HDM avoidance has been practiced as a part of lifestyle modification with extrinsic AD patients for quite a period. Yet as a more active treatment modality, SIT is receiving more attention. SIT was initially practiced in allergic rhinitis or asthma patients. Up until now, SIT is the only disease-specific treatment modality that suppresses allergic responses for a long period of time. SIT aims to induce allergen-specific tolerance otherwise known as allergen vaccination21 through acquiring immune tolerance with induction of allergen-specific regulatory T cells (Tregs).

The acute phase of AD is closely associated with production of Th2 cytokines and commonly observed Th2-biased profiles are suggested to be results of increased clonal expansion or differentiation of Th2 cells or increased tendency to activation and apoptosis of high IFN-γ producing Th1 cells.22 These Th1 cells are known to be involved in apoptosis of epithelium in AD. Thus, induction of Treg cells during the SIT consequently increases suppression of allergen-induced T-cell proliferation, and Th1 and Th2 cytokines.23 Thereby, we may observe clinical improvement of AD as a result of skin inflammation reduction and a diminution in epithelium apoptosis.

Tregs involved in mechanisms of SIT express IL-10, transforming growth factor β (TGF-β) to elicit early phase desensitization of mast cell, basophil, and eosinophil. These allergen-specific Tregs also suppress Th2 cells, thereby inhibiting IgE production, while at the same time stimulating expression of IgG4, a non-inflammatory immunoglobulin isotype. Also, cytokines such as IL-3, IL-4, IL-5, IL-9, and IL-13 that are expressed from Th2 play an important role in survival, activation, and differentiation of mast cells, basophil, and eosinophils, but SIT suppresses cytokine axes as well.

SIT can be divided into 2 major groups depending on the route of administration: sublingual (SLIT) and subcutaneous (SCIT) methods. While the routes may differ, both equally affect peripheral allergen-specific Tregs through similar mechanisms for inducing T-cell tolerance, inhibitory functions of IL-10, TGF-β, and reduction of mast cell and eosinophil. However, in early stages of treatment, expression of Treg, reduction in IgE or increase in IgG4 might not be evident in SLIT compared to SCIT.24

The most important factor to consider while choosing candidates for immunotherapy is finding those who are actually sensitized to HDM. Therefore, majority of previously reported studies also enroll patients who have positive allergen sensitization to HDM. Standards for choosing candidates for SIT in our institution is first selecting extrinsic AD patients with serum total IgE above 150, and then additionally selecting only those who have positive reactions (over 3+) to HDM on CAP-test or skin prick test. We initially start the therapy in weekly regimen for 16-18 weeks as initial build-up phase and slowly escalates dosage of HDM extract, and when the maintenance dosage is reached, the patient visits the clinic biweekly for four times. Afterwards, the monthly regimen can be installed. Depending on clinical response, the patient can continue on with the treatment for 3 to 6 years.

There is no exact consensus for treatment period, interval time between treatments, and follow-up period after termination of SIT, but most literature generally agree upon 3 years as an ideal treatment period.25 Our institution also maintains one year of treatment for all those started on SIT, and continues for 3 years unless complete remission is reached.

In the past, there has been a lack of evidence of SIT in AD compared to that in asthma or allergic rhinitis. However, with increasing reports of comparable efficacy and safety of SIT in AD, researches are actively seeking into the field of SIT in AD as well. Recently published meta-analysis on 8 different randomized controlled trials of SIT on AD showed excellent results of the therapy, strengthening rationale for the treatment.26

Results from previously performed randomized controlled SIT are summarized in Table 1. First, in Kaufman and Roth's study in 1974 (United States), quasi-randomized controlled study was performed among total of 52 adult and pediatric AD patients.27 A total of 26 patients completed the SCIT trial for a period of 2 years, and significant clinical improvement was seen in 81% of the treatment group and 40% of the placebo group. Warner et al.28 conducted randomized, double-blind, placebo-controlled study for children with asthma (United Kingdom) and among 20 children who possessed additional atopic features, there was subjective improvement of clinical eczema features as judged by the patients and parents in active treatment group (77.8%) compared to minimal improvement in the placebo group (27.3%) after 1 year of treatment. Later, Glover and Atherton performed randomized, double-blind, placebo-controlled trials for HDM SCIT for 24 pediatric AD patients.29 The first study did not reveal any statistical difference between the treatment and placebo groups. The second study was conducted with patients who underwent active treatment in the first study and found greater clinical improvement, suggesting that long-term treatment for at least 1 year is necessary. Persistent efforts of SIT in AD continued, and a double-blind, placebo-controlled trial was conducted, for 20 adult and pediatric AD patients.30 They used W-Atopowe zapalenie skóry (W-AZS), a Polish acronym for atopic dermatitis severity score to assess the extent and severity of skin inflammation index in AD patients concerning pruritus, sleep disturbances and extent and severity of skin inflammation, to evaluate the clinical efficacy. There was a significant decrease in clinical score of W-AZS index after a period of 12 months, supporting growing number of evidence for efficacy. A randomized, double-blind, placebo-controlled trial was performed among a larger population of pediatric patients31 as a sublingual method for 18 months. Scoring atopic dermatitis (SCORAD) showed a dramatic decrease 9 months after the treatment and disease-control medication for treatment of AD was significantly reduced in treatment group compared to placebo group. In addition, compared to baseline, visual analogue scale (VAS) showed tendency to decrease only in the treatment group, although did not show statistical significance. Another randomized double-blind placebo-controlled trial by Novak et al.32 was conducted with 168 adult AD patients for 18 months. Even though, the study did not reveal the efficacy in overall AD patients, SIT showed statistical significance of SCORAD reduction in subgroup of severe AD patients with SCORAD >50. Median reduction of total SCORAD of 18% was observed. The best outcome was shown during September to February, due to the use of indoor heating and subsequent high HDM exposure. The efficacy was more pronounced with longer duration. Lastly, most recent randomized control trial carried out by Qin et al.33 analyzed 107 patients undergoing SLIT for 12 months. A total of 84 patients finished the trial, compared to the placebo group (53.85%), treatment group (77.78%) showed improvement in symptoms. SIT for AD patients are practiced in Korea as well. But only little clinical studies have been conducted. There was one pilot study of SIT published by Nahm et al.34 Even though 20 AD patients showed significant decreased in SCORAD score with noticeable clinical improvement after 12 months, since it was modified treatment methods combining SIT and histamine-immunoglobulin complex treatment, it was difficult to see the sole and exclusive efficacy of SIT. Our institution performed retrospective review on patients who underwent at least 3 years of HDM SIT for 217 extrinsic AD patients selected through total IgE and CAP test or skin prick test with hypersensitivity to HDM.35 Clinical improvement was judged based on investigator global assessment (IGA) and patients' subjective assessment of symptoms. In overall, 88.4% of patients showed clinical improvement and among these patients, 63.9% patients showed complete or near-complete remission. Pruritus and loss of sleep was also significantly reduced with 87.2% of patients reporting improvement in pruritus, and 92.7% of patients with only mild or no disturbance of sleep. Hence, although the efficacy of SIT for extrinsic AD patients with positive reactions to HDM was believed to have controversial results for patients in the past, there is a growing trend of thought through many double-blind placebo-controlled trials and meta-analysis, that SIT is indeed an efficient and safe treatment modality for AD patients. While 3 to 6 years of treatment period is generally recommended in literature, there is no set evidence stating long-term efficacy for AD patients receiving SIT for more than 3 years. Yet retrospective review from our institution support the long term efficacy of SIT indicating clinical improvements are most significant when the treatment is continued for a minimum of 3 years.

Both local and systemic complications can occur due to SIT. Based on a survey of systemic side-effects occurring SCIT in the past 3 years (2008-2011), there were noticeable systemic side-effects in only 0.1% of the total 18.9 million SCIT treatment performed, and there was no single case of fatal complications.36 Majority of systemic complications occurred within 30 minutes of injection, and some of the delayed type response were mild symptoms such as a flu-like illness.37

Common local side-effects that can occur in SCIT are urticaria or pruritus, but majority of these reactions persist for less than 24 hours and are rarely regarded as noticeable complications. Comparing with results from our institution and other RCTs previously performed, mild urticarial eruptions and pruritus occurred in only <1% of patients.38 Furthermore, in one double-blind placebo-controlled trial, incidence of pruritus lasting for 1-2 days and discomfort, mild exacerbation of atopic lesions, urticaria, headaches or rhinitis were almost similar between the treatment and placebo group,26,27,31 leading to a conclusion that SIT is relatively a safe treatment modality. From RCTs of those who underwent SLIT,30,32 fatigue, headache, localized delayed hyper-responsiveness (>1 hour) occurred in first injection of the treatment, and among these side-effects, localized pruritus was most common. Other noted side effects were facial edema and gastrointestinal discomfort. Yet most of symptoms were mild with spontaneous resolution. There were reports of sudden worsening of allergic reactions or generalized pruritus in both placebo and control group, but the patients were all manageable with a brief symptomatic treatment; no other serious adverse events were reported.39,40

According to data collected from our institution, we witnessed urticaria, localized eruption, pruritus, exacerbation of previous atopic lesions, and relapse of previously known asthma in <1% of patients. However, the degree of symptoms was very mild, and the symptoms were all controllable with antihistamines. We believe that it is actually very difficult to accurately determine whether such reactions occur due to SIT or by exposure to other exogenous trigger factors. Nevertheless, from evidences collected thus far, SIT is a very safe treatment modality to incorporate in a clinic setting.

There are only few reports on immunological changes observed in serum or skin after SIT since most of studies thus far were concentrated on clinical efficacy and safety. Articles elaborating on changes in serum level of IgE and IgG4 are beginning to appear on surface, but works on variety of cytokines and chemokines are lacking. Considering a role of allergen as a potent aggravating factor in AD and complicated axes of immunology in AD pathomechanism, it is an important task to find efficacy of inducing immune tolerance through SIT and acquiring data that shows intricate interplay of immunologic changes before and after treatment.

An explanation is needed for serum IgE level changes in response to SIT in regards to highly activated B cells and deregulation of IgE synthesis,41 but there is no clean-cut evidence. Studies up until now show trend of allergen-specific IgE level gradually decreasing after SIT.31,42,43,44,45,46 For total IgE, there was a general trend for decrease, but statistically, the results were conflicting with those showing significance31,46 and those that did not.27,29 Serum IgE begins to change relatively at a slow rate with no noticeable drop in its levels; moreover, since there is no evident correlation between clinical improvements after SIT treatment, it is hard to explain loss or decrease of response to specific allergen only through changes in IgE.47 To many scholars, the role of IgE as a measurement of clinical sensitivity remains questionable in reality.43 Other works have stressed a significant decrease in Der p-specific IgG4,31,32,45,48,49 and in one pilot study, treatment with SIT led to decrease in markers of AD activity such as IL-16 and thymus and activation regulated chemokine (CCL17) in accordance with clinical improvement.44

Although finding a biomarker that can accurately predict treatment response is a necessary task, it is a challenging process considering multifaceted and intricately woven immunologic mechanisms and axes involved in allergic patients. Since the late 1990s, there have been many attempts to find biomarker candidates. In the early years, most studies concentrated on endothelial cell adhesion molecules,50,51,52,53,54 and works on chemokines were published in 2000.55,56,57,58 Brief summary on history of biomarker studies are summarized in Table 2. Reviewing studies on biomarker up until now, there have been reports of allergen-specific non-IgE antibody increasing through SIT,59 and several studies have shown that serum antibodies can reduce in vitro responses mimicking allergic reactions, such as IgE binding to allergen, IgE-facilitated antigen presentation and basophil activation.60,61,62 In a double-blind placebo controlled study of grass pollen SIT, there was increase in IgG4, IgE blocking factor along with suppression of facilitated allergen binding.63 The authors stressed that not only IgG4, but combined assessment of IgG4 and IgE blocking factor can be done in order to more comprehensively observe functional and clinical efficacy.

Recently, grass pollen SLIT experiment was performed in experimental exposure chamber, and the results showed complement component 1 and the receptor stabilin-1, 2 protein induction from tolerogenic DC also known as regulatory DC has correlation with clinical tolerance induced by SIT.64 In addition, the study opened a possibility into readily selecting clinically responsive and unresponsive group through proteins that are easily detected through quantitative polymerase chain reaction in peripheral blood mononuclear cells, and explained relationship of short-term efficacy with regulatory immune response.

What exact immunologic mechanisms underlie changes induced in SIT is a field of excitement that raises many questions. There still remains a room to search deeper into discovering biomarkers and choose appropriate candidates, mechanism, treatment response, surrogate end points, and clinical trial for new drug development.65 Hence, it will not be an understatement to say that the new era of AD expects a discovery of biomarker that can assess and standardize treatment response. If biologic marker can show clear-cut correlation with clinical symptoms, it will be an outbreak in the field of science, but considering variegated clinical pictures and associated immunological changes, the quest for a search will not be easily answered upon. But through future endeavors in creating more high-quality standardized experiments that reflect clinical improvement and enable predictions of treatment end-points, we will be building cornerstone for biomarker discovery.