Economic evaluation of sublingual vs subcutaneous allergen immunotherapy Jitka Pokladnikova, MSc, Pharm*; Irena Krcmova, MD ; and Jiri Vlcek, PhD*

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1 Economic evlution of sublingul vs subcutneous llergen immunotherpy Jitk Pokldnikov, MSc, Phrm*; Iren Krcmov, MD ; nd Jiri Vlcek, PhD* Bckground: Sublingul llergen immunotherpy (SLIT) is commonly used lterntive route of dministrtion to stndrd subcutneous immunotherpy (SCIT) in Europe. Despite its wide use, the cost-effectiveness of SLIT vs SCIT hs not been well estblished. Objective: To evlute the cost nd effectiveness of SLIT compred with SCIT in ptients with llergic rhinoconjunctivitis during 3-yer specific llergen immunotherpy (SIT) from third-prty pyer s, ptient s, nd society s perspectives. Methods: We performed n open-lbel rndomized clinicl tril of ptients receiving SLIT (n 19), ptients receiving SCIT (n 23), nd control group (n 22). The outcome mesures were Rhinoconjunctivitis Qulity of Life Questionnire score, visul nlog scle score, symptomtic mediction reduction, nd direct nd indirect costs. Results: SLIT offered clinicl benefits to ptients comprble to those provided by SCIT. From the perspective of third-prty pyer, the totl verge direct medicl cost per ptient of 3-yer SIT ws estimted t 416 vs 482 in the SLIT nd SCIT groups, respectively. A ptient who received SLIT pid less thn ptient who received SCIT for ll out-of-pocket costs ( 176 for SLIT vs 255 for SCIT) but more for sole llergen extrcts ( 72 for SLIT vs 55 for SCIT). When both direct nd indirect costs were considered, the 3-yer SIT expenditures per ptient reched 684 vs 1,004 in the SLIT nd SCIT groups, respectively. Conclusions: SLIT represents less expensive lterntive reltive to subcutneous dministrtion from ll perspectives. However, from ptient s perspective, SCIT offers less expensive lterntive for ptients who do not experience loss of income nd trvel costs ssocited with tretment. Ann Allergy Asthm Immunol. 2008;100: INTRODUCTION Allergic rhinitis is chronic condition with high prevlence in most highly developed countries. 1 The overll costs ssocited with llergic rhinitis nd certin dverse effects of phrmcologic tretment, such s discomfort, somnolence, nd cognitive impirment (impired lerning, memory, nd performnce), re substntil nd crete significnt economic burden to the society. 2 From both n economic nd ptient well-being perspective, llergen immunotherpy offers rel lterntive becuse of its bility to reduce symptom-mediction scores in the long term nd improve the qulity of life. 3 Tody, specific llergen immunotherpy (SIT) is the only tretment tht ddresses the cuse of IgE-medited immunopthology nd modultes the nturl course of the disese. 4 Furthermore, SIT hs been shown to prevent further progress of the disese nd the onset of new sensitiztions nd sthm long fter it ws discontinued. 5 7 Subcutneous llergen immunotherpy (SCIT) is Affilitions: * Deprtment of Socil nd Clinicl Phrmcy, Fculty of Phrmcy, Chrles University in Prgue, Hrdec Krlove, Czech Republic; Deprtment of Allergology nd Clinicl Immunology, University Hospitl nd Fculty of Medicine, Chrles University in Prgue, Hrdec Krlove, Czech Republic. Disclosures: Authors hve nothing to disclose. Finncil Support: The study received public funding in the form of 3-yer grnt from the Ministry of Helth of the Czech Republic (MZ CR NI/7470 3). Received for publiction My 21, 2007; Received in revised form October 23, 2007; Accepted for publiction October 23, well-estblished stndrd of cre in ptients with llergic rhinitis, rhinoconjunctivitis, topic sthm, nd Hymenopter nphylxis for whom symptomtic tretment nd llergen voidnce re not sufficient wy to control the disese. 4 Sublingul llergen immunotherpy (SLIT) is n lterntive dministrtion route recently proven to be effective nd sfe, with less serious systemic dverse effects thn SCIT. 8 The cost-svings potentil of SCIT nd SLIT compred with stndrd phrmcologic therpy hs only been described in few studies Our comprtive study is, to the best of our knowledge, the first economic evlution tht directly compres SLIT to SCIT. The purpose of this study ws to evlute the effectiveness nd costs of SCIT nd SLIT in ptients with sesonl llergic rhinoconjunctivitis (SARC) fter 3 yers of SIT dministrtion from 3 perspectives: third-prty pyer, ptient, nd society. METHODS The design ws n open-lbel rndomized clinicl tril (Jnury 1, 2002, to Jnury 1, 2006). Sixty-four ptients were rndomly ssigned to 3 study groups: SLIT, SCIT, nd control. The SCIT ptients were treted with stndrdized grss pollen extrct (Phostl; Stllergènes SA, Antony, Frnce) dministered t clinic. Stndrdized grss pollen extrcts (Stlorl; Stllergènes SA) for SLIT ptients were self-dministered t home. Ptients were treted continuously from Jnury 2003 ccording to the mnufcturer s instructions. All ptients, including the control group, followed stndrd symptomtic tretment ccording to World Helth Orgniz- 482 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

2 tion nd Allergic Rhinitis nd Its Impct on Asthm (ARIA) guidelines. 1 The study ws conducted ccording to the guidelines of good clinicl prctice nd ws pproved by n independent ethics committee. Informed written consent ws obtined from ll ptients. Ptients All ptients were 18 yers or older, hd history of SARC for t lest 2 yers uncontrolled by symptomtic tretment, nd hd moderte persistent rhinitis (ccording to the clssifiction of sesonl llergic rhinitis severity bsed on ARIA recommendtions, 2001). 1 The dignosis of the SARC ws bsed on medicl history nd clinicl symptoms nd ws verified by positive skin prick test results nd the presence of grss pollen specific IgE. Ptients with concomitnt dignosis of intermittent or mild persistent sesonl grss pollen induced sthm were llowed to prticipte. Exclusion criteri were concomitnt perennil llergic rhinitis nd stndrd contrindiction for immunotherpy. 4 Effectiveness The Rhinoconjunctivitis Qulity of Life Questionnire (RQLQ) ws used to mesure helth outcomes in our study. 14 We compred the proportion of cliniclly improved ptients in the third yer compred with the first yer of SIT. A chnge in the score of greter thn 0.5 point for ech of the domins nd overll scores is interpreted s the miniml importnt difference tht is considered cliniclly significnt. 15 This evlution ws supplemented by visul nlog scle, 100-mm scle with 0 mm indicting no impirment nd 100 mm indicting mximl impirment, which ws used to estimte the helth improvements both before nd during SIT. Ech yer ptients were sked to evlute severity of rhinoconjunctivitis symptoms during the high pek pollen seson before nd fter SIT tretment. Decrese in the consumption of symptomtic mediction relted to SARC ws expressed s men defined dily dose (DDD) per ntomicl therpeutic clss (ATC) using the ATC/DDD methodology. 16 Cost Evlution Direct medicl costs included costs of mediction nd helth cre services. Costs rising from dverse effects of tretment (mediction, emergency deprtment visit, hospitliztion) were lso considered. Helth cre service costs included specilist visits (consulttions, lbortory tests, dignostic tests, nurse services), emergency deprtment visits, nd hospitliztions. The economic nlysis excluded services tht were provided strictly for the purposes of the study. Ptients costs covered mediction copyment, over-the-counter drugs, trvel costs, loss of income due to llergy symptoms, nd tretment. From society s perspective, costs lso included productivity loss s n indirect cost. Costs tht resulted from productivity reduction s consequence of llergy symptoms, such s ftigue nd concentrtion loss, were neglected. Fixed costs included the costs for mediction nd helth cre services. The cost of helth cre services ws clculted by multiplying the number of units per service nd the unit price. The cost of mediction ws clculted from the number of DDDs nd cost per DDD. 16 Ptient trvel costs were computed by multiplying the number of specilist visits nd trvel costs per specilist visit. A humn cpitl pproch ws used to clculte indirect cost (productivity loss). 17,18 Direct nd indirect costs were discounted t rte of 3% per yer. The unit costs re given in Tble 1. Resource Use Dt such s mediction use, physicin time, nd helth cre service costs (specilist visits, emergency deprtment visits, nd hospitliztions), demogrphics, nd comorbid conditions were retrieved from the centrl dtbse of ptient mediction records mnged by the Deprtment of Economy t the University Hospitl. The number of units for helth cre services nd the cost per unit were set by the Czech Republic s Helth Cre Directive of The reimbursement costs of drugs were retrieved from the Czech Ntionl Drug Price List of There is no centrl informtion source on retil sle prices of drugs in the Czech Republic. Prices of prescribed mediction nd over-the-counter drugs were represented by n verge price clculted from the ctul 2002 retil prices obtined from smple of retil nd hospitl phrmcies in the study loction. The following dt were collected by using ptient questionnire: over-thecounter mediction use, hospitliztions nd emergency deprtment visits, sick leves, work nd school bsenteeism, nd time ssocited with specilist visits. Trvel costs were bsed on the distnce between the ptient s plce of residency nd the llergist office nd price estimte of 0.01 per kilometer. 21 The monetry vlue of productivity loss ws expressed in terms of lost workdys per employee. Ech workdy loss ws vlued t 2002 gross slry verge for employees in the Czech Republic nd divided by the number of working dys Tble 1. Unit Cost Unit Cost, Mediction b Allergen extrcts (sublingul dministrtion), pckge (reimbursement/copyment) Initition phse 41.57/9.42 Mintennce phse 41.25/10.12 Allergen extrcts (subcutneous dministrtion), pckge (reimbursement/copyment) Initition phse 40.04/11.30 Mintennce phse 33.88/9.08 Helth cre service, unit 0.03 Productivity or income loss, working dy Trvels, km Euro Czech korun. b Prescription nd over-the-counter drugs were reimbursed bsed on the Czech Ntionl Drug Price List of 2002 nd priced t the verge price clculted from ctul retil prices obtined from smple of retil nd hospitl phrmcies in the study loction in VOLUME 100, MAY,

3 per yer, published in the 2002 Sttisticl Yerbook by the Czech Sttisticl Office of the Czech Republic. 22 Costs were expressed in Euros using the purchsing power prity vlue in the Czech Republic in Sttisticl Anlysis Ctegoricl dt mong the groups were nlyzed using the 2 test or Fisher exct test (2-tiled). Kruskl-Wllis, Wilcoxon tests, nlysis of vrince, nd pired t test were used for continuous vribles, depending on norml distribution. P.05 ws considered sttisticlly significnt. Costs were nlyzed using nonprmetric bootstrp-t method (1,000 itertions). This technique is recommended for mking inferences bout rithmetic mens for modertely sized smples of highly skewed dt such s cost. 24 The ptients nnul drug consumption nd reduction of mediction were expressed s the men DDD using the ATC/DDD methodology or the men number of pckges in the cse of llergen extrcts. 16 Helth cre service costs nd resources were expressed s the verge cost or use per ptient per yer or totl cost or resource use per 3 yers of SIT per ptient. Sensitivity nlysis ws performed vrying costs by 50% of the bse cse key prmeters t 0% discount rte (cost of llergen extrcts nd helth cre services). All nlyses were performed using SPSS sttisticl softwre, version 12.0 (SPSS Inc, Chicgo, Illinois). RESULTS Ptients A totl number of 64 ptients were ssigned to receive llergen immunotherpy sublingully (SLIT group, n 19), llergen immunotherpy subcutneously (SCIT group, n 23), or symptomtic tretment lone (control group, n 22). Four ptients from the SLIT nd control group were withdrwn from the study within the first 3 yers becuse of inconvenience (chnge of residency). There were no sttisticlly significnt differences between groups in the bseline chrcteristics. The ptient chrcteristics re given in Tble 2. Effectiveness After 3 yers of SIT the number of cliniclly improved ptients s mesured by the RQLQ nd the visul nlog score did not significntly differ between the SIT groups (medin visul nlog score for the SLIT vs SCIT group: 38 mm vs 49 mm, P.07; RQLQ for the SLIT vs SCIT group: 41% vs 48%, P.75) (Tble 3). Ech yer there ws noticeble decrese in the need for symptomtic mediction of SIT in ll 3 groups except for the control group (SLIT group [R06]: 56 DDD; SCIT group [R06]: 70 DDD; control group [R06]: 6 DDD; P.002) (Tble 3). A significnt decrese in symptomtic mediction consumption ws reched s erly s the first or second yer of tretment. SCIT ptients showed slightly better improvements in ll clinicl outcomes. Helth Cre Utiliztion Averge nnul physicin office visits of SCIT ptients were substntilly higher thn those of SLIT ptients, with the highest frequency of visits in the first yer becuse of the SIT initition phse. On verge, SCIT ptients visited their llergist 6 times more frequently thn before the SIT tretment (Tble 4). No hospitliztions nd emergency deprtment visits relted to rhinitis were reported during the study. No systemic dverse effects developed within 30 minutes of the subcutneous dministrtion. Costs The overll men cost per ptient from ll the perspectives is given in Tble 5 nd Figure 1. Tble 2. Chrcteristics of Ptients Completing Specific Allergen Immunotherpy Chrcteristics SLIT group (n 17) SCIT group (n 23) Control group (n 20) Age, y Men (SD) 27.4 (6.5) 31.3 (7.6) 28.4 (8.7) Medin Femle, No. (%) 8 (47) 10 (43) 14 (70) History of sthm, No. (%) 5 (29) 8 (35) 5 (25) Positive fmily history of llergy, No. (%) 13 (77) 20 (87) 14 (70) Durtion of SARC, y Men (SD) 10.5 (4.8) 8.8 (6.6) 10.1 (8.5) Medin Smokers, No. (%) 2 (12) 3 (13) 2 (10) Visul nlogue score, medin, mm Drug consumption (ATC/DDD) Orl ntihistmines (ATC R06) Employees, No. (%) 15 (88) 22 (96) 17 (85) Employees (unpid hours), No. (%) 3 (18) 3 (13) 2 (10) Plce of residency (locl ptients), No. (%) 8 (47) 12 (52) 15 (75) Abbrevitions: ATC/DDD, ntomicl therpeutic clssifiction/defined dily dose; SARC, sesonl llergic rhinoconjunctivitis; SCIT, subcutneous llergen immunotherpy; SLIT, sublingul llergen immunotherpy. 484 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

4 Tble 3. Chnge in Clinicl Outcome From Bseline Yers to the Annul 3-Yer Specific Allergen Immunotherpy Outcome SLIT group (n 17) SCIT group (n 23) Control group (n 20) SLIT vs SCIT (95% CI), RQLQ, No. (%) Ptients improved 7 (41) 11 (48) 8 (40) 4 Ptients stbilized 8 (47) 10 (43) 8 (40) 2 Ptients impired 2 (12) 2 (9) 4 (20) 0 RQLQ totl score, men (SD) Second yer of SIT 0.41 b (0.67) 0.59 b (1.07) 0.38 b (0.58) 0.18 ( 0.38 to 0.74) Third yer of SIT 0.30 (0.73) 0.74 b (0.95) 0.30 (1.42) 0.44 ( 0.12 to 1.00) Visul nlog score, mm First yer of SIT 18 c ( 25, 8) 21 c ( 29, 11) 21 b ( 30, 0) 1 ( 10 to 8) Second yer of SIT 30 c ( 40, 18) 31 c ( 38, 25) 18 b,d ( 38, 0) 2 ( 7 to11) Third yer of SIT 38 c ( 48, 22) 49 c ( 58, 35) 20 b,e ( 34, 2) 10 ( 1 to21) Symptomtic mediction reduction (R06/DDD), men (SD) First yer of SIT 14 b (44) 11 b (78) 3 (35) 3 ( 42 to 37) Second yer of SIT 42 b (56) 49 b (66) 24 (62) 7 ( 34 to 47) Third yer of SIT 56 c (48) 70 c (78) 6 1 (59) 14 ( 30 to 57) Abbrevitions: CI, confidence intervl; DDD, defined dily dose; SCIT, subcutneous llergen immunotherpy; SIT, specific llergen immunotherpy; SLIT, sublingul llergen immunotherpy; RQLQ, Rhinoconjunctivitis Qulity of Life Questionnire. Medin (25th, 75th percentile). b P.05 (within-group comprison). c P.001 (within-group comprison). d P.05 (mong-group comprison). e P.001 (mong-group comprison). Tble 4. Men Use of Resources During 3-Yer Sublingul nd Subcutneous Allergen Immunotherpy Resource SLIT group (n 17) SCIT group (n 23) Control group (n 20) Bseline yer Mediction (ATC/DDD) Orl ntihistmines (ATC R06), DDD Outptient visits, No Productivity loss, No. of working dys Loss of income, No. of unpid working dys Three-yer SIT Mediction (ATC/DDD) Allergen immunotherpy, No. 1/6.38 1/4.96 Orl ntihistmines (ATC R06), DDD Outptient visits, No SCIT-relted visits, No Productivity loss, No. of working dys Loss of income, No. of unpid working dys Abbrevitions: ATC, ntomicl therpeutic clss; DDD, defined dily dose; SCIT, subcutneous llergen immunotherpy; SIT, specific llergen immunotherpy; SLIT, sublingul llergen immunotherpy. Number of pckges of llergen extrcts: initition/mintennce phse. Third-prty pyer perspective. The totl direct medicl costs fter 3 yers of SIT were higher in the SCIT compred with the SLIT group ( 416 for SLIT vs 482 for SCIT, P.001). Overll, SIT-relted expenses ccounted for 318 (77%) nd 398 (82%) of the totl direct costs in the SLIT nd SCIT groups, respectively. Although the cost of llergen extrcts during the 3-yer period ws 94 less in the SCIT group thn in the SLIT group ( 297 vs 204, P.001), the higher frequency in specilist visits relted to subcutneous dministrtion ccounted for higher helth cre service costs in the SCIT group by 173 ( 21 for SLIT vs 194 for SCIT, P.001). The initil cost for SIT ssignment ws the sme for both groups ( 21). In ptients treted subcutneously, most of the overll direct medicl costs were ttributble to outptient visits ( 214; 44%), llergen extrcts ( 204; 42%), nd symptomtic mediction ( 64; 13%). On the other hnd, the composition of direct medicl costs of ptients treted sublingully ws VOLUME 100, MAY,

5 Tble 5. Comprison of Men Bseline nd Overll Costs of 3-Yer Sublingul nd Subcutneous Allergen Immunotherpy Men cost per ptient (95% CI), Bootstrp-t P vlue SLIT group (n 17) SCIT group (n 23) Bseline yer Mediction Mediction reimbursement ( ) ( ).54 Mediction copyment 2.60 ( ) 1.99 ( ).4 Over-the-counter mediction 0.11 ( ) 0.18 ( ).74 Outptient visits ( ) ( ).88 Trvel costs ( ) 7.75 ( ).38 Loss of income ( ) 21.5 ( ).52 Productivity loss ( ) ( ).04 Three-yer SIT Mediction Allergen extrcts reimbursement ( ) ( ).001 Allergen extrcts copyment ( ) ( ).001 Mediction reimbursement ( ) ( ).12 Mediction copyment 3.74 ( ) 5.35 ( ).13 Over-the-counter mediction 0.23 ( ) 0.25 ( ).92 Outptient visits ( ) ( ).001 SIT-relted visits ( ) ( ).001 Trvel costs ( ) ( ).18 Loss of income b ( ) ( ).30 Productivity loss b ( ) ( ).001 Direct medicl costs ( ) ( ).001 Totl costs c ( ) ( ).001 Abbrevitions: CI, confidence intervl; SCIT, subcutneous llergen immunotherpy; SIT, specific llergen immunotherpy; SLIT, sublingul llergen immunotherpy. The CI ws computed with bootstrp-t procedure; costs re expressed in 2002 euro nd re discounted t 3% per yer. b Averge loss of income or productivity loss bsed on number of employed persons. c Direct (mediction, helth cre service, nd trvel costs) nd indirect costs (productivity loss). Figure 1. Men cost of 3-yer specific llergen immunotherpy from third-prty pyer s nd ptient s perspectives. SCIT indictes subcutneous llergen immunotherpy; SLIT, sublingul llergen immunotherpy. more skewed towrd llergen extrcts ( 297; 72%) rther thn outptient visits ( 67; 16%) nd symptomtic mediction ( 52; 12%). Svings ssocited with the decresed use of medictions for SARC during SIT therpy reched 39 nd 35 (P.67) in the SLIT nd SCIT group, respectively. A significnt reduction of mediction cost ws observed strting the first yer in the SLIT group only (SLIT: 23%, P.001; SCIT: 9%, P.10), reching significnt reduction for both groups during the second nd the third yer of tretment (third yer of SIT: 60% for SLIT vs 55% for SCIT; P.99). Ptient perspective. To ptient, SLIT ws less expensive thn the SCIT therpy ( 176 vs 255, P.34). Mediction copyments for llergen extrcts ( 72 for SLIT vs 55 for SCIT; P.001) nd loss of income were the min contributors to the overll costs. When considering fixed costs lone, SCIT ws less expensive thn the SLIT therpy, by lmost one third ( 27%, 76 vs 60; P.001) (Tble 5). Society perspective. From societl perspective, SLIT ws 32% less expensive thn the lterntive SCIT tretment ( 684 vs 1,004; P.001). Approximtely 82% vs 68% of the totl expenditures were ttributed to direct costs in the SLIT nd SCIT groups, respectively ( 492 vs 542; P.001). The higher cost ssocited with productivity loss in the SCIT group ccounted for most of the increse in the totl cost throughout the SIT dministrtion period ( 136 [6 workdys] vs 332 [14 workdys], P.001) (Tble 5). Sensitivity Anlysis The sensitivity nlysis results confirmed the dvntge of SLIT vs SCIT from the third-prty pyer s perspective (Tble 6). 486 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

6 Tble 6. Sensitivity Anlysis From Third-Prty Pyer s Perspective Men 3-yer SIT cost per ptient (95% CI), Bootstrp-t P vlue SLIT group (n 17) SCIT group (n 23) Totl cost ( 50%) b ( ) ( ).001 Totl cost ( 50%) b ( ) ( ).001 Abbrevitions: CI, confidence intervl; SCIT, subcutneous llergen immunotherpy; SIT, specific llergen immunotherpy; SLIT, sublingul llergen immunotherpy. The CI ws computed with bootstrp-t procedure. b Costs re expressed in 2002 euro nd re vrying by 50% of the bse cse key prmeters (cost of llergen extrcts, helth cre service) t 0% discount rte. DISCUSSION This study ws 3-yer, open-lbel rndomized clinicl tril tht evluted the clinicl benefits nd overll costs of SCIT vs SLIT tretment of SARC in dults from 3 perspectives (third-prty pyer, ptient, nd society) using cost-minimiztion model. The study demonstrtes tht both SLIT nd SCIT were comprble in their clinicl outcomes, ech producing sttisticlly significnt reduction of symptoms nd symptomtic drug intke. Nevertheless, the SCIT group exhibited slightly better improvement in visul nlog score nd greter reduction of systemic ntihistmines vs SLIT in the third yer compred with the bseline yer. We cn expect this improvement to become sttisticlly significnt in study with lrger study rms. SLIT proved less expensive lterntive reltive to SCIT from ll 3 perspectives. However, from ptient perspective, SCIT ws finncilly preferble to SLIT for those ptients who hd no loss of income or trvel expenses. From societl perspective, greter productivity loss in the SCIT group ccounted for most of the increse in the totl cost during the dministrtion period. Since llergologists cn dminister injection immunotherpy outside the working hours in some countries such s the United Sttes, costs ssocited with workdy loss due to SCIT dministrtion could eliminte the dvntge of SLIT. Nevertheless, in our study, hypotheticl elimintion of productivity loss nd trvel expenses would not mke enough of difference to shift the benefits from SLIT to SCIT. Although SLIT hs been recently vlidted s vible lterntive to SCIT, the benefits of SLIT compred with stndrd SCIT hve not yet been estblished on lrge scle. In study of 20 ptients with grss llergy by Ongri et l, 25 SLIT nd SCIT were similr in efficcy when compred with phrmcologic tretment. SLIT nd SCIT were found eqully effective fter 12 months in 2 other smll studies by Quirino et l 26 nd Mungn et l. 27 Yet nother study by Bernrdis et l 28 showed clinicl improvement with Alternri tenuis extrct in 23 ptients in both the SLIT nd SCIT groups fter 1 yer. Although these studies dd compelling dt to the discussion, the dt lck significnce becuse of multiple methodologic flws, including smll study sizes, the bsence of rndomiztion before study group lloction, the lck of plcebo control, nd the filure of the studies to encompss the recommended tretment durtion. The most methodologiclly vlid study ws performed by Khinchy et l. 29 Khinchy et l conducted double-blind, double-dummy, plcebo-controlled study of 58 ptients with birch llergy who were rndomized into SLIT, SCIT, nd plcebo groups. In the first yer of tretment (the only yer evluted), Khinchy et l did not find ny significnt difference in either symptoms or drug intke reduction between the SLIT nd SCIT groups. As in our study, both SCIT nd SLIT showed clinicl efficcy, with SCIT being slightly better in terms of reduced disese severity. In contrst to our findings, Khinchy et l did not see ny improvement in qulity of life within the 2 groups. The difference in our findings could hve been cused by the fct tht Khinchy et l used generl helth-relted qulity-of-life questionnire but the questionnire used in our study ws disese specific. Additionl studies of either SLIT or SCIT confirm improvement of qulity of life. 30,31 It is not cler whether the improvement cn be ttributed to greter effect of SCIT on meditors of inflmmtion in contrst to SLIT. 32 More dt re needed. Additionl spects of SIT outside the scope of our study need to be considered, nmely, durbility, preventive chrcter of SIT, nd complince. A 3-yer study of SCIT ws found to exert durble effect fter its discontinution. 6 On the other hnd, the durbility of SLIT is still uncertin. Severl studies hve demonstrted long-lsting efficcy of SLIT fter tretment, but the evidence is limited nd the preventive effect on sthm onset of both SLIT nd SCIT ws so fr demonstrted only in children. 33,34 A few studies cpture the long-term cost-effectiveness of either SLIT or SCIT s result of durbility. 12,35,36 A long-term comprtive study is needed to properly determine the mgnitude of the longterm cost-svings potentil for ech dministrtive route. Our study suggests dditionl cost fctors tht we did not mesure, such s incresed productivity due to improved symptoms. On the other hnd, costs would hve incresed hd we encountered serious systemic dverse effects, which rrely occur with SCIT. 4 A cost increse relted to severe dverse effects my rise in lrger study in which those rre dverse effects cn mnifest. Despite recently reported nphylxis in specific cses of multiple extrct SLIT tretment, we do not expect to see the sme incresed cost in SLIT, since SLIT hs been estblished s sfer dministrtion route compred with SCIT. 37,38 VOLUME 100, MAY,

7 It is not cler which type of SIT dministrtion hs better complince rte. Although SCIT complince is expected to be higher thn SLIT (which is home dministered), published studies report SCIT noncomplince rtes of up to 50%, citing inconvenience nd dverse effects s the primry resons for SCIT discontinution. 39,40 In contrst, SLIT complince rtes were shown to be reltively high The limittions of our study include bsence of plcebo rm, bsence of double-blind method, smll size, nd limited possibilities for vlid sttisticl nlysis between the rms bsed on these considertions. The study s dvntge is its rndomized prospective chrcter, with its collection of both cost nd efficcy dt, including qulity of life, during the entire recommended tretment period. In conclusion, our study showed tht SLIT nd SCIT reduced clinicl symptoms nd the need for symptomtic mediction in dults with grss pollen induced rhinoconjunctivitis compred with stndrd phrmcologic tretment. The clinicl efficcy of SLIT nd SCIT ws not significntly different in the third yer of SIT. Overll, SLIT showed better cost profile from ll 3 perspectives. SCIT ws finncilly fvorble from ptient perspective, where no loss of income or trvel costs were present. Lrger studies tht exmined the cost-effectiveness of the sublingul nd subcutneous routes of dministrtion, including the durbility nd preventive effect of immunotherpy, s well s sfety nd complince, must be conducted to evlute the weighted benefits of ech dministrtion route nd its cost-sving potentil in different popultions. ACKNOWLEDGMENTS We thnk Iv Selke-Krulichov, PhD, t the Deprtment of Medicl Biophysics t Fculty of Medicine of Chrles University in Prgue, for her sttistics dvice. REFERENCES 1. Bousquet J, vn Cuwenberge P, Khltev N. Allergic rhinitis nd its impct on sthm. J Allergy Clin Immunol. 2001;108: Reed SD, Lee TA, McCrory DC. The economic burden of llergic rhinitis: criticl evlution of the literture. 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