universityof Tennessee Health Science Center, Memphis, TN, 2Schering Corp., a Divisionof Merck & Co., Kenilworth, NJ, 3Asthma and Allergy Associates,Upland, PA, 4Allegheny General Hospital, Pittsburgh, PA.RATIONALE: One European sublingual immunotherapy trial with grassAIT has shown efficacy and tolerability in children with allergic rhinoconjunctivitis(ARC). This phase III trial investigated daily administration ofSQ-standardizedgrass AIT (oral lyophilisate, Phleumpratense, 2,800BAU, 75,000 SQ-T, ~15 mg Phl p 5) in a North American grass-allergic pediatricpopulation.METHODS: 345 children (ages 5-17 years) with grass pollen ARC wererandomized 1:1 to once-daily treatment with grass AIT or placebo >8weeks prior to and throughout the 2009 grass pollen season (GPS).Rescue medications and symptoms were recorded in e-diaries daily fromrandomization with efficacy measured during GPS. The primary efficacyendpoint comprised the total combined daily symptom score (DSS) anddaily medication score (DMS). Secondary endpoints were individualDSS, DMS and the Juniper (pediatric or adolescent) RhinoconjunctivitisQuality of Life Questionnaire (RQLQ). Immunological endpoints includedspecific IgG4 and IgE-blocking factor. Safety was assessed by adverseevents (AEs).RESULTS: 89% of the subjects were multisensitized. The AIT group hada statistically significant improvement (26%, P50.001) in total combinedscore compared to the placebo group. The DSS (25%, P50.002), DMS(32%, P50.066), and RQLQ (mean difference 0.32 (18%, P50.028)also improved for the active group. The majority of treatment-relatedAEs were local, application site reactions, with no reports of anaphylacticshock.CONCLUSIONS: This was the first successful phase III trial in NorthAmerica investigating grass AIT in children. Once-daily administrationof grass AIT preseasonally and during GPS is clinically effective, well-tolerated,and may be a new therapeutic modality for children with grass pollenallergy.J ALLERGY CLIN IMMUNOLFEBRUARY 2010AB358 Late-Breaking Abstracts
  • Mean duration of SLIT was 87.7 days during the firsttreatment season. Compared with baseline values, thecombined score (symptom and medication) decreasedsignificantly with SLIT compared with placebo(P = 0.043) during the first season. The magnitude ofefficacy was 33.9% for symptom score in favour of SLIT(P = 0.0366). The difference in intake of rescue medication()18% for SLIT) was not statistically significant(P = 0.3512).Patients in the SLIT group had sequentially lowercombined symptom and medication scores comparedwith placebo over the following two seasons and,importantly, in the follow-up period. By the third season,the median of the combined symptom and medicationscores had decreased by )44.7% in the SLIT group and)14.7% in the placebo group compared with baselinevalues (Fig. 2A)
  • A high-quality study (few protocol deviations).
  • Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy 2009;64:1570-9.Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy 2009;64:1570-9.Recent meta-analyses documented the efficacy and safety of sublingual immunotherapy (SLIT) in patients with allergic rhinitis (AR) and asthma (AA). Although SLIT appeared globally effective, the sub-analyses for single allergens provided uncertain results. This study is aimed to investigate the efficacy of SLIT with house dust mite (HDM) extracts in AR and AA through an updated reassessment of randomized controlled trials. Electronic databases were searched up to March 31, 2008, for randomized DBPC trials, assessing the efficacy of SLIT in AR and AA due to HDM sensitization. Outcomes were symptom scores and rescue medications use. For AR, eight studies fulfilled the selection criteria. A significant reduction in symptoms of AR (SMD -0.95; CI 95%-1.77 to -0.14 P = 0.02) was found in 194 patients (adults and children) receiving SLIT compared to 188 receiving placebo. For AA, with nine studies, similar results were found for symptoms (SMD -0.95; CI 95%-1.74 to -0.15 P = 0.02) in 243 patients (adults and children) receiving SLIT compared to 209 receiving placebo. A reduction in rescue medication use was found for AR (SMD -1.88; CI 95%-3.65 to -0.12 P = 0.04) in 89 patients, and AA (SMD -1.48; CI 95%-2.70 to -0.26 P = 0.02) in 202 patients. A relevant inter-study heterogeneity was detected. Promising evidence of efficacy for SLIT, using mite extract in allergic patients suffering from AR and AA, are herein shown. These findings suggest that more data are needed, derived from large-population-based high quality studies, and corroborated by objective outcomes, mainly for AA.
  • Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy 2009;64:1570-9.Compalati E, Passalacqua G, Bonini M, Canonica GW. The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: results of a GA2LEN meta-analysis. Allergy 2009;64:1570-9.Recent meta-analyses documented the efficacy and safety of sublingual immunotherapy (SLIT) in patients with allergic rhinitis (AR) and asthma (AA). Although SLIT appeared globally effective, the sub-analyses for single allergens provided uncertain results. This study is aimed to investigate the efficacy of SLIT with house dust mite (HDM) extracts in AR and AA through an updated reassessment of randomized controlled trials. Electronic databases were searched up to March 31, 2008, for randomized DBPC trials, assessing the efficacy of SLIT in AR and AA due to HDM sensitization. Outcomes were symptom scores and rescue medications use. For AR, eight studies fulfilled the selection criteria. A significant reduction in symptoms of AR (SMD -0.95; CI 95%-1.77 to -0.14 P = 0.02) was found in 194 patients (adults and children) receiving SLIT compared to 188 receiving placebo. For AA, with nine studies, similar results were found for symptoms (SMD -0.95; CI 95%-1.74 to -0.15 P = 0.02) in 243 patients (adults and children) receiving SLIT compared to 209 receiving placebo. A reduction in rescue medication use was found for AR (SMD -1.88; CI 95%-3.65 to -0.12 P = 0.04) in 89 patients, and AA (SMD -1.48; CI 95%-2.70 to -0.26 P = 0.02) in 202 patients. A relevant inter-study heterogeneity was detected. Promising evidence of efficacy for SLIT, using mite extract in allergic patients suffering from AR and AA, are herein shown. These findings suggest that more data are needed, derived from large-population-based high quality studies, and corroborated by objective outcomes, mainly for AA.
  • Safety of Sublingual House Dust Mite (HDM) Immunotherapy:A Randomized, Double-blind, Placebo-controlled U.S. TrialR. Bush1, C. Swenson2, B. Fahlberg2, J. Bernstein2, K. Gaworski2,H. Sanchez1, R. Esch3, W. Busse2; 1William S. Middleton VA Hospital,Madison, WI, 2University ofWisconsin, Madison, WI, 3Greer Laboratories,Lenoir, NC.RATIONALE: In this first placebo-controlled, double-blind trial of HDMsublingual immunotherapy (SLIT) conducted in the U.S., we evaluated thesafety of high and low dose SLIT in adults with allergic rhinitis 1/2 mildpersistent asthma sensitized to HDM.METHODS: Of 74 eligible participants, thirty-one subjects were randomizedto receive daily SLIT maintenance; high dose (4200 AU, N 5 10) orlow dose (60 AU, N 5 10) of a standardized D. farinae vaccine (GreerLabs) or placebo (0.038 mg histamine, N 5 11) over the course of 12-18months.RESULTS: Ten subjects withdrew from the study, 6 of 10 for non-treatmentrelated events. Four of 10 withdrawals were associated with possibletreatment effects, one each in the high and lose dose groups (GI symptoms)and two in the control group (headache, increased allergic symptoms).Twenty-one subjects completed the study (high dose N 5 9, low doseN57, placebo N55). Fifteen of the 21 subjects who completed the studyexperienced possible/probable treatment-related events (GI symptoms,oral/throat irritation) of mild to moderate severity (high dose N 5 6, lowdose N 5 4, placebo N 5 5). These adverse events all resolved spontaneouslyand the participants subsequently completed the study. No systemicreactions (urticaria, anaphylaxis) were observed in any group.CONCLUSIONS: In this trial of high and low dose HDM SLIT, we concludethat HDM SLIT was generally safe and tolerable.
  • HDM allergic rhinitis is a persistent disease with a high adaptability of the patient to the constraints of his pathology Consistent level of HDM exposure day to day
  • These two studies using the same allergen, cat and same outcome measure, 90 minute cat room challenge highlight the uncertain relationship with dose and efficacy. The study in the top row used avery low dose 0.05 mcg a day or a cumulative dose of 17 mcg a year and found a significant difference between the SLIT group compared with placebo after one year of treatment wheras the study in the lower row used a much higher dose 40 mcg of fel d 1 a daily day equal to 2. 3 times the annual dose of the previous study and did not find a significant difference between the placebo and treatment group in the outcomes measure . This was a shorter study 105 days and the room housed 4 cats whereas the previous study housed one cat but I don’t think these differences can account for the unexpected different outcomes with vastly different doses
  • 99 were analyzable for efficacy (I: 48; P: 51) and 106 analyzable for safety (I: 53; P: 53). After a 28-day progression phase, the patients received a maintenance treatment during 6.5 months. Efficacy variables included a global assessment of efficacy (patient/ investigator), symptoms and medication scores as well as the frequency of asthma attacks. RESULTS: In the active treatment group, 43 patients completed the study, versus 49 on placebo. During the whole period of pollination, the difference favoring immunotherapy was highly significant for the global assessment by the patient (p = 0.004) and by the investigator (p = 0.005). Adverse reactions were reported more often in the active treatment but mild or moderate, and they abated after dose adjustment. A subgroup analysis of those patients receiving the highest dose of immunotherapy (3 tablets 3 times a week) showed a highly significant response for rhinitis and conjunctivitis total scores by comparison to lower dosages. CONCLUSION: This study confirms the efficacy and safety of sublingual immunotherapy and strongly suggests a dose-response relationship
  • Methods: In May 2006, a total of 115 patients with ragweedinducedrhinoconjunctivitis were randomly allocated to placebo(n 5 40), medium-dose extract (4.8 mg Amb a 1/d; n 5 39), orhigh-dose extract (48 mg Amb a 1/d; n 5 36). In a 1-day (rush)dose-escalation regimen, ragweed pollen extract wasadministered sublingually in incremental doses until maximumtolerable or scheduled dose was reached and then maintainedduring the ragweed pollen season. Patient diaries were used tomonitor nasal and ocular symptoms and medication. Theprimary endpoint was symptom score.Results: Both active treatment groups achieved a 15% reductionin total rhinoconjunctivitis symptom scores compared withplacebo during the entire ragweed pollen season, but thedifference was not statistically significant (P > .10) However, inan analysis of covariance correcting for preseasonal symptoms,both mean daily symptom scores (0.19 6 1.16 vs 1.00 6 2.30)and medication scores (0.0003 6 1.64 vs 0.63 6 1.06) for theentire pollen season were significantly reduced in the high-doseversus placebo groups, respectively (P # .05). Ragweed-specificIgG, IgG4, and IgA antibodies were increased after treatment inthe medium- and high-dose groups and not the placebo group.Frequency of adverse events was similar between the placeboand treatment groups, but oral-mucosal adverse eventsoccurred more often with treatment.Conclusion: Standardized glycerinated short ragweed pollenextract administered sublingually at maintenance doses of 4.8 to48 mg Amb a 1/d was safe and can induce favorable clinical andimmunologic changes in ragweed-sensitive subjects. However,additional trials are needed to establish efficacy
  • Methods: In May 2006, a total of 115 patients with ragweedinducedrhinoconjunctivitis were randomly allocated to placebo(n 5 40), medium-dose extract (4.8 mg Amb a 1/d; n 5 39), orhigh-dose extract (48 mg Amb a 1/d; n 5 36). In a 1-day (rush)dose-escalation regimen, ragweed pollen extract wasadministered sublingually in incremental doses until maximumtolerable or scheduled dose was reached and then maintainedduring the ragweed pollen season. Patient diaries were used tomonitor nasal and ocular symptoms and medication. Theprimary endpoint was symptom score.Results: Both active treatment groups achieved a 15% reductionin total rhinoconjunctivitis symptom scores compared withplacebo during the entire ragweed pollen season, but thedifference was not statistically significant (P > .10) However, inan analysis of covariance correcting for preseasonal symptoms,both mean daily symptom scores (0.19 6 1.16 vs 1.00 6 2.30)and medication scores (0.0003 6 1.64 vs 0.63 6 1.06) for theentire pollen season were significantly reduced in the high-doseversus placebo groups, respectively (P # .05). Ragweed-specificIgG, IgG4, and IgA antibodies were increased after treatment inthe medium- and high-dose groups and not the placebo group.Frequency of adverse events was similar between the placeboand treatment groups, but oral-mucosal adverse eventsoccurred more often with treatment.Conclusion: Standardized glycerinated short ragweed pollenextract administered sublingually at maintenance doses of 4.8 to48 mg Amb a 1/d was safe and can induce favorable clinical andimmunologic changes in ragweed-sensitive subjects. However,additional trials are needed to establish efficacy
  • Polysensitization is a feature of allergic rhinitis (AR) that significantly impairs the quality of life (QoL) of AR patients. Allergen-specific immunotherapy is the only causal therapy for AR. However, the polysensitization phenomenon may represent a crucial obstacle as far as it concerns the choice of the allergen extract which should be used for immunotherapy. Therefore, a real-life based multi-centre study, named POLISMAIL, has been designed which aims at evaluating the behaviour of some allergists managing polysensitized AR patients. The effect of two-year SLIT treatment in those patients was also evaluated. A single allergen extract was used for two-thirds of patients, whereas a mix of two allergens was chosen for the remaining patients. The severity grade of AR and the type of diagnosis were significantly improved by 2-year SLIT. In addition, SLIT significantly improved QoL. Both outcomes confirm that SLIT with one or two allergen extracts achieves a significant improvement in polysensitized patients. In conclusion, the POLISMAIL study demonstrates that polysensitization should not represent a counter-indication for prescribing immunotherapy. The choice to limit SLIT to 1-2 allergen extracts was sufficient and effective in improving symptoms and QoL.
  • Efficacy of sublingual immunotherapy with house dust mite extract in poly-allergen-sensitised allergicrhinitis patientsChoi, Yoon-Seok; Rhee, Chae-Seo; Lee, ChulHee; Kim, Dong-YoungSeoul National University College of Medicine, Department of Otorhinolaryngology, Seoul, Republic of KoreaBackground: Recently, interest has increased in sublingual immunotherapy (SLIT) for treating allergic rhinitis. It isoften suggested that polysensitized patients might not benefit from specific immunotherapy as much asmonosensitized patients, although further research on this subject is needed. This study compared the efficacy ofSLIT with standardized house dust mite extract in mono- and polysensitized allergic rhinitis patients.Method: Patients who were sensitized to house dust mites and treated with SLIT for house dust mites for at least 1year between November 2007 and March 2010 were included. The mono-allergen sensitized group (Mgr) wasdefined as the patients who were sensitized to Dermatophagoidespteronyssinus (Dp) or D. farinae (Df; n = 70). Thepoly-allergen sensitized group (Pgr) was defined as the patients who were simultaneously sensitized to house dustmites and other allergens (n = 64). A standardized extract of house dust mites was used for immunotherapy.Anti-allergic medication and the total nasal symptom score (TNSS), including rhinorrhea, sneezing, nasalobstruction, and itchy nose, were evaluated before and 1 year after SLIT.Result: This study enrolled 134 patients. The TNSS improved significantly after SLIT in both groups, while thechange in the TNSS did not differ significantly between the groups. The anti-allergic medication scores alsodecreased significantly in both groups, but there was no significant difference between the groups.Conclusion: In polysensitized allergic rhinitis patients, SLIT for Dp/Df gave comparable improvements in both nasalsymptoms and rescue medication scores to those in monosensitized patients, regardless of other positive allergens.SLIT for Dp/Df might be considered in polysensitized allergic rhinitis patients.
  • Background: European studies provide a preponderance of evidence for sublingual allergen immunotherapy (SLIT) safety andefficacy, but they use allergen products that differ from those expected to be approved in the United States.Objective: To determine the safety and tolerability of 4 US-licensed standardized SLIT allergenic extracts.Methods: Adults 18 to 50 years old with allergic rhinitis with or without asthma due to timothy grass pollen, short ragweedpollen, house dust mite, or cat hair allergy completed a single-session dose escalation followed by an 8-week, open-label dailycourse of SLIT. Participants documented the presence and severity of adverse effects and adherence using a daily electronic diary.Results: Ninety-one participants initiated treatment, and 77 completed the phase 1 testing. Maximum tolerable doses rangedfrom 50 to 2,090 BAU for cat hair and dust mite extract, 31 to 91 Amb a 1 Units for short ragweed pollen extract, and 50 to21,090 BAU for timothy grass pollen extract. During the 8-week treatment course, 98.9% of participants reported at least 1 mild,70.4% at least 1 moderate, and 13.6% at least 1 severe adverse effect. Most adverse effects (94.6%) were rated as mild, 5.2%as moderate, and 0.1% as severe; nasal and oral-mucosal adverse effects were most commonly reported. No life-threateningadverse reactions occurred in more than 4,500 administered doses.Conclusions: Daily sublingual-oral dosing of standardized allergenic extracts at maximum tolerable doses was generally welltolerated. These results are a first step toward establishing the safety of US-licensed SLIT extracts when appropriatelyself-administered and monitored.
  • I spoke on this subject at this meeting 2 years ago at the World Allergy Organization symposium. Mike Kaliner was the moderator and he asked me to discuss barriers SLIT faced in the United States. So in preparing for this lecture a I reviewed my previous slides to see what hoops and hurdles we have cleared in the past 2 years. The first hurdle remains and that is the lack of an FDA approved formulation for SLIT or a CPT billing code which means most payers will not pay. Another hurdle is that we need to know the optimal dosing regimen for the products available in the US and I will spend the majority of time discussing these two issues related to these hurdles.The very negative perception of SLIT was an important barrier 2 years ago and this prejudice against SLIT is probably because it has been here in the US for many years in some form or another but not in the ‘mainstream ‘allergy community. In fact if you go to the upscale supermarket in my area that specializes in natural things you can find an entire shelf of sublingual drops for every imaginable ailment . Unfortunately I could not get pictures of the allergy section because my photo shoot raised the suspicions of the store employees who sent 2 mangers over to interrogate me. Needless to say I did not try to explain what the purpose of the pictures was.
  • In the 94% of physicians that did not prescribe SLIT, lack of an FDA-approved formulation was the most cited reason . If there were an FDA-approve SLIT product 65% said they would prescribe it for rhinitis patients, 40% would treat moderate to severe asthmas and 45% would treat children under age 5.So in summary , although the vast majority of US allergist do not current prescribe SLIT many would be willing to prescribe it if there were an approved formulation and many would be will to treat patient groups that are generally not offered this treatment such as children under 5 and moderate to severe asthmatics
  • Sublingual Immunotherapy From Efficacy, Safety to Practical Considerations

    1. 1. Sublingual immunotherapy Review and Update<br />Kentucky Allergy, Asthma & Immunology Society<br />Linda Cox, MD<br />
    2. 2. Linda Cox, MD Disclosure<br />Allergist/Immunologist: solo private practice<br />Associate Clinical Professor of Medicine Nova Southeastern University <br />Medical advisory board/consultant: Stallergenes, Genentech/Novartis, ISTA<br />Speakers fee: Phadia<br />Organizational interests:<br /><ul><li>FDA Allergenic Products Advisory Committee –consultant
    3. 3. AAAAI-Secretary/Treasurer
    4. 4. Joint Task Force on Practice Parameters-member
    5. 5. ABAI Board of Directors -member</li></li></ul><li>Sublingual Immunotherapy: a review and updateLearning Objectives<br /><ul><li>SLIT historical background
    6. 6. Advantages /disadvantages
    7. 7. Status in Europe and US
    8. 8. Efficacy review of data: meta-analysis, clinical trials
    9. 9. SLIT safety
    10. 10. SLIT Adherence
    11. 11. SLIT in the US- practical considerations</li></li></ul><li>SCIT Timeline<br />Cox L, Wallace D. Specific allergy immunotherapy for allergic rhinitis: subcutaneous and sublingual. Immunol Allergy Clin North Am. 2011;31(3):561-99. Epub 2011/07/09.<br />
    12. 12. Subcutaneous Immunotherapy: Rationale for Exploring Alternative Approaches<br />EPI given<br />Noting the inconvenience of the weekly build-up, Freeman began experimenting with more rapid schedules “Rush desensitization”: <br />
    13. 13. SLIT Timetable<br />Cox L, Wallace D. Specific allergy immunotherapy for allergic rhinitis: subcutaneous and sublingual. Immunol Allergy Clin North Am. 2011;31(3):561-99. <br />
    14. 14. 39 studies provided both symptom & medication scores: in first treatment year <br />38% not effective in either-included highest dose<br />35% effective in both-included lowest dose<br />First draft: Aspen, Colorado July 2005<br />A consistent relationship between allergen dose, treatment duration and clinical efficacy had not been established. <br />Questions: <br />Is optimal dose range same for all allergens?<br />Optimal schedule: daily, three times a week seasonal , perennial etc???<br />Conclusion: more research needed<br />
    15. 15. WAO Sub-lingual Immunotherapy Position Paper Efficacy Conclusions<br />Up to June 2009, there were 60 DBPC-RCTs of SLIT, of which 41 conducted with grass or HDM extracts.<br />48 trials provided overall positive results and 12 were totally or almost totally negative.<br />Available meta-analyses are in favor of SLIT although the conclusions are limited by the great heterogeneity of the studies. <br />Literature suggests that overall, SLIT is effective, although differences exist among allergens.<br />Canonica et al, World Allergy Organization Position Paper 2009. Allergy 2009;64 Suppl 91:1-59.<br />8<br />
    16. 16. SLIT Efficacy: Examining the Evidence <br />Swim With Dolphins, Cut DepressionWebMD Health News 2005. © 2005 WebMD Inc.<br />Design 2 wk single blind, RC of 30 people with mild to moderate depression : snorkel with dolphins for an hour daily <br />or spend a similar amount of time in the water, without dolphins in Roatan Institute for Marine Sciences in Honduras... <br />Cox-WolfgramFamily working through their depression in Group Dolphin Therapy at Discovery Cove, Orlando , Florida<br />Antonioli BMJ. 2005; 331(7527): 1231<br />
    17. 17. Pitfalls of Many SLIT Studies<br />Significant heterogeneity in design & interpretation<br />Dose provided in proprietary units (e.g., ST-U, IR) and not mcg of major allergen <br />No true placebo:<br />High incidence of local AEs with active SLIT<br />Placebos used in SLIT trials do not have the same characteristics as the active extract<br />Histamine under the tongue does not elicit itching <br />Concealment of treatment allotment info not provided <br />Small number of patient studied (underpowered)<br />Casale et al, J Allergy ClinImmunol 2009;124:665-70.<br />10<br />
    18. 18. Cochrane Meta-analysis of Immunotherapy for Allergic Rhinitis Comparing SCIT and SLIT<br />SCIT SLIT<br /> SMD (95% CI) SMD (95% CI)<br />Calderon M et al 2007 Wilson D et al 2005<br />Symptoms -0.73(-0.97,-0.50)-0.42(-0.69, -0.15)<br />Medication -0.57(-0.82,-0.33)-0.43(-0.63, -0.23)<br />Out of 22 studies: 21 provided symptom score data ;484 SLIT & 475 placebo<br />Out of 1111 studies: 15 met symptom score criteria; 597 SCIT & 466 placebo<br />SMD=Standardized Mean Difference is the difference of the means of both treatment arms divided by the pooled standard deviation. <br />
    19. 19. Updated Cochrane Meta-analysis SLIT for Allergic RhinitisEffectsize is greatest with the treatment lasting more than 12 months<br />Similarly to the previous version of this Cochrane review, the investigators were unable to identify a significant reduction in either symptoms or medication scores in children<br />Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011;66(6):740-52<br />
    20. 20. Sublingual immunotherapy for treating allergic conjunctivitis. Cochrane Database<br />42 trials (n = 3958 total; n= 2011 SLIT and n = 1947 placebo) <br />SLIT induced a significant reduction in compared with placebo<br />total ocular symptom scores (SMD -0.41; 95% CI -0.53 to -0.28; P < 0.00001)<br />red eyes (SMD -0.33; 95% CI -0.45 to -0.22; P < 0.00001), <br />itchy eyes (SMD -0.31; 95% CI -0.42 to -0.20; P < 0.00001; <br />watery eyes (SMD -0.23; 95% CI -0.34 to -0.11; P < 0.0001) <br />CPT (SMD 0.35; 95% CI 0.00 to 0.69; P = 0.05) <br />No significant reduction was observed in ocular eye drops use<br />AUTHORS' CONCLUSIONS: Overall, SLIT is moderately effective in reducing total and individual ocular symptom scores in participants with ARC and AC.<br />Calderon et al, Sublingual immunotherapy for treating allergic conjunctivitis. Cochrane Database Syst Rev 2011:CD007685<br />13<br />
    21. 21. Meta-analyses suggest the size of the treatment effect for immunotherapy trials is comparable to that for pharmacotherapy trials<br />Presentation to FDA Allergenic Products Advisory Committee 12th May 2011: provided with permission by Professor Stephen Durham<br />
    22. 22. Analysis of the SLIT Meta-analyses<br />Objective: To assess the consistency, magnitude, & robustness 5 meta-analyses (MAs) that seem to prove the efficacy of SLIT in asthma & AR. <br /> Results:<br /><ul><li>Discrepancies among the MAs in 16 of those 17 studies.
    23. 23. Funnel plots showed asymmetry in 7 outcomes
    24. 24. Correction with trim-and-fill method lead to loss of statistical significance in 4 of 10 </li></ul> Conclusion: “Because of discrepancies, inconsistencies, and lack of robustness, the MAs on SLIT do not provide enough evidence to support its current routine management in patients with asthma or AR. Sensitivity to potential publication bias should be tested and reported in all MAs” <br />Nieto A, et al., J Allergy ClinImmunol 2009;124:157-61<br />
    25. 25. SLIT, meta-analysis, and knowledge in the age of information<br />‘‘All men by nature desire knowledge,’’ wrote Aristotle (384-322 BC). All human beings wish to understand the world around them, and to that end, some construct theories of various kinds to help make sense of it. Plato (428-348 BC), <br />“ For a very novel therapy, such as SLIT, initial studies might provide inconsistent results because they are assessing many fundamental variables…As knowledge of and technology for SLIT advance, it is conceivable that both trial results and meta-analyses will become more consistent and positive. In searching for knowledge, be ready for the unexpected.”<br />Milgram H, Tran Z ., J Allergy ClinImmunol 2009;124: 162-63<br />
    26. 26. Comparison of Magnitude of Improvement Between SLIT and SCIT<br />SCIT1 SLIT2 SLIT3<br />20 µg Phl p 5T ~15 µg Phl p ~ 25 µg group 5<br /> n = 187 SLIT n = 282 SLIT n = 136 SLIT<br /> n = 89 placebo n = 286 placebo n = 148 placebo<br />Symptom scores<br />Rescue medication <br />scores<br />- 29%<br />- 30%<br />- 37%<br />- 46%<br />- 32%<br />- 38%<br />Approximately 35% improvement over placebo with SCIT & SLIT<br />Alum-precipitated grass pollen extract (Alutard SQ®, ALK-Abello).Frew et al, JACI 2006;117:319-25.<br />Lyophilized grass pollen tablet (Grazax®, ALK-Abello) Dahl et al, JACI2006;118:434-40.<br />Lyophilized grass pollen (Oralair®, Stallergenes) Didier et al, JACI 2007;120:1338-45<br />17<br />
    27. 27. US Prescribing Information: treatment effect intranasal steroids and anti-histamines between 8.8% and 18.8% <br />Presentation to FDA Allergenic Products Advisory Committee: provided with permission by Professor Stephen Durham<br />
    28. 28. SLIT Efficacy: Specific Allergens<br />Grass<br />Dust mite<br />Cat<br />Ragweed<br />19<br />
    29. 29. Datamonitor estimates that global AIT sales of reached around $835m in 2006, about 8% of the total allergic rhinitis market. <br />Most of the sales in 2006 came from SCIT with $443m and SLIT-drops with sales of $313m.<br />Datamonitor expects a grass tablet SLIT to be able to reach annual sales of $780m to $1.3 billion, depending on the patient population , duration and product price.<br />Commercial and Pipeline Insight Allergic Rhinitis © Datamonitor (Published 10/2007)<br />
    30. 30. Durham et al JACI 2006;117: 802-9<br />
    31. 31. Progressive Effect Of SLIT Grass Tablet Ongoing Study Year 2 Extension Study<br />Treatment Beginning 4 months before seasonSymptom and Medication Score (median)<br />Year 2005: n=634 Year 2006: n=351<br />Mean 36% (p< .0001) <br />Mean 46% (p< .0001) <br />Dahl et al., J Allergy ClinImmunol 2008; 121 <br />
    32. 32. First Successful North American Grass Tablet Study<br />Methods: DBPC study of 345 children (ages 5-17 years)<br />received daily grass tablet or placebo >8 weeks pre/co-seasonal during 2009 grass pollen season <br />Results: 89% of the subjects were multisensitized. <br />SLIT compared with placebo had statistically significant improvement<br />Combined score (26%, P=0.001) <br />DSS (25%, P= 0.002), <br />AEs; Majority were local reactions with “no reports of anaphylactic shock.”<br />Conclusions: First successful phase III trial in North America investigating grass tablet in children. <br />Blaiss et al., J Allergy Clin Immunol. 2011;127(1):64-71<br />
    33. 33. This study is ongoing, but not recruiting participants. First Received on February 1, 2010. Last Updated on August 26, 2011<br />Detailed Description: <br />Investigation of the effect of Grazax on asthma prevention in children with grass pollen allergy.<br />Children in the age of 6-12 years will be randomised to either placebo or Grazax treatment.    <br /><ul><li>Time Frame: 5 years
    34. 34. Primary Outcome Measures: evaluation of allergy and asthma symptoms
    35. 35. Secondary Outcome Measures: QOL 
    36. 36. Estimated Enrollment: 1000
    37. 37. Study Start Date: January 2010
    38. 38. Estimated Study Completion Date: September 2015
    39. 39. Location: Finland; PI ErkkaValovitra</li></ul>From www.clinicaltrials.gov <br />
    40. 40. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis<br />Method:Pre and coseasonal DBPC study of 628 patient with grass-pollen AR randomized to 100 IR, 300 IR, 500 IR (ORALAIR®, Stallergenes ) or placebo tablets beginning 4 months before grass season.<br />5 day induction <br />300 IR = ~25 mcg of Phl p 5<br />Primary outcome: Average Rhinoconjunctivitis Total Symptom Score <br />Didler et al, JACI 2007 2007;120<br />
    41. 41. Daily mean RTSS and grass pollen counts (2005)<br />300 IR (37%) & 500 IR (35%<br />Didier et al., J Allergy ClinImmunol 2007; 120:1338-45<br />
    42. 42. Early onset of action of a 5-grass-pollen 300-IR SLIT tablet evaluated in an allergen challenge chamber<br />Horak et al., J ClinImmunol 2009;124:471-7, 7 e1.<br />27<br />
    43. 43. Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study<br />METHODS: DBPC study of 213 patients (7.9-64.7 years) randomized placebo or grass pollen allergy administered with ultra-rush titration with increasing doses (30, 90, 150 and 300 IR) of a 5-grass pollen mixture every 20 min at the start of the pollen seasons<br />Ott H, et al. y. Allergy. 2009;64(1):179-86..<br />28<br />
    44. 44. Grass pollen SLIT started in the beginning of season resulted in first season efficacy with progressive improvement<br />RESULTS:<br />CMS improved progressively across treatment seasons up to 44.7% compared with baseline (P = 0.0508)<br />Symptom scores in 1st season decrease of compared with placebo (p=.0366)<br />Medication scores 18 % improvement was not significant (p=.35).<br />Ott H, et al, Allergy. 2009;64(1):179-86<br />29<br />
    45. 45. Comparison of 2 Grass-pollen tablet SLIT Schedules: 2 vs. 4 Month Pre & Co-seasonal Grass-pollen Tablet in an Intermittent Regimen<br />Didier et al, J Allergy Clin Immunol. 2011;128(3):559-66.<br />30<br />
    46. 46. Full analysis set of patients over 4 evaluation seasons<br />Randomized patients = 633<br />300IR (4M) = 207 <br />year 1<br />(2007)<br />year 1<br />(2007)<br />188 (91%)<br />172 (79%)<br />155 (75%)<br />160 (77%)<br />year 2<br />(2008)<br />year 2<br />(2008)<br />Placebo = 219<br />300IR (2M) = 207 <br />year 3<br />(2009)<br />year 3<br />(2009)<br />165 (75%)<br />147 (71%)<br />149 (72%)<br />188 (91%)<br />205 (94%)<br />year 4<br />(2010)<br />year 4<br />(2010)<br />155 (71%)<br />137 (66%)<br />143 (69%)<br /><ul><li>The three groups were homogeneous and remained balanced.
    47. 47. Low rate study withdrawals.</li></ul>31<br />
    48. 48. Average Combined Score (ACS):Worst Pollen Period - years 1 to 4<br />- 23%<br />- 15%<br />- 29%<br />- 29%<br />- 34%<br />- 32%<br />- 26%<br />- 27%<br />ACS (adjusted means)<br />End of treatment<br />p value<br />< .0001<br />< .0001<br />< .0001<br />< .0001<br />0.0002<br />0.0057<br />0.0067<br />0.0060<br />ANCOVA – (FAS)<br /><ul><li>The Average Combined Score results are consistent with the Average Adjusted Symptom Score throughout the 4 years at worst pollen period. </li></ul>EAACI 2011 Annual Congress presentation Professor Sabina Rak-provided with permission Robert Zeldin, MD<br />32<br />
    49. 49. Treatment Emergent Adverse Events (≥ 5% in any treatment group) <br />Season 1<br />2007<br />Season 2 <br />2008<br />% of patients<br />% of patients<br />% of patients<br />Season 3<br />2009<br />Compared with treatment at season 1, treatment at seasons 2 and 3 showed a progressive:<br /><ul><li>Decrease in the incidence of AE
    50. 50. Decrease in the intensity of AE</li></ul>33<br />
    51. 51. Studies with Grass-pollen SLIT Doses That Were Not Clearly Effective Note: Both Studies Used Extract Solutions<br />Lima: DBPC study of 59 AR pts treated for 18 months with 30 mcg of Phl p 5 daily or placebo (SoluprickSQ/ALK-Abello)<br />Results: No significant difference in symptoms or medication use between groups but global assessment improved in SLIT group<br />Bufe: DBPC study of 132 AR pts treated with 9.1 mcg of Phl p 5 daily or placebo for 3 years (Sublivac B.E.S.T HALAllergy)<br />Results: Efficacy only seen in a sub-group analysis: of most severe group using combined index of symptom + medication scores <br />34<br />1.Lima et al., Clin Exp Allergy 2002; 32:507-14.<br />2.Bufe et al., Allergy 2004; 59:498-504.<br />
    52. 52. SLIT Efficacy: Specific AllergensDust Mite<br />Dust mite<br /> Monthly dosing ranging from ~15 mcg to ~700mcg Der p 1+ Der f 1 a month <br />35<br />
    53. 53. Efficacy of SLIT for house dust mites respiratory allergy: results of a GA2LEN meta-analysis<br />Methods: Searched up to March 31, 2008, for randomized DBPC trials, assessing the efficacy of SLIT in AR and AA due to HDM sensitization.<br />Compalati E, Passalacqua G, Bonini M, Canonica GW. Allergy 2009;64:1570-9.<br />
    54. 54. Efficacy of SLIT for HDM Respiratory AllergyMeta-analyses Conclusions<br />A relevant inter-study heterogeneity was detected. <br />Promising evidence of efficacy for SLIT, using mite extract in allergic patients suffering from AR and AA, are herein shown. <br />Findings suggest that more data are needed, derived from large-population-based high quality studies, and corroborated by objective outcomes, mainly for AA.<br /> <br />Compalati E, Passalacqua G, Bonini M, Canonica GW. Allergy 2009;64:1570-9.<br />
    55. 55. Safety & Efficacy of Sublingual House Dust Mite Immunotherapy: A Randomized, DBPC U.S. Trial<br />Methods: Randomized trial of 31 HDM SLIT in the U.S designed to evaluate safety & efficacy of high and low dose SLIT in adults with AR± asthma randomized for 12-18 months to daily <br />10 high (4200 AU, ~ 70 ugof Der f 1) , <br />10 low (60 AU,~ 1 ug of Der f 1) D. farinaeSLIT<br />11 placebo (0.038 mg histamine, N=11).<br />Safety results: 21 completed (high N = 9, low= 7, placebo N=5) <br />Withdrawals and possible treatment-related AE similar in the 3 groups<br />Efficacy: significant difference in high dose vs. placebobut none with placebo vs. low dose: <br />↑D farinae-sIgG4 ( 9 SLIT, 5 placebo, p=.02)<br />Increased bronchial threshold to DF challenge (7 SLIT, 3 placebo, p=.04)<br />Bush et al, House dust mite sublingual immunotherapy: results of a US trial. JACI 2011;127(4):974-81 e1-7.<br />38<br />
    56. 56. Efficacy & Safety of Dust Mite SLIT Tablets<br />Prof. Karl- Christian Bergmann EAACI 2011 Annual Congress oral presentation<br />39<br />
    57. 57. Main efficacy criterion Average Adjusted daily Symptom Score (AAdSS)- Full Analysis Set (FAS)<br /><ul><li>Significant difference in both active groups 300 IR and 500 IR </li></ul>vs placebo<br /><ul><li> No significant difference between 300 IR and 500 IR groups</li></ul>40<br />
    58. 58. Change over time in the symptom score (years one and two)<br />year1 (treatment) <br />year 2 (no treatment) <br />NS<br />NS<br />*<br />*<br />*<br />*<br />*<br />*<br />*<br />a persistent effect 8 months after treatment cessation<br />AAdSSMeans<br />- 7%<br />- 20%<br />- 16%<br />- 20%<br />- 18%<br />-14%<br />- 14%<br />-15%<br />-24%<br />- 3%<br />- 3%<br />- 15%<br />- 20%<br />- 15%<br />-12%<br />- 9%<br />-15%<br />- 7%<br />- 12%<br />-18%<br />In year two, the effect in the 300 IR group is statistically significant <br />(vs. placebo) through to month 20 (inclusive) .<br />
    59. 59. Tertile analysis for years 1 and 2 (FAS) The relationship between disease activity and<br /> treatment efficacy <br />Placebo<br />300 IR<br />year 1<br />year 2<br />- 30%<br />- 39%<br />- 5%<br />+ 10%<br />- 7%<br />- 5%<br />AAdSS (Mean)<br />AAdSS (Mean)<br /><ul><li>A marked improvement in the highest tertile in year 1 and in year 2</li></ul>(39% and 30%) <br />  The 300 IR tablet's treatment effect increases with disease activity<br />In the tertile analysis, centres are pooled according to a low, medium or high level of symptoms observed in the respective placebo groups.<br />42<br />
    60. 60. Tertile analysis for years 1 and 2 (FAS)Quality of life: the treatment's effect on sleep<br />Placebo<br />300 IR<br />year 1<br />year 2<br />- 37%<br />- 36%<br />- 37%<br />- 17%<br />+ 3%<br />+ 6%<br />- 14%<br />+ 3%<br />+ 6%<br /> Adjusted sleep score (mean)<br /> Adjusted sleep score (mean)<br /><ul><li>After one year of treatment, there was a significant improvement in</li></ul>the sleep score (vs. placebo): 36% in the high AAdSS tertile.<br /><ul><li> This improvement was still present after treatment cessation.</li></ul>43<br />
    61. 61. Rescue Medication Score (300 IR) year 1 - (FAS)<br /><ul><li> Overall use of rescue medication was low
    62. 62. No difference between active and placebo</li></ul>44<br />
    63. 63. SLIT Efficacy: Specific AllergensCat &Dog<br />Cat: Effective dose not clearly established<br />Dog: never studied<br />45<br />
    64. 64. Two Cat Doses: Same Outcome Measure 2 Outcomes<br />Nelson, JACI 1993;92:229-36, Alvarez-Cuesta Allergy 2007; 62:810-17<br />
    65. 65. Cat US Study<br />Planet technology/Antigen Labs Cat 0.21 Units (~0.48 µg) vs. 2.1 Units (~4.8 µg): <br />Primary Endpoint<br /><ul><li>Symptoms scores during environmental chamber exposure (ECC) at Week 20 </li></ul>Secondary Endpoints: <br /><ul><li>change in ECC scores from baseline
    66. 66. daily total, nasal, non-nasal, proportion of rescue medication-free days, recue medication use index</li></ul>47<br />
    67. 67. SLIT Efficacy: Specific AllergensRagweed<br />Ragweed: effective dose not established<br />48<br />
    68. 68. Highest Effective & Ineffective DoseTwo Ragweed Studies<br />France<br />Method: DBPC study of 99 pts with ragweed AR treated for 6.5 months with up to 300 IR tablets (~314 mcg Amb a 1) QOD or placebo. Dose based on tolerance<br />Results: subgroup analysis efficacy found in highest dose group in symptoms & OCS. <br />Canada<br />Method: DBPC of 57 pts with ragweed AR treated with up to 314 mcg Amb a 1 solution or placebo for ~ 3 months. Treatment began July 16 -30th<br />Result: No significant difference between placebo & SLIT unless low pollen count site eliminated: then nasal pruritis & sneezing significant<br />Andre et al., Int Arch Allergy Immunol 2003; 131:111-8.<br /> Bowen et al., Ann Allergy Asthma Immunol 2004; 93:425-30.<br />
    69. 69. Methods: DBPC study of 115 patients with ragweed induced RC randomly allocated to placebo, 4.8 mcg Amb a or 48 mcg Amb a 1 daily; via a a 1-day rush escalation<br />Results: Both SLIT groups achieved a 15% reduction in TRCSS compared with placebo during the entire ragweed pollen season but <br />The difference was not statistically significant (P > .10)<br />Ragweed-specific IgG, IgG4, and IgA were increased after treatment in SLIT but not placebo<br />Skoner et alJ Allergy Clin Immunol 2010;125:660-6, 6 e1-6 e4.<br />50<br />
    70. 70. Sublingual Immunotherapy for Ragweed: Post-hoc Analysis<br />Results: Analysis of covariance correcting for preseasonal symptoms in high dose group compared with placebo during entire pollen season there was a significant decrease in (P≤.05) <br />mean daily symptom scores <br />medication scores<br />AE similar all groups, but oral-mucosal AE in SLIT groups<br />Conclusion: Ragweed extract SLIT at doses of 4.8 to 48 mg Amb a 1/d was safe and can induce favorable clinical and immunologic changes. However, additional trials are needed to establish efficacy<br />Skoner et alJ Allergy Clin Immunol 2010;125:660-6, 6 e1-6 e4.<br />51<br />
    71. 71. Cockroach Sublingual Immunotherapy<br />Sublingual Cockroach Safety Study: A Safety and Pilot Dosing Study for Sublingual-Oral Administration of Glycerinated German Cockroach Allergenic Extract in Pediatric and Adult Subjects With Cockroach Allergy and PAR ± asthma<br />Sponsored by NIAID<br />Principle investigator: Robert Woods, MD<br />Results: not published but reportedly no immunological changes (e.g. sIgE)-personal commincaioon Bill Busse,MD<br />
    72. 72. Alternaria<br /> DBPC 26 pts- 10 months SLIT with 5 drops, 10,000 RU QOD (single dose= 1.25 µg Alt a 1, cumulative dose 60 µg)1<br />Results: SIT compared with placebo had a significant improvement in symptoms/medication & SPT. No change seen in sIgG4<br />Randomised, parallel group study in 52 subjects for 3 yrs SLIT improved VAS & medication scores.2<br />Low dose SLIT vs SCIT for 2 years 23 pts: both groups improvement in symptoms/meidcations but favored sLIT. Significant changes in objective parameters –sIgG, SPT & sIgE only in SCIT3<br />Cortellini et al. Annals of allergy, asthma & immunology 2010;105(5):382-6.<br />Pozzan et al ,Current medical research and opinion. 2010;26(12):2801-6<br />Bernardis et al, J InvestigAllergolClinImmunol. 1996;6(1):55-62<br />53<br />
    73. 73. The passion…the romance…and they said it wouldn’t last.<br />Duration of SLIT Efficacy<br />
    74. 74. Subject Disposition<br />2005 - Year 1 (100%)<br />Grazax n=316Placebo n=318<br />Withdrawals 2005<br />Grazax n=42Placebo n=46<br />Did not cont. into extension<br />Grazax n=85Placebo n=110<br />(closure of sites n=68, chose not to participate n=127)<br />2006 - Year 2 (55%)<br />Grazax n=189Placebo n=162<br />Withdrawals 2006<br />Grazax n=19Placebo n=24<br />2007 - Year 3 (49%)<br />Grazax n=170Placebo n=138<br />Withdrawals 2007<br />Grazax n=13Placebo n=12<br />2008 - Year 4 (45%)<br />Grazax n=157Placebo n=126<br />Withdrawals 2008<br />Grazax n=12Placebo n=13<br />2009 - Year 5 (41%)<br />Grazax n=145Placebo n=113<br />Withdrawals 2009<br />Grazax n=10Placebo n=10<br />Provided with permission Professor Stephen Durham<br />
    75. 75. 44%<br />32%<br />37%<br />31%<br />31%<br />Long-term efficacyEffect sustained 2 years after treatment<br />Total daily rhinoconjunctivitis symptom score1,2,3(median values)<br />Symptomatics alone<br />Grazax<br />End of treatment<br />Provided with permission Professor Stephen Durham<br />1. Grazax SPC; 2. Durham et al. JACI 2010; 3. Data on file: ALK-Abelló A/S<br />
    76. 76. Long-term changes in IgG4<br />1.50<br />Grazax<br />1.25<br />Symptomatics alone<br />1.00<br />0.75<br />0.50<br />Change log IgG4 (with 95% CI)<br />0.25<br />0.00<br />-0.25<br />-0.50<br />0<br />1<br />2<br />3<br />4<br />5<br />Years from initiation of treatment<br />1. Durham et al. JACI 2010; 2. Data on file: ALK-Abelló A/S<br />
    77. 77. Long-Term Clinical Efficacy of Grass-Pollen Immunotherapy (SCIT)<br />Initial Placebo Trial<br />Current Trial<br />Pollen Count<br />(grains/m3)<br />Study group<br /> Immunotherapy<br /> Placebo<br />Immunotherapy<br /> Maintenance<br /> Discontinuation<br /> None (control)<br />Symptom<br />Score<br />May<br />June<br />July<br />Aug.<br />May<br />June<br />July<br />Aug.<br />May<br />June<br />July<br />Aug.<br />May<br />June<br />July<br />Aug.<br />1989<br />1993<br />1994<br />1995<br />Durham SR et al N Engl J Med 1999; 341: 468-475<br />
    78. 78. Optimal Duration for Sublingual Immunotherapy<br />METHODS: In this prospective open controlled study we followed up patients with respiratory allergy who were monosensitized to mites for 15 years. <br /><ul><li>4 groups receiving drug therapy alone or SLIT for 3, 4, or 5 years.
    79. 79. Clinical scores, skin sensitizations, MCH, and nasal eosinophila evaluated yearly during the winter months.
    80. 80. 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. </li></ul>Marognaet al. J Allergy Clin Immunol. 2010;126(5):969-75<br />
    81. 81. Optimal Duration for Sublingual Immunotherapy= 4 Years (?)<br />RESULTS: 59 out of 79 enrolled patients completed the study. Persistence of clinical benefits:<br /><ul><li>SLIT for 3 years: 7 years.
    82. 82. SLIT for 4 or 5 years:8 years.
    83. 83. BHR and nasal eosinophils paralleled the clinical score.
    84. 84. New sensitizations in all control subjects >15 years
    85. 85. < 25% SLIT pts (21%, 12%, and 11%, respectively).
    86. 86. 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.</li></ul>Marognaet al. J Allergy Clin Immunol. 2010;126(5):969-75<br />
    87. 87. Questions To Consider When Applying Current SLIT Literature to The Average US Allergic Patient<br />The average US allergic patient is polysensitized<br />All of the studies reviewed have been with single allergens: <br />Is SLIT effect in polysensitized patients?<br />Is multiallergen SLIT effective?<br />61<br />
    88. 88. US is a Polysensitized Nation<br />NHANES 3:10,508 subjects in general population tested to10 allergens from 1988 -1994” number of +SPT1:<br />Mean 3.5, median 3: HDM (27.5%), Perennial rye (26.9%), German cockroach (26.1)<br /><ul><li>ACRN trials: 1338 subjects to SPT to 12+ allergens/mixes:81% had positive reactions to ≥ 3 allergens2
    89. 89. Based on 1151 extract mixtures formulated in 2002 at Greer; mean number of component extracts was 83
    90. 90. CPT code 95165 is based on average cost of using 6 allergens.</li></ul>Arbes et al., JACI 2005;116:377-83 2. Craig et al., JACI 2008; 121:671-7.<br />3. Esch R, Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M 2003:17-22; discussion 3.<br />
    91. 91. Single allergen SLIT effective in polysensitized patients<br />Ciprandi G, et al, J BiolRegulHomeost Agents 2009;23:165-71.<br />prospective, open, observational study, polysensitized adult patients with AR ± asthma 1 year of SLIT 165 with single extract and 65 received a mixture of two extracts-reduced sx & med use<br />Ciprandi et al, InvestigAllergolClinImmunol 2010;20:274-9.<br />167 polysensitized patients treated :2 extracts in 31 patients (18.6%), >2 extracts in 13 patients (7.8%) improved QOL<br />Ciprandi et al,. Int J ImmunopatholPharmacol 2010;23:637-40.<br />The POLISMAIL lesson Open 87 patients (2/3 received single allergen extract) improved QOL after 2 years in both groups<br />63<br />
    92. 92. Efficacy of sublingual immunotherapy with house dust mite extract in polysensitized allergic rhinitis patients<br />Method: Efficacy of 1 year of HDM SLIT in 70 monsensitized vs. 64 poly-sensitized patients. <br />Result: <br />Symptoms: TNSS improved significantly after SLIT in both groups, while the change in the TNSS did not differ significantly between the groups. <br />The anti-allergic medication scores also decreased significantly in both groups, but there was no significant difference between the groups.<br />Choi et al EAACI 2011 Annual Congress Oral Presentation<br />
    93. 93. Is Multiallergen SLIT Effective? Effects Of Sublingual Immunotherapy For Multiple Or Single Allergens In Polysensitized Patients<br />Methods: RC, open, study of 58 AR + BHR patients sensitized to birch and grasses treated for 4 years<br />SLIT for: birch only, grass only , both allergens or drugs<br />Results: Single allergen SLIT groups had significant improvement vs. baseline & untreated controls at yr 2 & 4<br />Symptom , medication, MTC & nasal eosinophils in target & unrelated season<br />Birch Season<br />baseline<br />2 yr 4 yr <br />Drugs Birch Grass Both<br />Marogna Annals Allergy, Asthma and Immunol 2007;98<br />
    94. 94. Efficacy of SLIT with a Single Extract or as part of a Multi-Allergen-Extract Mixture in Patients with Grass SAR<br /><ul><li>54 randomized patients treated for 10 months
    95. 95. CMD : Timothy ~ 30 x SCIT dose (19 mcg Phl p 5 qday), others 15-20x
    96. 96. SCIT dose: 0.25-0.28 ml q am, held under tongue for 2 minutes, then swallowed</li></ul>Amar SM, et al., J Allergy Clin Immunol. 2009;124(1):150-6 e1-5<br />
    97. 97. Denver Grass Counts<br />The normal precipitation for the first 6 months in Denver is 8.09 inches. The precipitation for this period in 2007 was 6.44 inches and in 2008 only 3.04 inches. Due to this record low rainfall the grass pollen counts in Denver 2008 were much lower than in the observational season of 2007.<br />Amar S, et al., J Allergy Clin Immunol 2009;124:150-6<br />
    98. 98. Efficacy of SLIT with a Single Extract or as Part of a Multi-Allergen-Extract Mixture<br />No significant difference in the symptom or medication scores in either treatment groups compared with placebo<br />Perhaps due to very low grass pollen season 2008<br />Timothy alone: significant improvement in tSPT, NC, sIgG4, and decreased IFN-g levels compared to placebo<br />Multiallergen: significant improvement in tSPT compared to placebo, but less than with TM<br />Timothy alone arm demonstrated efficacy with 19 mcg Phl p 5 daily<br />Amar S, et al., J Allergy Clin Immunol 2009;124:150-6<br />
    99. 99. General Summary of SLIT Efficacy<br />Optimal schedule –some conflicting data <br />May need at least 8 weeks before season BUT<br />May be effective first onset of season<br />2 and 4 months pre & co-seasonal equal efficacy<br />Optimal duration and persistent effect<br />3 years provides at least 1- 2 years of efficacy<br />4 years may be opitmal<br />Appears to have similar efficacy in adults and children<br />Although not supported by Cochrane MA, other MA and individual studies have demonstrated similar effective <br />Single allergen SLIT appears to be effective in polysensitized patients<br />69<br />
    100. 100. General Summary of SLIT Efficacy<br />Grass tablet efficacy at 15-25 mcg major allergen well established but<br />Effective dose for other allergen formulations not well established<br />Single allergen SLIT appears to be effective in polysensitized patients<br />SLIT with 2 allergens appears effective administered separately but<br />Multi-allergen SLIT mixture efficacy not established<br />70<br />
    101. 101. SLIT Safety : How Safe is Safe????Frequency and Severity Of SLIT Adverse Events <br />Interaction With Dolphins May Be Beneficial in Mild to Moderate Depression AntonioliBMJ. 2005; 331(7527): 1231<br /> There were no adverse effects noted, but the authors mention the potential for accidental injuries, and they point out that water phobia and inability to swim represent limitations of the treatment.<br />Nancy Cox minutes before her harrowing ‘near drowning’ dolphin ride<br />
    102. 102. SLIT Safety in Published Literature<br />No reports of SLIT-related fatalities to date in an estimated ___billion doses<br />Most AE occur in the beginning of treatment<br />Dose-response relationship with AEs in some studies<br />No apparent relationship with updosing schedule and AEs<br />Several large (>300 patients) grass-pollen tablet studies in adults & children demonstrate good safety profile with no updosing<br />Few reported cases of anaphylaxis (at least 6 )<br />
    103. 103. Most Adverse Reactions Occur During Beginning of SLIT Treatment<br />Dosing Range 5 to 200 mcg Phl p 5:<br />Most AEs occurred within the 1st few weeks then declined<br />Pattern similar to other studies<br />Higher doses=more AEs<br />Kleine-Tebbe Allergy 2006; 61: 181-184<br />
    104. 104. Two Cases SLIT Anaphylaxis with First Grass Table Dose<br />17 yo male d/c grass SCIT due to SR-developed urticaria, facial and tongue angioedema within15 minutes 1st grass tablet<br />24 yo female with AR & asthma also d/c grass SCIT due SRs<br />After 1st grass tablet taken at home, she immediately experienced asthma sx, generalized itching, faintness and abdominal cramps; she recognized this from the SCIT side effect, but felt much worse !<br /> She took a lot of antihistamines, ICS & sympaticomimetica, and rushed to the GP office; <br />In distress on arrival: wheezing, pale, nearly fainting, BP 90/50 mmHg. Given adrenaline.<br />She recovered in the next few hours.<br />74<br />de Groot H, Bijl A. Anaphylactic reaction after the first dose of sublingual immunotherapy with grass pollen tablet. Allergy 2009; 64:963-4.<br />
    105. 105. EAACI Immunotherapy Task Force Recommendations<br />“The scientific documentation for treatment schedules and dose modifications is limited. For routine treatment following the guidelines from the manufacturers is sensible.<br />• The administration of SLIT must be postponed in the following circumstances:<br /><ul><li>– In the presence of oro-pharyngeal infection.
    106. 106. – In the case of major dental surgery.
    107. 107. – Acute gastroenteritis.
    108. 108. – Exacerbation of the asthma.
    109. 109. – PEFR <80% of personal best value.
    110. 110. – Simultaneous administration of viral vaccines.”</li></ul>Alvarez-Cuesta et al. Standards for practical allergen-specific immunotherapy. Allergy 2006; 61 Suppl 82:1-20.<br />
    111. 111. Sublingual Immunotherapy Safety Summary<br />Specific instructions should be provided regarding the management of AE, unplanned interruptions in treatment and situations when SLIT should be withheld.<br />SLIT should only be prescribed by allergy-trained physicians <br />Canonica et al, Sublingual Immunotherapy: WAO Position Paper 2009 in press<br />
    112. 112. Sublingual Immunotherapy Safety Summary<br />SLIT appears to be better tolerated than SCIT<br />Majority of SLIT AE’s appear to occur during the beginning of treatment<br />A few cases of SLIT-related anaphylaxis have been reported but no fatalities<br />Risk factors for the occurrence of SLIT SAE have not yet been established <br />There is a need for a generally accepted system of reporting adverse reactions/anaphylaxis<br />Canonica et al, Sublingual Immunotherapy: WAO Position Paper 2009 in press<br />
    113. 113. Status of US SLIT Clinical Trials and Other Practical Considerations<br />
    114. 114. Sublingual-oral administration of standardizedallergenic extracts: phase 1 safety and dosing results<br />Methods: Adults 18 to 50 yo with AR ± asthma 7 dose escalation in a single-session followed by 8-week, open-label daily SLIT.<br />Results: 77/91 completed the phase 1 testing. <br />Maximum tolerable doses ranged from :<br /><ul><li>50 to 2,090 BAU for cat hair and dust mite
    115. 115. 31 to 91 Amb a 1 Units for short ragweed
    116. 116. 50 to 21,090 BAU for timothy grass</li></ul>Esch et al., Ann Allergy Asthma Immunol. 2008;100:475–481<br />
    117. 117. Ongoing & Planned US Studies<br />Planet technology: Cat 0.21 Units (~0.48 µg) vs. 2.1 Units (~4.8 µg): database locked; statistical efficacy reportedly not established . May repeat with differentdoses<br />Greer: Ragweed: phase IIb post hoc analysis efficacy in high dose, III: completed fall of 2008; results have not been released<br />Merck/Schering-Plough/Alk-Abello: <br />Grass: adult and pediatric studies (with grass tablet (15mcg Phl p 5) efficacy in both<br />Phase I ragweed completed-results not released<br />Phase III completed, results not released <br />3 arms: placebo ,6 and 12 U Amb a 1 U,<br />Stallergenes: phase III grass tablet adutl study completed<br />80<br />
    118. 118.
    119. 119. No FDA- approved formulation for SLIT thus<br />As a result no CPT code for SLIT<br />Effective dose for SLIT US licensed extracts not known<br />Efficacy of multi-allergen SLIT mixtures has not been established & most US patients are polysensitized<br />Risk factors for SLITs have not been established<br />Questions remain concerning appropriate patient instructions for management of this ‘at-home’ treatment <br />
    120. 120. Perception of SLIT Among US Practicing Allergists <br />  <br />Methods: On behalf of ACAAI IT/AD Committee, electronic survey sent to allergists early 2007<br />Results: 828 (25.7%) respondents<br /><ul><li>45 (5.9%) U.S. allergists reported using SLIT  
    121. 121. 94.1% did not prescribe SLIT:
    122. 122. Most cited reason lack of FDA approval: (61.7%)
    123. 123. Other barrier: effective dose is not known (27.5%) 
    124. 124. But if approved would prescribe SLIT for:
    125. 125. Rhinitis- 65.7%
    126. 126. Moderate to severe asthmatics- 40.9%
    127. 127. Children <5 years-45.5%</li></ul>  <br />Tucker MH, Tankersley MS. Perception and practice of sublingual immunotherapy among practicing allergists. Annals of Allergy, Asthma and Immunology 2008; 101:419-25<br />
    128. 128. JCAAI Survey of US Allergist October 2009<br />Are you currently providing sublingual allergy immunotherapy (SLIT)?<br />Response: <br />Yes 5.3% (26) No 94.7% (468)<br /> If answer to question 1 is "No", what is the biggest barrier preventing you from using SLIT in your practice? <br />Joint Council of Allergy, A.I., SLIT Usage in Your Area survey. Oct 2009. <br />
    129. 129. Barrier to SLIT Prescribing in 2009<br />Other (please specify)<br />Sample Response: not sure multiple allergens can be used or are effective; not FDA approved; quality extracts not<br />readily available; less effective than SCIT; reimbursement – not paid by insurance; waiting for allergy organizations to<br />take a clear stand; SLIT can trigger angioedema and anaphylaxis as well other adverse affects. Why would you<br />prescribe such a therapy outside of a physician’s office?; poor compliance; I am about to start High Dose Therapy on<br />some pilot patients. Additional responses available on request.<br />
    130. 130. The Time Line For CPT Code Approval Is LengthyRequires Use of Interim Code Until Permanent Code Assigned<br />Interim CPT code used for claims<br />FDA Approval<br /> Year 1 – Year 2<br />Year 3 – Jan 1<br />Payers<br />adopt <br />new code <br />April Year 2: RUC recommendation sent to CMS, which makes adjustments and finalizes RVUs<br />CPT application <br />Submitted to AMA<br />CPT Committee meets quarterly – assume approved at June or October Year 1 meeting<br />August Year 2: CPT with RVUs published, effective Jan 1 Year 3<br />Feb Year 1: Application circulated to advisory board and specialty societies<br />Feb Year 2, when CPT code approved, referred to RUC for relative value units<br />
    131. 131. Assortment of remedies can be found Over-the-Counter in US that have not gone through any formal approval process<br />Ingredients: Animal, Dust, & Mold Isodes 12x. Antimonium crudum, Arsenicum album, Baptisia tinctoria, China, Ipecacuanha, Lycopodium clavatum, Nux vomica, Podophyllum, Rhus toxicodendron 10x. Carduus benedictus, Iris versicolor, Solidago virgaurea 3x. Alcohol 20%.<br />
    132. 132. Allergen Immunotherapy General Take Home Points<br /><ul><li>Efficacy of SLIT for some allergens has been established
    133. 133. Each formulation must establish its own effective dosing regimen
    134. 134. 2-4 pre & co-seaonal seems effective
    135. 135. Sustained efficacy after 3-4 years of treatment
    136. 136. Efficacy of multiallergen SLIT (>2 allergens not established)
    137. 137. Sustained benefits after discontinuation
    138. 138. Mechanisms appear similar to SCIT
    139. 139. Safety: Most AE, primarily oral-mucosal in beginning of treatment
    140. 140. Risk factors not established but SR with SCIT may be one.</li></li></ul><li>Why People Move To Florida<br />TAMPA, Fla. - Raymond Rodriguez was changing a tire when an 18-inch chunk of ice plummeted from the sky with a piercing whistle, then a metallic crunch. The ice chunk crushed the roof of a nearby Ford Mustang on Sunday morning. No one was hurt.<br />Tailgating Dolphin<br />Everglades City, Florida<br />Manatee stopping by for a palm frond snack from Chris Cox Wolfgram<br />Photo courtesy GG my snowbird aunt<br />

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