Sublingual immunotherapy - World Allergy Organization Journal

52 Pages·2014·2.3 MB·English

Canonicaetal.WorldAllergyOrganizationJournal2014,7:6 journal
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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.
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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.
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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].
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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
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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
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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,
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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.