Allergen Immunotherapy for Atopic Dermatitis: Is There Room for Debate?

Pro/Con Review

Allergen Immunotherapy for Atopic Dermatitis: Is There Room for Debate? Linda Cox, MDa, and Moises A. Calderon, MD, PhDb

Ft. Lauderdale, Fla; and London, United Kingdom

Allergen immunotherapy (AIT) is a disease-modifying intervention indicated for the treatment of allergic rhinitis (AR) and/ or rhinoconjunctivitis, asthma, and Hymenoptera-induced anaphylaxis. Multiple placebo-controlled trials, systematic reviews, and meta-analyses have confirmed the efficacy of AIT in these conditions. Studies suggest that AIT may be beneficial in other allergic conditions, for example, atopic dermatitis (AD), food allergy, and large local reactions to Hymenoptera sting. With the exception of AD, the use of AIT in these other conditions is considered investigational. AD has been included as a possible indication for AIT in individuals with aeroallergen sensitivity in US practice guidelines on AIT and AD.1,2 Although the practice guideline recommendations are assigned an evidence rating B,3 there continues to be debate about the effectiveness of AIT for AD.4 One of the primary questions arising from this debate is which type of patient and which allergens are most effective in AIT for AD.

Is AIT effective for:
all patients with AD or certain subpopulations?
all aeroallergens or only specific allergens such as dust mite? At the AAAAI 2015 Annual Meeting in Houston, Texas, we debated the current evidence in favor (pro speaker: Moises A. Calderon) and against AIT for AD (con speaker: Linda Cox). The objective of this paper is to present this debate, which focused on the clinical trials and systematic reviews of AIT for AD. We aim to provide some perspective for readers to better “weigh in” on this debate. The paper also includes the discussion of AD heterogeneity (eg, different phenotypes) and the efficacy of non-AIT interventions for AD, for example, medications and avoidance measures.

AD BACKGROUND AD is a complex disease with a genetic predisposition influenced by innate and adaptive immune responses to a number of environmental factors including allergens, irritants, and microbes. a

Department of Medicine, Nova Southeastern University, Ft. Lauderdale, Fla Imperial College London, National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts. Received for publication September 28, 2015; revised December 6, 2015; accepted for publication December 18, 2015. Available online -Corresponding author: Linda Cox, MD, Department of Medicine, Nova Southeastern University College of Osteopathic Medicine, 5333 North Dixie Highway, Ft. Lauderdale, FL 33334. E-mail: [email protected]. 2213-2198 Ó 2016 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.12.018 b

Although referred to as a single disease, there is considerable heterogeneity in the natural history, clinical, and biophysical features of the disease, such that it has been suggested that different phenotypes and endotypes exist, in a manner similar to asthma and rhinosinusitis subgroups.5 AD is characterized by genetic or acquired epithelial skin barrier dysfunction, which allows for the penetration of allergens and microbes into the skin. Immune dysfunction also plays a key role in AD pathogenesis. The majority of patients with AD have elevated serum specific IgE (sIgE) and/or positive skin test reactivity (SPT) to food or inhalant allergens. In some patients, aeroallergen exposure through inhalation or direct skin contact can lead to severe AD exacerbations.6 It is believed that an inflammatory response is initiated when allergens on the skin are internalized by IgE receptor-bearing epidermal dendritic cells.7 This relationship between aeroallergen exposure, inflammation, and AD disease activity suggests that there may be a role for AIT in the treatment of AD. Considering the heterogeneity of AD, it is unlikely that AIT would benefit all AD phenotypes and/or endotypes. Although most patients with AD have evidence of allergen sensitivity on blood or skin test, approximately 20% do not have sIgE or SPT to any inhalant or food allergens.5 In addition, not all positive allergy (sIgE or SPT) tests are clinically relevant. Attempts to determine an allergen’s clinical relevance can be challenging in individuals with persistent skin inflammation, particularly if the allergen is perennial. Unlike AR, where allergen sensitivity can be confirmed in an allergen environmental chamber or nasal provocation challenge, there are no validated tests to confirm the role of an aeroallergen in triggering AD.

HOW ARE AD OUTCOMES ASSESSED? One of the challenges in evaluating the efficacy of AD treatment is the lack of a common standardized, validated outcome assessment tool. Generally, AD clinical trials utilize a scoring method that includes symptoms and examination findings. At present, there are more than 20 named instruments designed to measure the severity of AD.8,9 The instruments vary in how each component is scored and weighed. Thus, it is difficult to compare the results of clinical trials utilizing different outcome tools to assess AD severity. To address this lack of standardization, an international collaboration, the Harmonising Outcome Measures for Eczema initiative, through a structured process of systematic reviews and international consensus, identified a core outcome measurement instrument for AD clinical trials.9 The systematic review indicated that the Scoring Atopic Dermatitis (SCORAD) index and the Eczema Area and Severity Index (EASI) were the extensively validated and widely used instruments in AD clinical trials (see Figures 1 and 2 for example of the EASI and SCORAD scoring method).10,11 The international consensus group, which included patients, health care professionals, methodologists, and pharmaceutical industry 1

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Abbreviations used AD- Atopic dermatitis AIT- Allergen immunotherapy AR- Allergic rhinitis DBPC- Double-blind, placebo-controlled EASI- Eczema Area and Severity Index GRADE- Grading of Recommendations Assessment, Development, and Evaluation HDM- House dust mite RCT- Randomized controlled trial SCIT- Subcutaneous allergy immunotherapy SCORAD- Scoring Atopic Dermatitis sIgE- Specific IgE SLIT- Sublingual allergy immunotherapy SR- Systemic reactions

representatives, agreed on recommending the EASI as the preferred core instrument for the following reasons: it included only the 4 essential signs—erythema, excoriation, edema and/or papulation, and lichenification—and the severity is assessed at multiple body sites for each of the signs.

HOW EFFECTIVE ARE AD INVENTIONS AND MEDICAL TREATMENTS? Avoidance measures House dust mite (HDM) is the most common aeroallergen in AD and respiratory allergic disease. It has been estimated that as many as a third of AD patients with HDM hypersensitivity experience worsening of AD or respiratory symptoms with dust exposure.12 Interventions directed at reducing dust mite exposure might be expected to result in AD disease severity improvement. A Cochrane systematic review that searched databases through August 2014 for randomized controlled trials (RCTs) that assessed “... the effects of all house dust mite reduction and avoidance measures for the treatment of eczema” evaluated 7 studies (4 multiple interventions; 3 single intervention) that included 324 patients. Four studies assessed their primary outcome “. clinician-assessed AD severity with a named score” and no study provided information on the secondary primary outcomes—“caregiver-assessed quality of life.”12 The review found a modest treatment response in people with sensitivity to one or more aeroallergens, but noted the effectiveness of avoidance measures in the “.eczema population as a whole is unknown.” In their conclusion, the authors state the “.very lowquality evidence” precluded them from making any clinical practice recommendations. At present, there is no substantive evidence that HDM avoidance measures lead to AD severity improvement in HDM allergic individuals. Efficacy for medication treatments for AD To date, none of the available medications for AD are disease modifying. Analogous to asthma treatments, current AD therapies are aimed at controlling symptoms and/or disease exacerbations, but none address the underlying cause. Limitations of medical therapies include incomplete and/or partial response and adverse effects and/or toxicity. A systematic review evaluated 12 different systemic treatments for moderate-to-severe AD in 34 RCTs that included 1653 patients.13 The authors concluded “.the methodological limitations in the majority of trials

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prevented evidence-based conclusions.” They determined that strong recommendations were only possible for the short-term use of cyclosporin A and it was “. impossible to make recommendations for mycophenolate, montelukast, intravenous immunoglobulins, and systemic glucocorticosteroids due to limited evidence.”

ALLERGEN IMMUNOTHERAPY FOR ATOPIC DERMATITIS Considering the limited proven efficacy of HDM avoidance measures and AD medication as disease-modifying therapies, we will proceed to debate the role of AIT in AD treatment. Our debate will begin by examining the findings of the systematic reviews and meta-analysis, which includes the strength of the evidence for AIT in the treatment of AD (Table I). The value of meta-analyses is that they combine several studies with small subject numbers to increase the power of the analysis, allowing for a more objective appraisal of the evidence than a traditional narrative synthesis of findings. A meta-analysis aims to quantify a pooled effect of the same outcome across different studies. Such statistical analyses are performed with the assumption that the studies included are sufficiently comparable in design, for example, similar patient populations, outcomes assessment tools, etc.14 We will then explore the individual clinical trials to see what lessons can be learned (Table II). We will conclude the debate with a summary of unmet needs and recommendations for future investigations. Most of the pitfalls described earlier in the paper regarding the clinical trial design of AD also apply to AIT trials. In general, there is considerable heterogeneity in AR and asthma AIT trial designs, with significant variability in key components that greatly impact the study’s findings, for example, inclusion criteria, primary outcomes, and treatment duration. Recently, European and US regulatory authorities have provided guidance on AIT clinical trial design recommending the primary outcome assessment be the combined symptom-medication score.15,16 This is consistent with the recommendation of the World Allergy Organization’s (WAO) guidance document on appropriate trial design for AIT. The WAO Guidelines recommend that AIT products demonstrate at least a 20% improvement in combined symptom-medication score over placebo to be considered to be effective.17 However, the requirement for a 20% improvement is not uniformly applied, as the Food and Drug Administration required a point estimate difference of 15% or more in the combined score over placebo for approval of the grass and ragweed sublingual tablets demonstration in 2014.16,18,19 To date, the European Regulatory Authorities have not established a required magnitude of improvement for AIT product approval. The WAO’s AIT guidelines do not specifically address AD, but they do suggest using a validated questionnaire, such as the Dermatologic Life Quality Index, if skin symptoms are being considered.17 AIT FOR AD CLINICAL EFFICACY: EVIDENCE FROM SYSTEMATIC REVIEWS AND META-ANALYSES Pro: Moises A. Calderon Over the last few decades, several clinical trials have been conducted assessing the efficacy and safety of AIT for AD. From these studies, only 9 were randomized placebo-controlled trials: 7 studies for subcutaneous allergy immunotherapy (SCIT) and

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FIGURE 1. The EASI score is a tool that measures the extent (area) and severity of atopic eczema. The EASI includes an assessment of the intensity of clinical signs at 4 different body regions. Clinical signs considered include the intensity of erythema, edema/papulation, excoriation, and lichenification.10

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FIGURE 1. (Continued).

2 studies for sublingual allergy immunotherapy (SLIT). For SCIT, 2 studies were in children,21,22 1 in adults,28 and 4 in a mixed population of adults and children.23,24,29,33 SLIT was evaluated only in 2 pediatric studies.26,30 Most of the studies used HDM AIT preparations. Four different systematic reviews and meta-analysis have been performed to evaluate the efficacy of AIT compared with placebo for AD.4,7,31,34 The main limitation of these reviews is the heterogeneity of studies regarding clinical outcomes, study size population, and treatment interventions. A well-performed meta-analysis performed by Bae et al7 analyzed 8 RCTs that included a total of 385 subjects. The authors found that AIT has a significant positive effect on AD (odds ratio [OR], 5.35; 95% CI, 1.61-17.77; number needed to treat, 3; 95% CI, 2-9). AIT also showed significant efficacy in long-term treatment (OR, 6.42; 95% CI, 1.50-27.52) for

patients with severe AD (OR, 3.13; 95% CI, 1.31-7.48), and when administered subcutaneously (OR, 4.27; 95% CI, 1.3613.39). This well-conducted meta-analysis provides moderatelevel evidence for the efficacy of AIT against AD. Another systematic review using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system determined that the strength of recommendation for use of AIT in patients with AD was weak.31 The authors concluded that high-quality evidence from methodologically sound doubleblind, placebo-controlled (DBPC) trials is needed to support a stronger recommendation for use of AIT in AD.

Con: Linda Cox To date, there have been 5 systematic reviews (4 included meta-analyses) that have evaluated the RCT of AIT for AD.4,7,20,31,34 All reviews noted the significant heterogeneity

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Based on SCORAD European Task Force on atopic dermatitis Name of assessor

Date of visit First name

Date of birth

Topical steroid used

(G)

Potency (brand name)

Number of flares/month

(8.5)

4.5

(8.5)

4.5

Mark the inflamed areas on the diagram and calculate percent of body surface affected. (Do not include dry but non-inflamed areas).

4.5

4.5

4.5

4.5

18

1

18

1

1

9

9

(6)

9

9

(6)

Figures in brackets for children under two years

A: Extent

(Please indicate the area involved)

For a typical affected area

B: Intensity Intensity

Means of calculation Intensity items (average representative area)

Swelling or roughness 0 = absence Oozing/crust 1 = mild Scratch marks 2 = moderate Thickening of skin and deeper skin creases 3 = severe Dryness of unaffected skin

C: Subjective symptoms pruritus + sleep loss SCORAD A/5 + 7B/2 + C

Visual analog scale

Pruritis (0 to 10)

(average for the last 3 days or nights)

0

10

Sleep loss (0 to 10) Recommended treatment: Remarks:

FIGURE 2. The Universite de Nantes AD Information Server (http://adserver.sante.univ-nantes.fr) can used to calculate the SCORAD score. The total SCORAD index is a composite measure that covers both clinical signs and symptoms. The objective SCORAD index is the subscore that measures the severity of the clinical signs of atopic dermatitis. The objective SCORAD index asks the investigator to assess the intensity of an average AE lesion. Clinical signs considered include: intensity of erythema, edema/papulation, excoriation, lichenification, intensity of oozing/crusting and dryness of unaffected skin.9,11

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and considerable variations in the included studies’ treatment protocols. The first systematic review of AIT for AD found some improvement in objective and subjective findings in the 5 DBPC studies analyzed.25 In one study, a significant improvement was only seen in the mild-to-moderate group after 9 months of treatment, whereas there was no improvement in the severe group at any time point.26 The first systematic review concluded that even though the positive effect of AIT on AD seemed to predominate, “no general conclusion on the value of AIT in AD can be drawn at present.”20 Compalati et al4 performed a subsequent systematic review that included 4 additional RCT studies (2 SCIT and 2 SLIT). They found variable improvement in AD severity, but noted the methodological interstudy heterogeneity and shortcomings in the available trials, which included small dimensions and incomplete reporting. They concluded that “. the evidence of efficacy has not critically changed from previous systematic observations.” The most favorable systematic review conducted by Bae et al7 included a total of 8 RCTs of 385 patients, who received either SCIT (6 studies; 177 patients), SLIT (2 studies; 42 patients), or placebo (166 patients). The primary outcome considered was “. the proportion of patients whose condition improved, as assessed by the investigators or patients, regardless of different evaluation methods” and the evidence rating was based on the GRADE system. The authors concluded that there was moderate-level evidence for the efficacy of AIT in AD treatment, but noted that this determination was based on a small number of RCTs with considerable heterogeneity. Subgroup analysis found a significant effect with SCIT, in severe AD, and longer treatment duration, whereas no effect was found in children or with SLIT. The GRADE method was also used in a systematic review conducted by Gendelman and Lang.31 Despite using the same grading methodology and nearly the same database—5 of the 7 studies included in the Bae et al review—they reach a different conclusion. They determined that the strength of recommendation for use of AIT in AD is weak. They also noted that there were “serious methodological shortcomings. including, but not limited to, many enrolled patients not completing participation; small study [size]; and incomplete descriptions of randomization, blinding, allocation concealment, and/or data analysis not by intention to treat.”31

LESSONS LEARNED FROM INDIVIDUAL STUDIES Pro: Moises Calderon The efficacy of 18-month treatment with HDM SLIT for AD was evaluated in an RCT of 56 children aged 5 to 16 years.26 A significant improvement versus baseline SCORAD was seen only in the SLIT group starting from month 9. There was also a significant reduction in the use of medications only in the SLIT group. A separate subgroup analysis of patients with mildmoderate (SCORAD < 40) and severe (SCORAD > 40) AD was performed. A significant improvement in considered parameters was only found in patients with a mild-moderate disease, whereas patients with a severe disease had only a marginal benefit. The efficacy of HDM SCIT with the use of depigmented polymerized extract as an add-on therapy to usual (eg, topical and, as necessary, systemic) medication was assessed in a phase

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III RCT of 168 adults with AD aggravated by HDM.28 The primary study end points were the assessments of the total SCORAD score’s area under the curves and medication use during the 18-month treatment period. Interestingly, the overall efficacy analysis of the intention-to-treat and perprotocol study populations showed no statistically significant differences between the active treatment and placebo groups. However, the subgroup of patients with severe AD (SCORAD > 50) showed a statistically significant reduction of the median total SCORAD by 18% (P ¼ .02) compared with placebo. Results were significant when data were evaluated during the winter season. In general, these studies suggest that AIT (both SCIT and SLIT) is an effective treatment for some patients with AD. However, it is unclear from the current literature to which AD subpopulation AIT is most indicated. We have learned that the selection of patients according to severity is fundamental.

Con: Linda Cox It is generally accepted that the evidence for a medical treatment efficacy must be established in appropriately designed placebo-controlled clinical trials. It is clear from the above discussion of the systematic reviews conducted to date that there is a paucity of such evidence supporting the role of AIT in AD treatment. Only 7 DBPC trials were identified in the mostly favorable systematic reviews, all of which noted the considerable limitations of their analyses due to the heterogeneity and methodological shortcomings in the trials that met criteria for consideration. However, the findings from individual studies may help determine which AD patients will benefit from which AIT protocols. For example, although Novak et al28 found no statistically significant overall effect of SCIT in a DBPC study of 168 adults with HDM-aggravated AD, post hoc analysis showed a significant reduction in median total SCORAD scores (18%) in the severe AD (SCORAD > 50) subgroup. This might suggest that only patients with severe AD would benefit from AIT. However, the opposite effect was found in Pajno et al26 evaluating the efficacy of HDM SLIT in children with AD. In this DBPC study of 56 children (28 SLIT), the significant improvement in SCORAD scores was found only in the subgroup with mild-moderate AD, whereas only a marginal benefit was seen in patients with severe AD. In addition to demonstrating efficacy compared with placebo, medications generally need to demonstrate a dose response. This dose-response requirement is applicable to SLIT and SCIT for AR and/or asthma. To date, there has been only 1 dose-response study of AIT for AD.25 This RCT evaluated the effect on SCORAD scores and topical corticosteroid use of 3 doses of SCIT administered weekly for 1 year. Although both outcome parameters improved in a dose-dependent manner, the lack of a placebo group would preclude this study from being considered in many systematic reviews, which are the basis for most practice guideline recommendations. In closing, these individual studies provide conflicting data on which the subgroup of AD patients would benefit from AIT. Although a dose response is suggested, clearly more research is needed to identify the optimal AIT dose and/or dosing regimen and AD subgroup most likely to benefit.

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TABLE I. Comparison of systematic reviews of AIT for AD RCT studies included

Author

Comment† Primary outcome(s)

Conclusion/findings

Pro

Con

“In summary, even if the proportion of studies showing a positive effect of AIT on AD seems to predominate, no general conclusions on the value of AIT in AD can be drawn at present” “New findings support the concept that AIT may be beneficial for AD”

Overall, the studies reviewed which included open and DBPC trials demonstrated AIT was effective in AD treatment

Conclusions based on only 4 DBPC trials with considerable heterogeneity in all aspects of trial design in small patient population

Again this provides more support for the benefit of AIT in AD

AIT for AD
Significant positive effect: OR, 5.35 (95% CI, 1.61-17.77)
NNT, 3 (95% CI, 2-9) The use of AIT in patients with AD The “strength of recommendation is weak”

This meta-analysis “provides moderate-level evidence” for the efficacy of AIT against AD

Authors note: “Lack of large RCT and long-term observations ... examining efficacy, diseasemodifying effects and safety determines the scarce evidence supporting the use of AIT in AD.” Authors note: Findings are “based on an analysis of a small number of RCTs, with considerable heterogeneity.” Authors note: “Serious methodological shortcomings were noted.” Studies differed in which patients with AD—mild versus severe— benefited most from AIT

Bussman et al

5


Proportion improved per group (4)
SCORAD (1)

Compalati et al*4

226,27

“All the outcomes related to disease severity were considered.”

Bae et al*7

821-24,26,28-30

Gendelman and Lang*31

722,23,25,26,28,29,32

Percentage:
Improved per investigator or patient
Reduction of any scoring system Objective measurement of AD severity:
SCORAD (3),
Various tools (4)

20

21-25

Weakness of the recommendation is due to the studies’ design and not due to AIT being ineffective

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AD, Atopic dermatitis; AIT, allergen immunotherapy; CI, Confidence interval; DBPC, double-blind, placebo-controlled; NNT, numbers needed to treat; RCT, randomized controlled trial; SCORAD, Scoring Atopic Dermatitis. *Reviewed literature in 5 y after the Bussman review. †Pro: Moises Calderon; Con: Linda Cox.

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TABLE II. Randomized-controlled trials of allergen immunotherapy for atopic dermatitis Patients (age in years)

Study

Allergen (dose)

Design/duration (mo)

Outcome assessed

SCIT

Multiple (“maximum dose 400 PNU”)

DBPC (24)

Treatment success assessed by the physician

Warner et al21

20 (5-14)

SCIT

HDM (NA)

DBPC (12)

Treatment success assessed by the patient

Glover and Atherton22

24 (5-16)

SCIT

HDM

DBPC (8)

Treatment success assessed by the patient

Leroy et al29

24 (15-64)

SCIT

DBPC (4)

Disease intensity index assessed by the physician

Werfel et al25

80 (18-55)

SCIT

Intradermal injection of autologous antibody and HDM HDM

RCT (12) (no placebo)

SCORAD assessed by the physician

Silny and Czarnecka-Operacz24

20 (5-40)

SCIT

HDM, grass

DBPC (12)

W-AZS index (clinical score) assessed by the physician

Pajno et al26

56 (5-16)

SLIT

HDM

DBPC (18)

SCORAD as assessed by the physician

Novak et al28

168 (18-66)

SCIT

HDM

DBPC (18)

SCORAD and medication use

SCIT (3-25)

HDM

RCT (no placebo) (12)

SCORAD, SS. and medication use

Caraballo and Villa33

60

Significant improvement with SCIT 13/16 (81%) versus placebo 4/10 (40%; P < .05) SCIT had higher proportion of improved patients Improved
SCIT: 7 (77.8%)
Placebo 3 (27.3%) No change or worsening
SCIT 2 (22.2%)
Placebo (72.7%) No difference between groups but higher proportion in placebo improved versus SCIT (82% vs 62%) Significant difference in treated patients at 1 y; 82% had the mean improvement of 83% Significant decline in SCORAD and medication use in the 2 high-dose groups only Significant difference (P < .01); active group: 80% improved, placebo group: 90% worse Significant difference from baseline at 9 mo in SLIT only; significant difference between SLIT and placebo in the mild-moderate group only No difference between SCIT and placebo; post hoc analysis— significant improvement in the severe group only

At 6 mo significant reduction in SCORAD and medications in SCIT

Safety*

NA

Exacerbation
SCIT 48%
Placebo 41%

No SR Exacerbation
Both groups 46% No SR Exacerbation
SCIT 74%
Placebo 3% SR in <1% of injections No exacerbations No SR

SR
SLIT 7% Exacerbation
SLIT 14% SR
SCIT 8%
Placebo 10% Exacerbation
SCIT 39%
Placebo 35% NA

DBPC, Double-blind, placebo-controlled; HDM, house dust mite; NA, not available; PNU, protein nitrogen unit; RCT, randomized-controlled trials; SCIT, subcutaneous immunotherapy; SCORAD, Scoring Atopic Dermatitis; SLIT, sublingual immunotherapy; SR, systemic reaction; W-AZS, atopic dermatitis severity score (Polish). *Exacerbation refers to atopic dermatitis.

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52 adults and children (2-47)

Efficacy

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Kaufman and Roth

23

Route

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SAFETY OF AIT IN AD Pro: Moises A. Calderon Local and systemic reactions (SR) were reported in most of the studies of AIT for AD. The incidence of these reported adverse effects varied among studies. In the systematic review conducted by Bae et al,7 the AIT and control groups had comparable proportions of systemic (0%-8.0% vs 0%-10.7%, respectively) and local reactions (6.3%-80.0% vs 0%-60.0%, respectively). For SCIT, systemic adverse reactions are usually mild in severity, reported as grade 1 or 2. The most common systemic symptoms were eczema flare-ups, urticaria, rhinitis, pruritus, headache, and asthma.28 For SLIT, the local reactions reported were mild in severity, transient in duration, and did not require medication treatment. Mild lip swelling and mouth or lip itchiness were most commonly reported. Transient AD exacerbations were as common among patients in AIT groups (14.3%-74%) as the control groups (0%-83.3%).7 At present, there have been no fatal or near-fatal adverse events reported with AIT for AD. Con: Linda Cox The adverse effects of AIT include common local application site reactions and less frequently, SR, which could be life threatening. Local reactions are common to SCIT and SLIT, but the incidence of SR significantly varies between the 2 routes favoring SLIT as being safer. The risk of severe SCIT SR appears to be greater in patients with asthma than those with AR. There are limited data on the safety of AIT in patients with AD in terms of SR. It has been suggested that AIT poses a risk of exacerbating AD. This is largely anecdotal without confirmation in the published clinical trials. There was a comparable incidence of AD disease exacerbations and SR in the AIT and control groups in the 8 studies considered in the Bae et al7 systematic review (385 patients; 177 SCIT, 42 SLIT, and 166 placebo). However, the authors noted that the adverse events were not clearly defined and that it would be a “. challenge to combine the data from all studies.” Considering the relatively low incidence of SR, approximately 0.1% of injections per a large multiyear AIT safety surveillance study,35 and even lower incidence of severe SR (1 in 1 million injections),36 data from a considerably larger population than the 385 patients in the Bae et al review are needed to make any conclusions regarding the safety of AIT in patients with AD. AIT FOR AD OTHER CONSIDERATIONS: COSTEFFECTIVENESS AND LONG-TERM EFFICACY There have been no prospective controlled trials evaluating the long-term efficacy of AIT in AD in terms of persistent clinical benefits after discontinuation or prevention of disease progression. One study of 15 patients with AD treated with SCIT for HDM or grass found a significant difference between the Dermatology Life Quality Index before and 2 to 12 years after discontinuation of AIT.37 There are no studies comparing the cost-effectiveness of AIT for AD with any other standard AD therapy. However, systematic reviews have found AIT to be cost-effective compared with standard drug treatment for AR38,39 and asthma.39 Varying cost-effective “break-even” points have been reported that range from as early as 3 months after treatment initiation40 to several years after discontinuation. One systematic review of AIT for AR

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concluded that the cost-effective time point was generally 6 years after treatment initiation.38 Whether these systematic reviews and individual study findings supporting the cost-effectiveness of AIT for AR can be applied to AD is unknown. We both agree that further research is needed to determine the cost-effectiveness of AIT as compared with other AD treatment interventions.

UNMET NEEDS Despite our opposing views in Houston, we both agree that this treatment is worth further investigation and that the following are unmet needs regarding AIT for AD:
Need well-designed RCTs that compare efficacy of AIT with standard treatment in well-defined AD “phenotypes”.
Need a uniform method for assessing AD efficacy in clinical trials and practice.
To optimize treatment; need to determine if AIT efficacy. B Depends on specific allergens (eg, dust mite) or applies to all. B Depends on AD severity. B Depends on disease duration.

CONCLUSIONS At present, few studies have evaluated the efficacy of AIT in AD. The heterogeneity and methodological limitations of these studies make comparisons difficult and thus, nearly impossible to base conclusions about the treatment efficacy. Additionally, in the studies demonstrating efficacy, there are conflicting data on which patient population benefits, for example, severe versus moderate. Although AD is included as a potential indication for AIT in current practice guidelines, this may be reconsidered in the future as guideline criteria have become more stringent. To be considered in the National Guideline Clearinghouse, a repository for national and international practice guideline, recommendations should be based on systematic review and analysis of the evidence.41 As indicated by the discussion earlier, such a review and evidence analysis would not lend strong support to an AIT for AD treatment recommendation. In conclusion, more research is needed with randomized trials of well-defined patient populations with AD using uniform, standardized outcome assessment tools to establish comparative effectiveness of AIT in AD. REFERENCES 1. Schneider L, Tilles S, Lio P, Boguniewicz M, Beck L, LeBovidge J, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol 2013;131:295-299.e1-27. 2. Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, et al. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol 2011;127(Suppl):S1-55. 3. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ 1999;318:593-6. 4. Compalati E, Rogkakou A, Passalacqua G, Canonica GW. Evidences of efficacy of allergen immunotherapy in atopic dermatitis: an updated review. Curr Opin Allergy Clin Immunol 2012;12:427-33. 5. Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol 2014;134:769-79. 6. Novak N. New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy 2009;64:265-75. 7. Bae JM, Choi YY, Park CO, Chung KY, Lee KH. Efficacy of allergen-specific immunotherapy for atopic dermatitis: a systematic review and meta-analysis of randomized controlled trials. J Allergy Clin Immunol 2013;132:110-7.

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