Immunotherapy in allergic rhinitis


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Immunotherapy in allergic rhinitis

  1. 1. Immunotherapy in AllergicRhinitis: What is the evidence?Prof DR Dr Ariyanto Harsono SpA(K)
  2. 2. IntroductionEpidemiologic data shows a high and increasingprevalence of allergic rhinitis (AR) worldwide. ARis particularly frequent in children, in whom theatopic disease usually starts with atopicdermatitis and then develops into AR and asthmaby the picture of the so-called “allergic march”.AR is generally managed by allergen avoidance,which in reality is rarely feasible, drug treatment,which is mainly based on antihistamines andtopical corticosteroids, and allergen-specificimmunotherapy (AIT)2Prof DR Dr Ariyanto Harsono SpA(K)
  3. 3. In 1987, the sublingual route was proposed for AIT ,and in the ensuing years it emerged as the bestoption for immunotherapy, by demonstrating acomparable efficacy and better safety whencompared to the classical subcutaneous route ofadministration. Today, a high number of studiesshowing the efficacy of sublingualimmunotherapy (SLIT) have made the use of thistreatment more frequent than subcutaneous IT(SCIT) in several European countries, and recentstudies are paving the way for the introduction ofSLIT also in the USA3Prof DR Dr Ariyanto Harsono SpA(K)
  4. 4. The World Health Organization and variousallergy, asthma, and immunology societiesthroughout the world met on January 27through 29, 1997, in Geneva, Switzerland towrite guidelines for allergen immunotherapy.Over the ensuing year, the editors and panelmembers reached a consensus about theinformation to include in the WHO positionpaper “Allergen immunotherapy: Therapeuticvaccines for allergic diseases.”4Prof DR Dr Ariyanto Harsono SpA(K)
  5. 5. The goal of this review is to analyze up to date therole of SLIT in the treatment of AR through theevidence which demonstrates its efficacy andsafety, while highlighting the pharmacoeconomicissue.5Prof DR Dr Ariyanto Harsono SpA(K)
  6. 6. LeukotrieN C4Prostaglandin D2TryptaseHISTAMINECYTOKINEIL-1IL-3IL-4IL-5IL-6IL-13TNF-ChemokineIL-8EotaxinRANTESAdhesion MoleculesP-selectinICAMEarly onset Response•Sneezing•Itchy nose,•Watery eyes•Rhinorhoe•Stuffy noseRapid Type Response of inflammationOverview: Allergic RhinitisEarly Onset Mediator RapidReaction interaction withtarget cells6Prof DR Dr Ariyanto Harsono SpA(K)
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  11. 11. 11Prof DR Dr Ariyanto Harsono SpA(K)
  12. 12. Allergic Rhinitis and co-morbid conditionsAllergic rhinitisNasal polypsSleep disturbance,including sleep-disordered breathingRhinosinusitis (acute and chronic)Asthma with ARCongestionInflammationCommon cold12Prof DR Dr Ariyanto Harsono SpA(K)
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  20. 20. ARIA = Allergic Rhinitis and its Impact on Asthma.Bousquet et al. J Allergy Clin Immunol. 2001;108 (5 suppl):S147.ARIA Guidelines: Recommendations forManagement of Allergic RhinitisMildintermittentModeratesevereintermittentMildpersistentModerateseverepersistentImmunotherapyAllergen and irritant avoidanceIntranasal decongestant (<10 days) or oral decongestantSecond-generation nonsedating H1 antihistamineLeukotriene receptor antagonistsLocal cromoneIntra-nasal steroid20Prof DR Dr Ariyanto Harsono SpA(K)
  21. 21. EFFICACY OF SUBLINGUALIMMUNOTHERAPYThe clinical efficacy of SLIT in AR, similarly to AIT in general, is evaluated by thedecrease in symptom scores of rhinitis and in the consumption of symptomatic anti-allergic drugs. Currently, more than 60 double-blind, placebo-controlled studies areavailable, and provided the material for numerous meta-analyses on SLIT.The first meta-analysis was published in 2005, 22 controlled trials were available,showing a significantly higher efficacy of SLIT versus placebo, with a standardizedmean difference (SMD) corresponding to -0.42 for symptom scores (p = 0.002) andto -0.43 for medication scores (p = 0.00003) [12]. In 2011, the same group updatedmeta-analysis: 60 controlled trials were retrieved from the literature and 49 weresuitable for pooling in meta-analysis. A significant reduction was found in symptoms(SMD -0.49, p < 0.00001) and in medication use (SMD -0.32, p< 0.00001)compared to the placebo. Therefore, the authors concluded that the updated reviewreinforced the statement of the previous meta-analysis that SLIT is effective for AR.21Prof DR Dr Ariyanto Harsono SpA(K)
  22. 22. However, a subsequent meta-analysis on SLIT inchildren, concerning only the efficacy on AR,showed positive outcomes, with a significantreduction of symptoms (SMD -0.56, p = 0.02)and medication scores (SMD -0.76, p = 0.03)22Prof DR Dr Ariyanto Harsono SpA(K)
  23. 23. Compalati et al. considered 8 controlled studiesfor house dust mite-induced AR, including 194adults and children, and found a significantreduction in symptoms of AR (SMD -0.95; p =0.02) and in antiallergic medication use (SMD -1.88; p = 0.04) in SLIT treated patients whencompared to the placebo23Prof DR Dr Ariyanto Harsono SpA(K)
  24. 24. In a study on SLIT performed by a dust mite extract, 137 patientswere divided in 2 groups, 67 receiving the treatment for 2years and 70 receiving the treatment for 3 years; all patientswere followed-up for 3 years after stopping SLIT, and a greaterimprovement of symptoms was found in patients treated for3 years. In a prospective open controlled study, patientsmonosensitized to mites were divided in 4 groups, 1 receivingonly drug treatment and the other 3 receiving SLIT for 3, 4, or5 years. The observation period was extended to 15 years,and the clinical scores showed that the clinical benefitcontinued for 7 years in patients treated for 3 years, while itcontinued for 8 years in those treated for 4-5 years.24Prof DR Dr Ariyanto Harsono SpA(K)
  25. 25. SAFETY AND TOLERABILITY OFSUBLINGUAL IMMUNOTHERAPYThe first observations on safety and tolerability ofSLIT were reported in the meta-analyses onefficacy, and showed that the most commonadverse events were local reactions in the mouthfollowed by gastrointestinal reactions (includingvomiting and diarrhea), that systemic reactionssuch as asthma, rhinitis, or urticaria were quiterare, and that no anaphylactic reaction wasdescribed in controlled trials. However, reviewsspecifically addressing SLIT safety are alsoavailable, concerning only children or patients ofany age.25Prof DR Dr Ariyanto Harsono SpA(K)
  26. 26. Of interest, differently from SCIT, a dose-dependence of safety was not apparent, sincethe rate of systemic reactions was comparablein studies using low doses and in studies usinghigh doses. The local reactions are generallyestimated to affect 20-40% of patients, butthey can be easily managed and generally donot require to withdraw the treatment26Prof DR Dr Ariyanto Harsono SpA(K)
  27. 27. We found significant reductions in symptoms (SMD-0.49; 95%CI (-0.64 to -0.34, P < 0.00001)) andmedication requirements (SMD -0.32; 95%CI (-0.43 to -0.21, P < 0.00001)) compared withplacebo. None of the trials reported severesystemic reactions, anaphylaxis or use ofAdrenaline. This updated review reinforces theconclusion of the original 2003 Cochrane Reviewthat sublingual immunotherapy is effectivefor allergic rhinitis and appears a safe route ofadministrationAllergy, 2011;66:740-5227Prof DR Dr Ariyanto Harsono SpA(K)
  28. 28. 28Prof DR Dr Ariyanto Harsono SpA(K)
  29. 29. SCITThe weighted mean RCI of SCIT on TNSSs (-34.7% ± 6.8%) washigher than those of mometasone (-31.7% ± 16.7%, P <.00001) and montelukast (-6.3% ± 3.0%, P < .00001). Theweighted mean RCI of SCIT on TSSs (-32.9% ± 12.7%) washigher than that of desloratadine (-12.0% ± 5.1%, P <.00001). The overall ES of SCIT in terms of TNSSs (SMD, -0.94; 95% CI, -1.45 to -0.43) was similar to that ofmometasone (SMD, -0.47; 95% CI, -0.63 to -0.32; P > .05)and higher than that of montelukast (SMD, -0.24; 95% CI, -0.33 to -0.16; P < .05). The overall ES of SCIT in terms ofTSSs (SMD, -0.86; 95% CI, -1.17 to -0.55) was comparablewith that of desloratadine (SMD, -1.00; 95% CI, -1.68 to -0.32; P > .05).J Allergy Clin Immunol 2011 Oct;128(4):791-79929Prof DR Dr Ariyanto Harsono SpA(K)
  30. 30. Subcutaneous immunotherapy and pharmacotherapy inseasonal allergic rhinitis: a comparison based on meta-analysesThe weighted mean RCI of SCIT on TNSSs (-34.7% ± 6.8%) was higherthan those of mometasone (-31.7% ± 16.7%, P < .00001) andmontelukast (-6.3% ± 3.0%, P < .00001). The weighted mean RCI ofSCIT on TSSs (-32.9% ± 12.7%) was higher than that of desloratadine(-12.0% ± 5.1%, P < .00001). The overall ES of SCIT in terms of TNSSs(SMD, -0.94; 95% CI, -1.45 to -0.43) was similar to that ofmometasone (SMD, -0.47; 95% CI, -0.63 to -0.32; P > .05) andhigher than that of montelukast (SMD, -0.24; 95% CI, -0.33 to -0.16;P < .05). The overall ES of SCIT in terms of TSSs (SMD, -0.86; 95% CI,-1.17 to -0.55) was comparable with that of desloratadine (SMD, -1.00; 95% CI, -1.68 to -0.32; P > .05).J Allergy Clin Immunol. 2011 Oct;128(4):791-799.30Prof DR Dr Ariyanto Harsono SpA(K)
  31. 31.  We retrieved 1111 publications of which 51 satisfied our inclusion criteria. Intotal there were 2871 participants (1645 active, 1226 placebo), each receiving onaverage 18 injections. Duration of immunotherapy varied from three days to threeyears. Symptom score data from 15 trials were suitable for meta-analysis andshowed an overall reduction in the immunotherapy group (SMD -0.73 (95% CI -0.97 to -0.50, P < 0.00001)). Medication score data from 13 trials showed anoverall reduction in the immunotherapy group (SMD of -0.57 (95% CI -0.82 to -0.33, p<0.00001)). Clinical interpretation of the effect size is difficult. Adrenalinewas given in 0.13% (19 of 14085 injections) of those on active treatment and in0.01% (1 of 8278 injections) of the placebo group for treatment of adverseevents. There were no fatalities. This review has shown that specific allergen injection immunotherapy in suitablyselected patients with seasonalallergic rhinitis results in a significant reduction insymptom scores and medication use. Injection immunotherapy has a known andrelatively low risk of severe adverse events. We found no long-termconsequences from adverse events.Cochrane Database Syst Rev. 2007 Jan 24;(1):CD00193631Prof DR Dr Ariyanto Harsono SpA(K)
  32. 32. 32Prof DR Dr Ariyanto Harsono SpA(K)
  33. 33. 33Prof DR Dr Ariyanto Harsono SpA(K)
  34. 34. 34Prof DR Dr Ariyanto Harsono SpA(K)
  35. 35. SCIT versus SLITSpecific immunotherapy (SIT) is the only diseases-modifying treatmentoption for allergies. Meta-analysis reveals standardized mean differencesin allergic rhinitis symptom scores of -0.73 forsubcutaneous immunotherapy (SCIT) and -0.49 forsublingual immunotherapy (SLIT); the corresponding mean differencesin medication scores are -0.57 and -0.32, respectively. The treatmentshould be carried out for at least three years. It is indicated when thesymptoms are severe and allergen avoidance is not a realistic option. Theefficacy of treatment depends on the allergen dose; thus, every allergenpreparation should be evaluated individually, independent of route ofadministration. SCIT can cause systemic adverse effects, includinganaphylaxis. SLIT is safer but often causes allergic symptoms of the oralmucosa at the beginning of treatment.35Prof DR Dr Ariyanto Harsono SpA(K)
  36. 36. • Subcutaneous and sublingual immunotherapy with grassallergens for seasonal allergic rhinitis: The overall effect sizeof SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administeredvia drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets(SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results werereported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00.SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16).• Our results provide indirect but solid evidence that SCIT ismore effective than SLIT in controlling symptoms and inreducing the use of anti-allergic medications in seasonalallergic rhino-conjuntivitis to grass pollen.J Allergy Clin Immunol 130, 1097-1107.e2, 201236Prof DR Dr Ariyanto Harsono SpA(K)
  37. 37. 37Prof DR Dr Ariyanto Harsono SpA(K)
  38. 38. PHARMACOECONOMIC ASPECTSThe significant reduction in the use of symptomaticdrugs showed by all meta-analyses on SLIThighlights the cost-effectiveness of thistreatment. In fact, a number of studies addressedthe pharmaco-economics of AIT. The review ofsuch studies in 2008 led to the conclusion thatthere was clear data that substantiated thecapacity of both SCIT and SLIT to be verybeneficial to the healthcare system. The majoradvantage of AIT takes place when the treatment,usually after 3 years, is stopped, because theeffectiveness of AIT persists over time38Prof DR Dr Ariyanto Harsono SpA(K)
  39. 39. Such persistence is related to the immunologicchanges induced by AIT, especially regardingthe T lymphocytes and their cytokine profileand the production of IgG blocking antibodies[38] and the consequent modification of thenatural history of respiratory allergy39Prof DR Dr Ariyanto Harsono SpA(K)
  40. 40. Recent studies expanded the concept ofeconomic advantage of AIT even before itstermination. In a study performed in US,children with AR treated with AIT hadsignificantly lower 18-month median totalhealth care costs ($ 3247 vs $ 4872),outpatients costs of AIT-related care ($1107 vs$ 2626), and pharmacy costs ($1108 vs $1316) compared with matched controls (p <0.001 for all comparisons)40Prof DR Dr Ariyanto Harsono SpA(K)
  41. 41. This data has led the authors to conclude that“This study demonstrates the potentialSublingual immunotherapy in allergic rhinitis175 for early and significant cost savings inchildren with AR treated with immunotherapy.Greater use of this treatment in children couldsignificantly reduce AR related morbidity andits economic burden”41Prof DR Dr Ariyanto Harsono SpA(K)
  42. 42. Of interest, the direct comparison of costs betweenSCIT and SLIT was in favour of the latter, asexpected because of the lack of the necessity forhospital visits for the injections. In France, thereported savings compared with drug treatmentover a 6-year period were € 393 for dust mite and€ 1327 for pollen allergy with SCIT, but they were€ 3158 for dust mite and € 1708 for pollen allergywith SLIT. In the Czech Republic, the sum of directand indirect costs recorded, over a 3-yeartreatment, € 684 for SLIT and € 1004 for SCIT.42Prof DR Dr Ariyanto Harsono SpA(K)
  43. 43. CONCLUSIONSLIT has achieved sound evidence of efficacy and safety andcurrently in some European countries is more frequentlyused than the classical SCIT, due to better safety. Otheradvantages over SCIT concern the cost as well as thecompliance , because SLIT does not need to beadministered in a medical setting. Still, it is important tonote that such outcomes take place only if SLIT meets itsneeds, that is, the administration of high doses iscontinued on a regular basis for at least 3 consecutiveyears. In fact, SLIT efficacy is dose-dependent and asufficient duration is crucial to elicit the immunologicchanges underlying its clinical effectiveness.43Prof DR Dr Ariyanto Harsono SpA(K)
  44. 44. Thank You 44