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ALLERGEN IMMUNOTHERAPY EXPERT EXCHANGE

This newsletter is based on two presentations from the 68th Annual Scientic Meeting of the Canadian Society of Allergy and Clinical Immunology. Prof. Moiss A. Caldern from United Kingdom and Prof. Pascal Demoly from France are leading experts in research and clinical treatment with allergen immunotherapy and especially sublingual immunotherapy.

Prof. Moiss A. Caldern is based at the Royal Brompton Hospital, Imperial College, National Heart and Lung Institute in London. As the Director of the Clinical Trials Unit, Prof. Caldern is conducting clinical research, investigating the efficacy and safety of allergen immunotherapy. In addition, he participates, as an independent allergy expert, in safety committees and clinical investigations, focusing particularly on sublingual immunotherapy tablets. He is an Executive Committee Member of the European Academy of Allergy and Clinical Immunology (EAACI), an author and reviewer of a long list of peer-reviewed publications in international journals, and a key opinion leader on allergen immunotherapy at many international meetings. Prof. Caldern was educated at the University of Costa Rica where he obtained an MD in Internal Medicine and at the University of London where he obtained his PhD in Allergy and Clinical Immunology. He joined the Imperial College London and the Royal Brompton Hospital in 2002.

WELL-POWERED CLINICAL TRIALS IN GRASS POLLEN SUBLINGUAL IMMUNOTHERAPY (SLIT)


By Prof. Moiss A. Caldern, MD PhD
Learning objectives: 1. Recognize that SLIT is safe 2.  Review clinical data supporting effectiveness of SLIT in adults and children 3.  Examine patient subgroups and dosing parameters that are associated with SLIT effectiveness 4. Compare SLIT therapy in mono- vs. polysensitized patients 5. Understand long-term and preventative benets of SLIT
Historically, evidence in support of the clinical efcacy and safety of sublingual allergen immunotherapy (SLIT) has been heterogeneous, but a recent decade of well-powered, randomized, double-blind clinical trials has shown that this therapeutic intervention is both a very safe and effective option for patients with moderate to severe allergies to grass pollen. Studies in both Europe and North America used similar SLIT preparations and clinical inclusion and exclusion criteria. SLIT is much less likely to cause serious adverse reactions than subcutaneous immunotherapy (SCIT) and has not had any documented mortalities. SLIT has been shown to be effective in adults and in children with comparable effectiveness in monoand polysensitized patients. Higher doses of SLIT, longer duration of therapy and close adherence positively affect the outcome. Starting therapy at least 8 weeks prior to the grass pollen season increases success, and visible improvement is expected in the rst year of treatment, followed by further reductions in symptoms in subsequent years. Both subcutaneous and sublingual immunotherapies appear to have prolonged duration of efcacy after discontinuation of treatment, and both can prevent the development of asthma and new allergen sensitivities.

and inducing specific long-term tolerance. Born in Europe in the 80s, sublingual immunotherapy is not considered a replacement to the more traditional subcutaneous immunotherapy but an alternative route in allergen immunotherapy.1 Overall, it was estimated that more than 50% of patients in Central Europe receiving allergen immunotherapy are using SLIT.2 There are regional preferences in terms of modality; for example, in France and Italy, the sublingual option is prescribed to 95-98% of patients receiving specific immunotherapy while in Germany and Spain the subcutaneous option is preferred. SLIT is safer than SCIT Safety is a very relevant issue when patients are given allergen immunotherapy. The usual side effects of SLIT are oral pruritus (43%), throat irritation (26%), ear pruritus (12%) and mouth edema (10%).3 Using SCIT, there are 83 confirmed deaths in North America; however no fatalities have been reported so far with sublingual immunotherapy. Anaphylaxis with SLIT is extremely rare. Possible risk factors for anaphylaxis using SLIT are: i) severe/ uncontrolled asthma, ii) multiple allergens, iii) high doses of allergen and iv) previous SCIT anaphylaxis. SLIT is effective in children and adults One of the hottest topics of debate in the field of clinical allergy has been the question of whether sublingual immunotherapy is effective. Historically, the trials were small and heterogeneous (clinically and methodologically),4 making it challenging to draw definitive conclusions. Patients included in the trials had a large variety of symptoms and used different formulations, often with ad hoc dosing regiments. Fortunately, in the past 10 years a number of well-powered, randomized, double-blind, placebo-controlled clinical trials (RCTs) have been published that enabled several meta-analyses, subgroup analyses and comparisons of both subcutaneous and sublingual immunotherapy. SLIT in adults Overall, results clearly demonstrate5 that the efficacy of SLIT is excellent for patients with respiratory allergy. The 2010 Cochrane systematic review of 49 SLIT trials found significant reductions in symptoms of rhinitis (standardized mean difference [SMD] 0.49; p < 0.00001) and medication requirements (SMD 0.32; p < 0.00001) compared with placebo.5 There are very few trials comparing SCIT and SLIT for the same allergen within the same study. A set of parallel meta-analyses of SCIT (n = 6 trials), SLIT (drops; n = 12 trials) and SLIT (tablets; n = 6 trials) in patients with grass pollen rhinitis found the level of efficacy was greater for SLIT tablets (SMD -0.41) and

SLIT as an alternative to SCIT Since the first randomized controlled study published a century ago, allergen immunotherapy remains the only causative treatment for respiratory allergies. It works by modifying the allergic response

Sponsored by an unrestricted educational grant from Paladin Labs.

SCIT (SMD -0.46) than for SLIT drops (SMD -0.14).4 In addition to symptoms and medication use, quality of life scores also improved. The predetermined subgroup analyses in the Cochrane review showed that SLIT is highly effective in both seasonal and perennial allergic rhinitis, however the effect is greater with the treatment lasting longer than 12 months and with higher doses of the major allergen protein (>20 g of major allergen protein).4 A longer duration of pretreatment (prior to the pollen season) also improves efficacy (See Figure 1).6 Ideally, SLIT therapy should begin at least 8 weeks prior to the pollen season. Patients with moderate to severe rhinitis are best responders. Patients with milder disease often withdraw from treatment and hence results for this patient group are inconclusive. Currently, SLIT is indicated for patients 5 to 50 years of age with moderate to severe allergic disease who do not respond adequately to rescue medications or avoidance measures.3 Negative studies tend to remain unpublished, however at least one study that concluded SLIT to be ineffective has been published in 2007.7 In this study, patients were receiving low doses of immunotherapy, twice or once per week rather than daily, and were often selected by their family physicians rather than allergy specialists. These results further highlight the importance of appropriate patient selection and dosing regimen to achieve desired results with SLIT. SLIT in children SLIT represents a particularly attractive alternative to injection immunotherapy in this patient group because of its oral administration, convenience and safety. In several meta-analyses, marked reductions in symptom scores with SLIT were noted in both young children and teenagers, ranging from SMD -0.32 to SMD -0.95.8,9,10,11 Figure 2 shows results from a multinational, randomized, doubleblind, placebo-controlled study which assessed 278 children (5-17 years of age). SLIT significantly reduced rhinoconjunctivitis total symptom score by 30% after one pre-coseasonal treatment. Rescue medication use decreased by 24% in this study.9 SLIT has been shown to be effective in both school children (5-11years of age) and teenagers (12-17 years of age). However, adherence to treatment has to be carefully evaluated in the paediatric population. Adherence seems to be better in the younger group due to parent supervision. Adherence to SLIT is more difficult to assess in the teenage population.10,11 Mono- vs. polysensitized patients Patients with moderate-to-severe respiratory allergies are often polysensitized. There is a debate as to whether polysensitized patients are best treated with multiple allergens (chosen according to the sensitization profile) or a single allergen (chosen according
50% 45% 40%
< 8 weeks 17% symptoms 23% medication > 8 weeks 37% symptoms 47% medication

4.0

Total RTSS LS mean score

3.0

3.51

p = 0.0002

30%

2.0

2.44

1.0

0.0

Placebo (n = 135)

ORALAIR 300 IR (n = 131)

FIGURE 2. Least-Squares (LS) mean of total daily rhinitis total symptom scores (RTSS) during the pollen season for ORALAIR 300 IR vs. placebo (repeated measures, ITT).Total score = total of the six individual symptom scores (sneezing, runny nose, itchy nose, watery eyes, itchy eyes, nasal congestion), each assessed on a 4-point scale (from 0 = absent to 3 = severe). Oralair Product Monograph.

to the most clinically problematic allergy). In RCTs with SLIT, polysensitized patients benefited at least as much from the treatment as monosensitized patients.12 Continuous and long-term results Based on the clinical evidence with subcutaneous immunotherapy, SLIT is recommended for 3 years (3 pre-coseasonal treatments) in adults and children. During the first pollen season, patients can expect a 27% improvement in symptom scores13, followed by further progressive improvements in the second and third years.14,15 SLIT has shown prolonged duration of efficacy after discontinuation of treatment and can prevent the development of asthma and new allergen sensitivities.16 Unmet needs Well-powered, well-designed RCTs in asthmatic patients with the use of different allergens (e.g. house dust mites) are urgently needed. The first double-blind, placebo-controlled randomized trial (GAP) is currently assessing the preventive effect of allergen-specific immunotherapy on asthma development in 812 children (5-12 years of age). Results are expected in 2015. Conclusion In conclusion, we have a solid body of evidence to support the efficacy and safety of SLIT in both children and adults. Single allergen immunotherapy is efficacious in polysensitized patients and induces long-term allergen effect after treatment discontinuation. Correct dosing, administration and patient selection are crucial to success of therapy. Patients need to be instructed about the importance of adherence and ways to improve it. A thorough discussion of side effects and expectations will improve patient comfort and adherence to therapy.
REFERENCES:

n = 934

Reduction (%)

35% 30% 25% 20% 15% 10% 5% 0%


0 4 8 12 16 20 24 28 32 36

Reduction in medication scores Reduction in symptom scores Projected values

1. Sub-Lingual Immunotherapy. World Allergy Organization Position Paper 2009. 2. B  ousquet J et al. Specific immunotherapy an optimistic future. Allergy 2006;61:1155-8. 3. Oralair Product Monograph. Paladin Labs Inc. March 2012. 4. C  aldern MA et al. Immunotherapy:The meta-analyses. What have we learned? Immunol Allergy Clin North Am 2011;31:159-73. 5. R  adulovic S et al. Systematic reviews of sublingual immunotherapy (SLIT). Allergy 2011;66:740-52. 6. C  aldern MA et al. Prolonged preseasonal treatment phase with Grazax sublingual immunotherapy increases clinical efficacy. Allergy 2007;62:958-61. 7. R  oder E et al. Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. J Allergy Clin Immunol 2007;119:892-8.

Weeks prior to start of pollen season


FIGURE 1. Longer SLIT grass tablet pretreatment is associated with increased

efficacy. Significant clinical effect (p < 0.05) is observed when the treatment is started approximately 8 weeks prior to the pollen season. Adapted from Allergy 2007;62:958-61.

8. P  enagos M et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol 2006;97:141-8. 9. W  ahn U et al. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol 2009;123:160-6. 10. R  oder E et al. Sublingual immunotherapy with grass pollen is not effective in symptomatic youngsters in primary care. J Allergy Clin Immunol 2007;119:892-8. 11. B  ufe A et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol 2009;123:167-73. 12. C  aldern MA et al. Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: looking at the published evidence. J Allergy Clin Immunol 2012;129:929-34.

13. D  idier A et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007;120(6):1338-45. 14. D  urham et al. Long-term clinical efficacy in grass pollen rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy. J Allergy Clin Immunol 2010;125:131-8. 15. D  idier et al. American College of Asthma, Allergy & Immunology (ACAAI) 2010; poster 326. 16. B  urks AW et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report.

Prof. Pascal Demoly is a Professor of Pulmonology at the University of Montpellier, France, and the Head of the Clinical Department of Allergology at the University Hospital of Montpellier. In the past years, he focused on research in allergic rhinitis, asthma diagnosis and treatment, allergen immunotherapy and drug allergy. He has extensive lecturing experience in these areas and has published more than 500 articles, of which more than 300 have been published in international peer-reviewed journals. Prof. Demoly is the Vice-President for Education & Specialties of the European Academy of Allergy and Clinical Immunology (EAACI) and a WHO expert for allergy (International Consensus on Specific Immunotherapy, Allergic Rhinitis and its Impact on Asthma). From 2010 to 2012, he was the President of the French Allergy Society. In addition, Prof. Demoly is an Associate editor of the journal ALLERGY, a member of the editorial board of several national and international medical allergy journals and a member of the French National Academy of Medicine.

DOGMAS, FALLACIES AND MISCONCEPTIONS REGARDING ALLERGEN IMMUNOTHERAPY


By Prof. Pascal Demoly, MD PhD
Learning objectives: 1.  Dispel common misconceptions about allergen immunotherapy 2.  Recognize that safety and efcacy of allergen immunotherapy has been unambiguously validated by well-powered robust clinical trials
Understanding of allergen immunotherapy has been built on personal beliefs and empiricism, which prompted the appearance of false dogmas concerning its efcacy, onset of action and administration regimens. Fortunately, the past decade of wellpowered clinical trials has validated the efcacy and safety of this only causative allergy treatment, dispelling the false beliefs. Regulatory changes and better clinical development have turned allergen products into a new therapeutic class, with a dened standard for dosing and administration. Today, allergen immunotherapy is a proven and very effective treatment for patients with moderate to severe allergic rhinitis who are not relieved by rescue pharmacotherapy.

Dogma 2: Allergen immunotherapy has never been properly tested Allergen immunotherapy is widely used, hence regulatory agencies across the world have issued guidelines with respect to the standards regarding clinical trial design for allergen immunotherapy. These guidelines require the same level of randomization, robustness and evidence as is with regular pharmacotherapy. To date, for grass pollen allergic rhinitis allergen immunotherapy tablet we have randomized clinical trial (RCT) data in more than 6,600 patients with information about short-term therapy, long-term therapy, carryover effect and ongoing prevention.18 Hence, the notion that allergen immunotherapy has not been properly tested is incorrect. Dogma 3: Allergen immunotherapy is less effective than pharmacotherapy This dogma is largely due to the initial abundance of small clinical trials and the expected heterogeneity observed in meta-analyses for both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). In the past decade, trial size and design have significantly improved, providing a large pool of RCTs and enabling meta-analyses as well as subgroup analyses. Direct comparisons between allergen immunotherapy and pharmacotherapy are impossible because immunotherapy treatments are long in duration and it is not ethical to put patients on a placebo instead of rescue medication they might need during the pollen season. Trials with only pharmacotherapy tend to be short in duration, with patients assigned to either medication or placebo for approximately 2 weeks. Since pharmacotherapy trials are conducted at the peak of the pollen season (when allergic symptoms are most pronounced), the effect size is significant. Allergen immunotherapy trials for grass pollens consider the entire allergic season which decreases the overall symptom score in the placebo group and therefore the effect size is diluted. Also, seasons vary with respect to pollen counts, further increasing variability of results. It is only possible to consider and compare effect sizes of pharmacotherapy and allergen immunotherapy in separate metaanalyses. Two published meta-analyses19,20 evaluated effects of nasal steroids, H1 antihistamine and leukotriene antagonists in almost 17,000 allergic rhinitis patients. The greatest effects were seen with nasal corticosteroids (17-26% reduction in symptoms). Antihistamine and leucotriene antagonist produced smaller effects (from 5% to 9%). At the same time, treatment with sublingual immunotherapy showed 30-40% reduction in symptoms over placebo during the pollen

Dogma 1: There is no need for allergen immunotherapy There is a false perception that allergic rhinitis is a trivial and homogenous disease. In reality, there are different phenotypes of allergic rhinitis. Some patients have no symptoms outside of the pollen season or even during the pollen season. Other patients experience symptoms that can be easily alleviated with over-the-counter antihistamines or, if needed, prescription antihistamines and corticosteroids. Yet, there is a subgroup of patients who experience severe discomfort (usually with a constellation of symptoms that are not fully relieved with medication) and have decreased quality of life because of the allergy.17 Hence, allergic patients have different therapeutic needs. Those with persistent disease are referred to allergists, often after extensive doctor-hopping. Allergen immunotherapy helps this subgroup of patients.17

Table 1. Efcacy of allergen immunotherapy in monosensitized vs. polysensitized patients. Demonstrated in the VO34 Oralair adult study Placebo Sensitization status RTSS (ITT population)
Monosensitized Polysensitized Monosensitized

300 IR
Polysensitized

n mean

63 4.59

85 5.18

66 3.93

70 3.25

J Allergy Clin Immunol 2012;129:929-34.

season.18,21,22,23 Hence, symptomatic medications are less effective in relieving the symptoms of allergic rhinitis. Dogma 4: Allergen immunotherapy has to be taken for several years to be efcient The fact that several consecutive seasons of allergen immunotherapy are recommended for full treatment efficacy has given rise to a false belief that benefits only appear after this long period of treatment. However, studies show that significant benefits are seen in the first treatment season and even from the first month of treatment onwards. Figure 3 shows the onset of action and efficacy of 300 IR (index of reactivity) SLIT tablets as evaluated by an allergen chamber challenge. The symptom score improves from the first week of treatment with grass pollen SLIT tablets, with a significant effect at 1 month, a plateau after 2 months, and maintenance of the effect at 4 months.21,24 Dogma 5: Allergen immunotherapy doesnt work in polysensitized patients In 2001, the Allergic Rhinitis and its Impact on Asthma (ARIA)17 guidelines stated that allergen immunotherapy might be less effective in polysensitized patients than in monosensitized patients. Since then, rigorous clinical trials have shown that polysensitized patients benefit from single-allergen immunotherapy to a similar extent as monosensitized patients for grass pollen allergic rhinitis (See Table 1). On the other hand, the safety of multiallergen immunotherapy in polysensitized patients needs more supporting data from large clinical trials.12
10 9
n = 89 p = 0.0647 n = 88 p = 0.0042 n = 83 p = 0.0203

Dogma 6: SCIT secures better compliance than SLIT The notion that SCIT increases patient compliance is due to perception that subcutaneous treatment is easier to control through medical office appointments. In reality, many patients fail to keep their appointments over the course of treatment. A Medicaid survey reported that only 16% of children finished a 3-year course of SCIT.25 In a study of allergen immunotherapy perceptions in Germany, persistence with SLIT was significantly higher than persistence with SCIT during 2 years of treatment.26 Conclusion The false beliefs about allergen immunotherapy are no longer justified. We have entered the second age with robust clinical trials and rigorous evaluation of products that gain approval for treating patients. Allergen immunotherapy is moving from experience and dogma to evidence-based medicine and facts. The efficacy of allergen immunotherapy has been unambiguously demonstrated. Allergy specialists should apply the principles of evidence-based medicine in their daily practice and thus contribute to the next 100 years of allergen immunotherapy.
REFERENCES: 17. B  ousquet J et al. Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs. J Allergy Clin Immunol 2012;130:1049-62. 18. R  adulovic S et al. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev 2010;8:(12):CD002893. doi: 10.1002/14651858.CD002893. 19. B  enninger M et al. Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol 2010;104(1):13-29. 20. W  ilson AM, OByrne PM, Parameswaran K. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. Am J Med 2004;116(5):338-44. 21. H  orak F et al. Early onset of action of a 5-grass-pollen 300 IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. J Allergy Clin Immunol 2009;124:471-77. 22. D  idier A et al. Agreement of efficacy assessments for five-grass pollen sublingual tablet immunotherapy. Allergy 2009;64(1):166-71. 23. D  ahl R et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;118 (2):434-40. 24. R  adulovic S et al. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev 2010;8:(12):CD002893. doi: 10.1002/14651858.CD002893. 25. H  ankin CS et al. Allergy immunotherapy among Medicaid-enrolled children with allergic rhinitis: patterns of care, resource use, and costs. J Allergy Clin Immunol 2008;121:227-32.

SLIT Placebo 300 IR

Adjusted mean +/- SE

Difference vs. placebo in each test


n = 83 p = 0.0007

8 7 6 5 4 0 15

30

45

60

75

90

105

120

Time (days)
FIGURE 3. Early onset of action of a 5-grass-pollen 300 IR sublingual

26. S  ieber J et al. Medication persistence with long-term, specific grass pollen immunotherapy measured by prescription renewal rates. Curr Med Res Opin 2011;27(4):855-6.  r. Demolys presentation at the 68th Annual Scientic Meeting of D the Canadian Society of Allergy and Clinical Immunology and this article are partly based on the publication Caldern MA et al. Allergen immunotherapy and allergic rhinitis: false beliefs. BMC Medicine 2013;11:255.

immunotherapy tablet evaluated in an allergen chamber. J Allergy Clin Immunol 2009;124:471-7.

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