Two hundred and fifty one patients with AD (103 females and 148 males) between 5 and 55 years of age (19.9±10.1; mean±SD) with AD who fulfilled all of the criteria below were included in this study (Table 1). The patients showed the typical clinical features of AD compatible with the diagnostic criteria for AD suggested by Hanifin and Rajka.10 All included patients showed a positive result for serum-specific IgE antibody to Dermatophagoides pteronyssinus (D. pteronyssinus) or Dermatophagoides farinae (D. farinae) (≥3.5 kU/L) using the ImmunoCAP assay (Phadia US, Portage, MI, USA). The exclusion criteria for SCIT in patients with AD were 1) patients with concomitant significant systemic diseases, such as autoimmune disorders, malignancy, cardiovascular diseases, chronic infections, immunodeficiencies, mental diseases, or other chronic inflammatory disorders; 2) children of age less than 5 years; 3) pregnancy; and 4) patients with poor compliance to long-term therapy. All of the patients provided written informed consent for SCIT, and this study was performed in accordance with local clinical practice guidelines. This study was approved by Institutional Review Board.

This study was conducted as an observational cohort study to assess the clinical efficacy of SCIT and clinical characteristics of patients with AD showing a favorable clinical response to SCIT. Systemic immunosuppressants, including cyclosporine, were not administered during the SCIT. All patients received premedication with fexofenadine or levocetirizine to minimize allergic side effects of SCIT. The use of topical corticosteroids and topical calcineurin inhibitors were adjusted according to the clinical condition of the patients by physicians.

Standardized allergen extract containing a mixture of D. pteronyssinus and D. farinae extract (50%:50%) adsorbed to aluminum hydroxide (Novo-Helisen Depot®; Allergopharma Joachim Ganzer KG, Reinbeck, Germany) was used for SCIT. The HDM allergen extract for SCIT was composed of three vials (labeled as No. 1, 2, and 3) with ten-fold increases in allergen concentrations. The schedule of SCIT was divided into an initial build-up phase and a maintenance phase. According to the schedule for initial build-up phase, we choose either a cluster schedule or an accelerated schedule to reach a maximal maintenance dose of HDM extract. In a cluster schedule for initial build-up phase, two increasing doses of HDM extract (in order of 0.1, 0.2, 0.4, and 0.8 mL of each vial) were injected subcutaneously to 181 of 251 patients (72.1%) at 30-minute intervals between two injections weekly for 6 weeks. In an accelerated schedule for initial build-up phase, subcutaneous injections of increasing doses of HDM extract were completed with a 1-day protocol (ultra-rush) or a 3-day protocol (rush) upon admission to a hospital for safety reasons, as previously described.11 Selection of the schedule for the initial build-up phase was determined by a physician considering the distance of each patient's living place from the hospital, ability to make frequent hospital visits, and the patients' occupations. In the maintenance phase of SCIT, 0.8 mL of the highest maintenance concentration of HDM extract (labeled as No. 3; 5000 TU/mL) was directly mixed with histamine-immunoglobulin complex (Histobulin®; Green Cross Co., Seoul, Korea), containing 12 mg of human immunoglobulin and 0.15 µg of histamine dichloride, and injected subcutaneously at monthly intervals as described in previous reports.1213

The primary efficacy outcome was change in clinical severity measured using standardized clinical severity scoring system for AD (SCORAD) values at 12 months in comparison with the values at baseline in patients with AD who received SCIT.14 In this study, severe AD was defined as a baseline total SCORAD value above 50 as previously described.15 A favorable clinical response to SCIT was defined as a decrease in total SCORAD value at 12 months greater than 50% compared to baseline value. To assess the safety of the SCIT, details of systemic reactions were recorded according to European Academy of Allergy and Clinical Immunology (EAACI) criteria for the classification and grading of systemic reactions associated with SCIT, as previously reported.16

Serum concentrations of total IgE, specific IgE antibody to D. pteronyssinus, and specific IgE antibody to D. farinae were measured using ImmunoCAP assay (Phadia US, Portage, MI, USA). This measurement system has limitations of detection levels for total IgE (2–5000 kU/L) and for the allergen-specific IgE (0.1–100 kU/L). If the result of measurement was above the upper detection limit, serum concentration of total IgE was regarded as 5000 kU/L and serum concentration of allergen-specific IgE was regarded as 100 kU/L for statistical analysis. Peripheral blood eosinophil count was measured using an automated hematology analyzer (Coulter Counter STKS; Beckman Coulter, Fullerton, CA, USA).

The data are expressed as mean±SD. The statistical significance of changes in SCORAD values before and after SCIT were analyzed using Wilcoxon signed-rank test. Differences in parameters between the two groups were analyzed using the Mann-Whitney U test. The χ²-test was used to compare the clinical efficacy of SCIT between the two groups. A p value <0.05 was regarded as statistically significant.

The overall compliance rate for SCIT was 66.5% (167 of 251 patients) at 12 months. There was no significant difference in the compliance rate for SCIT between patients with mild to moderate AD and patients with severe AD (p>0.05). In addition, there was no significant difference in the compliance rate for SCIT between cluster schedule group and accelerated schedule group for the initial build-up phase of SCIT (p>0.05).

Overall, SCORAD values were measured in 144 of 167 patients (86.2%) who received SCIT for 12 months and the clinical efficacy of SCIT over 12 months was calculated in these patients. SCORAD values significantly decreased from 44.4±19.3 at baseline to 13.7±9.2 at 12 months (Wilcoxon signed-rank test, p<0.001) (Fig. 1A). The mean decrease in SCORAD value at 12 months, compared to baseline values, after SCIT was 62.5% in patients with AD. In patients with severe AD, the SCORAD value significantly decreased from 64.9±12.4 at baseline to 14.6±10.9 at 12 months (p<0.001). In patients with mild to moderate AD, the SCORAD value significantly decreased from 32.1±9.9 at baseline to 13.2±8.1 at 12 months (p<0.005). There was a significant difference in the mean percentages of decreases in SCORAD values at 12 months, compared to baseline, between patients with severe AD (77.2±17.2%) and patients with mild to moderate AD (53.9±31.7%) (Mann-Whitney U test, p<0.001) (Fig. 1B). However, there was no significant difference in the mean percentages of decreases in the SCORAD values at 12 months, compared to baseline, between the accelerated schedule group (64.1±23.1%) and cluster schedule group (59.9±41.6%) (p=0.741). A favorable clinical response to SCIT with a decrease in SCORAD value at 12 months greater than 50%, compared to baseline value, was observed in 106 (73.6%) of 144 patients (Table 2). The proportion of patients with a favorable clinical response was significantly higher in patients with severe AD (90.6%, 48/53) than patients with mild to moderated AD (63.7%, 58/91) at 12 months after SCIT (p<0.001). The proportion of patients showing a decrease in SCORAD value at 12 months greater than 75%, compared to baseline value, was significantly higher in patients with severe AD (66.0%, 35/53) than patients with mild to moderated AD (29.7%, 27/91) (p<0.001) (Table 2).

Baseline clinical and laboratory parameters were compared between patients showing a favorable clinical response to SCIT (responders) and patients showing no significant clinical response to SCIT (non-responders) among the 144 patients with AD who received the 12 months of SCIT. Baseline SCORAD values were significantly higher in the 106 responders (48.4±18.3) than 38 non-responders (31.6±16.8) (p<0.001) (Table 3). In 53 patients with severe AD who received 12 months of SCIT, 48 responders showed a significantly shorter duration of AD (12.3±8.5 years) than five non-responders (20.6±10.9 years) (p<0.05) (Table 4). In 53 patients with severe AD who received 12 months of SCIT, age of onset of AD was significantly higher in the 48 responders (9.1±10.5 years) than the five non-responders (1.2±2.2 years) (p<0.001) (Table 4).

Laboratory parameters, including serum total IgE, specific IgE antibody to D. pteronyssinus, specific IgE antibody to D. farinae, and peripheral blood eosinophil count, were measured in 131 of 167 patients (78.4%) with AD at baseline and 12 months after SCIT. Serum total IgE concentrations significantly decreased from 2379.4±1956.2 kU/L at baseline to 2165.7±1837.8 kU/L at 12 months (p=0.012) (Table 5). In patients with severe AD, serum total IgE concentrations significantly decreased from 3387.0±1788.8 kU/L at baseline to 3017.9±1773.9 kU/L at 12 months (p<0.005). There was no significant difference of serum total IgE concentrations between baseline (1777.4±1806.7 kU/L) and 12 months (1656.4±1689.4 kU/L) in patients with mild to moderate AD (p>0.05). Peripheral blood total eosinophil counts significantly decreased from 610.0±681.4 µL at baseline to 398.1±332.0 µL at 12 months (p<0.001) (Table 5). In patients with severe AD, peripheral blood total eosinophil counts significantly decreased from 895.4±961.7 µL at baseline to 500.0±398.3 µL at 12 months (p<0.001). In patients with mild to moderate AD, peripheral blood total eosinophil counts significantly decreased from 439.5±344.3 µL at baseline to 335.3±267.7 µL at 12 months (p<0.001). However, there was no significant difference in serum concentrations of specific IgE antibody to D. pteronyssinus (p=0.77) and specific IgE antibody to D. farinae (p=0.48) between baseline and 12 months after SCIT (Table 5).

Twenty six of the 251 patients (10.4%) showed systemic reactions during the initial build-up phase of SCIT. Localized or generalized urticarial was observed in 21 patients (8.4%) and mild bronchospasm (mild dyspnea without wheezing) was seen in 5 patients (2.0%). In 70 patients who received accelerated schedules for initial build-up phase of SCIT, localized or generalized urticaria was observed in 13 patients (18.6%), and mild bronchospasm (mild dyspnea without wheezing) was observed in 5 patients (7.1%). In 181 patients who received cluster schedules for initial build-up phase of SCIT, localized or generalized urticaria was observed in 8 patients (4.4%). Systemic reactions were significantly more frequently observed in patients who received accelerated schedules (18 of 70 patients, 25.7%) than the patients who received cluster schedules (8 of 181 patients, 4.4%), for the initial build-up phase (p<0.001). Grades of systemic reactions associated with SCIT ranged from grades 1 to 2 according to EAACI criteria. There was no case of patients who experienced anaphylaxis. Urticaria or bronchospasm rapidly resolved following intravenous administration of 4 mg of chlorpheniramine and 5 mg of dexamethasone and/or inhalation of short-acting bronchodilator.