Analysis of the long-term efficacy and safety of subcutaneous immunotherapy for atopic dermatitis

Abstract

Introduction:

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by severe pruritus and eczematous skin lesions. Subcutaneous immunotherapy (SCIT) refers to repeated contact with gradually increasing doses of allergen extracts, which improve patient tolerance to such allergens and controls, or reduces allergic symptoms. This study aimed to explore the long-term efficacy and safety of SCIT for patients with AD sensitized to house-dust mite (HDM).

Methods:

We conducted a retrospective analysis of 378 patients with HDM-sensitized AD. Among these patients, 164 received SCIT plus pharmacotherapy for 3 years (SCIT group) and the other 214 patients received only pharmacotherapy (non-SCIT group). The scoring atopic dermatitis (SCORAD) and pruritus visual analog scale (VAS) scores, laboratory test results, and adverse effects were recorded.

Results:

The SCORAD and pruritus VAS scores significantly decreased in the SCIT group. Also, the SCIT group showed higher reduction ratios of SCORAD and pruritus VAS scores than those observed in the non-SCIT group at 3 years after treatment initiation. The risk of development of new sensitization was higher in the non-SCIT group than in the SCIT group (relative risk 1.92 [95% confidence interval {CI}, 1.30–2.85]; p < 0.05). The eosinophil count of the participants significantly differed in the complete response (CR) group (p < 0.05) but not in the non–CR group (p = 0.098). However, the serum total immunoglobulin E value was not significantly reduced (p = 0.204). Of 8421 injections given to the patients, 231 injections (2.74%) showed adverse effects during the treatment period.

Conclusion:

Three years of SCIT can significantly reduce the severity and pruritus of moderate-to-severe AD with HDM sensitization. Patients who are multisensitized can also benefit from HDM SCIT. Patients can achieve long-term effects, such as prevention of neoallergen sensitization and inhibition of the allergy march.

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by severe pruritus and eczematous skin lesions. This condition is commonly associated with allergic rhinitis, asthma, and other atopic diseases, which significantly affect quality of life.¹ The pathogenesis of AD is strongly correlated with genetic and environmental factors; that is, skin barrier dysfunction and environmental allergen infiltration play relevant roles in causing or aggravating eczematous skin lesions.² House-dust mite (HDM) is a common environmental allergen, which can destroy tight junctions, cause skin barrier dysfunction, increase allergen penetration, promote the polarization of T helper (Th) type 2 (Th2) cells, and aggravate the symptoms of AD.³

Specific immunotherapy (SIT) refers to repeated contact with gradually increasing doses of allergen extracts, which improve patient tolerance to such allergens and controls, or reduces allergic symptoms. At present, SIT is considered an effective method that can modify the natural course of allergic diseases.⁴ With regard to the different methods of administration, SIT can be divided into subcutaneous immunotherapy (SCIT), sublingual immunotherapy, intralymphatic immunotherapy, and epicutaneous immunotherapy. In previous studies, we confirmed the efficacy of SIT in the treatment of AD.⁵ However, the long-term efficacy and adverse effects of SIT are still unknown. To explore the long-term efficacy and safety of SCIT for AD in patients who are sensitized to HDM, we conducted a retrospective analysis of 378 patients with HDM-sensitized AD at our department of dermatology.

METHODS

Participants and Treatment

The participants were selected by retrospectively assessing medical records at the Department of Dermatology, Southwest Hospital. In total, 378 patients with AD and who were HDM sensitized from January 2011 to June 2018 were selected. Among these patients, 164 patients received SCIT plus pharmacotherapy for 3 years (SCIT group) and the other 214 patients received only pharmacotherapy (non-SCIT group). All the patients fulfilled the diagnostic criteria of Hanfifin and Rajka, with a value of >3.5 kU/L for specific immunoglobulin E (s-IgE) to HDM (Thermo Fisher, Waltham, MA) and scoring atopic dermatitis (SCORAD) score of ≥25. The patients in the SCIT group were followed up at 6 months and 1, 2, and 3 years after treatment initiation.

The patients in the SCIT group received repeated subcutaneous injections of dust-mite therapeutic vaccines (50% Dermatophagoides pteronyssinus and 50% Dermatophagoides farinae) (Allergovit, Reinbek, Germany). The procedure had two stages, which were as follows: initial buildup period and maintenance treatment period. The initial buildup period lasted 4–6 months, and it comprised weekly vaccine injections at gradually increasing doses until the recommended maintenance dose (1.0 mL, 5000 TU/mL) was reached. The maintenance dose was administered at 4–6 weeks intervals. The ethics committee of the Southwest Hospital of Army Medical University approved this study (KY2020166). Written informed consent was provided by all the participants before data collection.

Evaluation of Efficacy

In the SCIT group, the SCORAD and pruritus visual analog scale (VAS) scores were recorded during each follow-up. In addition, we collected data on serum total IgE (t-IgE) and eosinophil counts at baseline and 3 years after SCIT initiation. In the non-SCIT group, because of the limited clinical data, we collected the SCORAD and pruritus VAS scores at baseline and 3 years later. The changes in the SCORAD and pruritus VAS scores were presented as reduction ratios by using the following formula: (baseline score − follow-up score)/(baseline score × 100%). In this study, the patients with a reduction ratio of ≥90% for SCORAD scores were considered as those who showed a complete response (CR). However, ratios between 60% and 89% were indicative of significant efficacy, those between 20% and 59% were indicative of moderate efficacy, and those with ≤ 19% were indicative of inefficacy. ImmunoCAP (Thermo Fisher, Waltham, MA) test findings and a history of other atopic diseases, such as allergic rhinitis and allergic asthma, were recorded at baseline and 5 years after treatment initiation to all patients.

Assessment of Safety

All adverse effects during SCIT treatment were recorded on the patient's immunotherapy card. The adverse effects of SCIT were divided into local and systemic reactions. The local reactions included flushing, swelling, papules, induration, and itching at the injection site. The severity of the systemic adverse reactions was graded according to the European Academy of Allergology and Clinical Immunology.⁴

Statistical Analysis

To analyze the data with a significance level of p < 0.05, we used the IBM Statistical Package for the Social Sciences software version 26.0 (SPSS, Inc., Armonk, New York). Continuous variables were presented as mean ± standard deviation (SD). Statistical differences in terms of means between the two groups were assessed by using the Student's t-test or the Wilcoxon signed rank test. The odds ratios with relevant 95% confidence intervals (CI) were calculated to evaluate possible associations.

RESULTS

Efficacy

The baseline characteristics of the SCIT group (n = 164) and non-SCIT group (n = 214) are presented in Table 1. Demographic data were comparable between the two groups. In the SCIT group, after 3 years of treatment, the mean ± SD SCORAD score decreased, from 56.70 ± 12.42 to 4.23 ± 9.48 (p < 0.05) (Fig. 1 a), and the mean ± SD pruritus VAS score decreased, from 7.10 ± 1.66 to 0.68 ± 1.55 (p < 0.05) (Fig. 1 b; Table 2). According to the reduction ratio of SCORAD scores, 3 years after SCIT initiation, 124 of the 164 patients (75.61%) had a CR. Moreover, the treatment was significantly effective in 34 patients (20.73%), moderately effective in 5 (3.05%), and ineffective in 1 (0.61%) (Fig. 1 c). The cumulative numbers of patients who were complete response (CR) 1, 2, and 3 years after treatment initiation were 18 (10.98%), 71 (43.29%), and 124 (75.61%), respectively (Fig. 1 d). The mean reduction ratio of the SCORAD scores was higher in the SCIT group (93.07%) compared with the non-SCIT group (87.79%) (p < 0.05) (Fig. 1 e). Also, the mean reduction ratio of pruritus VAS scores was higher in the SCIT group (90.99%) compared with the non-SCIT group (85.11%) (p < 0.05) (Fig. 1 f).

Table 1.

Baseline demographic characteristics of SCIT group and non-SCIT group

SCIT = Subcutaneous immunotherapy; SD = standard deviation; VAS = visual analog scale; SCORAD = scoring atopic dermatitis.

Figure 1.

Changes in clinical symptoms after subcutaneous immunotherapy (SCIT) from 6 months to 3 years of follow-up. (a) Mean scoring atopic dermatitis (SCORAD) score. (b) Pruritus visual analog scale (VAS) score. (c) Overall treatment response to SCIT after 3 years. (d) Cumulative number of complete response (CR) patients over time. (e and f) The reduction ratios of the SCORAD and pruritus VAS scores in the SCIT group compared with the non-SCIT group.

Table 2.

Follow-up outcomes of patients in the SCIT group (n = 164)

SCIT = Subcutaneous immunotherapy; SCORAD = scoring atopic dermatitis; SD = standard deviation; VAS = visual analog scale.

*Statistical analysis was performed by using the Wilcoxon signed rank test (p < 0.05).

In addition, we performed subgroup analyses according to patient's age, AD severity, and mono- or multisensitization. In terms of age, there were significant differences in the SCORAD scores 3 years after treatment initiation between the children and adolescents group (5–16 years old) and the adults group (17–45 years old) in the SCIT group (p < 0.05) (Fig. 2 a). However, the reduction ratio of SCORAD scores among the different age groups did not significantly differ both in the SCIT group (p = 0.216) and in the non-SCIT group (p = 0.088). The reduction ratio of the SCORAD scores in the SCIT group was higher than that in the non-SCIT group both in the children and adolescents group (p < 0.05) and the adults group (p < 0.05) (Fig. 2 b).

Figure 2.

(a and b) Subgroup analysis according to patient age, (c and d) atopic dermatitis severity, and (e and f) mono- or multisensitization.

Moreover, there was no significant correlation between the reduction ratio of the SCORAD scores and age (p = 0.52). With regard to AD severity at baseline, in the SCIT group, there was a significant clinical improvement after treatment in the mild group (SCORAD score < 25), moderate group (25 ≤ SCORAD score ≤ 50), and severe group (SCORAD score > 50) (p < 0.05) (Fig. 2 c). We use SCORAD score to grade the severity of the disease. The differences in the reduction ratio of the SCORAD scores between the moderate and the severe groups were not significant both in the SCIT group (p = 0.199) and the non-SCIT group (p = 0.245).

The reduction ratio of the SCORAD score in the SCIT group was higher than that in the non-SCIT group both in the moderate group (p < 0.05) and the severe group (p < 0.05) (Fig. 2 d). Further, there was no significant correlation between AD severity and efficacy (p = 0.162). In terms of mono- or multisensitization, the patients who were only sensitized to HDM were more likely to respond better than those sensitized to more allergens based on positive ImmunoCAP test results in the SCIT group. However, the difference was not statistically significant (p = 0.1) (Fig. 2, e and f). After 3 years of SCIT, the mean ± SD eosinophil count of the participants significantly decreased, from 0.687 ± 0.462 to 0.262 ± 0.237 × 10⁹/L (p < 0.05) (Fig. 3 a). However, the serum t-IgE value did not significantly reduce (p = 0.204) (Fig. 3 b).

Figure 3.

Changes in laboratory test results 3 years after subcutaneous immunotherapy. (a) Serum total IgE (t-IgE). (b) Eosinophil count. (c) Serum t-IgE levels in the CR and non-CR groups. (d) Eosinophil count in the CR and non-CR groups.

To evaluate the biomarkers used for predicting the treatment outcome, the initial serum t-IgE values and eosinophil counts between the CR (SCORAD reduction ratio ≥ 90%) and non-CR (SCORAD reduction ratio < 90%) groups were compared. The mean ± SD baseline serum t-IgE value and eosinophil count in the CR group were 1967.60 ± 2093.14 kU/L and 0.585 ± 0.342 × 10⁹/L, respectively. Meanwhile, those of the non-CR group were mean ± SD 1698.00 ± 1199.24 kU/L and 0.890 ± 0.629 × 10⁹/L, respectively. No significant differences were observed in the baseline serum t-IgE value (p = 0.819) and eosinophil count (p = 0.195) between the CR and non-CR groups. After 3 years of SCIT, there was no significant difference in the serum t-IgE values in the CR group (p = 0.179) and the non-CR group (p = 0.979) (Fig. 3 c). However, the eosinophil count significantly differed in the CR group (p < 0.05) but not in the non-CR group (p = 0.098) (Fig. 3 d).

With regard to the long-term benefits of SCIT, all the patients in the SCIT group and non-SCIT group were followed up for new atopic diseases and sensitizations 5 years after the treatment initiation. There were 34 patients without allergic rhinitis or asthma at baseline in the SCIT group and 58 patients in the non-SCIT group. Results showed that 6 of 34 patients (17.6%) developed allergic rhinitis or asthma in the SCIT group compared with 18 of 58 patients (31.0%) in the non-SCIT group (relative risk [RR] 1.76 [95% CI, 0.77–4.00]; p = 0.163). Moreover, in the SCIT group, 19 of 91 patients (20.9%) who had allergic rhinitis alone at baseline developed asthma compared with 45 of 116 patients (38.8%) in the non-SCIT group during the 5-year treatment period (RR 1.86 [95% CI, 1.17–2.95]; p < 0.05). According to the ImmunoCAP test results, 87 patients were monosensitized to HDM at baseline in the SCIT group. After the 5-year period, 64 patients (73.6%) did not show a new sensitization compared with 58 of 118 patients (49.2%) in the non-SCIT group. The risk of development of new sensitization was higher in the non-SCIT group than in the SCIT group (RR 1.92 [95% CI, 1.30–2.85]; p < 0.05).

Safety

In this study, among the 164 patients in the SCIT group, a total of 8421 injections were given to all the patients. Of the 8421 injections given to these patients, 231 (2.74%) showed adverse effects during the treatment period. The majority of these adverse effects resulted in local (n = 208 [2.47% of all injections]), followed by systemic reactions (n = 23 [0.27% of all injections]), respectively. Of the systemic reactions, 15 were grade I, 7 were grade II, and 1 was grade III. Of the injections administered during the initial period (n = 2492), 5.74% (n = 143) resulted in local and 0.2% (n = 5) occurred as systemic reactions. Meanwhile, during the maintenance period (n = 5929), 1.1% (n = 65) resulted in local and 0.3% (n = 18) occurred as systemic reactions. The frequency of local reactions was significantly higher during the initial period than during the maintenance period (χ² = 156.95; p < 0.05). In addition, systemic reactions were more likely to occur in the maintenance period with no statistical significance (χ² = 0.683; p = 0.409) (Table 3). Moreover, the occurrence of local reactions during the course of treatment was considered a risk factor for systemic reactions (odds ratio 3.662 [95% CI, 1.307–10.257]; p < 0.05). In addition, in 130 of 4439 injections (2.93%) and 101 of 3982 injections (2.54%) in the mono- and multisensitized groups, respectively, the patients presented with adverse effects. However, the results did not significantly differ between the two groups (χ² = 1.210; p = 0.27).

Table 3.

Incidence of adverse effects in the SCIT group (n = 164)

SCIT = Subcutaneous immunotherapy.

DISCUSSION

The World Health Organization emphasized that SIT is a disease-modifying therapy for allergic diseases. At present, SIT has been included in the management guidelines on allergic rhinitis and asthma in several countries.^6,7 In recent years, an increasing number of studies used SIT to treat patients with AD; however, evidence of its long-term efficacy and safety is still insufficient. In this study, we conducted a retrospective analysis of 378 patients with HDM-sensitized AD. In terms of clinical symptoms, the SCORAD score significantly decreased in 164 patients treated with SCIT for 3 years, and the mean reduction ratio of the SCORAD scores was 93.07% compared with 87.79% in the non-SCIT group. In total, 124 patients (75.61%) had a CR in the SCIT group compared with 144 patients (67.29%) in the non-SCIT group. Pruritus is the most common clinical symptom of AD. The itch–scratch vicious cycle can cause skin barrier dysfunction, which aggravates the development of inflammation. In our study, SCIT significantly relieved itching symptoms. The SCIT group showed a higher mean reduction ratio of the pruritus VAS scores (90.99%) than did the non-SCIT group (85.11%) at 3 years after treatment initiation.

In addition, we performed subgroup analyses according to patient age, AD severity, and mono- or multisensitization. SCIT had a good clinical effect in both the children and adolescents group and the adults group compared with the non-SCIT group. However, the result did not significantly differ between different age groups. Moreover, there was no significant correlation between treatment efficacy and age. Based on the analysis of baseline disease severity, patients with mild, moderate, and severe AD experienced significant clinical improvement after SCIT. There was no significant correlation between baseline disease severity and therapeutic efficacy. However, due to the small number of patients in the mild group in this study, the results might have been biased. A large sample size should be included to further validate the efficacy of SCIT in patients with mild AD.

HDM is a common environmental allergen, which does not only induce skin inflammation but also disease aggravation. Our study found that the SCIT clinical efficacy of monosensitization was better than that of multisensitization. However, the difference was not significant, which thereby indicated that patients who were multisensitized could also benefit from HDM SCIT. This finding might be because SCIT with a single allergen can induce the expression of regulatory T cells and regulatory B cells, regulate the Th1/Th2 balance of Th cells, inhibit the activation and migration of eosinophils, and induce immune tolerance. These mechanisms then improve atopic physique and alleviate the symptoms of atopic diseases.^8,9 In the future, in patients who are multisensitized, the best allergen and whether to use multiple allergens for treatment should be further investigated.

In terms of laboratory test results, there was no significant difference in patients' serum t-IgE values after SCIT. This result was consistent with those of our previous randomized controlled study.⁵ A significant difference was noted in terms of the eosinophil count after treatment in the CR group alone. This result indicated that the eosinophil count may be a potential biomarker for predicting therapeutic efficacy. However, more studies should be conducted to validate this result. At present, the immunologic mechanism of SIT in the treatment of allergic diseases has not been fully elucidated, and there are no biomarkers for predicting the efficacy of SIT in patients with AD. In the future, more clinical and basic studies should be conducted to further explore the possible treatment mechanisms and biomarkers of AD.

In terms of the treatment course, a previous study showed that long-term SCIT is required to obtain satisfactory clinical outcomes.¹⁰ The Chinese guidelines on the diagnosis and treatment of AD recommend that the treatment cycle of SCIT must be ≥ 3 years.¹¹ In our study, after 6 months of treatment, the improvement in the SCORAD scores was statistically significant. The annual increase in the number of complete response patients was significantly higher in the second year than in the first year of treatment, and it remained constant in the third year. This result indicated that the treatment cycle of SCIT was ≥ 3 years and that the treatment was highly beneficial.

The natural process of allergic diseases, also known as the allergy march, refers to the progression of atopic diseases from AD and food allergy in infants to allergic rhinitis and asthma in children, adolescents, and adults.¹² SIT can play a secondary preventive role in allergic diseases by preventing disease development among individuals who are sensitized and inhibiting the allergy march, or new allergenic reactions in individuals who had been sensitized to a specific allergen.¹³ According to a systematic review, Kristiansen et al.¹⁴ showed that patients who developed allergic rhinitis after SIT treatment had a reduced short-term risk of developing asthma, and another systematic review provided a low level of evidence that supported the role of SIT in preventing neoallergen sensitization.¹⁵ In our study, based on a 5-year follow-up after the initiation of treatment, new sensitizations to allergens developed less frequently in patients who received SCIT for 3 years than in those who did not. Moreover, the risk of development of asthma was higher in the non-SCIT group than in the SCIT group. The effect of SCIT against the allergy march is similar to that reported by Pajno et al.¹⁶ and Inal et al.¹⁷

In this study, the common local adverse reactions of SCIT were local redness, swelling, papules, induration, and pruritus. The incidence ratio, according to the number of injections, was 2.47%. The symptoms of most patients were relieved, and other patients were completely cured after local symptomatic treatment. The incidence ratio of systemic adverse reactions was 0.27%. All the systemic adverse reactions were immediately relieved after treatment with antihistamines and/or glucocorticoids. Further, no grade IV systemic adverse reactions occurred. Local adverse reactions were commonly observed in the initial treatment period. The incidence ratio of systemic adverse reactions in the maintenance treatment period was slightly higher than that in the initial treatment period (0.30% versus 0.20%).

However, no statistically significant difference was observed. The possible cause was that the cumulative dose gradually increased in the maintenance treatment period, which thereby resulted in systemic adverse reactions. Our study found that the occurrence of local adverse reactions was a risk factor for systemic adverse reactions. This result was consistent with that reported by Gur Cetinkaya et al.¹⁸ In patients with local adverse reactions, the injection dose should be accurately adjusted and systemic adverse reactions must be actively prevented. However, a previous study reported that local adverse reactions cannot predict systemic adverse reactions.¹⁹ Therefore, further research should be conducted to evaluate the effects of local adverse reactions on systemic adverse reactions in patients receiving SCIT. In addition, there was no significant difference in the incidence of adverse effects between the mono- and multisensitized groups during treatment with HDM SCIT. In brief, SCIT was found to be safe in our treatment practice.

CONCLUSION

Three years of SCIT can significantly reduce the severity and pruritus of moderate-to-severe AD with HDM sensitization. Patients sensitized to HDM, which is a single allergen, can have better treatment outcomes, and patients who are multisensitized can also benefit from this treatment. Long-term (≥3 years) regular treatment is required to achieve satisfactory therapeutic efficacy. After SCIT, patients can achieve long-term effects, such as prevention of neoallergen sensitization and inhibition of the allergy march. In the future, with further elucidation of the treatment mechanism of SCIT, assessment of reliable biomarkers for predicting therapeutic efficacy, and continuous development of new immune adjuvants, we can establish a better treatment plan that involves SCIT to further shorten the treatment cycle, reduce allergen dosage, promote immune tolerance more effectively and quickly, and simultaneously reduce the adverse effects of SCIT.