Allergen immunotherapy in atopic dermatitis

Introduction

Atopic dermatitis (AD) is a genetically determined chronic skin disease that changes over time. It belongs to a group of atopic diseases characterized by an abnormal immune response to small doses of antigens. The response results in excessive production of IgE antibodies.
Over the past 30 years, the prevalence of AD has doubled or tripled in industrialized countries. The condition affects up to 20% of children and up to 10% of adults. However, the prevalence varies considerably among countries. The reasons for these differences are still poorly understood [1]. This condition mainly occurs in the first year of life (about 60% of cases). However, it can occur at any age. Late-onset AD is diagnosed at around the age of 40, while very late-onset AD is diagnosed after the age of 60. Early disease onset, a positive family history of atopy and early exposure to allergens are risk factors for a prolonged course of the disease and its persistence into adulthood [2]. The mode of inheritance is polygenic. There is a strong association between atopy in parents (particularly AD) and the onset and severity of early AD in children. When both parents present with atopic disease, the risk of AD is 80% in a child. When one parent is affected, the risk is about 40%.

Pathogenesis

The pathogenesis is complex and has not been completely elucidated. It is believed to result from several factors, including innate susceptibility, environmental and infectious agents, impaired immune response, impaired structure and function of the skin barrier, and abnormal colonization of the skin by microorganisms (mainly Staphylococcus).

Impaired immune response

The European Academy of Allergy and Clinical Immunology (EAACI) Position Paper provided a modern nomenclature for allergic diseases, which respects the earlier classifications dating back to the early 20th century. Hypersensitivity reactions originally divided by Gell and Coombs into four different types were extended to nine types [3]. Individual mechanisms of hypersensitivity often occur simultaneously, for example in those diagnosed with AD in whom there is a predisposition to the development of IgE-mediated hypersensitivity to antigens in type I, IV and V hypersensitivity reactions [4].
House dust mites are among the typical allergens that initiate type I hypersensitivity. It involves 2 phases: the sensitization phase and the effector phase. The former depends on T2 cell signals that regulate the production of allergen-specific IgE. It begins during the first exposure to a particular allergen, which is deposited on the skin. Next, it is internalized by antigen-presenting cells (APCs), mostly by dendritic cells, which present the antigen to Th0 lymphocytes. Alarmins produce cytokines that activate ILC2, which further promote the T2 cell response. It results in the development and maturation of the B-cell response. These cells produce IgE antibodies of high specificity [3].
In turn, in the effector phase, during another exposure to the same allergen, it combines with the IgE antibodies on the surface of mast cells and basophils. As a result, they degranulate and a direct release of inflammatory mediators is reported (including histamine, LTC4, PGD2, IL-8, TNF, chymase, or tryptase), which results in increased inflammation in the skin [5].
The normal immune response is determined by the balance between Th1 and Th2 lymphocytes (differentiating from Th0 helper T cells). These two subpopulations have an inhibitory effect on each other. A characteristic phenomenon of AD is the preference for CD4+ lymphocyte differentiation towards the Th2 lineage with impaired proliferation of Th1-type cells [4, 6].
The type IVb reaction mainly involves Th2, ILC2, NK-T cells, eosinophils and macrophages.
In the early phase of the IgE-mediated immune response, the predominance of Th2 lymphocytes is reported. They secrete primarily IL-4, IL-5 and IL-13. The increase in IL-4 and IL-13 stimulates B lymphocytes to produce IgE through direct (from IgM) and indirect (from IgG1) mechanisms.
ILC2 cells play a role in the recruitment of eosinophils and basophils and the activation of antigen-presenting cells, promoting the T2 response. NK-T cells produce IL-4, contributing to the activation of T2 CD4+ and CD8+ cells and the initiation and maintenance of inflammation. However, the main mechanism associated with type IVb hypersensitivity is the activation of eosinophils by IL-5. Activated eosinophils release cytotoxic granules containing proteins that can cause tissue damage and contribute to the induction of allergic inflammation. Th1 lymphocytes are predominant in the chronic phase. They produce IFN-γ, TNF-α, IL-2 and many other pro-inflammatory cytokines responsible for chronic inflammation such as dermatitis [3, 4, 6].
The mutual regulation of mechanisms associated with type I and type IVb is crucial in the development of allergy during sensitization and the chronic phase of allergic disease. The reactions overlap at the last stage when IgE synthesis occurs. In turn, type IVb and V hypersensitivity overlap in epithelial cell activation and opening of the epithelial barriers [3].

Impaired structure and function of the skin barrier

Type V refers to the activation of the immune system facilitated by the disturbance of the epidermal barrier function, which consequently leads to chronic inflammation [3]. The protective properties of the skin are impaired due to the abnormal filaggrin expression, which is responsible for proper skin cell structure, skin tightness and adequate hydration. As a result of the impaired skin hydration and the loss of skin cell adhesion, the skin is no longer a barrier to microorganisms, allergens or other agents. It allows them to penetrate deep into the skin and contact Langerhans cells in the skin (whose number increases in individuals with allergic diseases). As a result, the development of allergy occurs by stimulating T lymphocytes.

Environmental impact

Non-genetic factors influencing the disease course include macro- and microclimate, nutrition, contact with allergens, skin irritation by physical and chemical stimuli, sweating, or psychological factors (e.g. stress).

Symptoms

Atopic dermatitis is a heterogeneous disease with different genetically determined phenotypes. Many genes are involved in the development of clinical symptoms. These genes determine a completely different clinical picture and the disease course. Therefore, each patient requires an individual diagnostic and therapeutic approach. However, certain clinical features characteristic of the disease can be distinguished. These include the criteria for the diagnosis of AD, in particular the Hanifin and Rajka criteria. Frequent exposure of the skin to an allergen is followed by the development of skin inflammatory lesions with the morphology of eczema, accompanied by generalized dryness of the skin and very intense itching, as a result of which the patient scratches the affected area, thus further damaging the skin. Recurrent periods of exacerbation are typical, which may occur due to a viral infection or severe stress. Atopic skin does not have primary immunity. Therefore, skin bacterial or viral superinfections can occur very often, which further obscures the clinical picture and makes a correct diagnosis difficult.
Disease location is age-dependent. Lesions appear primarily on the skin of the face in infants. In older children, they are present in cubital and popliteal fossae, while in adults the skin of the neck, nape, palms and popliteal fossae is usually affected.

The role of allergen immunotherapy in the treatment of allergic diseases

Allergen immunotherapy (AIT) with a specific allergen is currently the only causal treatment for atopic diseases. It is indicated in patients who have specific antibodies against relevant allergens. Immunotherapy is an effective treatment in patients with allergic rhinoconjunctivitis, allergic asthma and allergic reactions to insect bites [7–10]. Controlled clinical trials suggested that subcutaneous or sublingual AIT could also be beneficial in AD.
AIT has disease-modifying properties and provides long-term clinical improvement in many patients by alleviating or resolving symptoms associated with allergen exposure, thus reducing the need for antihistamines taken on an as-needed basis [11].
AIT involves repeated administration of the allergy vaccine to induce immune tolerance. Allergy vaccines administered subcutaneously or sublingually are the most commonly used. The criteria for AIT include the presence of allergen-specific IgE in skin tests or serum and the occurrence of clinical symptoms due to exposure to a specific allergen. AIT is not used in asymptomatic patients because allergy to environmental allergens alone is not always clinically significant. In the case of symptomatic allergy to many allergens, the selection of allergen for immunotherapy depends on the length of exposure to the allergen during a year, symptom severity and the possibility of avoiding exposure to the allergen.
AIT modifies multiple cellular and humoral immune mechanisms that lead to clinical improvement. Such processes as rapid desensitization to the allergen, induction of long-term specific immune tolerance and suppression of the allergic inflammatory response are associated with improvement. The effect of AIT on the immune system is very complex. Regardless of the type of allergen used and the route of vaccine administration, the AIT mechanisms are similar and involve anti-inflammatory effects by modifying the function of many cells. Additionally, AIT leads to inhibition of the Th2 response, induction of regulatory T cells and an increase in Th1 mechanisms accompanied by an increase in IL-10 synthesis by T and B cells, monocytes and macrophages. Additionally, an increase in the synthesis of TGF-β occurs. Together with IL-10, it contributes to the regulation of the T-regulatory cell response and immunoglobulin class switching from IgE to IgG1, IgG4 and IgA. These antibodies compete with IgE for allergen binding, thus reducing allergen uptake and its presentation. AIT regulates the number of mast cells and basophils, and reduces the release of inflammatory mediators. In addition, it inhibits the recruitment of eosinophils and macrophages to tissues, thus reducing organ sensitivity to the allergen [8, 12].
Specific immunotherapy starts with an initial dose that is gradually increased at regular intervals until a maintenance dose is reached. The regimen of administration is specified by the manufacturer. However, it can be subject to modification by an experienced allergist, e.g. if adverse reactions occur after vaccine administration. Then the maintenance dose should be adjusted to the maximum tolerated dose by the patient. In subcutaneous AIT, once the target maintenance dose is reached, other doses are usually administered every 4–6 weeks. The current guidelines recommend at least 3 years of AIT to achieve the desired therapeutic effects [13].
Objective assessment of the effectiveness of AIT is conducted based on the measurable parameters, such as the severity of clinical symptoms at the time of exposure to a given allergen, drug requirement and the results of respiratory function tests. A decrease in the severity of clinical symptoms is an early indicator of AIT efficacy. To date, immunological markers of AIT efficacy have not been determined.
AD can be the first step in the so-called atopic march that leads to the development of asthma or allergic rhinitis over time. Patients with AD develop significant clinical deterioration in the areas of the skin exposed to sensitizing allergens after exposure to these allergens. AIT should be considered in such cases, mainly when respiratory symptoms develop. Currently, there are no recommendations for the routine use of AIT in AD patients. However, clinical improvement can be observed in cases of house dust mite allergy treated with this method. Evidence of efficacy is based on controlled clinical trials.
AIT can block the atopic march. It changes the natural course of allergy in the long term, reduces the risk of developing further atopic diseases, improves the quality of life and allows for a reduction in doses of symptomatic medications and even drug discontinuation.

Discussion

The aim of this review is to investigate the possible role of allergen immunotherapy for house dust mites in the treatment of AD. The role of specific AIT in AD is not as evident as in asthma or rhinoconjunctivitis. Given the heterogeneity of AD, it is unlikely that AIT can offer benefits to all phenotypes and/or endotypes of the disease. There have been reports on the improvement of AD symptoms due to subcutaneous and sublingual immunotherapy with selected allergens, mainly house dust mites. These observations may be a rationale for allergists to consider immunotherapy with inhaled allergens in patients with AD. Before making such a decision, it is necessary to prove the relationship of disease etiology with an IgE-dependent mechanism and a specific allergen. Unfortunately, the involvement of an allergic factor in the pathogenesis of AD in patients is not always easy to establish.
We analyzed studies that met the following criteria: the presence of patients with AD as the main indication for desensitization to mites. Finally, our analysis included a total of 1,355 AD patients allergic to house dust mites, of whom 550 subjects were randomly assigned to the control group and 805 to AIT. In the group of patients undergoing desensitization, 185 subjects received subcutaneous immunotherapy (SCIT) and 620 sublingual immunotherapy (SLIT). Immunotherapy was effective in both groups, in children and adults, and in different stages of AD severity. Table 1 summarizes the characteristics of each study.
In their randomized, double-blind, placebo-controlled study, Liu et al. [14] enrolled 239 patients aged 18-60 years with mild-to-moderate AD (SCORAD 10-40). SLIT was applied with extracts of Dermatophagoides farinae (D. farinae drops provided by Zhejiang Wolwo Bio-pharmaceutical Co., Ltd.). Their conclusions were based on the results of patients from 4 groups: placebo patients (n = 57) and three sublingual D. farinae drops groups (high-dose (n = 60), medium-dose (n = 55) and low-dose (n = 54)). A total of 48 patients did not complete the study for various reasons. After 36 weeks of treatment, the following were reported: some decrease in SCORAD, a reduced need for medication, decreased skin lesion area and the dermatology life quality index (DLQI) mainly in the medium-dose D. farinae drops group, which suggests that such a dose might be appropriate for treatment.
Zhou et al. [15] conducted a retrospective analysis of 378 patients aged 5–45 years with moderate-to-severe AD (SCORAD ≥ 25). Of those subjects, 164 were given SCIT and pharmacotherapy for 3 years (SCIT group), and 214 patients received only pharmacotherapy (non-SCIT group). The subjects in the SCIT group were given repeated subcutaneous injections of vaccines (50% Dermatophagoides pteronyssinus and 50% Dermatophagoides farina; Allergovit, Germany). After 3 years of treatment, the SCORAD and pruritus VAS scores significantly decreased in the SCIT group. The risk of development of new sensitization was higher in the non-SCIT group.
In their randomized controlled study, Huang et al. [16] enrolled 440 patients aged 4-13 years with AD. The SLIT group (n = 309) received Dermatophagoides farinae drops and pharmacotherapy, while 131 patients received pharmacotherapy alone. Each group was divided into subgroups based on the duration of treatment (1, 2 and 3 years of treatment). After 3 years, the SCORAD scores in all SLIT subgroups were significantly lower than those of the corresponding control subgroups (p < 0.05). At 1 year after treatment completion, the SLIT group’s SCORAD score was significantly lower compared to the baseline score and the scores from the control group (p < 0.05). Huang et al. considered SLIT with Dermatophagoides farinae drops to be safe and effective in pediatric patients with AD. The effectiveness was maintained even after treatment cessation.
There are many studies on the beneficial effects of specific immunotherapy in the treatment of allergic rhinitis and/or asthma induced by house dust mites. In these papers, AD often appears as a comorbid condition, but it is not in primary or secondary outcomes. Therefore, no precise assessment of skin improvement was performed.
Chan et al. [17] conducted a 12-month prospective study evaluating the efficacy of sublingual immunotherapy for house dust mite-induced allergic rhinitis and its co-morbid conditions, i.e. asthma, allergic conjunctivitis and/or AD. The study included 120 patients. Eighty subjects underwent SLIT with Dermatophagoides pteronyssinus and Dermatophagoides farinae extract (SLITone Ultra HDM ALK-Abellò). Controls were defined as age- and sex-matched patients (n = 40) who were never treated with SLIT. In the SLIT group, 26.25% of patients also presented with AD, compared to 27.5% of the controls. The efficacy of immunotherapy for AD was assessed by the SCORAD score. Only the SLIT group showed a significant decrease from 46.40 to 29.38 (p = 0.0004).
Yu et al. [18] conducted a randomized open-label trial to evaluate the efficacy of cluster and conventional immunotherapies in patients with allergic rhinitis who were allergic to house dust mites. Some patients also presented with asthma and/or AD. The study included 149 patients aged 5–56 years with allergic rhinitis, 15 of whom also presented with AD. SCIT was administered using a commercial standardized depot preparation of D. pteronyssinus extract (Alutard SQ; ALK-Abelló). The efficacy was assessed based on the severity of symptoms typical of allergic rhinitis and skin prick test results. No other skin assessment was performed.
However, the subject of the paper is the analysis of research in which AD was the main inclusion criterion, yet there are very few such studies. Therefore, we analyzed studies with different methodology and clinical evaluation. Most of them were randomized trials with a control group receiving placebo or pharmacotherapy alone [14, 16, 19–23]. One study was a retrospective analysis of medical records, based on which a SCIT group and non-SCIT group that received only pharmacotherapy were selected [15].
One of the first successes in immunotherapy for AD was observed by Silny and Czarnecka-Operacz [24]. In 2005, they proposed the index for AD (W-AZS) that assesses subjective as well as objective symptoms of the disease [25, 26]. The researchers conducted a one-year double-blind placebo-controlled study to evaluate the efficacy of AIT in the treatment of AD caused by allergy to house dust mites or grass pollen. After 12 months of therapy, they observed a significant improvement in the index and a non-significant decrease in specific IgE levels. The study found that specific AIT seems to be an effective method for treating AD, and further controlled studies are warranted in this respect [24].

Conclusions

Currently, single observations are insufficient to extrapolate the recommendations to the whole group of patients. The observed divergent end points of the analyzed studies lead to doubts when assessing them collectively. Therefore, well-designed, multi-center clinical studies are needed to assess the role of AIT in AD patients with allergy to house dust mites. It will be probably an important recommendation as personalized treatment for AD in contemporary medicine.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References