Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 journal http://www.waojournal.org/content/7/1/6 REVIEW Open Access Sublingual immunotherapy: World Allergy Organization position paper 2013 update Giorgio Walter Canonica1*†, Linda Cox2†, Ruby Pawankar3†, Carlos E Baena-Cagnani4, Michael Blaiss5, Sergio Bonini6, Jean Bousquet7, Moises Calderón8, Enrico Compalati9, Stephen R Durham10, Roy Gerth van Wijk11, Désirée Larenas-Linnemann12, Harold Nelson13, Giovanni Passalacqua14, Oliver Pfaar15, Nelson Rosário16, Dermot Ryan17, Lanny Rosenwasser18, Peter Schmid-Grendelmeier19, Gianenrico Senna20, Erkka Valovirta22, Hugo Van Bever21, Pakit Vichyanond23, Ulrich Wahn24 and Osman Yusuf25 Abstract We have prepared this document, “SublingualImmunotherapy: World Allergy Organization Position Paper 2013 Update”,according to theevidence-based criteria, revising and updating chapters oftheoriginally publishedpaper, “SublingualImmunotherapy: World Allergy Organization Position Paper 2009”, available atwww.waojournal.org. Namely,thesecomprise:“Mechanismsofsublingualimmunotherapy;”“Clinicalefficacyofsublingualimmunotherapy”– reportingallthedataofallcontrolledtrialspublishedafter2009;“Safetyofsublingualimmunotherapy”–withthe recentlypublishedGradingSystemforadversereactions;“Impactofsublingualimmunotherapyonthenaturalhistory ofrespiratoryallergy”–withtherelevantevidencespublishedsince2009;“EfficacyofSLITinchildren”–withdetailed analysisofallthestudies;“DefinitionofSLITpatientselection”–reportingthecriteriaforeligibilitytosublingual immunotherapy; “The future of immunotherapy in the community care setting”; “Methodology of clinical trials according to the current scientific and regulatory standards”; and “Guideline development: from evidence-based medicine to patients' views” – including the evolution of the methods to make clinical recommendations. Additionally,wehaveaddednewchapterstocoverafewemergingcrucialtopics:“Practicalaspectsofschedulesand dosagesandcounselingforadherence”–whichiscrucialinclinicalpracticeforalltreatments;“Perspectivesandnew approaches”–includingrecombinantallergens,adjuvants,modifiedallergens,andtheconceptofvalidityofthesingle products.Furthermore,“Raisingpublicawarenessaboutsublingualimmunotherapy”,asaneedforourpatients,and strategiestoincreaseawarenessofallergenimmunotherapy(AIT)amongpatients,themedicalcommunity,all healthcarestakeholders,andpublicopinion,arealsoreportedindetail. Keywords:Sublingualimmunotherapy,Allergen-specificimmunotherapy,MechanismsofSLIT,SafetyofSLIT, EfficacyofSLIT,ClinicaltrialsmethodologyinSLIT Foreword scientificadviceand marketingauthorizationforbiologics AnintroductoryaddressbyProfessorGuidoRasi, andimmunologicaltreatmentstotheEuropeanMedicines ExecutiveDirector,EuropeanMedicinesAgency(EMA) Agency (EMA), but these therapies call for new methods Immunotherapy and Biologics represent some of the of research, strategies for development, evaluation, use mostimportanthottopicsinthefieldofmedicine.Infact, andpharmacovigilance. notonlyisthereatremendousincreaseintherequestsfor The allergen products used for both the diagnosis and treatment of allergic diseases require particular attention amongtheimmunologicalandbiologicaltherapeuticareas, *Correspondence:[email protected] †Equalcontributors due to the increase in the prevalence and social relevance 1RespiratoryandAllergyClinic,DIMI—DepartmentofInternalMedicine, ofallergiesaswellastheregulatoryactionsbeingrequested UniversityofGenoa,IRCCSAouSanMartino,LargoRosannaBenzi10,Genoa by the Directive 2001/83/EC and the following amending 1-16132,Italy Fulllistofauthorinformationisavailableattheendofthearticle ECDirectives. ©2014Canonicaetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycredited.TheCreativeCommonsPublicDomain Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle, unlessotherwisestated. Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 Page2of52 http://www.waojournal.org/content/7/1/6 In order to discuss the available EMA Guidelines on The next figure displays the evidence base for sublin- Allergen Products and to address the many issues that gual immunotherapy since the publication of the first need harmonizing, and the regulatory aspects of allergen position paper (Figure 2). products in Europe, the EMA on February 28, 2013 called a workshop in London with the participation of Chapter 2 Allergen-specific immunotherapy allstakeholders. There were no changes indicated for this chapter, and re- The WAO SLIT document presented in this issue of latedupdateddetailswereintegratedintootherchapters. the World Allergy Organization Journal, and the EAACI “Task Force Report on Clinical Outcomes to be used in Chapter 3 Mechanisms of sublingual studies of Allergen Products”, represent relevant contri- immunotherapy butions to answer the recommendations emerging from thisworkshop. (cid:1) Allergenimmunotherapy provides anopportunityto From our side, we are working on a document, to be studyantigen-specific toleranceinhumans. sharedwith allstakeholders,onpossible pathways for fa- (cid:1) Subcutaneousimmunotherapy (SCIT)suppresses cilitating marketing authorization of allergen products. allergicTh2-mediated inflammationandincreases Thesemightinclude: antigen-specificIgG, probablybyinduction of regulatoryTcells(Tregs), immune deviation(Th2 ▪awider utilizationofcollaborativetrials,withthe toTh1), and/orapoptosisofeffectormemory advantageofusingthe same controlgroupforstudies Th2cells. ofcomparable activeproducts,a substantial (cid:1) Theoralmucosaisanatural siteofimmune advantageforpediatricinvestigational plans; tolerance(Langerhanscells,FcR1,IL-10,IDO ▪ new facilitated pathways of marketing authorization [indoleamine2,3-dioxygenase]). allowing a faster access for patients to (cid:1) Sublingual immunotherapy(SLIT)inoptimaldoses immunotherapy without affecting an evidence- iseffective;SLIThasbeen showntoinduce based risk/benefit ratio; long-term remissionafterdiscontinuationand may ▪new studydesigns forwell-conductedpost- preventnewsensitizations,featuresconsistentwith registrationtrials,which, withthe helpofregistries, theinductionoftolerance. willallowaprogressiveevaluationofefficacy and (cid:1) SLITinducesmodest systemicchangesconsistent safety ofnewproductsandapharmacovigilancein withSCIT,butadditionallocalmechanismsinthe linewith thenew adhoclaw; oralmucosa and/orregionallymphnodes arelikely ▪adequateinformation technology to takefull important. advantageofawider accessto individual dataof (cid:1) Sublingual immunotherapyisassociatedwith registrationtrials. ○retention ofallergeninsublingualmucosafor severalhours. The harmonization of regulatory aspects of allergen ○early increasesinantigen-specific IgE and products represents however a work still in progress, as bluntingofseasonalIgE. shown by the concordant position on efficacy but the ○persistentincreasesinantigen-specific IgG4and different end-points adopted as well by the different IgEblockingactivity thatparallellong-term safety considerations in the recent FDA Advisory Com- clinicalbenefitsof bothSCITand SLIT. mittee votes on two SLIT products already approved by ○inhibition ofeosinophilsand reductionof EMAandmarketedinmostEuropeanCountries. adhesionmoleculesintargetorgans. Therefore, we expect that the regulatory bodies, scien- ○an early(at 4-12weeks)increaseinperipheral tific societies, manufacturers of allergen products, and phenotypicTregsanddelayed(at12months) allergy patients’ organizations will continue their joint immunedeviation infavorofTh1 responses. commitment with the common goal of providing world- ○detection ofCD25+FOXP+phenotypicTreg wide to the many millions of subjects suffering from al- cells inthesublingualmucosa. lergic diseases an early and harmonized access to safe ○alterations indendriticcellmarkers andeffectiveproducts. (e.g., increasesinexpressionofcomplement component C1Q)thatcorrelatewith Chapter 1 Introduction and historical background clinicalresponsetotreatmentand merit to sublingual immunotherapy furtherstudy. Theupdateofchapteroneconsistsoftwofigures.Figure1 (cid:1) Biomarkersthatare predictive oforsurrogatesfor providesanoverviewofthehistoryofthedevelopmentof the clinical responsetoimmunotherapy are not thefirstpositionpaper,whichwaspublishedin2009. currentlyavailableforroutine use. Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 Page3of52 http://www.waojournal.org/content/7/1/6 Figure1ThehistoricalprocessleadingtotheWAOSLITPositionPaper2009. ○Molecular diagnosis ofIgE sensitivitieswillaid allergic rhinitis [1] and conjunctivitis [2]. Several large patient selection forimmunotherapy. ‘definitive’ trials have now confirmed the efficacy and ○SerumIgG–associatedfunctionalblocking safety for seasonal rhinitis in both children and adults. activityand basophilactivationtestsmerit Long-term benefits of SLIT for at least 1 [3] or 2 [4] furtherstudy. years following discontinuation of treatment have been ○StudiesofperipheralTcellanddendriticcell demonstrated in 2 large independent trials of immuno- signatureshaveyieldedimportantinformation, therapy with grass pollen allergen tablets in adults. These but these testsare currentlyimpracticalfor studies provide evidence for long-term disease remission routine clinicaluse. and disease modification consistent with the induction of antigen-specific tolerance. In parallel with these novel Clinicalevidencefordiseasemodificationandinduction clinical data, there have been advances in our under- oftolerance standing of the underlying mechanisms of SLIT that Since 2009, Cochrane meta-analyses have confirmed the may give rise to putative biomarkers to predict the clin- efficacy and safety of SLIT for seasonal and perennial icalresponse[5-8]. Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 Page4of52 http://www.waojournal.org/content/7/1/6 Figure2HighlightsoftheevidencesinSLIT,from2009to2013,thescientificbasisfortheupdatingof“SublingualImmunotherapy: WorldAllergyOrganizationPositionPaper2009”. Theoropharyngealmucosaasatolerogenicorgan targeting the vestibule withallergen vaccinewithorwith- The oral cavity is a naturally tolerogenic environment, out adjuvant has the potential to induce enhanced im- remaining noninflamed despite being exposed continu- mune deviation or tolerance, possibly with a lower ously to multiple foreign proteins. The presence of Lang- potential for mast cell–related local side effects, although erhans cells and monocytes capable of producing IL-10 thisremainstobetested. and TGF-β are major contributors to the maintenance of Palomares et al. [13] recently highlighted that the ton- tolerance(seeChapter3ofthe2009WAOpositionpaper sils and surrounding lymphoid tissue are located in the [9]). A recent study [10] has shown that Tcells isolated gateway of both the alimentary and respiratory tracts from the human buccal mucosa, in contrast to those iso- and may be important for local induction of tolerance to lated from skin, express TGF-β1, IL-10, interferon-γ and both food and inhalant allergens. Abundant FOXP3+ IL-17, particularly in the vestibular region, and markedly Treg cells were detected in lingual and palatine tonsils. express toll-like receptor (TLR) 2 and TLR4. Another Tonsil-derived plasmacytoid dendritic cells (DCs) were studyfromthesamegroup[11]confirmedthatoralLang- shown to have the ability to generate functional CD4+ erhanscellswithinfreshhumanoralmucosalbiopsiesare CD25+ CD127– FOXP3+ Treg cells. Triggering of tonsil- capable of rapidly takingupPhlp 5 (within 5 minutes)in derived Tcells withTLR4 or TLR8 agonists or the pro- a dose-dependent fashion, resulting in their attenuated inflammatory cytokines IL-1β or IL-6 was able to break maturation and enhanced production of inhibitory cyto- allergen-specific T-cell tolerance through a mechanism kines (IL-10 andTGF-β).Takentogether withthe paucity dependent on the adaptor molecule myeloid differenti- of mast cells in the oral vestibule compared to the sub- ation primary response gene 88 (MyD88) [14]. In par- lingual region [12], these data raise the possibility that ticular, myeloid DCs and stimuli that activate them Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 Page5of52 http://www.waojournal.org/content/7/1/6 broke the tolerance of allergen-specific CD4+ T cells, mediators, antibodies, and cytokines correlate with the whereas plasmacytoid DCs and stimuli that activate clinicalresponsetoimmunotherapyremainstobetested. them, such as TLR7 and TLR9 agonists, did not have anyeffect.Thesehumanexvivodataraisethepossibility Effectorcellsintheperiphery that immunotherapy strategies that target tonsillar tis- Basophil activation can be measured ex vivo by short- suemayenhancetheinductionoftolerance,butthis re- term (1 h) allergen stimulation of freshly harvested mains to be tested in the context of different strategies whole blood. Techniques include measurement of baso- oforalimmunotherapy. phil histamine release and expression of surface activa- In a double-blind 18-month controlled trial of high- tion markers, including CD63 and CD203b. Inhibition of dose grass pollen SLIT (20 mcg Phl p 5 daily), biopsies basophil activation has been shown following SLIT with of the sublingual mucosa demonstrated more CD3+ a combined grass and mite extract [20]; however, an- FOXP3+ and CD25+ FOXP3+ Tcells in SLIT-treated pa- other study of grass pollen SLIT [21] found no changes tients than in placebo-treated patients, and some CD3+ inbasophil activationandnocorrelation withclinicalre- FOXP3+ cells were shown with triple immunofluores- sponsetotreatment. cence to express IL-10, a direct illustration of the induc- tion of local phenotypic Treg cells following successful Tcellsanddendriticcells treatment[15]. Studies of peripheral blood T cell phenotype, prolifera- tion, and cytokine production following SLIT have given Specificantibodylevels variable results. This is in part due to the different aller- Studies of sublingual grasspollen immunotherapy in gen- gens, doses, and protocols employed for immunotherapy eralshow anincreaseinserum allergen-specific IgG4and and the varying methods of Tcell purification, process- IgG,althoughtheincreaseisnotasgreatasthatseenwith ing, and storage, that are difficult to standardize in SCIT[16,17].Transientearlyincreasesinallergen-specific multicenter studies. Evaluation of T cell phenotype and IgE have also been observed and are associated with function overall favor the induction of Tregs and/or im- blunting of seasonal increases in IgE [4]. However, some mune deviation in favor of Th1 cells. Thus, birch pollen SLITstudies have not shown increases in IgG levels, par- SLIT in one study resulted in the induction of CD25+ ticularly following house dust mite immunotherapy [18]. FOXP3+ Tcells at 4 weeks [22]. CD25+ Tregs suppressed – In a study of high-dose grass pollen SLIT, increases in antigen-stimulated CD25 T cell proliferation. This sup- grass pollen–specific IgA2 as well as IgG and IgG4 pression was reversible at 4 weeks but not at 12 months occurred in parallel with local increases in sublingual by the addition of an anti-IL-10 antibody to the culture FOXP3+Tregs[15].Theseincreaseswereaccompaniedby medium. In a study of house dust mite SLIT, suppression increases in serum inhibitory activity for binding of of antigen-stimulated purified CD4+ T cell proliferation allergen-IgE complexes to B cells (IgE-FAB), a validated was reversible at 6 but not 12 months by treatment with surrogateofIgE-facilitatedantigenpresentationtoTcells. soluble TGF-β receptor [18]. These data support that Furthermore, the long-term clinical benefit observed for Tregs are induced early, followed by delayed immune de- 2yearsfollowinga3-yearcourseofgrasspollenSLITwas viation in favor of Th1 responses at 12 months. Several associated with persistent elevations in serum levels of otherrecentstudiessupporttheseobservations[23-27]. both allergen-specific IgG4 [3,4] and functional IgG- In a double-blind study [20] of daily SLIT with the associated inhibitory activity for IgE-FAB when compared combination of house dust mite and timothy grass pollen tothelevelsinplacebo-treatedpatients[4]. indual-sensitizedadults(n=30),clinicalimprovementand decreased nasal allergen sensitivity were accompanied by Effectorcellsinthetargetorgan an increase in allergen-stimulated CD4+ CD25+ CD127low Eosinophils and inflammatory mediators are elevated in CD45RO+ Foxp3+ Tcells with reduced DNA methylation nasal lavage fluid and nasal biopsies after nasal allergen atCpGsites[20],implyingthattolerancemightresultfrom challengeandduringseasonalpollenexposure[Chapter3 epigeneticmodificationofmemoryTregcellsattheFoxp3 ofref. 9]. Recent attempts have beenmade to standardize locus. In contrast, a double-blind placebo-controlled study the collection of cytokines, mediators, and antibodies in of4monthsofgrasspollenSLIT(n=89)thatexaminedT fluid collected on filters and sponges applied directly to cell phenotype and antigen-specific T cells [28] found the nasal mucosa after nasal challenge [19]. For example, that clinical improvement was accompanied by only tryptase levels peak at 5 minutes, consistent with early minor changes in the proportions of CD4+ T cells mast cell activation, whereas increases in eosinophil cat- expressing markers for Th1 (CCR5+, CXCR3+), Th2 ionic protein (ECP), a marker of eosinophils and Th2 cy- (CRTh2+,CCR4+),orTreg(CD25+,CD127–,Foxp3+).A tokines(IL-4,IL-5,andIL-13),peakat3to8hoursduring modest downregulation of IL-4 and IL-10 gene expres- the late nasal response. Whether alterations in these local sion and IL-10 secretion (P<0.001) and a decrease in Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 Page6of52 http://www.waojournal.org/content/7/1/6 the frequency of potential “pro-allergic” CD27– Th2 to Phl p 5 and Phl p 1 for grass allergy, rather than only cells did not correlate with clinical benefit. Class II- cross-reactiveIgEtopanallergenssuchasPhlp4or Phlp tetramer analyses of antigen-specific T cells failed to 12 [35]. When there is discordance between the history showanymajorimpactoneithernumbersorpolarization and IgE testing, local provocation to the relevant target ofcirculating CD4+ Tcellsspecific for Phl p 1 or Phl p 5. organ (eye, nose, bronchi) could be helpful, as might the Further and more prolonged studies are required to con- presence oflocal IgEinnasal,lacrimal, or bronchoalveolar firm or exclude whether tetramer tracking of T cells is lavage fluid, although whether provocation testing or local valuableasabiomarkerofearlyonsetofSLITefficacy. IgE is predictive of response to immunotherapy has not Tetramer studies of antigen-specific cells are limited by beentested. class II restriction and the need to identify relevant Tcell Based on knowledge of the mechanisms of SLIT, it is epitopes. For this reason, Wambre and colleagues have attractive to consider that alterations in peripheral Tcell usedTcellsurface/intracellularmarkerexpressionwithor ordendriticcellsignatures[31]wouldbeusefulformoni- without associated tetramer staining to characterize sub- toring responses, although the complexity of processing jectsallergictograsspollenandmites,withtheaimofdis- and performing these assays makes them unlikely candi- tinguishing antigen-specific Tcells from bystander Tcell datesforroutineclinicaluse.Basophilactivationtestingis responses [29]. These and other studies [30] have identi- of potential value, although conflicting results have been fied CD154 (CD40 ligand) as a potentially useful T cell obtainedwithSLIT[20,21].Basophiltestingrequiresfresh markerforfutureimmunotherapystudies. processingof whole blood and access to a flow cytometer Human effector and regulatory dendritic cells are within hours. Collection of nasal fluid on sponges or ab- important in directing T cell differentiation, phenotype, sorbent filters with measurement of mediators and cyto- and function. Following a detailed evaluation in vitro of kineshasbeenvalidatedinresponsetonasalprovocation, human effector and regulatory dendritic cells from hu- but not in the context of immunotherapy trials [19], al- man monocytes cultured under deforming conditions, thoughstudiesareinprogress. candidate dendritic cell markers were evaluated at the Serum-based assays are feasible in the context of clin- messenger RNA and protein levels before and after grass ical trials and are largely restricted to measurements of pollen allergen tablet SLIT [31]. Complement compo- antibodies (specific IgE, IgG, IgG4, and IgA) and func- nent 1 (C1Q) and Stabilin-1 (STAB1) were increased in tionalantibodyassays,suchasdetectionofseruminhibi- PBMCs from clinical responders in contrast to that seen tory activity for antigen-stimulated basophil activation in nonresponders or placebo-treated patients. Further tests [36] and inhibitory activity for binding of IgE- evaluation of C1Q and STAB1 expression as candidate allergen complexes to B cells [37]. The latter has been biomarkers during large trials of sublingual allergen im- shown to persist for at least 2 to 3 years following sub- munotherapy arejustified. lingual immunotherapy [3] and to correlate modestly but more convincingly with clinical response than meas- Biomarkersofclinicalresponsetoimmunotherapy urement of serum immunoreactive IgG antibodies alone A useful biomarker is one that is either predictive of or [38]. At the present time, apart from the use of serum a surrogate for the clinical response to immunotherapy. allergen-specific IgE for patient selection [39], there are A predictive biomarker might aid in selecting patients no biomarkers that can be reliably recommended for who will respond (or in excluding potential nonre- selection of individual patients in routine practice for sponders), whereas a surrogate biomarker might be ef- immunotherapy, nor for monitoring the response to fective in monitoring the clinical response to treatment. treatment. However, rapid advances in the molecular Ideally, the biomarker should be practical, easy to meas- diagnosis of individual allergen IgE sensitivities com- ure, technically robust, generalizable, and have good bined with better information on the constituents of the sensitivity and specificity. Skin prick testing and raised allergenextractsavailablefortherapyprovideanexciting serum allergen-specific IgE are essential predictive bio- opportunity to relate this new knowledge to prediction markers that clearly augment information obtained from ofresponse toimmunotherapy[34]. the history alone. Nonetheless, these tests produce both false positive and false negative results. One study sug- Chapter 4. Clinical efficacy of sublingual gested thatthe ratio of specific IgE to total IgE might re- immunotherapy late to the response to immunotherapy [32], whereas an earlier study suggested that the ratio of allergen-specific ▪AsofJune2013,therewere77 randomized, IgG4 to IgG1 may be more informative [33]. These hy- double–blind, placebo-controlled (RDBPC)trialsof pothesesdeservefurtherevaluation.Theadventofmolecu- SLIT,ofwhich62 were conducted with grassor lar diagnosis may enhance predictive value by identifying house dustmite(HDM)extracts.Themajority of IgEsensitivitytorelevantmajorallergens[34],forexample thesestudieswereheterogeneous forallergendose, Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 Page7of52 http://www.waojournal.org/content/7/1/6 duration,and patient selection.Allstatementson Overall, there have now been 77 RDBPC trials investi- efficacyofSLIT dorefertoproductswhich have gating SLIT (Figure 3): 39 with grasses, 23 with mite, 5 demonstrated efficacyinappropriatestudies. with Parietaria, and 10 with other allergens (ragweed, ▪Seventeentrials,ofwhichonewastotallynegative, cypress,cat,olive,birch,cedar).Ofthe77trials,5wereto- werepublishedafterthepreviousWAOpositionpaper. tally negative. Nonetheless, several trials consistently re- ▪Theliterature suggeststhat,overall,SLITis clinically portedefficacytobedosedependent(forreviewsee[56]), effective inrhinoconjunctivitisand asthma,although reinforcingtherobustnessoftheresultssofarreportedin differences existamongallergens. clinicaltrials. ▪Theavailablemeta-analyses areinfavorofSLIT (rhinitisand conjunctivitisinadults;asthmaand rhin- Meta-analyses itis inchildren), although the conclusionsarelimited After the previous WAO position paper [9], 4 new bytheheterogeneity ofthestudiesintermofdoses, meta-analyses of SLITfor respiratory allergy were pub- duration,and patient selection. lished [2,57-59]. So far, the most comprehensive meta- ▪Clinicalefficacyand dosedependency havebeen analysis of SLIT in allergic rhinitis is that by Radulovic demonstrated forrhinoconjuntivitis duetograss etal.[58],whichincluded22trialsandatotalof979pa- pollen inadequately powered,well-designedRDBPCs. tients. The overall results favored SLIT over placebo for ▪Someopen,controlled trialssuggested thatthe rhinitis symptoms and medication scores. For symptoms, clinicalefficacy ofSLITissimilartothat ofinjection the standardized mean difference (SMD) was –0.42 (95% immunotherapy. CI –0.69 to –0.15, P=0.002). For medications, the SMD ▪Dose-finding trialsand largestudieswith properly was–0.43(95%CI–0.63to–0.23,P=0.00003).However, definedoutcomesand samplesizes areneeded forthe great heterogeneity remained (I2 between 40% and 95%, other relevantindividual allergens. depending on the outcome analyzed) due to the largely differentinclusioncriteria,outcomes,doses,anddurations Double-blind,randomized,placebo-controlledtrials amongthe trials.In addition,thisanalysis did not include ThepreviousWorldAllergyOrganization(WAO)Position themostrecentlargetrials.However,theincreasingnum- Paper[9]included60RDBPCstrialsconductedwithSLIT. ber of available studies has enabled more detailed meta- From then through June 2013, 17 new RDBPC trials were analyses, for instance according to the allergen or the published in English [40-55] (Table 1), 8 with grass ex- disease. One meta-analysis was limited to mite [59]. An- tracts,5withHDM,1withAlternaria,and3withragweed. other that considered only grass allergens [57] clearly Six studies were conducted in children [40,47-49,53,54], showed the superiority of SLIT over placebo for both and 1 in elderly patients [50]. The number of patients symptomsandmedications.Finally,anothermeta-analysis enrolled ranged from about 30 to more than 700, and the limitedtoconjunctivitissymptoms[2]confirmedasignifi- durationvariedfrom 4monthsto 3 years.Fivestudies en- cant difference in favor of SLIT, with an SMD of 0.41 rolled more than 400 patients [40,44,51,52]. Dropouts and (95% CI 0.28 to 0.53) and moderate heterogeneity (I2: patientdispositionswerereportedinalltrials,and11trials 59%). The new meta-analyses substantially confirmed the [40,42,44,46,50-55] declared a formal sample size calcula- previous results, showing an overall efficacy of SLIT for tion. All of the trials but one [53] demonstrated a signifi- different outcomes. However, the great heterogeneity of canteffectofSLIT,independentoftheallergenconsidered. theresults(duetotheinherentheterogeneityoftrials)still Therelativechangeversusplacebo,whenreported,ranged limitsthereliabilityoftheresults[60,61]. between20%andmorethan35%. Of note, the only totally negative trial published after ComparisonoftheefficacyofSLITandSCIT the previous WAO Position Paper [53] was conducted The problem of comparing the efficacy of subcutaneous in more than 200 children recruited in a primary care immunotherapy (SCIT) and SLIT is still open. The com- setting. In this case, the authors hypothesized that the parison is technically difficult, because head-to-head amount of allergen given was too low to produce a clin- comparisons need a double-blind, double-dummy design, icalbenefit. with a careful choice of outcomes and dosages. Surpris- Of the mentioned trials, one was performed using the ingly, given the technical difficulty, 3 comparative studies Vienna challenge chamber [43] and demonstrated that [24,27,62] were carried out after the 2009 WAO position the effect of SLIT begins quite early (at 4 months). This paper [9], as summarized in Table 2. The study by Eifan relatively early onset of the effect was confirmed in an- et al. [27] was randomized, open, and controlled and in- other trial with natural allergen exposure [55]. One of volved 48 children monosensitized to mite. They received the trials [45] investigated only immunological parame- SCIT, SLIT, or pharmacotherapy alone for 1 year. The 2 ters and showed a significant effect in the active group routesofimmunotherapydidnotdifferintermsofclinical but notintheplacebo group relative tobaseline. efficacy,andbothweresuperiortopharmacotherapy.The hC Table1Randomized,double-blind,placebo-controlledtrialsofSLITperformedsince2009 ttpan Author,year Ages(y) A/P Dropouts Allergen Duration Doseand Disease Manu- Mainpositiveresults Negativeresults ://wonic [reference] (A/P) administration facturer wa we Horak,2009[43] 18-50 45/44 3/4 Grass 4mo 20mcg RC STA SignificantreductioninRCscore Nasalairflow .wta PTahbllpet5s/day i4pnlamVcioeebninonaS(tLchIhTeavrlelsednbugacesteioclihnnaevmsabnedrvast WBaesiogphhtiloafcsteivcaretitoionns aojournl.World pInlcarceeabsoedwIagsE2a9n%d)IgG4 al.org/cAllergy oO Skoner,2010[46] 18-50 334960mhpilgaechd 453 Ragweed 6mo 4AM.m8etboerrae4d18/pmduacmygp RC GRE Cdroumgbsicnoerdesvyemrsputsopmlasc+edbrougsand NSdyuamrsianplgtcohpmaelalsekcnosgereea,sIognE ntent/7/1/6rganization Cortellini,2010[42] 16-44 15/12 0/1 Alternaria 10mo 60mcgAlta1cumul. RCA ANA Significantreductionin SpecifcicIgEandIgG4 Jo u 6mcg/mo combinedscore(−38%versus rn a placebo). l 2 0 Drops Significantreductioninskin 14 reactivity ,7 :6 Panizo,2010[45] 18-65 52/26 2/1 Grass 5mo 25mcgPhlp5/day RC ALK IncreaseinIgE,IgG4,andIgE Tablets blockingactivityonlyinactive Yonekura,2010[48] 7-15 20/11 1/2 Mite 1y 0.5mcgDerf1once RC TOR Significantdecreaseinsymptoms Medicationscore aweek andcombinedscoreinwk0–3 and37–40onlyinSLIT Blaiss,2011[40] 5-17 349/358 33/30 Grass 6mo 450gPhlp5/mo RC STA Significantreductionin Asthmasymptoms combinedscore(−26%)versus placebo.QualityofLife38% improvementvsplacebo Nelson,2011[44] 18-63 213/225 33/33 Grass 10mo 450mcgPhlp5/mo RCA STA Significantreductionin Dailymedicationscore Tablets combinedscore(−20%and medicationscore(−20%)versus placebo Bush,2011[41] 18-50 High10 2 Mite 18mo 70or1mcg RA GRE Significantreductioninspecific Symptomsandmedication bronchialreactivity scores Low10 3 (Derf) Derf1perdose. Pla11 5 Drops IncreaseinIgG4 Stelmach,2012[47] 6-18 Cont20 3 Grass 2y Cumulative7.3and RCA ALK Significantimprovementin Symptomscore 3.6mcgPhlp5. drugs+symptomswithboth Prec20 1 Medicationscore Drops continuousandprecoseasonal Pla20 2 regimen.ReductioninFeNO Pulmonaryfunction deBot,2012[53] 6-18 126/125 15/17 Mite 2y 4.06mcg RC ART Symptomscore Derp1/week QoL P a Drops Medicationscore ge 8 Welldays o f 5 2 Table1Randomized,double-blind,placebo-controlledtrialsofSLITperformedsince2009(Continued) hC ttpan A20h1m2a[d4i9a]sfshar 5-18 12/12 2/2 Grass 6mo C6,u0m00uIlRatiSvper:aaybout RC STA Ssyigmnpifticoamntainmdpmroevdemicaetniotninscores ://wwonica we Reductionofskinwhealdiameter .wta Wahn,2012[54] 4-12 158/49 26/2 Grass 8mo Cmugmgurloautipve5:7.2–8.4 RC ALL Spilgacneifbicoanintrceodmucbtiinoendvseyrmsupstom/ aojournl.World Cox,2012[51] 18-65 233/240 26/17 Grass 6mo CDurompuslative:approx RC STA Smigendiifcicaatinotnreadnudcitniodniviodfualscores Itchynosesymptomscore al.org/cAllergy T3ala.6lebrmlgetegsng.roup5 cmpooflaemlcdifeebicbianote)iodannsdyscmoopvreteor(am−ll2+q8%ualviteyrsus versusplacebo ontent/7/1/6Organization Bozek,2013[50] 60-75 51/57 7/9 Mite 3y NS RC STA Totalnasalscoresdecreasedby Symptomsafterspecificnasal Jo 44%frombaselineinSLITandby provocationversusplacebo u 6%inplacebo. rna l 2 Medicationscoredecreased35% 0 1 frombaselineinSLITgroup. 4, 7 Wang,2013[55] 4-65 60/60 12/23 Mite 6mo NS RC ZHE Significantdecreaseineach Nochangeversusplaceboin :6 individualrhinitissymptom medicationintake versusplacebostartingfrom week14. Nolte,2013[18] 18-50 High187 142 Ragweed 1y 6or12mcg RCA MSD Significantdecreaseincombined symptom+medicationscorefor Low190 overall Amba1daily bothactivegroupsVSplacebo Pla188 Tablets (21%and27%) Creticos,2013[52] 18-50 Low197 40 Ragweed 1y Cumulativedose RCA MSD Onlythehighdosedecreased Lowdoseoveralllesseffective dailysymptom,medication,and thanthe2otherdoseson Med195 43 4.38mgAmba1 combinedscoresduringpeak symptoms/medicationsinpeak High194 57 Tablets pollenseasonandwholeseason pollenandwholeseason versusplacebo. Pla198 38 Abbreviations:A/Pactive/placebo,NSnotstated,RCrhinoconjunctivitis,RCArhinoconjuntivitis/asthma,STAStallergenes,GREGreer,ANAAnallergo,ALLAllergopharma,ALKALK-Abellò,MSDMerckSharpandDome, TORToriiPharmaceuticals,ZHEZhengWolwoBioPharma. P a g e 9 o f 5 2 Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 Page10of52 http://www.waojournal.org/content/7/1/6 WAO position paper [9]. These studies, despite their methodological limitations, provided some interesting insights into the efficacy of SLIT. One study compared coseasonal and continuous regimens in children suffer- ing from grass allergy [63]. In this study, the continuous (all year long) regimen started in the preseason. The main results were that in the first pollen season the con- tinuous regimen performed better on symptoms, but starting from the second season, the 2 regimens became more and more similar, so that at the third season no difference could be detected. Another study was con- Figure3Numberofdouble-blind,placebo-controlledtrials ducted in a randomized single-blind fashion for 3 years investigatingSLITuptoJune2013. with an Alternaria extract [64]. There was a progressive reductioninsymptoms,asmeasuredwithavisualanalog scale, which became significant after the first year in the second study [24] was a double-blind, double-dummy, 4- active group. Only few mild adverse events were re- parallel-group trial to assess the efficacy and feasibility of ported. Another open randomized trial in adults (33 SCIT induction followed by SLIT maintenance. The 2 patients) showed that a preseasonal regimen was equiva- single routes were also compared. The combined regi- lent in efficacy, as measured by visual analog scale, to men did better than the 2 taken separately, with a slight the continuous administration [65]. These results are advantage for SCITalone over SLITalone on some out- further reinforced by those of a previous RDBPC trial comes. The third study [62] was again a double-dummy comparing precoseasonal and continuous regimens in study versus placebo in which both treatments achieved children [47]. A study in the United States [66] com- a significant clinical improvement versus baseline, with pared the efficacy of HDM SLIT in 134 monosensitized SCIT doing on average better than SLIT in the direct or polysensitized patients. After 1 year, symptoms and comparison. drug scores decreased significantly in both groups, but no difference between groups was detected. The same Non-RDBPCtrials was observed in another trial comparing the quality of Additional open, randomized, controlled clinical trials life in patients receiving SLIT who were either mono- or were performed after the publication of the previous polysensitized, wherenodifferencebetweenthe2groups Table2DirectcomparisonsofSLITandSCITforefficacy Author,yeardesign Ages(y) Treat-ment Dropouts Allergen Duration Cumulativedoses Disease Mainresults Eifan,2010[27] 5–12 16SCIT 2 Mite 1y SCIT111mgDer RA Significantreductionof p1/156mgDerf1 totalrhinitisandasthma Randomized, 16SLIT 1 score,medicationscore, open,controlled 16CON 2 SLIT295.5mgDer VAS,andskinreactivity p1/f1 P<0.05versus pharmacotherapyfor bothSCITandSLIT.No differencebetween routesofadministration. Keles,2011[24] 5–12 15SCIT 2 Mite 18mo Derp1:53mcgSLIT A Decreasedasthmaattacks and42mcgSCIT anduseofsteroidsat4, Doubleblind,double 15SLIT 2 12,18moforSCITand dummy,controlled 15SLIT 1 SCIT+SLIT,at12moonly forSLIT.Nochangein +SCIT VASforasthmawithSCIT 15CON 3 orSITalone. Yukselen,2012[62] 7–14 10SCIT 1 Mite 1y 173,733TU(86,866.5 RA Significantreductionin TUDpt.and86,866.5 symptomandmedication Doubleblind,double 10SLIT 1 TUDf). scoreversusbaselinewith dummy,placebo 10PLA 0 bothtreatments.SCIT controlled betterthanSLITversus placebo. Abbreviations:CONcontrol,PLAplacebo,SCITsubcutaneousimmunotherapy,SLITsublingualimmunotheapy,RARhinitiswithasthma,Aasthma,VASvisual analogscale.