Introduction
Atopic dermatitis (AD) is an IgE-dependent, allergic disease with complex pathogenesis, which affects children in particular, but is also found in adults. Depending on the data, its occurrence is estimated at 0.5–20% of the population. In most patients, AD is transient but prone to relapse and requires periodic treatment [1–3]. In some patients, AD is a form of moderate or severe disease accompanying the patients throughout their life and often requires intensive treatment [1, 3]. In patients with AD, allergic rhinitis and asthma frequently coexist [1].
As a result, the local and systemic treatment methods of this disease are constantly being improved and based on: local steroid therapy or calcineurin inhibitors, antihistamines, PUVA, periodic immunosuppression, and now primarily biological treatment [4, 5].
The position of allergen immunotherapy in AD therapy still needs to be stronger, which results from the lack of clear evidence of its effectiveness. Several studies indicate the usefulness of allergen immunotherapy (AIT) in alleviating the disease, especially in patients allergic to house dust mites (HDM) [6–8].
Patients with an allergy to mites: D. pteronyssinus and D. farinae, have different molecular allergy profiles. The number of discovered antigenic components of these mites continues to increase, but their clinical significance is confirmed for some [9–12]. According to the EAACI recommendation, AIT is used in allergic rhinitis and HDM-driven asthma, but its use in AD is not recommended [6, 13, 14]. However, the possibility of the variety of HDM molecular profiles may suggest that some AD patients achieve clinical success after AIT.
Aim
The study aimed to verify the hypothesis that the effect of HDM AIT in AD patients may be derived from the baseline molecular profile of mite allergy. A secondary aim of the study was to evaluate the efficacy of AIT in monosensitised mite patients compared to patients with polysensitisation to other inhalant allergens.
Material and methods
The study was a prospective, observational, randomised, double-blind, placebo-controlled study on AIT. Sixty-one patients with moderate-to-severe AD allergy and house dust mite allergy were included in the study. All included patients have received a 12 months’ allergen injection immunotherapy with the use of HDM allergen extract or placebo.
The inclusion criteria were: diagnosis of AD with a minimum of 1 year of therapy before inclusion, moderate-to-severe AD symptoms: according to Eczema Area and Severity Index (EASI), at least 7.1 points, and %BSA (Body Surface Area) scale at least 16 points, a positive skin prick test (SPT) and positive for specific immunoglobulin E (sIgE) to extract of D. pteronyssinus and D. farinae.
The exclusion criteria were: other active skin diseases, immunosuppressant treatment including oral corticosteroids, other chronic diseases, and allergen immunotherapy.
The characteristics of the patients are presented in Table 1.
Table 1
Characteristics of the study patients at baseline
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Medical University of Silesia in Katowice, Poland (KNW-1-131/N/9/K). Informed consent was obtained from all subjects involved in the study.
The study was registered at ClinicalTrials.gov under no. NCT03209245.
Treatment
The patients received Purethal Mites (20,000 AUeq/ml, HAL Allergy BV, Leiden, Netherlands) with extract of allergens: D. pteronyssinus and D. farinae (50/50%) or a placebo. Purethal was administered as perennial therapy using the following regimen: 1 dose – 0.1 ml, 2 doses – 0.2 ml, 3 doses – 0.5 ml every week, and 0.5 ml every 4 weeks. The average cumulative dose was 375,000 BAU (Bioequivalent Allergy Units) administered to each patient undergoing active treatment [15].
During therapy, patients with bacterial infection were allowed to receive treatment with topical Bactroban (mupirocin ointment) and/or a 7-day course of amoxicillin and/or prednisolone 0.5 mg kg during 10 days was administered on any occurrence of skin exacerbation including superinfection.
Depending on individual diseases, the placebo group had oral antihistamines added such as desloratadine and topical medications.
Symptomatic treatment was scored as medication score: one point for desloratadine, mometasone furoate cream, and mupirocin ointment use every day, 7 points for every course of amoxicillin and also 10 points for the course of encortolon. The patients were required to record symptomatic drug use in the diary card [16].
Efficacy of AIT
The authors adopted their AD improvement criterion after 1 year of AIT treatment as a reduction of all examined indicators by at least 50% from the baseline for %BSA and TMS, and EASI scores.
Diagnostic procedures
Careful examination of the eyes, ears, nose, and dermatological examination was performed on all patients.
Scales
The EASI assesses the extent of the disease on a scale of 0 to 6 in 4 defined body regions plus an assessment of erythema, infiltration and/or population, excoriation, and lichenification, each on a scale of 0 to 3. A formula is then used to calculate the total score for each of the 4 regions, which are then added together. Interpretation of the EASI result: 0 = no change, 0.1–1.0 = almost no change, 1.1–7.0 = mild intensity, 7.1–21.0 = moderate intensity, 21.1–50.0 = high intensity, 50.1–72.0 = very severe.
In this analysis, %BSA was categorised according to severity bands: clear (0%), mild (> 0 to < 16%), moderate (16 to < 40%), and severe (40–100%)
Skin prick tests
The SPT was performed with inhalant allergens (HAL Allergy B.V, Leiden, Netherlands) from the following panel: D. pteronyssinus, D. farinae, mixed five types of grass (Phleum pratense, Dactylis glomerata, Anthoxanthum odoratum, Lolium perenne, and Poa pratensis), mixed tree, mugwort, Alternaria, Cladosporium, and dog and cat allergens. Positive (10 mg/ml of histamine) and negative (saline) controls were included. A positive skin test for allergens was defined when a minimum wheal diameter of 3 mm greater than the negative control was noticed. Patients with negative tests for histamine sensitivity were excluded from further analyses [17].
Clinical assessment
In all included patients, clinical assessments with the use of EASI and %BSE scales and medication score were performed at the start and at 12 months of treatment.
Laboratory tests included: sIgE assay: Serum-specific IgE levels to D. pteronyssinus, D. farinae, and to rDer p 1, rDer p 2, rDer p 5, rDer p 7, r Der p 10, rDer p 11, rDer p 21, rDer p 23, rDer f 1, rDer f 2 were determined by Immuno CAP (ThermoFisher Scientific, Uppsala, Sweden), following the manufacturer’s instructions at the start of the study and at 12 months. Values were expressed in kU/l.
New sensitisations
A new sensitisation was defined as a rise of IgE levels against analysed HDM antigen molecules from < 0.15 kU/l to > 0.35 kU/l. An assessment of the occurrence of new sensitisations was performed in the 12th month of the study.
Statistical analysis
The statistical analysis was performed using Statistica version 8.12 (SoftPol, Cracow, Poland). The non-parametric tests were used because the data are not normally distributed. The Wilcoxon test was used to analyse differences between the groups. The odds ratio (OR) and 95% confidence interval (CI) were estimated to assess the impact of the presence of individual HDM molecules on the effect obtained after AIT. The ANOVA test was used to compare scale scores. Differences were considered significant at p < 0.05 [15].
Results
Efficacy of AIT
Finally, 24 patients completed AIT and 33 placebo-completed observations. The remaining patients discontinued treatment due to failure to return to the following appointments; 1 patient was infected with COVID-19 and stopped therapy for this reason.
The data are presented in Table 2. Of the 24 desensitised patients, 15 achieved the positive expected effect according to the agreed improvement criteria after 12 months of HDM AIT. The other desensitised patients did not reach an effect, but 4 had a noticeable improvement at the level of the assessment of about 30%. None of the patients who received a placebo had an improvement in AD of at least 50% after 1 year of follow-up. Patients with polysensitisation less frequently achieved the expected HDM AIT effect than patients monosensitised to mites (p < 0.05).
Table 2
The obtained effects of AD treatment after AIT or placebo in the study groups
Molecular profile and AIT
The patients enrolled in the study had 63 different variants of molecular allergy profiles to HDM. The percentage of allergies to individual antigens is presented in Table 3. The presence of sensitisation to rDer p 1 (OR = 4.35, 95% CI: 4.01–4.56) and/or rDer p 2 (OR = 2.16, 95% CI: 1.98–2.33) and/or rDer f 2 (OR = 1.41, 95% CI: 1.55–1.78) molecules significantly increased the effectiveness of immunotherapy in AD patients if they were only simultaneously monosensitised against mites.
Table 3
Prevalence of IgE reactivity in patients with success or not after SCIT
There was no correlation between the presence of the individual HDM molecules and the effect of AIT in polysensitised patients (p > 0.5) and also in the entire analysed group of patients (mono- + poly-sensitised; p > 0.05).
Discussion
The obtained results indicate the effectiveness of HDM AIT in patients with advanced AD allergy, but mainly in patients with monosensitised HDM. Not many studies evaluate the effectiveness of HDM allergen injection immunotherapy in adult AD patients [18–21]. Zhou et al. confirmed that 3 years of injection allergen immunotherapy to HDM significantly reduced the severity and pruritus of moderate-to-severe AD [19]. Research by other authors also indicates that such desensitization may be effective in treating AD during 1 year using similar criteria of improvement by 50%, however, with the use of the SCORAD skin assessment scale [18]. This last scale dominates as a parameter assessed in similar studies; however, the combination of EASI, %BSA and TMS scales seems more reliable and accurate [19–21]. In many studies, similar AD patients had the presence of allergic rhinitis with or without allergic asthma, which was significantly improved after HDM AIT [19–21]. These observations are consistent with the statements in the presented study. However, the results concerning improving allergic rhinitis and asthma were not presented due to the assumed research goals. It should be emphasized that some patients with severe AD were not qualified for the study due to their inability to withdraw from immunosuppressive treatment, which could weaken or exclude the effects of AIT. In these patients, the AD mechanism is usually very complex, and apart from the dependent IgE mechanism, autoimmune and infectious inflammation coexist [1, 22].
On the other hand, some authors are critical of the effectiveness of HDM AIT in treating AD and emphasize that a weak effect after AIT occurs in patients with a severe and persistent form of AD [23].
In each of the analysed studies, there were different criteria for including patients, which led to problems with appropriate comparing results of AIT. The observed lack of AIT effects in most patients with polysensitization indicates a significant limitation of eligibility for this treatment. It was compatible with previous observations where patients with polysensitization also obtained the worse effect after desensitization, even after 3 years of AIT [19]. It is worth adding that such a relationship between the clinical severity of AD and exposure to mite allergen is more difficult to confirm than in respiratory allergic diseases.
A recent observation is a link between the efficacy of HDM AIT in treating AD on the mite molecular profile. In this study, 63 variants of HDM molecular profiles were confirmed in patients diagnosed with AD, the most common ones being rDer p 1, rDer p 2, rDer p 23 and Der f 2: 61.5%, 56.6%, 39.1% and 43.2%, respectively.
Gonzales-Perez et al. observed a similar, large number (n = 72) of HDM molecular profile variants in AD patients, but a significantly higher frequency of the same tested molecules, reaching even 80% in the case of rDer p 1 and 60% for rDer p 5 [24]. A similar prevalence of profile molecules of HDM was noticed in another Spanish observation [25]. This may be because there is a significant variety of allergies in different populations depending on the geographical region (area of Spain compared to Poland).
In the presented study, the presence of major allergens, such as rDer p 1, rDer p 2 or rDer f 2, a positive predictor of AIT efficacy, was confirmed. It is similar to HDM AIT in the therapy of allergic rhinitis and allergic asthma [25]. At the same time, it was impossible to establish negative predictors of effectiveness depending on individual molecules, which may result from a too small group of subjects. It is one of the main limitations of the study. It results from the restrictive inclusion criteria, which shows that AIT can only be useful in a small group of patients. Other limitations are the short observation time, consistent with similar studies, and the lack of in vitro biomarker evaluation during desensitization.
In particular, it was impossible to confirm the pessimistic prediction of rDer p 10 for no AIT effect, according to earlier data [26]. However, it should be remembered that other HDM principal molecules dominate AD patients’ images, which may be the key to AIT effectiveness [25]. It requires further research.
The analysis of new allergies in the scope of the analysed molecular profile of HDM indicates a protective effect of AIT. It is consistent with other observations confirming new allergy inhibition in desensitized patients. Because the groups are too small, this requires further research.
Conclusions
HDM AIT could be helpful in patients with moderate-to-severe AD and sensitized to HDM as an add-on therapy. The presence of various HDM molecules may affect the effectiveness of the expected AIT, just as in the case of allergic rhinitis, it may inhibit new sensitization of individual HDM molecules; however, this requires further research.
