Subcutaneous Immunotherapy with a Depigmented Polymerized Birch Pollen Extract A New Therapeutic Option for Patients with Atopic Dermatitis

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1 Originl Pper DOI: / Received: June 16, 2010 Accepted fter revision: August 6, 2010 Published online: Februry 2, 2011 Subcutneous Immunotherpy with Depigmented Polymerized Birch Pollen Extrct A New Therpeutic Option for Ptients with Atopic Dermtitis Ntlij Novk Dimnt Thci b Mtthis Hoffmnn c Regin Fölster-Holst d Thilo Biedermnn e Bernhrd Homey f Knut Schekel g Josef A. Stefn h Thoms Werfel i Thoms Bieber Angelik Sger j Torsten Zuberbier k Deprtment of Dermtology nd Allergy, University of Bonn, Bonn, b Deprtment of Dermtology, University of Frnkfurt, Frnkfurt, c Dermtology Prctice, Witten, d Deprtment of Dermtology nd Venerology, University Hospitl Schleswig-Holstein, Cmpus Kiel, University of Kiel, Kiel, e Deprtment of Dermtology, University of Tübingen, Tübingen, f Deprtment of Dermtology, University of Düsseldorf, Düsseldorf, g Deprtment of Dermtology, University of Dresden, Dresden, h Dermtology Prctice, Hennef, i Deprtment of Dermtology, Medicl University of Hnnover (MHH), Hnnover, j Leti Phrm, Witten, nd k Deprtment of Dermtology nd Allergy Chrité, Allergy Centre Chrité, Universitätsmedizin Berlin, Berlin, Germny Key Words Atopic dermtitis Birch pollen Specific immunotherpy Abstrct Bckground: Birch pollen is n importnt outdoor llergen ble to ggrvte symptoms in topic dermtitis (AD). Specific immunotherpy (SIT), n estblished procedure for llergic irwy diseses, might lso represent n ttrctive therpeutic option for the cusl tretment of llergen-triggered cutneous symptoms in these ptients. Studies with house dust mite SIT hve lredy shown beneficil effects in AD ptients, wheres the sfety nd efficcy of SIT with birch pollen extrct in AD ptients hve not been studied so fr. The im of this study ws to evlute for the first time the sfety nd efficcy of SIT with depigmented polymerized birch pollen extrct in AD ptients. Methods: Fifty-five dult ptients with moderte-to-severe AD nd cliniclly relevnt sensitiztion to birch pollen received SIT for 12 weeks. SIT ws continued during birch pollen seson. The ssessment of sfety, the totl SCORAD vlue, nd the Dermtology Life Qulity Index (DLQI) were evluted. Results: The medin totl SCORAD vlue ws reduced by 34% (p! 0.001) during the course of tretment nd the men DLQI improved by 49% (p! 0.001) despite strong simultneous birch pollen exposure. Eight ptients (14.5%) developed systemic rections nd 19 ptients (34.5%) developed locl rections which were of mild intensity in most cses. No ptient discontinued the study premturely due to dverse drug rections. Cosesonl tretment ws well tolerted. Conclusion: SIT with depigmented polymerized birch pollen extrct leds to significnt improvement of the SCORAD vlue nd the DLQI in ptients suffering from moderte-to-severe AD sensitized to birch pollen. Copyright 2011 S. Krger AG, Bsel Fx E-Mil krger@krger.ch S. Krger AG, Bsel /11/ $38.00/0 Accessible online t: Correspondence to: Dr. Ntlij Novk Deprtment of Dermtology nd Allergy, University of Bonn Sigmund-Freud-Strsse 25, DE Bonn (Germny) Tel , Fx E-Mil ukb.uni-bonn.de

2 Introduction To dte, therpy for topic dermtitis (AD), frequent chronic inflmmtory skin disese, is limited to symptomtic nti-inflmmtory, ntipruritic, or immunomodultory tretment pproches [1]. However, rtionle-bsed tretment conducted to counterct diseseggrvting pthwys induced by trigger fctors for AD would be much more effective in reducing the number of flre-ups nd the severity of AD, thereby improving the qulity of life of these ptients. Although it is still uncler whether llergic sensitiztions mirrored by elevted totl serum immunoglobulin E (IgE) nd llergen-specific IgE levels detectble in mjority of AD ptients represent primry or secondry disese-relted fctors, indoor llergens such s house dust mites (HDM) s well s sesonl llergens including birch nd grss pollen llergens hve been clerly shown to promote excerbtions nd impirment of the disese [2]. Allergens represent importnt triggers in mjority of AD ptients. Allergen-specific immunotherpy is successfully in use s long-term tretment of sensitiztions in ptients with relted topic disorders such s rhinitis nd mild sthm. The efficcy of specific immunotherpy (SIT) in rhinitis nd mild sthm is well proven nd is relted to immunologic chnges such s shift of Th2 immune responses into modified Th1 immune responses s well s the induction of regultory T cells nd other tolerogenic pthwys [3, 4]. Thus, the first open-lbel nd controlled studies on SIT hve been conducted in AD ptients with sensitiztions to HDM. Altogether, most of these studies hve provided very promising results [5, 6]. However, most of the controlled nd uncontrolled studies published on this topic so fr hve focused on the tretment of sensitiztions to HDM or grss pollen llergens in AD ptients [7], but none of the studies hve investigted the sfety nd efficcy of SIT in AD ptients sensitized to birch pollen llergen. As consequence, t present there re no dt vilble which would llow ny relible ssessment of the vlue of SIT with birch pollen llergens s rtionle-bsed tretment pproch for AD. Therefore, we performed multicenter, open, pilot study in dult ptients with AD nd cliniclly relevnt sensitiztions to birch pollen llergen. Methods Ptients nd Dignostic Criteri A totl of 55 AD ptients between 18 nd 65 yers of ge with moderte-to-severe AD dignosed ccording to the criteri of Tble 1. Summry of the demogrphic bseline chrcteristics Demogrphic vribles Overll Gender Mle, n (%) 20 (36.4) Femle, n (%) 35 (63.6) Age, yers Totl serum IgE, ku/l 2, ,169.9 Birch pollen-specific IgE, ku/l Vlues re presented s mens8sd unless otherwise specified. Hnifin nd Rjk were included. Disese severity ws ssessed using severity scoring of topic dermtitis (SCORAD) [8]. Ptients with SCORAD vlue 6 25 nd durtion of eczem longer thn 2 yers were selected. Birch pollen sensitiztion ws ssessed by specific serum IgE ginst birch pollen in CAP-RAST 63, positive topy ptch test, nd/or positive skin prick test for birch pollen llergen s well s symptoms of AD relted to birch pollen exposure. The demogrphic dt of the study cohort re summrized in tble 1. Of the AD ptients, 10.9% hd concomitnt llergic sthm nd 5.5% hd llergic rhinoconjunctivitis. Obligtory exclusion criteri were: FEV 1! 70% of the predicted vlue mesured by the pek flow; SIT ginst Betul Verrucos ( Bet v 1 ; birch pollen) during the lst 5 yers; pretretment with systemic corticosteroids, immunosuppressive gents or UV therpy 1 month before SIT or during SIT; cute tuberculosis; inflmmtory or infectious diseses of the trget orgn; immunopthologicl diseses in which utoimmune mechnisms ply role; immune deficiencies; tretment with -ntgonists; ny disese prohibiting the use of drenline; serious psychitric nd psychologicl disturbnces; concomitnt tretment with substnces interfering with the immune system; pregnncy; immuniztion with vccines 7 dys prior to SIT nd 14 dys post-sit, nd cute nd chronic eczem t the skin prick test site. Study Design The study ws designed s n open-lbel pilot study to ssess the sfety nd efficcy of SIT with depigmented birch pollen extrct in AD ptients. The study ws conducted from Jnury 2008 to Jnury The regionl pollen count mesurement ws documented t ech center. The use of concomitnt medictions with emollients nd topicl nd systemic drugs ws regulrly documented in ech ptient. The study ws pproved by the ethics committee nd informed consent ws obtined from every individul prticipting in the study. Allergen Preprtion nd Tretment Schedule The tretment ws subdivided into build-up phse of 3 weeks followed by mintennce tretment period of 12 weeks with SIT using depigmented polymerized birch pollen extrct. The initil build-up period during the first 3 weeks fter screening consisted of weekly dministrtions of grdully incresing mounts of vil 1 t concentrtion of 100 DPP/mI nd vil 2 t concentrtion of 1,000 DPP/ml (1 DPP ws the result of depigmenting nd po- SIT with Birch Pollen in AD 253

3 Tble 2. S ummry of the SIT schedule Vil Injection No. Intervl Milliliters week week week 1 week weeks 0.5 Tble 3. Summry of side effects observed during the study Totl SCORAD w0 w1 w2 w3 w9 (n = 51) w15 (n = 48) w17 (n = 54) Symptoms Ptients, n (%) Symptoms, n 10 Eczemtous flre 2 (3.6) 2 Pruritus 2 (3.6) 2 Procedurl hedche 1 (1.8) 1 Allergic rhinitis 1 (1.8) 1 Urticri 1 (1.8) 1 Vertigo 1 (1.8) 1 Locl rections 19 (34.5) 36 DLQI lymerizing 1 HEPL of birch pollen llergenic extrct). Tretment strted with 7-dy dministrtion intervls of grdully incresing single doses of extrct until the recommended dose ws reched (i.e. 0.2 ml vil 1, 0.5 ml vil 1, 0.2 ml vil 2, nd 0.5 ml vil 2). This dose (0.5 ml of vil 2) ws further mintined over the remining tretment period in 6-week intervls for totl mintennce phse of 12 weeks ( tble 2 ). Regulr ptient visits were before SIT s well s t weeks 1, 2, 3, 9, nd 15. A follow-up visit ws conducted 2 weeks fter the end of SIT. Tretment ws strted before nd continued during the birch pollen seson. Sttisticl Anlysis Sttisticl nlysis ws performed with SPSS 17.0 for Windows using t test for normlly distributed smples. The clculted vlues shown re mens 8 stndrd error of the men (SEM). R e s u l t s Significnt Improvement of the SCORAD Vlue nd the Dermtology Life Qulity Index under SIT The medin totl SCORAD vlue decresed by 34% (p! 0.001) during the course of tretment ( fig. 1 ). The men Dermtology Life Qulity Index (DLQI) improved by 49% (p! 0.001), indicting profound positive influence of SIT not only on the clinicl symptoms of AD but b 0 w0 w1 w2 (n = 49) w3 w9 (n = 50) w15 (n = 49) w17 (n = 54) Fig. 1. The SCORAD vlue nd the DLQI decrese significntly under SIT. The men vlues of the totl SCORAD vlue 8 SEM during different weeks of SIT re depicted. b The men vlues of the DLQI 8 SEM during tretment re shown. p! 0.05; p! 0.001; no indiction = Not significnt; w = week. lso on ptients qulity of life ( fig. 1 b). Furthermore, it is importnt to note tht improvement ws lredy noticeble fter the build-up phse, with continuous improvement of the totl SCORAD vlue nd the DLQI until the end of tretment. The Frequency of Side Rections Ws Comprble to Other Studies on SIT with Depigmented Birch Pollen Extrct A totl of 24 ptients developed dverse drug rections. Eight ptients (14.5%) developed systemic rections which were mostly of mild intensity nd consisted of flre-ups of eczemtous (2 ptients) or urticril skin lesions, worsening of the symptoms of rhinitis, n increse in pruritus, trnsient hedche, or vertigo. Nine- 254 Novk et l.

4 teen ptients (34.5%) developed locl rections, 30% of which occurred immeditely fter injection. Locl side rections were mostly of mild intensity ( tble 3 ). No ptient discontinued the study premturely due to dverse drug rections. Bsed on clculted weekly dose, usge of the concomitnt medictions ws constnt before, during, nd fter SIT, indicting tht there ws no negtive influence of SIT on AD. Moreover, the use of systemic ntihistmines nd nsl sprys decresed during SIT s compred to bseline. Furthermore, it is importnt to note tht SIT ws continued during birch pollen seson; thus, the SCORAD vlue nd the DLQI improved despite simultneous birch pollen exposure. On verge, every ptient ws treted for 19.2 dys during birch pollen seson. About 60% of ptients reched the mintennce dose until the onset of birch pollen seson. Discussion Here, we demonstrted tht the tretment of AD ptients sensitized to birch pollen with SIT leds to profound improvement of the SCORAD vlue nd the DLQI lredy within the first few weeks of therpy. Therefore, this study provides the first evidence of the sfety nd efficcy of SIT with depigmented polymerized birch pollen extrct in ptients with moderte-tosevere AD. These dt confirm the conceptul pproch of using SIT for the long-term tretment of sensitiztions in AD ptients, s hs been done in rhinitis nd mild sthm for severl yers now [9, 10]. Furthermore, the dt mend the observtions on the sfety nd efficcy of SIT gined in the context of the tretment of AD ptients with sensitiztions ginst HDM. Despite improvement of the skin lesions, reduction in CCL17, CCL22, nd other serum fctors known to go long with the severity of AD hs been observed in AD ptients during SIT, with no significnt increse in the totl nd llergen-specific IgE serum levels [11, 12]. Therefore, the results of this study might represent the first steps towrds n expnsion of the therpeutic options of SIT in AD ptients to ptients with sensitiztions to birch pollen llergen. When compring the results of this tril with other open-lbel or controlled studies on SIT in AD, the reltively short tretment phse of only 12 weeks in this study hs to be considered [5, 13]. This llows reltively cler ssessment of sfety but only preliminry conclusion bout the efficcy of this tretment, which is lredy very stisfctory fter 12 weeks but is likely to be even stronger fter longer tretment period. Since this study ws conducted to ssess the first dt on the sfety nd efficcy of SIT using depigmented birch pollen extrct in dult ptients with AD, n openlbel study design ws been selected. Therefore, bsed on previous studies with comprble invsive tretments, plcebo effect of up to 30% improvement of AD severity hs to be considered. However, the improvement chieved in this study clerly exceeds this effect. The frequency of locl nd systemic side rections in AD ptients ws comprble to the rte observed in so-fr unpublished double-blind plcebo-controlled studies on SIT with depigmented birch/tree pollen extrct performed in ptients with llergic rhinitis. Despite HDM, birch nd grss pollen llergens represent strong exogenous trigger fctors in subgroup of AD ptients. The relevnce of birch pollen llergens for eczem development is further documented by reltively high rte of positive topy ptch test rections to birch pollen llergens s compred to other erollergens such s grss pollen or ct dnder in sensitized AD ptients [14]. Moreover, the skin of AD ptients with high sensitiztion levels to birch pollen llergens is much more colonized with enterotoxin-producing Stphylococcus ureus bcteri, nd those ptients were demonstrted to suffer from more severe forms of AD [15]. In ddition, birch pollen-relted foods hve been observed to provoke flreups of AD s well s the ccumultion of birch pollenspecific T cells in the AD skin lesions of birch pollensensitized ptients [16, 17]. In the long term, treting birch pollen-sensitized AD ptients with SIT would not only llow the efficient therpeutic reduction of birch pollen-triggered flre-ups of AD, but it would lso puttively impct on the impirment of AD by other cofctors ssocited with birch pollen sensitiztions modifying the severity of AD, such s bcteril coloniztion n birchrelted food llergens. However, bsed on the first dt on the sfety nd efficcy of birch pollen SIT in AD presented here, double-blind, plcebo-controlled, pivotl studies re required to confirm nd further verify the vlue of birch pollen SIT s n lterntive therpeutic option for ptients with AD. Acknowledgement s The study ws funded by LETI Phrm, Witten, Germny. N.N. is supported by Heisenberg-Professorship of the Germn Reserch Council (DFG; NO454/5-2). SIT with Birch Pollen in AD 255

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