Allergen immunotherapy in patients with atopic dermatitis allergic to house dust mite: A systematic review and meta-analysis

To the Editor: Atopic dermatitis (AD) is the most common chronic allergic skin disease worldwide. House dust mite (HDM) is the most prevalent aeroallergen and pathogenic cause, which triggers skin barrier disruption and polysensitization. Allergen immunotherapy (AIT) may be the only etiologic treatment to improve the natural history of AD by applying a dose of specific allergens to stimulate adaptive immunity in the body.^[1,2] However, the effects of HDM AIT showed controversial results recently. This study aimed to investigate the effectiveness and safety of AIT for HDM.

This systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, and the protocol was registered on PROSPERO (No. CRD42022327046, https://www.crd.york.ac.uk/PROSPERO/). Randomized controlled trials (RCTs) about “AD”, “mite”, and “immunotherapy” were searched on PubMed, Embase, Web of Science, Cochrane Library, and ProQuest databases up to November 8, 2022. The detailed searching strategies were presented in Supplementary Tables 1–5, http://links.lww.com/CM9/B898. The primary outcome was clinical efficacy. The secondary outcomes were dermatology life quality, serum immunological responses, and adverse events. The dichotomous or continuous variables were expressed as risk ratios (RRs) or mean difference (MD) with 95% confidence intervals (CIs). The Cochrane Risk of Bias 2 tool (http://www.riskofbias.info) was used to assess the RCT quality. RStudio 4.1.3 (RStudio, PBC, Boston, MA, USA) and meta-package were used to perform a meta-analysis. Heterogeneity analysis was performed using the chi-squared test and I² statistics. When P <0.1 and I² <50%, heterogeneity was considered small and a fixed-effects model was adopted. For all other cases, a random-effects model was used. Subgroup analyses were conducted as follows: (1) Administration route: Subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and intradermal injection; (2) Age: Children (0–18 years old) and adults (>18 years old); (3) AD severity: mild to moderate, moderate to severe, and mild to severe; and (4) Duration: Short-term (<6 months), medium-term (6–12 months), and long-term (>12 months).

In this study, fourteen trials included 1460 participants were available [Supplementary Figure 1, http://links.lww.com/CM9/B898]. The characteristics and quality assessment of the included studies were presented in Supplementary Table 6 and Supplementary Figure 2, http://links.lww.com/CM9/B898. The meta-analysis showed that the clinical efficacy assessed by physicians was improved in the AIT group compared to the non-AIT group (RR: 1.74, 95% CI: 1.46–2.06, I² = 0%; Figure 1A). Decreases in scoring atopic dermatitis (SCORAD, MD: −6.17, 95% CI: −8.11 to −4.22, I² = 24%) and visual analogue scale (VAS, MD: −1.80, 95% CI: −2.27 to −1.33, I² = 45%) in the AIT group compared to non-AIT group also indicated its effectiveness in patients with AD [Figures 1B, 1C]. In addition, the decrease of dermatology life quality index (DLQI) in the AIT group compared to non-AIT group (MD: −3.25, 95% CI: −5.66 to 0.84, I² = 0%; Supplementary Figure 3, http://links.lww.com/CM9/B898) indicated that the dermatology life quality was improved in AIT group. As for the serum immunological responses, significant improvements in serum-specific immunoglobulin G (sIgG) rather than serum-specific immunoglobulin E (sIgE) for HDM Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f) levels may reflect the ability to prevent relapse after AIT treatment (sIgG level for Der p: MD = 0.17 [95% CI: 0.12–0.22], I² = 0%; sIgG level for Der f: standardized mean difference (SMD) = 1.27 [95% CI: 0.24–2.31], I² = 91%; sIgE level for Der p: SMD = −0.32 [95% CI: −0.75 to 0.12], I² = 0%; sIgE level for Der f: SMD = 0.17 [95% CI: −0.16 to 0.51], I² = 0%; Supplementary Figure 4, http://links.lww.com/CM9/B898). These was no statistically significant difference at the risk of systemic adverse events (RR: 0.98, 95% CI: 0.52–1.84, I² = 30%) and local adverse events (RR: 1.49, 95% CI: 0.85–2.62, I² = 55%) between the AIT group and the non-AIT group, respectively [Supplementary Figure 5, http://links.lww.com/CM9/B898]. The results were mostly robust according to the sensitivity analysis [Supplementary Figures 6–13, http://links.lww.com/CM9/B898]. No severe publication biases were detected in all outcomes because those with mild detected biases did not affect the final results after trimming and filling [Supplementary Figure 14, http://links.lww.com/CM9/B898]. A summary of the main findings was presented in Supplementary Table 7, http://links.lww.com/CM9/B898.

Figure 1.

Forest plots of the effects of HDM AIT on patients with AD in terms of (A) clinical efficacy assessed by physicians, (B) SCORAD, and (C) VAS. AD: Atopic dermatitis; AIT: Allergen immunotherapy; CI: Confidence interval; HDM: House dust mite; MD: Mean difference; RR: Risk ratio; SCORAD: Scoring atopic dermatitis; SD: Standard deviation; VAS: Visual analogue scale.

Effect values in the SLIT and children subgroups were greater than those of the SCIT and adults subgroups (SLIT: MD = –7.22 [95% CI: –11.75 to –2.69], I² = 60%; SCIT: MD = –5.93 [95% CI: –8.08 to –3.77], I² = 0%; Children: RR = 1.96 [95% CI: 1.50–2.56], I² = 43%; Adults: RR = 1.42 [95% CI: 1.09–1.84], I² = 0%), respectively. Regarding the possible influence of treatment duration, in most cases, medium-term or long-term AIT was effective. Moreover, a cumulative effect of time was suggested because the VAS improved in the medium-term and long-term subgroups, but not in the short-term subgroup [Supplementary Figures 15–20, http://links.lww.com/CM9/B898].

Nevertheless, the decrease in SCORAD (6.17 points) did not meet the minimal clinically important difference (8.70 points). Moreover, the eczema area and severity index reported by Langer et al^[3] did not improve in the SLIT group when compared with the control group. In addition, the trend in the sleeplessness dimension (MD: −0.54, 95% CI: −1.05 to –0.02, I² = 0%) was consistent with that of the VAS in the AIT group, but the trend in the itching dimension did not (MD: −0.47, 95% CI: −1.12 to 0.18, I² = 0%) [Supplementary Figure 21, http://links.lww.com/CM9/B898]. The inconsistency between the VAS and its itching dimension existed probably because the itching measurement of the patients was objective and itching was associated with age, season, humidity, and latitude. Such subjective symptoms strongly influenced the quality of life, which showed good improvement in the AIT group. By increasing the number of trials, conclusive results may be obtained. Furthermore, we could not perform a combined analysis of conventional medication during the study period because of different evaluation indices, such as total drug consumption, daily drug scores, and total medication scores. However, most studies suggested that the long-term use of an appropriate dose of AIT could reduce the use of conventional medications, especially glucocorticoid use, which may reduce systemic side effects. It may also reduce overall costs owing to the use of fewer conventional medications.

We found that children (RR: 6.19; 95% CI: 2.09–18.38, I² = 0%) and patients with mild to moderate severity subgroups (RR: 4.11; 95% CI: 1.11–15.18, I² = 0%) experienced more local adverse events [Supplementary Figures 22 and 23, http://links.lww.com/CM9/B898]. All studies included in the mild to moderate severity subgroup contained children. Thus, we thought the adverse events were probably more associated with children. These local adverse events included swelling of the mouth, lips, and face as well as oropharyngeal itching, flares, and numbness, all of which were observed in the SLIT groups. In children with allergic rhinitis and asthma, SLIT showed a higher occurrence of local adverse events than SCIT, implying a close relationship between the route of administration and mild local adverse events.^[4] In addition, a higher risk of adverse events with high-dose SLIT was reported, thus medium-dose SLIT may be appropriate with a balance of efficacy and safety. Under the careful guardianship of mild and manageable adverse events, SLIT is better tolerated than SCIT and is more likely to be predominantly applied clinically in the future, especially for children.

Previous meta-analyses have investigated the efficacy of AIT in the treatment of AD with multiple allergens, but the efficacy was controversial, and the source of controversy may be different from the clinical response of different allergens to AIT.^[5,6,7] In this meta-analysis, we highlighted the critical role of HDM, one of the most common allergens, as a single allergen, in the pathogenesis and treatment of AD. Single allergen AIT is mostly used clinically, especially HDM AIT, and its cross-reaction and leading role against aeroallergens could decrease polysensitization. More supporting evidence of when and how to improve effectiveness is needed for multiple allergen AIT, although in theory, multiple allergen AIT could better address polysensitization. Notably, HDM AIT showed more convincing results compared with those reported in previous studies as it was a treatment for a single allergen. The insights gained may provide valuable guidance for future clinical interventions.

Unfortunately, the number of included trials was small, thus, the results should be interpreted with caution. Subgroup analyses were crude, particularly those of subgroups with poorly defined boundaries, such as subgroups by age. Moreover, the number of adverse events in the study of Langer et al^[3] exceeded the number of people in each group, which could not be included in the combined analyses but only contributed to qualitative judgments. Additionally, to reduce the heterogeneity of the studies, we only discussed the efficacy of AIT on HDM-sensitive AD, the relative results could not infer the effects of AIT on all patients with AD, which limited the extrapolation of the results.

In conclusion, HDM AIT might be effective in patients with AD, especially in children, although a higher risk of local adverse events was suggested in children. SLIT still showed greater advantages over SCIT. Therefore, more trials, especially those on SLIT with more credible data, are needed to further explore its comprehensive efficacy and safety in patients with AD.

Funding

This work was supported by grants from the National Key Research & Development Program of China (Nos. 2021YFC2701704 and 2021YFC2701700), the National Natural Science Foundation of China (Nos. 81971433, 82271749, and 82201905), Project of the Science and Technology Bureau of Sichuan Province (No. 2023NSFSC0544), and the Fundamental Research Funds for the Central University (No. SCU2023D006).

Conflicts of interest

None.

Supplementary Material

cm9-137-2245-s001.pdf ^{(4.3MB, pdf)}