The Benefit of Montelukast in Atopic Dermatitis Induced by Food Allergies

Background: Cysteinyl leukotriene levels are elevated in patients with atopic dermatitis, which can lead to eosinophilic infi ltration of the gastrointestinal tract. Objective: We examined the role that montelukast (a leukotriene receptor antagonist) might play in improving symptoms of atopic dermatitis induced by food allergies. Methods: We conducted a randomized, double-blind, placebo-controlled, parallel group study in 20 children, aged 1 to 8 years, with 4 study visits every 3 weeks for 9 weeks. Primary inclusion criteria consisted of: 1) positive reactivity to food (indicated by skin or RAST test); 2) 10–25 % body area affected with atopic dermatitis; and 3) gastrointestinal symptoms. Liquid cetirizine and 1% hydrocortisone cream were both given as rescue medications for atopic dermatitis fl are-ups. Pruritis and atopic dermatitis fl areup scores were used to collect clinical data. Laboratory values for nerve growth factor were evaluated preand post-treatment. Results: Our main endpoints were the effects of montelukast on the clinical presentation of atopic dermatitis. When comparing the treatment group to placebo, we noted a signifi cant reduction in the pruritis score (p=0.002); a trend toward a reduction in the use of rescue medication (cetirizine: p=0.056; hydrocortisone cream: p=0.056); and a reduction in the level of nerve growth factor; mean values: placebo=3.06 to montelukast=2.59. Conclusion: The infl ammatory pathway triggered by food allergies that may lead to atopic dermatitis can be modulated with montelukast. Furthermore, nerve growth factor may play a role in the pathogenesis of atopic dermatitis and montelukast may modify this pathway. Research Article The Benefi t of Montelukast in Atopic Dermatitis Induced by Food Allergies Isaac Melamed*, Lacey Robinson and Melinda Heffron IMMUNOe International Research Centers, Centennial, CO, USA Dates: Received: 10 April, 2017; Accepted: 03 May, 2017; Published: 04 May, 2017 *Corresponding author: Isaac Melamed, ImmunoE Health Centers, 6801 South Yosemite Street, Centennial, USA, Tel: 303-224-4678; 720-273-2863; Fax: 303-224-4699; E-mail:


Introduction
Atopic dermatitis (AD) is a chronic, relapsing, infl ammatory skin disorder [1]. The infl ammatory process seen in AD is characterized by a mixture of immunological and pharmacological abnormalities that can be detected in the serum and at the cellular level. Included in the immune histology of AD skin are infi ltrates of activated T-cells, dendrite presenting cells, eosinophils, and mast cells [2].
Commencement of the immune cascade can result from multiple activators/activations, including allergens (food or environmental), infectious pathogens, and numerous other distinctive triggers (eg, stress or anxiety) [3]. The cascade involves a series of reactions that culminate in different biologic responses, including entry into the cell cycle or cell death. While programmed cell death, or apoptosis, can be triggered under a variety of circumstances, the mechanism by which cells are directed to cell cycle progression as opposed to apoptosis is not well understood [4]. In recent years, increasing evidence has suggested that regulatory T-cells are involved in various skin diseases and that they play a pivotal role in the etiology of AD [5]. These roles are complex and may involve various mechanisms, showing that the immune response leading to infl ammation due to a failure of apoptosis is a crucial factor [6,7].
Cysteinyl leukotrienes (Cys-LTs) are the products of arachidonic acid metabolism and are released from various cells, including mast cells, basophils, and eosinophils; they have long been known to be potent mediators of allergic infl ammation. The secretion of these products (eicosanoids) and the occupation of the Cys-LT receptors have been correlated with the pathophysiology of both asthma and allergic rhinitis in numerous studies. It has recently been suggested that Cys-LTs may also play a role in food allergies and their subsequent immune response [8][9][10][11][12].
Recent studies have shown that some food allergens can increase the levels of Cys-LTs [8][9][10][11][12]. These studies suggested http://dx.doi.org/10.17352/2455-8141.000018 that leukotriene receptor antagonists could potentially interfere with the infl ammatory cascade induced by food allergens. A recent study by Adamek-Guzik et al found that the levels of Cys-LTs in patients with AD were signifi cantly higher during skin fl are-up compared to the remission phase [8]. It also noted that the clinical severity of skin lesions correlated with increased levels of Cys-LTs.
Other studies concur with the use of leukotriene receptor antagonists for AD patients [7,12]. These studies show a correlation between the occurrence of AD in patients with known food intolerances. In the presence of food allergens, increased Cys-LT production by peripheral leukocytes (specifi cally eosinophils) was observed in the majority of patients. Eosinophilic involvement in the pathogenesis of AD has previously been established. The immune response in AD causes an increase in the amount of Cys-LTs brought about by food intolerance. These studies also suggest the use of leukotriene receptor antagonists for reduction in the severity of AD for patients with food allergies.
The importance of eosinophilic involvement in the infl ammatory response is also found to occur in gastrointestinal (GI) disorders [10,11]. The infi ltration of eosinophils into the GI tract is seen in eosinophilic gastroenteritis (EG), which causes severe tissue damage to the gut. Food allergies are a triggering factor in the allergic response, thereby causing the accumulation of eosinophils in the tissues of the GI tract. EG and AD are strongly associated with known food allergies in about 70% of the cases.
In vitro studies examined the effect of leukotriene B 4 (LTB 4 ) antagonists on eosinophilic infi ltration in the gut and skin [13], BALB/c mice received an oral challenge to induce eosinophilic infi ltration into the gut and skin. Peak infi ltration occurred at 6 hours (gut) and 12 hours (skin) after the challenge. If an intraperitoneal dosage of a LTB 4 antagonist was administered before the oral challenge, a signifi cant inhibition of eosinophilic infi ltration was noted. A reduction of 53.3% in the skin and 73.3% in the gut was measured. Although these results were not conducted in humans, they point to the advisability of using a leukotriene inhibitor to prevent eosinophilic infi ltration in the skin and gut in cases of known food allergies.
Considerable evidence suggests a crosstalk between the nervous and immune systems. Previously, we investigated the role of nerve growth factor (NGF) in this crosstalk and showed an active role for NGF in B-cell cytoskeletal signaling [14][15][16][17][18][19].
It has been suggested that NGF plays a role in the infl ammatory process and in tissue repair [20]. Both skin and lung fi broblasts produce NGF and express tyrosine kinase receptor under basal conditions. In cutaneous infl ammatory responses, the expression of NGF receptor (TrkA) is reduced following an acute infl ammatory stimulus and also in association with chronic infl ammatory dermatitis [21,22], suggesting that NGF plays an active role in the pathogenesis of AD [23].
Leukotriene receptor antagonists are specifi c in blocking the Cys-LT receptor, thereby preventing the immune cascade response. Montelukast, the active ingredient in the product Singulair ® , has been shown to be a selective and potent leukotriene receptor antagonist and has been studied extensively for its use in the reduction or prevention of airway infl ammation and allergic rhinitis. As leukotriene B 4 (LTB 4 ) antagonists may reduce eosinophilic infi ltration into the gut and skin, we formed a hypothesis regarding the role of food allergens in the induction of eosinophilic activation and their contribution to dermatological symptoms.
Our hypothesis for this research study was that NGF may play a role in the infl ammatory process and that montelukast would possibly: 1. Downregulate the infl ammatory process caused by food allergy triggers 2. Downregulate NGF 3. Improve the symptoms of AD.

Study design
In this randomized, double-blind, placebo-controlled, parallel-group trial, participants diagnosed with AD and food allergies aged 1-8 years were enrolled. The study was

Subjects
Thirty-three subjects were screened for the trial; 20 subjects met all inclusion and exclusion criteria. Nine subjects were randomized to receive montelukast and 11 subjects were randomized to receive placebo. Eleven males and 9 females were enrolled. The mean age of participants was 5.4 years.
All entry criteria were assessed at the baseline visit. Using age at the time of screening (1-8 years inclusive), participants with mild to moderate AD affecting at least 5% of the body surface with a total severity score, rated by the study doctor, of 2 for any of the 4 signs, were enrolled. GI symptoms were rated by the Gastrointestinal Symptom Rating Scale (GSRS) and a total score of 2 was necessary for inclusion. If participants had previously tested positive for food allergens by skin or radioallergosorbent test (RAST) test, the previous results were used. If participants had not been tested for food allergens, then the necessary tests (RAST and skin tests) were performed to determine eligibility. Subjects were seen in clinic by a study doctor a total of 4 times, once every 21 to 23 days, over a 9-week study period. Standard of care in the clinic is to avoid foods that may lead to anaphylaxis as determined by RAST or skin testing.

Statistical analysis
Treatment effects were analyzed using repeated measures, including ANOVA methods, which take into account correlation within subjects. Individual contrasts were calculated to compare treatment means of interest. All p-values were twosided; all analyses were performed using SAS (SAS Institute, Inc., version 9.1). The overall skin level of discomfort using PADC, pruritis, and AD fl are-up was greatly improved in subjects using montelukast compared to those using placebo (Tables   1-3). Figure 1 depicts the average weekly pruritus scores by treatment group. Study visits compared to baseline followed a downward trend in the montelukast group, with the difference being most signifi cant by the last visit. When comparing   pruritis baseline scores to last study visit scores, the difference between placebo and montelukast was signifi cant (p=0.002).

Primary endpoint evaluations -Skin evaluations
There was a difference in use of cetirizine (p=0.056) and hydrocortisone cream (p=0.054) between the 2 groups, but it was not signifi cant. A similar trend was also noticed for PADC (p=0.248).
IGA appeared to be a timed response, with maximum effect noted by visit 4. The severity scoring showed the same trend (Table 4).

Secondary endpoints -Laboratory assessment and GI evaluations
Urinary marker LTE4 was collected at each visit and was reduced in the montelukast group compared to the placebo group ( Figure 2).
Laboratory serum markers were collected at baseline and at the last study visit. There were no differences between the study arms, with all levels within normal range limits.
Serum markers for TNF- alpha and NGF showed a slight difference between the 2 arms (values were calculated using log transformation) ( Table 5).
IL-13 showed a reduction from baseline. IL-5 levels were all below the sensitivity range of the assay. GI assessments using GSRS scoring were fi lled out weekly. These data showed a slight difference between arms, with montelukast showing some improvement over time (Table 6).

Discussion
There are various immune players in the cascade of AD, including T-cells, eosinophils, and mast cells. Mast cells were previously recognized primarily for their granulation upon IgE receptor aggregation in allergic diseases [24][25][26]     skin diseases and play a pivotal role in the etiology of AD.
The role of T cells in the development of AD is complex and may involve various mechanisms [6]. Immune abnormalities observed in AD include primary defects, such as epithelial barrier defects and defects in signaling or expression of innate receptors. Others are thought to be secondary to the effects of the adaptive immune response. These include defi ciencies in antimicrobial peptides due to the overexpression of T helper 2 cytokines such as interleukin-4 (IL-4) and IL-13. How these components interact is not fully understood [28].
We recently studied the role of perforin and granzyme B as factors that may lead to AD via apoptosis failure. The rationale underlying this study was that recent data suggest that AD is an immunological process resulting from the inability of T-cells or cutaneous tissue to be normally regulated due to a failure in the signaling of apoptosis. As a consequence of this failure, the immunological barrier is lost, which may have later immunological consequences.
The LT4 pathway is involved in various infl ammatory pathways mediated by mast cells and many other players. We have studied the role of NGF as a crosstalk between mast cells and the immune system. We have shown that NGF release is upregulated in persons with AD and we speculate that it may play a role in AD.
Our results suggest that montelukast can downregulate the infl ammatory pathway initiated by food allergies and leading to AD. We have also shown that montelukast has a signfi ciant effect on pruritus in patients with AD and food allergies, and we showed a trend in the downregulation of NGF. Although our study was small, we believe that further study is needed to determine if montelukast has a role in early intervention in the allergic march, which begins with eczema, progresses to allergic rhinitis and fi nally to asthma.

Conclusion
In this randomized, double-blind, placebo-controlled, parallel-group trial in children with food allergies and atopic dermatitis, montelukast led to a reduction in pruritus when compared to placebo, with trends toward a reduction in the use of rescue medication and a reduction in the levels of nerve growth factor.