100Clinical TrendsSpecific Immunotherapy in Atopic Eczemaby Thomas Werfel & Alexander KappBackground:Atopic eczema (AE) is a common chronic in-flammatory skin disease that is part of the atopic syndromeand is frequently associated with asthma and allergicrhinoconjunctivitis. Aeroallergens like house-dust-mites,pollen, and animal epithelia represent important trigger fac-tors in sensitised patients. Methods: While specific immunotherapy (SIT) is widely andmost effectively used in allergy to insect venoms and allergicrhinitis, its use in AE is still controversially discussed. In a re-cent multicenter study it was shown in a double-blind con-trolled dose finding study that higher doses of allergens usedfor specific immunotherapy are effective in AE. A blind ob-server documented a higher decrease of scoring atopic der-matitis (SCORAD) points in patients treated with house dustmite allergen concentrations of 2000 and 20000 SQ-U com-pared to patients who belonged to the “active placebo group”who was treated with 20 SQ-U only. Results: A number of smaller clinical trials confirm that aller-gen-specific immunotherapy appears to be a promising ap-proach for the treatment of patients with atopic eczema andclinically relevant sensitisation to house dust mites or otherinhalant allergens which may lead to clinical improvement ofeczema as well as subjective symptoms like pruritus andsleeplessness. Conclusions:Despite encouraging data the use of SIT as atherapeutic approach in the routine treatment of AE requiresfurther evaluation.Allergy Clin Immunol Int – J World Allergy Org 2007;19:100–103The Role of Allergens in Atopic EczemaAtopic eczema (AE) is one of the most common skin dis-eases which is characterised by a chronic course and intensiveitching. AE belongs together with allergic rhinitis, conjunctivi-tis, and allergic bronchial asthma to the so-called atopic dis-eases. Acute eczematous lesions are characterized by erythema,oozing, and crusting, whereas chronic lesions show thickenedskin and papules. Pruritus and sleeplessness are further charac-teristics of AE. In addition to local and systemic therapy adjust-ed to the stage of the disease, the search for relevant trigger fac-tors and consecutively their avoidance plays a crucial role in thereduction or even prevention of flare-ups. A causal therapy ofAE is not available yet and the complexity of the disease leadsto a polypragmatic therapeutical management [1].The majority of patients is sensitised to inhalant or food al-lergens. Sensitisations to house dust mite allergens which aredetectable with specific IgE tests are very common in adoles-cence and adult patients [1, 2].A T-cell-mediated delayed reaction is critical for the worsen-ing of skin eczema, which can be triggered by the epicutaneousapplication of house dust mite allergens in sensitised patients(Figure 1) [3, 4]. House dust mite antigens are able to penetrateinto the skin where they are trapped via specific IgE, which isbound on high affinity Fc-receptors on Langerhans cells.Langerhans cells may then subsequently present allergens to T-lymphocytes leading to a specific T-cell-proliferation and mani-festation of skin eczema [5].The Role of Specific ImmunotherapySpecific immunotherapy has proven to be effective mainlyin respiratory IgE-mediated allergic diseases [6, 7]. The theoret-Allergy Clin Immunol Int – J World Allergy Org, 19/3 (2007)? 2007 Hogrefe & Huber PublishersDOI: 10.1027/0838-1925.19.3.100Figure 1.Positiveatopy patch to housedust mite in atopiceczema.ical objection that specific immunotherapy may lead to a deteri-oration of AE by boostering the cell-mediated immune responsehas somewhat hampered studies on the efficacy of SIT in atopiceczema in the past although this has never been proven in con-trolled studies so far.Darsow et al. reviewed a number of controlled studieswhich were performed in patients with respiratory allergy butwho in addition also suffered from atopic eczema. In thesestudies an improvement not only of rhinitis and asthma but alsoof the skin condition was observed [8]. Moreover, a number ofopen observational studies directly addressing AE publishedbefore 1990 pointed to a positive effect of SIT in atopic eczema[9–11].The first double-blind placebo-controlled study which wasreported to be effective in atopic eczema used allergen-anti-body-complexes [12] which have, however, not been used inclinical practice thereafter. It is still not known how these aller-gen-antibody-complexes which contain autologous specific an-tibodies and house dust mite allergens work on a molecular orcellular basis. A further “early” unique study which howeverprovided negative results was flawed by the ineffective oralroute of extract administration [13].Recently Bussmann et al. conducted a systematic literaturesearch in the databases MEDLINE, EMBASE, and CENTRAL[14] using the key words “atopic dermatitis” or “atopic eczema”and “specific immunotherapy” or “hyposensitization” for thesearch. They combined their literature findings with a secondsearch for “side effect,s” or “adverse events” and “atopic der-matitis,” or “atopic eczema” and “specific immunotherapy,” or“hyposensitization,” and thus identified a total of 23 articlesClinical Trends101about studies on subcutaneous or sublingual allergen SIT in AEwith different allergens [14].Ten of these studies conducted between 1974 and 2006 wereobservational studies [9, 10, 15–21], eleven were controlledstudies [12, 13, 22–30], and two were classified as case reports[31, 32].Five placebo-controlled studies on subcutaneous allergenSIT were comparable [22, 23, 28–30] and used for a statisticalmeta-analysis. This showed a significant improvement of symp-toms in patients with AE under SIT using the inverse normalmethod or the inverse χ2method [33].Moreover, a combined statistical analysis of seven com-parable observational studies [9–11, 15, 16, 19, 20] showed amean proportion of improvement of 71% of AD under SIT, insupport of the hypothesis that SIT might represent a usefuladditional therapeutic option for a subgroup of patients withAE [14]. In the so far largest and most recent controlled study we in-vestigated the clinical efficacy of a subcutaneously applied im-munotherapy in patients with AE using a double-blind placebocontrolled protocol [30]. The study was a multicenter, double-blind trial with patients randomly assigned to treatment withspecific immunotherapy with ALK-depot SQ mites and maxi-mum concentrations of 20 SQ-U (active placebo), 2000 SQ-U,and 20000 SQ-U for one year. The double-blind design of thestudy was realized by a “blind observer” who evaluated theSCORAD. Prior to the treatment we assessed the patients for inclu-sion/exclusion criteria. The inclusion criteria were: IgE-mediat-ed sensitization against house dust mites (CAP RAST FEIAclass ≥3), SCORAD score > 40 points, age between 18 and 55years, a chronic course of AE. Patients were randomized intothree dose groups for treatment with subcutaneous specificimmunotherapy with ALK-depot SQ Dermatophagoidespteronyssinus/farinae: group 1 (“active placebo”):constantdose of 20 SQ-U, group 2:maintenance dose of 2000 SQ-U,group 3: maintenance dose 20000 SQ-U. Therapy was startedin all groups with 20 SQ-U. All injections were given at weeklyintervals. Treatment of AE was individually adapted to the clinicalseverity. Topical corticosteroids of European classes 1 to 3 andnonsedating antihistamines with a short half life (cetiricine, lo-ratadine) were allowed. Moreover, basic treatment of the skinwith ointments was allowed. There was a decline of the SCORAD score points in allstudy groups. The differences in the SCORAD between thebaseline value and the values in the last three months oftreatment were, significantly greater in groups 2 and 3 com-pared to group 1 (Figure 2). The response rate as definedabove was 66.0% in the pooled groups 2 and 3 and 46.2% ingroup 1.Allergy Clin Immunol Int – J World Allergy Org, 19/3 (2007)102Clinical Trends0N=26 N=26 N=27-5erocs DAR-10OCS ni eg-15nahc-20-2520200020000SQ-EFigure 2.Changes from baseline to endpoint in SCORAD sum-mary score at the end of treatment with specific immunotherapyversus baseline, mean (±SEM), data from [30].The decline of SCORAD in the verum groups was sig-nificantly higher compared to placebo already after twomonths of treatment (p < 0.05). The differences betweenplacebo and verum were maximal after 6 months of treatment(p < 0.005). There was a significant difference in the application of topi-cal corticosteroids with higher reduction in groups 2 and 3, buthigher increase in group 1. Similar differences in favor ofgroups 2 and 3 were seen in the use of systemic antihistamines,but these were statistically less pronounced.Markedly more patients assessed their skin to be improvedor completely healed in groups 2 and 3 (61.5% and 70.4%, re-spectively) compared to group 1. The final assessment of the“blinded” physician confirmed a better skin condition at the endof therapy for patients from groups 2 and 3 compared to thosefrom group 1.Thus allergen-specific immunotherapy appears to be effec-tive in patients with AD who are sensitized to house dust miteallergens and may be valuable in the treatment of this chronicskin disease. It has to be pointed out, however, that further stud-ies on the optimal doses and time intervals for SIT are neededbefore this therapy can be recommended for the therapy ofatopic eczema. Allergy Clin Immunol Int – J World Allergy Org, 19/3 (2007)SLIT for the Treatment of AtopicEczema ?In addition to the approaches with subcutaneous application,there are also pilot studies on allergen SIT in patients with ADusing the sublingual road of allergen administration with differ-ent therapeutic results [13, 17, 18, 21]. In the most recent study,children between 5 and 16 years of age with atopic eczema(SCORAD > 7) and sensitization to dust mites were enrolled ina randomized, double-blind, placebo-controlled study. SLIT orplacebo was given for 18 months [36]. The difference frombaseline in the SCORAD was significant between the twogroups starting from month 9 and there was a significant reduc-tion in the use of medications only in the active group. In con-trast to the findings with SCIT [35], a significant difference inthe considered parameters was found only in patients with mildto moderate disease, whereas severely affected patients had onlya marginal benefit. The authors concluded that sublingual im-munotherapy may represent an additional therapeutic tool forthe treatment of mild to moderate extrinsic atopic dermatitis inselected children. Further studies are clearly needed using thistherapeutic approach. Side EffectsAs previously described the side effects of specific im-munotherapy were in most cases confined to local reactions andon the long run negligible. In there systemic review Bussmann and colleagues [14]summarize the following side effects from single studies: Se-vere exacerbation of AD were decribed in 2 of 15 childrenunder SIT in one study [9] and worsening of the skin in 20% ofthe patients with AE was described in another study [28]. A fur-ther study reported adverse reactions in 19.5% of patients withAD treated via the subcutaneous route and in 14.6% of patientswith AD treated via the sublingual route [17].In particular patients who were treated in the “active treat-ment” groups showed a good compliance with treatment inmost clinical studies. Why Should SIT Work in AE?During the chronification of eczema a shift in cytokine pat-tern has been shown for the majority of nonspecific bystander T-lymphocytes [34] but also within the allergen-specific compart-ment in the skin [35] towards a TH1 cytokine pattern. Since SITboth leads to a shift from “TH2” towards “TH1” (in addition toits effects on T regulatory cells) the question can be raised whySIT should work in a TH1 polarized situation such as in chronicatopic eczema. It appears from the available clinical data that on the longerrun even TH1-dominated chronic skin lesions can be influencedby allergen-specific immunotherapy in sensitized patients prob-ably by mechanisms which are effective rather in lymphatic or-gans bearing a TH2 milieu than in the skin itself but immuno-logical studies on this issue (also addressing T regulatory cells)are urgently needed.References[1] Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M,Eigenmann P, et al. Diagnosis and treatment of atopic eczema in children andadults: European Academy of Allergology and Clinical Immunology/AmericanAcademy of Allergy, Asthma, and Immunology/PRACTALL Consensus Report.J Allergy Clin Immunol2006; l18:152–169 and Allergy2006; 61:969–987–[2] Werfel T, Kapp A. Environmental and other major provocation factors inatopic eczema AD. Allergy1998; 53:731–739[3] Ring J, Darsow U, Behrendt H. 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Immunol Today1998; 19:359–361[35] Werfel T, Morita A, Grewe M, Renz H, Wahn U, Krutmann J, et al.Allergen specificity of skin-infiltrating T cells is not restricted to a type-2cytokine pattern in chronic skin lesions of atopic eczema. J Invest Dermatol1996; 107:871–876[36] Pajno GB, Caminiti L, Vita D, Barberio G, Salzano G, Lombardo F,Canonica GW, Passalacqua G. Sublingual immunotherapy in mite-sensitizedchildren with atopic dermatitis: A randomized, double-blind, placebo-controlledstudy.J Allergy Clin Immunol2007 120:164–170Thomas Werfel (to whom correspondence should be ad-dressed) and Alexander Kapp are with the Department ofDermatology, Hanover Medical School, Ricklinger Str. 5,30449 Hanover, Germany (tel. +49 511 9246-450, fax +49 511 9246-440, e-mail werfel.thomas@mh-hannover.de)Allergy Clin Immunol Int – J World Allergy Org, 19/3 (2007)
Werfel T et al. SIT in Atopic Eczema
