Efficacy and safety of subcutaneous allergen-specific immunotherapy with depigmented polymerized mite extract in atopic dermatitis

doi:10.1016/j.jaci.2012.08.004

Journal of Allergy and Clinical Immunology

Volume 130, Issue 4, October 2012, Pages 925-931.e4

The results of this study were presented in part as oral presentation at the European Academy of Allergy and Clinical Immunology congress 2011 in Istanbul.

https://doi.org/10.1016/j.jaci.2012.08.004 Get rights and content

Background

Exposure to house dust mites (HDMs) aggravates the course of atopic dermatitis (AD) in patients sensitized to HDMs.

Objectives

This study investigated the efficacy and safety of subcutaneous allergen-specific immunotherapy with the use of depigmented polymerized mite extract as an add-on therapy to basic (ie, topical and, as necessary, systemic) medication.

Methods

Patients (n = 168) were recruited in a randomized, double-blind, placebo-controlled parallel group phase III study conducted in Germany (21 sites), in adult patients with AD aggravated by HDMs. The primary end points of the study were the assessments of the area under the curves of the total Severity Scoring Atopic Dermatitis (SCORAD) score and of the use of basic medication during the 18-month treatment period. Post hoc subgroup analyses were also performed.

Results

Overall efficacy analysis of the intention-to-treat and per-protocol 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 = .02) compared with placebo. The frequency of adverse reactions was similar in both groups, suggesting the safety of the active treatment.

Conclusion

Although subcutaneous allergen-specific immunotherapy showed no statistically significant difference in the overall population of patients with AD, statistically significant reduction of the total SCORAD could be achieved in a subgroup of patients with severe AD.

Section snippets

Patients and study design

This was a randomized, double-blind, placebo-controlled, parallel group study. One hundred sixty-eight adult patients (18-66 years of age) with moderate-to-severe AD were recruited at 21 centers in Germany from March 2007 to January 2009 and were randomly assigned to add-on therapy with SCIT treatment or to placebo, in addition to their basic medication, in an allocation ratio of 2:1 (Fig 1). A simple randomization procedure (computerized random numbers) was used. AD was diagnosed according to

AUC of the total SCORAD and use of basic medication

The AUCs of the total SCORAD and use of basic medication over the 18-month treatment period were compared between the 2 treatment groups for both the intention-to-treat (ITT) and per-protocol (PP) study populations.

No statistically significant difference was observed between the actively treated and placebo-treated groups for either AUC variable (Fig 2; see Table E2, Table E3 in this article’s Online Repository at www.jacionline.org). Median improvement of the AUC of the SCORAD over 18 months

Discussion

In this study we show that SCIT with a depigmented polymerized mite extract is effective as an add-on therapy in patients with severe AD, whereas no significant effect was seen in the overall study population. Post hoc analyses found that patients with severe AD at initiation showed significant improvement over placebo of the time-weighted total SCORAD score. Best efficacy was achieved during September to February, characterized by high HDM exposure because of the use of indoor heating.20, 21

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Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms
2023, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Applicable to all outcomes analyzed, 10 studies were at high or probably high risk of bias as a result of a lack of blinding (9 studies57,58,60,61,69,71,73,74,78) or missing outcome data (2 studies62,74) (see Fig E1 in the Online Repository at www.jacionline.org). One study67 reported QoL data from post hoc analyses of a subgroup showing statistically significant results, but not the nonsignificant results from the main analysis, leading this study’s outcome to be at high risk for selective reporting bias. We did not detect effect modification by risk of bias for any outcome (see Table E2 in the Online Repository).
Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear.
We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD.
As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel–defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence.
Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT’s effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings.
SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD.
Efficacy of House Dust Mite Sublingual Immunotherapy in Patients with Atopic Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Trial
2022, Journal of Allergy and Clinical Immunology: In Practice
Sensitization to house dust mites (HDMs) is frequent in patients with atopic dermatitis.
To investigate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides pteronyssinus extract in patients with atopic dermatitis sensitized to HDM.
In this randomized, double-blind, placebo-controlled trial, we enrolled 91 patients 3 years or older, with SCORing Atopic Dermatitis (SCORAD) score greater than or equal to 15 and positive skin test result and/or IgE to D pteronyssinus. Patients were stratified according to age (<12 and ≥12 years) to receive HDM SLIT or placebo for 18 months. Primary outcome was a greater than or equal to 15-point decrease in SCORAD score. Secondary outcomes were decreases in SCORAD and objective SCORAD, Eczema Area and Severity Index, visual analog scale for symptoms, and pruritus scale scores; Investigator’s Global Assessment 0/1; and decrease greater than or equal to 4 points in Dermatology Life Quality Index. Background therapy was maintained.
A total of 66 patients completed the study (35 HDM SLIT, 31 placebo). After 18 months, 74.2% and 58% of patients in the HDM SLIT group and the placebo group, respectively, showed greater than or equal to 15-point decrease in SCORAD score (relative risk, 1.28; 95% CI, 0.89-1.83). Significant SCORAD score decreases from baseline of 55.6% and 34.5% in HDM SLIT and placebo groups (mean difference, 20.4; 95% CI, 3.89-37.3), significant objective SCORAD score decreases of 56.8% and 34.9% in HDM SLIT and placebo groups (mean difference, 21.3; 95% CI, 0.66-41.81), and more patients with Investigator’s Global Assessment 0/1 in the HDM SLIT group as compared with the placebo group (14 of 35 vs 5 of 31; relative risk, 2.63; 95% CI, 1.09-6.39) were observed at 18 months.
Our results suggest that HDM SLIT may be effective in HDM-sensitized patients as an add-on treatment for atopic dermatitis.
Current Drug Treatments for Allergy
2021, Encyclopedia of Respiratory Medicine, Second Edition
Allergic diseases remain to be a substantial socioeconomic burden with increasing prevalence worldwide. Despite considerable efforts to identify safe and effective treatment, the lack of validated biomarkers and the existence of a complex disease phenotype and endotype remains the main challenge to advance precision medicine. Understanding the immunological and molecular mechanisms underlying the development of allergic diseases and pathways that drive immune tolerance is crucial in designing therapeutic approaches for treating allergic diseases. At present, allergen-specific immunotherapy and biologicals that target key molecules driving type-2 response (IgE, IL-4, IL-5 and IL-13) are used in the clinic. A few other candidate drugs and a combination of biologics as an adjunct to allergen immunotherapy are currently being tested in clinical trials to assess their safety and efficacy. This chapter describes the underpinning mechanisms of allergic diseases and associated therapeutic options available in the clinic, focusing on asthma, atopic dermatitis, chronic rhinosinusitis, and allergic rhinitis.
Recent developments and advances in atopic dermatitis and food allergy
2020, Allergology International
This review highlights recent advances in atopic dermatitis (AD) and food allergy (FA), particularly on molecular mechanisms and disease endotypes, recent developments in global strategies for the management of patients, pipeline for future treatments, primary and secondary prevention and psychosocial aspects. During the recent years, there has been major advances in personalized/precision medicine linked to better understanding of disease pathophysiology and precision treatment options of AD. A greater understanding of the molecular and cellular mechanisms of AD through substantial progress in epidemiology, genetics, skin immunology and psychological aspects resulted in advancements in the precision management of AD. However, the implementation of precision medicine in the management of AD still requires the validation of reliable biomarkers, which will provide more tailored management, starting from prevention strategies towards targeted therapies for more severe diseases. Cutaneous exposure to food via defective barriers is an important route of sensitization to food allergens. Studies on the role of the skin barrier genes demonstrated their association with the development of IgE-mediated FA, and suggest novel prevention and treatment strategies for type 2 diseases in general because of their link to barrier defects not only in AD and FA, but also in asthma, chronic rhinosinusitis, allergic rhinitis and inflammatory bowel disease. The development of more accurate diagnostic tools, biomarkers for early prediction, and innovative solutions require a better understanding of molecular mechanisms and the pathophysiology of FA. Based on these developments, this review provides an overview of novel developments and advances in AD and FA, which are reported particularly during the last two years.
Atopic Dermatitis Endotypes Based on Allergen Sensitization, Reactivity to Staphylococcus aureus Antigens, and Underlying Systemic Inflammation
2020, Journal of Allergy and Clinical Immunology: In Practice
Atopic dermatitis (AD) is a chronic inflammatory disease with significant local and systemic inflammation and barrier disruption. AD is associated with increased risk of allergen sensitization and skin colonization by Staphylococcus aureus. The heterogeneity of AD is unknown, and its complexity suggests its subdivision into several endotypes.
To evaluate allergy-driven endotypic differences in patients with AD and identify proteomic signatures to distinguish between inflammatory responses. To perform proteomic profiling of allergen sensitivity, antibody levels to S aureus antigens, and circulating inflammatory mediators to characterize AD subsets in 76 subjects with moderate to severe AD and 39 healthy controls (HCs).
Sera were collected from 76 subjects with moderate to severe AD and 39 HCs with no history of skin disease. Serum was tested for levels of total serum immunoglobulin E (IgE) and allergen-specific IgE using a panel of 119 allergens as well as IgE antibodies against S aureus antigens, and was profiled for more than 1100 proteins by SOMAscan to detect differential expression of inflammatory mediators.
Total serum IgE levels were significantly (P < .001) elevated in subjects with AD versus controls. A greater percentage of subjects with AD were allergic compared with HCs, and patients with AD tested positive to a greater number of allergens than did HCs. IgE was upregulated across 4 allergen subsets (food, perennial, seasonal, and mixed), and each allergen subset was associated with a distinct inflammatory signature marked by a specific suite of upregulated proteins. Finally, IgE antibodies against S aureus toxic shock syndrome toxin-1 were significantly upregulated in subjects with seasonal allergy (P = .0430) and perennial allergy (P = .00032).
Overall, this study addresses the heterogeneity of AD by characterizing subsets of AD on the basis of allergen sensitization. It also demonstrates the differential systemic inflammation and S aureus–specific antibody responses associated with the allergenic endotypes. These unique proteomic signatures may be valuable for precise disease characterization and subsequent personalized treatment.
Hyaluronan in the lymphatics: The key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking
2019, Matrix Biology
Citation Excerpt :
Unlike CD44 which is widely expressed in epithelial, mesenchymal, haemopoietic and blood (but not lymphatic) endothelial cell lineages, LYVE-1 is largely confined to lymphatic endothelia where it displays a punctate pattern of distribution on the luminal and basolateral plasma membrane surfaces as well as variable retention in a perinuclear, ER-derived intracellular compartment [8,24,25]. Notably however, the receptor is also expressed in liver and spleen sinus vascular endothelia, in pulmonary endothelia [8,26,27], and in a rare macrophage sub-population resembling so-called immune-regulatory M2–like cells with endothelial progenitor potential that are occasionally present in inflamed and tumour tissue [27–30]. The function of LYVE-1 in blood endothelium is not yet known, however it may as suggested mediate HA uptake as part of the reticulo-endothelial system for waste clearance [27].
LYVE-1, a close relative of the leucocyte receptor, CD44, is the main receptor for hyaluronan (HA) in lymphatic vessel endothelium and a widely used marker for distinguishing between blood and lymphatic vessels. Enigmatic for many years because of its anomalous HA-binding characteristics, the function of LYVE-1 has just recently been identified as that of a lymphatic docking receptor for dendritic cells, selectively engaging with their surface HA glycocalyx to regulate entry to peripheral lymphatics and migration to downstream lymph nodes for immune activation. Furthermore, LYVE-1 mediates the trafficking of macrophages, and is also exploited by HA-encapsulated Group A streptococci for lymphatic invasion and host dissemination. Consistent with a role in lymphatic trafficking, the interaction of LYVE-1 with HA and its degradation products can also activate intracellular signalling pathways for endothelial junctional retraction and lymphatic endothelial proliferation. Here we outline the latest findings on the receptor in the context of its peculiar biochemical properties and speculate on how the interaction of LYVE-1 with different HA sizes and conformations might variably influence cell function as a consequence of avidity and receptor crosslinking. Finally, we evaluate evidence that LYVE-1 can also bind growth factors and associate with kinase-linked growth factor receptors and conclude on how the LYVE-1·HA axis may be exploited as a target to either block inflammation or tissue allograft rejection, or potentiate vaccine and drug delivery.

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: Supported by LETI Pharma GmbH, Germany. LETI Pharma GmbH was involved in the design and conduct of the study and provided logistical support during the trial. Employees of the sponsor worked with the investigators to prepare the statistical analysis plan, but the analyses were performed by Pierrel Research Europe.

: Disclosure of potential conflict of interest: N. Novak has received research support from the German Research Council and ALK-Abelló; has received lecture fees from ALK-Abelló, Bencard Allergy Therapeutics, and Astellas; and has received consultancy fees from LETI Pharma. M. Hoffmann is on the advisory board for Janssen; has received consultancy fees from Medac and MSD; has provided expert testimony for Abbott; has received lecture fees from LEO Pharma and Spirig; and has participated in clinical trials sponsored by Allergopharma, ALK-Abelló, Almirall-Hermal, HAL Allergy, MEDA Pharma, Novartis, Pfizer, Schering-Plough, and Stallergenes. R. Fölster-Holst has received research support from Novartis, Pierre Fabre, Regeneron, LETI Pharma, and ALK-Abelló; is on the Johnson & Johnson advisory board; and has received lecture fees from Roche Posay. B. Homey has received consulting fees from ALK-Abelló. A. Sager is employed by LETI Pharma. The rest of the authors declare they have no relevant conflicts of interest.

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Atopic dermatitis and skin diseaseEfficacy and safety of subcutaneous allergen-specific immunotherapy with depigmented polymerized mite extract in atopic dermatitis

Background

Objectives

Methods

Results

Conclusion

Section snippets

Patients and study design

AUC of the total SCORAD and use of basic medication

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Pathol

J Allergy Clin Immunol

J Allergy Clin Immunol

Int J Surg

J Allergy Clin Immunol

Atopic dermatitis - from new pathophysiologic insights to individualized therapy

Allergy

House dust mite avoidance measures for perennial allergic rhinitis

Cochrane Database Syst Rev

The atopy patch test: an increased rate of reactivity in patients who have an air-exposed pattern of atopic eczema

Br J Dermatol

House-dust mite hypersensitivity, eczema, and other nonpulmonary manifestations of allergy

Allergy

Predictive features for persistence of atopic dermatitis in children

Pediatr Allergy Immunol

Atopic dermatitis and the atopic march: what is new?

J Allergy (Cairo)

Atopic dermatitis and skin disease
Efficacy and safety of subcutaneous allergen-specific immunotherapy with depigmented polymerized mite extract in atopic dermatitis