Journal of Clinical Pediatrics and Neonatal Care

News about Emollients with Rhealba Oat Plantlets Extract: Prevention and Treatment of Atopic Dermatitis

*Marketa Saint Aroman
Pierre Fabre Dermo Cosmetique, A-DERMA, Les Cauquillous, Bp 100, 81506 Lavaur Cedex, France

*Corresponding Author:
Marketa Saint Aroman
Pierre Fabre Dermo Cosmetique, A-DERMA, Les Cauquillous, Bp 100, 81506 Lavaur Cedex, France
Email:marketa.saint.aroman@pierre-fabre.com

Published on: 2018-09-23

Abstract

Atopic dermatitis (AD) is a common chronic inflammatory skin disease which has negative socioeconomic consequences. At the bottom of the AD therapeutic pyramid, the emollient strategy has been set up. It seems that all profits and success in terms of efficacy of the basic emollient therapy has been proven not only in relation to the control of the AD signs and symptoms but also in terms of their prophylactic, highly important effect in both primary and secondary prevention. Some clinical studies have already demonstrated that emollients containing Rhealba Oat plantlets extract, enriched with the Biovect system, counteract two fundamental factors responsible for the development of AD: they reconstruct the epidermal barrier and have an anti-inflammatory effect. In addition, they are free from proteins that could potentially lead to transcutaneous sensitisation causing classical allergic reactions. This study was set up to assess the tolerance of an emollient based on Rhealba Oat plantlets extract in newborns at risk to develop Atopic Dermatitis. Investigators considered that the three textures were very well tolerated by newborns at risk to develop Atopic Dermatitis. In consequence emollients based on Rhealba Oat plantlets extract are best suited for people with Atopic Dermatitis or at risk to develop one, from birth to adulthood. Clinical proofs obtained through multiple studies, performed in all age groups, support this statement.

Keywords

Newborns; Atopic Dermatitis; tolerance;dermatology; emollient; Rhealba Oat plantlets extract

Introduction

Atopic dermatitis (AD) is a common chronic inflammatory skin disease, characterized by periods of remission followed by exacerbation of the inflammatory process. It has been estimated that this highly complicated disease may affect 10-20% of children [1, 2] and 1.6-10.2% of adults [3, 4]. In Poland, the incidence of AD has been increasing mainly in large cities and displays a downward tendency in the countryside. AD prevalence among children ranges between 4.7% and 9.2% and between 0.9% and 1.4% in adults [5].Typically, first signs and symptoms of AD develop during early childhood. Atopic skin lesions occur during the first year of life in approximately 60% of patients. In 90% of patients they develop by the age of five [6]. Recurrent course of AD and its clinical manifestation accompanied by persistent pruritus and sleep disturbances, lead to a significant decrease in the quality of life of both patients and their families [7, 8]. In addition, it generally presents clear negative socioeconomic consequences [9-11]. AD may coexist with other atopic diseases such as bronchial asthma, allergic rhinitis and food allergy. This phenomenon, although more complicated than we had previously thought has a specific terminology of “atopic march” or even “marathon”. The highly complex pathogenesis of AD is obviously multi-factorial. And as it has been already proven, it develops as a result of an interplay of genetic, immunologic and environmental factors as well as skin barrier damage [12-14].

There is a strong relationship between atopy in parents and AD in their children. If one parent suffers from AD, the risk of developing the disease by the child is 56% and if both parents suffer from AD, it rises to 80%. The risk of atopy in children of healthy parents is 5-15%. Likewise, the risk of AD in monozygotic twins is higher (72-86%) than in dizygotic twins (21-23%) [15]. So far, several regions containing AD susceptibility genes have been identified. The genes may be divided into two main groups [15, 16] genes encoding structural and functional proteins of epidermis such as filaggrin gene (FLG), genes encoding intercellular junction proteins (e.g. tight junction proteins) and gene encoding serine protease inhibitor (SPINK-5/LEKT1); genes encoding proteins which play a role in immune responses such as genes encoding STAT transcription factors, genes regulating T cell differentiation, genes encoding cytokines and their receptors: IL-4, IL-13, IL-17, IL-18, Il-22, IL-25, IL31, TSLP, genes encoding chemokine’s and their receptors, genes encoding non-specific immunity proteins (TLRs). In the case of AD, immune disorders are related to the function of T cells, dendritic cells and mast cells. Thanks to the current state of knowledge, AD is looked upon not only in the context of overactive TH2 cells or increased levels of serum IgE – also a significant role of Th17, Th22 and Th1 in the pathogenesis of AD has been noticed. The predominance of a specific pool of T cells changes with the disease phase (acute, chronic) [17], and even some ethnicity-related differences have been observed [18]. This results in the excitation of different networks of cytokines defined by a specific T cell profile, translating into AD immunotype diversity, which is particularly important in the age of biologic therapies. As for immune factors involved in the pathogenesis of AD, one should take note of cytokines originating directly from keratinocytes, which are produced as a result of damage (e.g. from scratching) or in presence of enzymes produced by microorganisms. These cytokines include IL25, TSLP and IL-33. They appear to mediate between the epidermal barrier damage in AD and the initiation of systemic allergy by potentiating the Th2-mediated response, acting on other allergic inflammation cells such as basophils, mast cells and eosinophil’s, acting on the expansion of antigen presenting cells (APCs), interacting with ILC2 (innate lymphoid cells) and impacting the differentiation of naïve T cells [19, 20].

Decreased expression of antibacterial peptides in the skin of individuals with AD leads to its colonization by microorganisms, in up to 90% of cases by S. aureus, infection which frequently exacerbates inflammation [21, 22]. S. aureus activates T cells as well as expression of IL-31, known as pruritus interleukin [23]. It provokes resistance to Glucocorticoids (GCSs) [24] and worsens the epidermal barrier defect. The epidermal barrier defect is yet another factor in the pathogenesis of AD, even the key factor. It results from abnormalities in the structure and function of the stratum corneum (SC), tight junctions (TJs), and Langerhans cell dysfunction, overactivity of serine proteases and serine protease inhibitors as well as inflammation and overproduction of Th2 cytokines [25-27]. In 2006, R501X and 2282del4 mutations in the filaggrin gene (FLG), the best known cornified envelope protein, has been shown to be risk factors for the development of AD and are associated with a severe course of the disease, its early onset, high serum IgE levels and concomitant asthma [28]. FLG deficiency is responsible for xerosis in patients with AD as FLG degradation products are substrates for natural moisturizing factor (NMF). However, FLG mutations do not concern all patients with AD but only about a half [28]. Today we know that among multiple cornified envelope proteins FLG is not the only one that plays a role in the pathogenesis of AD. Other cornified envelope proteins are also involved [29, 30]. In addition, their expression in the skin is changed, most likely as a result of compensation [30]. Normal development of cornified envelope proteins in patients with AD is disturbed not only by genetic mutations but also by TH2 cytokines such as IL-4, IL-13 IL-25 and IL-31 [31-33]. Lipids in intercellular spaces of the stratum corneum also play a role in ensuring tightness, cohesion and integrity of the epidermal barrier, in addition to structural cornified envelope proteins. In patients with AD, the space between keratinocytes of the epidermal stratum corneum in patients with AD is ineffectively filled with intercellular lipids. Also, the secretion of lipids by lamellar bodies is defective [34]. The content of ceramides, sphingolipids and free fatty acids is reduced [35]. Ceramides are responsible for maintaining normal moisturization, corneocyte adhesion and epidermal barrier tightness; they play a role of intercellular transmitters and are involved in the regulation of growth, differentiation, apoptosis and desquamation of keratinocytes [36, 37]. 

The epidermal barrier defect manifests as loss of cohesion and integrity of the SC as well as excessive transepidermal water loss which worsens dry skin. It is conducive to bacterial colonization and penetration of external factors such as allergens, worsening skin inflammation. Defective epidermal barrier with an increased permeability of the epidermis in individuals suffering from atopic dermatitis facilitates the penetration of allergens. This very route leads to sensitisation and subsequent development of allergy and possibly allergic march [19, 20]. Logically, the repair of damaged epidermal barrier by emollient therapy plays a prominent role in the treatment of patients with AD [23] as well as primary prevention [38, 39], which protects against the development of AD, and secondary prevention, which protects against disease exacerbation [40-45]. Furthermore, restoration of the epidermal barrier appears to play a role in the inhibition of allergic march [19, 20].

Emolients in the Treatment of AD

The most recent European recommendations on the treatment of AD point to emollients as a vital therapy for AD, placed at the bottom of a personalized therapeutic pyramid [23].Emollients counteract the epidermal barrier defect. They replenish intercellular spaces of the stratum corneum with lipids. Thanks to humectants such as urea, lactic acid and glycerol, which absorb and maintain water in the stratum corneum, they fight the main symptom of AD, namely dry skin. Mineral oils or Vaseline in emollients, by forming occlusion, prevent transepidermal water loss [23-46]. There have been many reports of studies demonstrating emollient therapy efficacy in AD [40-45]. A simple method of one-week application of emollient improves the course of mild and moderate AD [47]. Long-term emollient therapy in children with AD reduces dry skin [48].

Emollients enable reduction in the use of topical glucocorticosteroids. The steroid-sparing effect was demonstrated in three randomized controlled trials [40, 49, 50]. Current recommendations of European experts distinguish one particular group of emollients, i.e. “plus” emollients which contain additional “non-medical” active substances such as flavonoids or saponins, which have anti-inflammatory and epidermal barrier-repairing properties [23]. When using emollients (and other topical products), special attention should be paid to the treatment of neonates and infants. The skin of infants below two years of age is characterized by thinner epidermis and stratum corneum, higher content of water, increased transepidermal water loss, high skin pH, increased desquamation and high proliferation index [51]. Neonates and infants have a high body surface areato-weight ratio, which translates into increased absorption of topical medicines. The 2018 consensus on the treatment of AD pays special attention to the use of emollients free from peanut proteins or colloidal Oatmeal, particularly in children below two years of age due to possible transcutaneous sensitization [52]. There is a concern that wide use of preventive emollients containing complete proteins with peanut allergen or colloidal Oat flour may lead to transcutaneous sensitisation and the development of allergy [53, 54]. For this reason, it is recommended to use only emollients free-from protein allergens which frequently cause contact allergy (such as lanolin or methylisothiazolinone), particularly in the highest-risk age group. 

Emollients in the Prevention of AD

Emollients play a vital role in the prevention of AD, both primary prevention which focuses on risk groups and secondary prevention which protects against AD exacerbation and recurrence. The studies by Simpson et al. have highlighted the importance of emollients in primary prevention of AD. The authors designed two studies. In the first one, emollients were used in 20 high-risk neonates aged 1-7 days, with monitoring at 1, 6 and 24 months. This prevented the development of AD. Subsequently, the authors conducted a randomized controlled study involving 124 high-risk neonates, in which emollients were applied on the entire body, starting three weeks after birth and continuing until the age of six months. They demonstrated 50% reduction in the risk of developing AD in the treated group [38-57]. Similar protective effects in high-risk neonates were obtained by Japanese investigators [39]. Regrettably, these two promising studies were limited by relatively short follow-up periods. Currently, studies with longer follow-up periods are underway [23].Epidemiological studies have shown a significant relationship between the diversity of foods given to the child during the first year of life and the protection against AD development [62]. Generally, primary prevention strategies should be employed as early as possible [63].

The research outcomes support the theory that sensitisation occurs through skin while tolerance is acquired through the gastrointestinal tract, emphasizing the importance of the selection of skin products as well as the timing of early intervention. Numerous studies have demonstrated efficacy of emollients in the prevention of AD and reduction in clinical signs of AD in neonates, infants and children [38- 42] as well as adults [43-45].Recently, the theory of emollients role in primary prevention of AD has become a subject of discussion.On one hand, to date, 3 randomized trials [38, 39, 64] have been published showing that regular application of emollients from the first weeks of life in a population with risk of atopy is associated with an approximate halving of the risk of developing AD [38, 39, 64]; larger studies are underway [65].On the other hand, there are studies, like the PreventADALL one [66] in which authors show the lack of prophylactic action of emollients in children, but in this study the general population of children, was considered, not a population of children with family history of atopy.

The potential hypothesis coming from all those studies is emollients can act as a primary prevention in children with family atopy history, but not in the general population. From the theoretical point of view, knowing the fact, that skin barrier impairment is one of the crucial mechanisms of AD pathophysiology, preventive application of emollient in newborns with atopy history in their family seems to be the primary AD prevention method but to present this as a reliable recommendation, further randomized studies with a precisely prepared, repeated clinical protocol on large population are needed. Factors such as the composition of emollients, compliance of application procedure, and proper choice of investigated population can have a direct impact on the final results of those studies. Based on these new, but weakly documented, studies with not clear methodology, we underline in this manuscript nowadays recommendation to use emollients since birth in newborns at AD risk (prophylaxis and primary prevention of AD).

Emollients in the Remission of AD

It is worth mentioning that the epidermal barrier defect applies to both affected skin of patients with AD and seemingly healthy skin. It has been demonstrated that subclinical inflammation may occur within seemingly unaffected skin of adults with AD [67, 68]. Therefore, treatment consisting in the reconstruction of the epidermal barrier and counteracting inflammation should not be limited to periods of exacerbation – an appropriate therapeutic intervention is also needed during clinical remission, which is apparent in nature from the molecular point of view. Stabilized remission following its induction with topical anti-inflammatory products can be maintained with emollients applied at least twice a week in both children and adults [23, 42, 44].

Emollients Containing Rhealba Oat Plantlets Extract

Manufacture and effects of the emollient containing the Rhealba Oat Plantlets Extract

The Rhealba Oat seedlings are grown in south-western France under strictly defined ecological conditions. The extract obtained from the over ground part of the plant is free from protein, thanks to which the risk of allergic reactions is minimized. And at the same time the product contains active substances such as flavonoids and saponins. Flavonoids exert an anti-inflammatory effect [69] by inhibiting the enzymes involved in the metabolism of arachidonic acid, namely phospholipase A2 (PLA2) and cyclooxygenase-2 (COX-2). The in vitro inhibitory effect of Rhealba Oat plantlets extract on PLA2 and COX-2 has been demonstrated by measuring of the production of prostaglandin E2 (PGE2) using an ELISA test [70]. 

Saponins are characterized by immunomodulating properties, they reduce the release of prostaglandin I2 (PGI-2) and the production of TH2 cytokines such as IL-13 and IL-4 [71]. The Rhealba Oat plantlets extract, depending on the dose, inhibits the production of IL-4 and IL-13, and has an immunomodulating effect on CD4+ T cells [71]. Furthermore, in an in-vitro context, the emollient containing Rhealba Oat plantlets extract inhibited the release of TSLP from keratinocytes by 44% compared to the 68% inhibition of TSLP release achieved with hydrocortisone (p<0.05) [71]. The effects of the Rhealba Oat plantlets extract was improved in 2017 by the addition of a naturally sourced enhancer – BioVect. It is composed of glycolipids and a combination of three molecules: glycerol (humectant, moisture retainer), capric/caprylic triglyceride (natural oily emollient) and cetearyl glucoside (natural emulsifier). Thanks to its glycolipid properties, BioVect has a very strong biological affinity for hydrophilic molecules of the Rhealba extract and at the same time for hydrophobic molecules of the epidermal lipid layer. Anti-inflammatory efficacy of the product containing the Rhealba Oat plantlets extract with BioVect technology has an increased anti-inflammatory effect, which was demonstrated in an in vitro experiment consisting in the reduction in prostaglandin PGI2 [72]. Emollients containing Rhealba Oat plantlet extract, in addition to their anti-inflammatory effects, are involved in the process of repair of the epidermal barrier defect in AD. They stimulate FLG and activate the synthesis and release of lipids into intercellular spaces of the epidermal stratum corneum [70].

Current risk factors understanding for sensitisation through the skin and subsequent development of allergy lead to the recommendation that emollients and cosmetics used in patients with AD should be free from potentially sensitizing proteins, which was emphasized by recent guidelines on the treatment of AD [23].

In order to verify that there is no crossing between glutelins and gliadins—a mixture of majority proteins found in some cereals and commonly called gluten— and the Plantlets extract, a commercial ELISA test was also conducted with the Plantlets extract by using Omega wheat and Mendez R5 anti-gliadin antibodies. No protein was detected within the limits of this test (1.5 ppm for Omega and 3 ppm for Mendez), confirming the absence of gluten in the extract and the absence of a cross-reaction between the gluten and the Plantlets extract [73].

Clinical studies with emollients containing the Rhealba Oat Plantlet Extract

The efficacy of emollients in primary prevention of AD in high risk neonates was demonstrated in 2014 [38, 39]. Children are a special group of patients as – due to immature skin and the skin surface-to-weight ratio – they require the selection of appropriate topical products to reduce the risk of adverse effects. Last year, a study was conducted to assess the tolerance of emollients containing Rhealba Oat plantlets extract in three galenic forms (balm, cream and lotion) in a group of neonates. The study involved 53 neonates with high-risk of AD, and skin products were applied once daily for three weeks. No adverse reaction to the product was observed. The tolerance of products containing Rhealba Oat plantlets extract with Biovect technology was considered very good by investigators, and especially high scores were awarded by the parents (Pierre Fabre, clinical study RV3424I201650) [74].

The Rhealba Oat plantlets extract-based emollient was also assessed in a group of 108 children with moderate AD between six months and six years of life [70]. After a 14- day run-in phase of treatment with topical GCSs, the emollient was used once daily for three months. A statistically significant reduction in both the duration of AD exacerbations and the number of AD exacerbations was observed (p<0.0001), in addition to an improved quality of life as per SCORAD and PO-SCORAD (p<0.0001) and a 50% reduction in the use of topical GCSs (p<0.0001) [72]. Another study, which involved 97 subjects with mild AD (SCORAD 10-25), assessed the efficacy of Rhealba Oat plantlet extract-based emollient. The cohort was composed of 32 infants aged 3-23 months, 33 children aged 2-11 years and 32 adults aged 18-45 years. After 21 days of application with an emollient containing Rhealba Oat plantlets extract enriched with the Biovect technology, the SCORAD score decreased on average from 20 to 4 (p<0.05). [72].

The Rhealba Oat plantlets extract-based emollient with Biovect technology was proven effective in reducing pruritus severity, the VAS score decreased on average of -4.57 when treated vs -0.82 when non-treated (p<0.0001). The study involved patients aged over 60 with pruritus persisting for more than six weeks. Applying the emollient reduced pruritus as measured on VAS (p<0.0001), improved sleep and reduced xerosis [75].

Summary

Emollients are a significant element of AD treatment recommended in all guidelines on the management of AD. They may be used at the beginning of AD treatment or as part of supplementary or maintenance treatment. Multiple studies have demonstrated efficacy of emollients in the treatment of AD and prevention of disease exacerbation, i.e. secondary prevention. Recent years have brought about revolutionary outcomes pointing to the efficacy of emollients, also in primary prevention in neonates from risk groups. Emollients are effective, inexpensive, easy to use and safe. They protect against the development of AD and delay its development, which translates into economic profits.AD is a disease that requires appropriate therapeutic strategies. The restoration of the skin barrier function, elimination of inflammatory lesions, reduction in pruritus and counteraction of skin infection plays a key role in the treatment of the disease.

Rhealba Oat plantlets extract-based emollients, as “plus” emollients containing active substances, have anti-inflammatory effects and restore the epidermal barrier. They are free from potentially sensitizing molecules and therefore can be used also in children below two years old. They are very well tolerated and reduce the severity of pruritus. The current state of knowledge about the skin structure, the pathogenesis and treatment of AD and the process of sensitisation and allergy emphasize the importance of the choice of the skin product as well as the timing of intervention.

Study

As mentioned above, in the etiopathogenesis of atopic dermatitis, heredity plays a very important role. Therefore, our study has been focused on newborns, whose prognosis for atopic dermatitis is expected due to genetic symptoms. Pierre Fabre Laboratories have developed for 20 years a specific range designed for the atopy-prone skin. The three emollients constitute the new generation of skin care products in this range. These non-rinsed cosmetic products are skin care for face and body. Rhealba Oat plantlets have anti-irritant and soothing properties. The extraction process of Oat plantlets ensures extract without detectable protein which minimizes the risk of sensitization or intolerance. Oenothera Biennis oil (Omega 6 essential fatty acids), niacinamide (vitamin B3) and 10-hydroxydecenoic acid allow strengthening the epidermal barrier. Emollients from birth represented a novel approach of the AD prevention. In this context, dermatologist or paediatrician could prescribe an emollient as preventive care for newborns with a family history of atopy. The objective of this study was to show, that the emollient use immediately after birth is safe for newborns identified at risk to develop AD.

Material and Methods

There were 4 centres in Poland and 4 centres in the Czech Republic. The trial was conducted according to the Declaration of Helsinki (1964) and its subsequent amendments, Good Clinical Practices (CPMP/ICH/135/95) and national regulations. This protocol and related documents (including the informed consent form) were submitted for approval to independent Ethics Committees before the study set up, according to national regulations. Six independent ethics committee reviewed the protocol and related documents and authorized the study. Eticka Komise FN Brno in Brno approved the modified study protocol on the 16th of May 2016; it was approved in Eticka Komise NH Hospital in Nemocnici on the 1st of May 2016. It was approved by the Bioethical Committee at Karol Marcinkowski Poznan University of Science on April 12, 2016, in Olomouc Eticka Komise on the October 20, 2016. Later it was approved by Eticka Komise Krajska in Usti nad Labem on the January 18, 2017. And finally, by the Bioethical Committee at Karol Marcinkowski Poznan University of Science on February 2, 2017. An amendment was submitted to decrease the number of subjects in group 2 (balm) and 3 (cream) in December 2017 due to recruitment difficulties.

Overall Study Design and Description

This study was conducted as a European, multicentre, open-label trial on 53 newborns identified in risk to develop atopic dermatitis.

Methodology

The whole population contained 53 newborns identified at risk to develop atopic dermatitis. The clinical study included 3 visits and the maximum duration of the study for each subject was 24 days. During Visit 1, on Day 1, newborns under 96 hours of life were included in the study, the 2nd visit was set up 8 ± 2 days after and finally the 3rd visit took place 22 ± 2 days following the beginning of the study. During this visit, subject’s parent(s) or guardian(s) received compensation for the total duration of the study. If the subject had been withdrawn early, the compensation was calculated in proportion to the number of visits.

Inclusion Criteria

In order to be eligible for the study, subjects from both genders had to be healthy full-term neonates (37 weeks of gestation - vaginal delivery or caesarean) under 96 hours of life, with a phototype I, II, III or IV according to Fitzpatrick classification, birth immediate adaptation to aerial life (Apgar’s score>7) and with a high risk of atopic dermatitis. Meaning that at least one parent or a full sibling who had been diagnosed with atopic dermatitis and/ or asthma and/or allergic rhinoconjunctivitis. Parents or guardian(s) had to be registered within the health social security, give their written consent for their child’s participation in the study (according to the local regulation) and use mild cleansers and shampoos designed specifically for babies.

Non-InclusionCriteria

Subjects were excluded from the study if they came from a multiple pregnancy, had dermatological conditions influencing the study parameters (outside the transient benign neonatal diseases), pathologies incompatible (in the opinion of the investigator) with the completion of the study, infectious or inflammatory dinase or any other diseases or birth defects. They were also excluded if they were participating or had been participating in another clinical study. If the subject’s parents are 18 years old, unable to understand the given information or study procedures, give their written consent for participation, report required information in the subject’s diary or unlikely to comply with the constraints of the study they were excluded from the study.

Related to the population

Subjects were excluded from the study if they were, at the time, under local or general drug treatment (apart from vitamin intake), if their mother started or continued an antibiotic therapy after the birth in case of breastfeeding (except for single dose antibiotics during caesarean), if they had a neonatal jaundice justifying phototherapy, or if the parents wished to use emollients other than those specified in the protocol.

Prohibited Treatments and Products

It was forbidden to use care products different from the study product on the face and body (except on cord, buttock and scalp area), to use any topical or systemic antibiotics, corticosteroids, immunosuppressant or anti-inflammatories, to use any topical or systemic treatment liable to interfere with the assessment of the cutaneous tolerance of the study products. Maternal antibiotic therapy (if the child is breastfed) and phototherapy weren’t allowed either.

Specific Requirements

The parents had to: avoid soap, bubble bath, bath oils; use a mild cleanser and shampoo designed specifically for babies; use the same hygiene products during whole the study; avoid baby wipes for face and body (except for the buttock). 3 products were tested during the study: a lotion, a balm and a cream. The three products were applied once daily, during 22 ± 2 days, on face and body (except on scalp, diaper and cord area) on dry skin, after bathing, if the child is bathed.

Primary Objective

The primary objective was to assess the global tolerance of the 3 products applied once daily during 3 weeks in full-term newborns identified at risk to develop atopic dermatitis, under dermatological and/or paediatric control.

Secondary Objective

Secondary objectives included assessing the local tolerance of the 3 products after 3 weeks of application and evaluating the cosmetic satisfaction of the subjects’ parents.

Evaluation Criteria

The investigator was asked to assess the global tolerance of the tested product during Visit 3, with a 4-point scale. This scale was structured as follows: 1, very good tolerance: no physical or functional signs related to the product observed by the investigator or reported by the subject, 2 good tolerance: transitory and very mild/mild physical or functional signs related to the product observed by the investigator or reported by the subject with no modification of application modalities, 3 moderate tolerance: persisting and/or moderate/severe physical or functional signs related to the product observed by the investigator or reported by the subject without definitive application discontinuation, 4 bad tolerance: physical or functional signs related to the product observed by the investigator or reported by the subject leading to definitive application discontinuation. The following physical signs were also assessed by the investigator: erythema, desquamation, dryness, oedema, vesicles, papules and excoriation.

Results

Lotion

In this group, 20 newborns (11 females and 9 males) were included with a mean age of 2.7 days in 5 centres, 3 in Poland, and 2 in the Czech Republic. 75% of them were born by vaginal delivery and 25% by caesarean. The mean gestational age was 39.6 weeks and 95% of the subjects were breastfed at inclusion. All subjects had a high risk of AD. The most frequent familial history of atopy was rhinoconjunctivitis (45.0%) and asthma (45.0%). 8 subjects (40%) had a familial history of atopic dermatitis. The total number of completed subjects at V3 was 20 (no subject withdrew from the study).

For all subjects, no adverse event related to the study product was reported, thus global tolerance of the lotion product was considered “very good” by the investigator after 22 days of application. Physical signs were reported by the investigator, they included: desquamation: 1 subject presented this symptom at D1, 11 at D8 and then 2 after 22 days of application. This may be explained by physiological desquamation of the skin of newborns which is common for this population. Dryness was present in 5 subjects at D1 baseline and D8, in 3 subjects at D1 after first product application and 2 at D22. The number of subjects presenting papules was stable during the study ranging from 4 to 5. The number of subjects who presented erythema decreased during the study from 8 subjects at D1 before first product application to 2 at D22. Concerning vesicles, the number of subjects who presented this sign decreased during the study from 3 subjects at D1 before first product application to 0 at D22. No edema, excoriation or other physical signs were reported.

The tested product was very appreciated by the subject’s parents with a mean grade (± SD) equal to 9.3 (± 0.7) upon 10. Directly after application, the subject’s parents thought that the skin of their child was soft (mean mark 8.1), hydrated (mean mark 9.2), nourished (mean mark 9.0), not oily (mean mark 3.9) or sticky (mean mark 3.4).After 22 days of application, 61% of the subject’s parents said that the skin of their child was modified. They thought that the skin was softer (mean mark 7.7), more hydrated (mean mark 8.0), and more nourished (mean mark7.9).

Balm

In this group, 18 newborns (9 females and 9 males) were included with a mean age of 2.2 days in 8 centres, 4 in Poland, 4 in the Czech Republic.66,7% of them were born by vaginal delivery and 33,3% by caesarean. The mean gestational age was 39.7 weeks and 100% of the subjects were breastfed at inclusion. All subjects had a high risk of AD. The most frequent familial history of atopy was atopic dermatitis (61, 1%) and asthma (38, 9%). 11 subjects (61, 1%) had a familial history of atopic dermatitis. The total number of completed subjects at V3 is 16 (two subjects prematurely withdrew from the study but not for safety reason).

The results of this clinical study showed that the balm, applied once daily for 22 days was very well tolerated in 15 newborns and well tolerated in 1 newborn with high risk of AD, according to the investigator. There was only one Adverse Event linked to the product; however our cosmetovigilance department determined that causality was unlikely and not clearly attributable. Physical signs were reported by the investigator, they included: desquamation: 1 subject presented this symptom at D1, at D8 3 subjects were affected and finally after 22 days of application no subjects were affected anymore. Dryness was present in 1 subject at D1 and D8, at D22 no dryness was reported anymore. The number of subjects presenting papules was 1 at D1 and D8 and 2 at D22. 5 subjects presented erythema at D1, 1 at D8 and none at D2. Concerning vesicles, the number of subjects who presented this sign was 1 at D1 and decreased to 0 at D8 and D22. No edema, excoriation or other physical signs were reported. No functional signs were reported in this group. The tested product was very appreciated by the subject’s parents with a mean grade (± SD) equal to 9.6 (± 0.7) upon 10.

Directly after application, the subject’s parent thought that the skin of their child was soft (mean mark 9.2), hydrated (mean mark 9.1), nourished (mean mark 9.1), not oily (mean mark 3.9) or sticky (mean mark 2.1). After 22 days of application, 73, 3% of the subject’s parents said that the skin of their child was modified. They thought that the skin was softer (mean mark 9.0), more hydrated (mean mark 9.0), and more nourished (mean mark 8.8). They considered the product suitable to the child’s skin (mean mark 9.7).

Cream

The total number of subjects included: 20 subjects planned initially, then 15 with amendment. The study was completed by 15 subjects at V3; no subject prematurely withdrew from the study. In this group, 15 newborns (6 females and 9 males) were included with a mean age of 3.1 days. 53.3% of them were born by vaginal delivery and 46.7% by caesarean. The mean gestational age was 39.9 weeks and 100% of the subjects were breastfed at inclusion. All subjects had a high risk of AD. The most frequent familial history of atopy was atopic dermatitis (66.7%) and allergic rhinoconjunctivitis (46.7%). The total number of completed subjects at V3 was 15 (no subject withdrew from the study). For all subjects, no adverse event related to the study product was reported, thus global tolerance of the cream was considered “very good” by the investigator after 22 days of application. The physical signs reported by the investigator included: Papules: the number of subjects who presented this sign was 1 at D8 and 1 at D22. The papules are linked to adverse event Acne Neonatorum according to the investigator. Desquamation: the number of subjects who presented this sign was 1 at D22, with two different locations on nose and right cheek. Erythema: the number of subjects who presented this sign was 1 at D22. The desquamation and erythema were linked to the seborrheic dermatitis according to the investigator. No dryness, no edema, no vesicle, no excoriation or other physical signs were reported. No functional signs were reported in this group.

The tested product was very appreciated by the subject’s parents with a mean grade (± SD) equal to 9.3 (± 1.2) upon 10. Directly after application, the subject’s parent thought that the skin of their child was soft (mean mark 9.3), hydrated (mean mark 9.0), nourished (mean mark 9.3), not oily (oily mean mark 3, 9) or sticky (sticky mean mark 3.7). After 22 days of application, 66.7% of the subject’s parents said that the skin of their child was modified. They thought that the skin was softer (mean mark 9.3), more hydrated (mean mark 9.4), and more nourished (mean mark 9.3). They considered the product suitable to the child’s skin (mean mark 9.5).

Discussion

A great number of randomized studies evaluating the efficacy of emollients in newborns at risk to develop Atopic Dermatitis exist. For example, we can cite Horimukai [39] 2014, in this article, an investigator-blinded, randomized, controlled and parallel-group study was set up. Expectant mothers with family histories of AD were invited to participate in the trial. A high familial risk of AD is defined as a history of physician-diagnosed AD for at least 1 of the parents or siblings. 118 neonates were enrolled and randomly assigned to 2 groups of 59 infants each, intervention and control group. The intervention group received daily application of an emulsion-type emollient from the 1st week of life and for 32 weeks. Visits were scheduled on weeks 4, 12, 24 and 32 of life. After the 2nd visit, the incidence of AD was significantly lower in the intervention group than in the control group. Moreover, the intervention group maintained intact skin for a significant longer period than the control group. In another studied conducted in 2014, Simpson [38] et al. wonder if enhancing skin barrier from birth represents a feasible strategy in reducing the incidence of atopic dermatitis in high-risk neonates. To do so they performed a randomized, multicentre, multinational, controlled trial on 124 neonates at risk to develop AD. Baseline characteristics were similar between treatment groups, notably the number of babies with a loss-of-function mutation in the skin barrier genre filaggrin. Daily use of emollient significantly reduced the cumulative incidence of atopic dermatitis at 6 months (43% in the control group vs 22% in the emollient group). This corresponds to a relative risk reduction of 50%.

Based on these already existing efficacy data, we set up a clinical study to evaluate the tolerance of an emollient containing Rhealba Oat plantlets extract in newborns at risk to develop AD. This study demonstrated that the three tested products (lotion, cream, balm) have a very good tolerance in newborns at risk to develop AD. Oat is often considered to be sensitizing and it is recommended to avoid in people at risk to develop AD. However, Rhealba Oat plantlets extract-based emollient with Biovect Technology doesn’t have any sensitizing effect. Indeed, Rhealba Oat plantlets extract is free-from protein thanks to their unique extraction process. This has been demonstrated thanks to two highly reliable technics: ELISA test and Western Blot. In these tests the plantlets extract is placed in contact with the specific antibody to be detected, then a second antibody paired with an enzyme reveals the possible presence of antigen. In both those tests Rhealba Oat plantlets extract is demonstrated to be free-from proteins. It has also been demonstrated, thanks to an ELISA test, that Rhealba Oat plantlets extract won’t trigger a cross-reaction with the majority of cereal proteins, commonly called gluten [73]. These results confirm that Rhealba Oat plantlets extract contains no detectable proteins and cannot create immunological cross-reaction with other types of cereals.

Conclusion

Rhealba Oat plantlets extract contains high levels of flavonoids and saponins and are free-from proteins to minimize the risk of allergic sensitization. It has a repairing effect on the disrupted epidermal barrier, stimulates keratinocyte differentiation along with filaggrin expression rise and activates the synthesis and secretion of the epidermal lipids [76]. It also has an anti-inflammatory effect, flavonoids inhibit PLA2 and COX2, saponins, on the other hand reduce the release of PGI2 and IL2 in activated T lymphocytes and the expression of the MHC-II, IL-4 and IL-13 levels responsible of Th2 activation [77, 78]. Rhealba Oat plantlets extract based emollient with BioVect Technology has no sensitization effect. Indeed, in Rhealba Oat plantlets extract there is no proteins, thus no allergic reaction. It has been shown that the use of emollients in newborns at risk to develop AD can reduce the risk by 50% if used since birth. Indeed, three major studies [38, 39, 79] have shown the efficacy of emollient in preventing AD in infants.

The first one was conducted in Japan on 118 neonates and demonstrated that the incidence of AD was significantly lower in the group treated with an emollient than in the control group. Moreover, the intervention group maintained intact skin for a significantly longer period than the control group (p=0.012). The second study was conducted on 20 patients and suggested a protective effect of emollients. The last study was conducted in the UK and USA on 124 neonates at high risk for AD. Results showed that daily emollient use significantly reduced the incidence of atopic dermatitis at 6 months, corresponding to a relative risk reduction of 50%.In that respect we set up a tolerance study in Poland and Czech Republic with an emollient of 3 different textures: lotion, cream and balm. In all three groups, the tolerance was considered very good by the investigators after 22 days of application. After 22 days of application, subject’s parents said that the skin of their child was modified. They thought that the skin was softer, more hydrated, and more nourished. As a result, we can conclude that emollients based on Rhealba Oat plantlets extract are the most suitable in people suffering from Atopic Dermatitis or at risk to develop one, from birth to adulthood. Clinical proofs obtained through multiple studies, performed in all age groups, support this statement.

Acknowledgment

The author would like to thank Marie-Dominique Thouvenin from Pierre Fabre Dermo-Cosmétique Clinical Development Department, Christophe Chamard and Aurore Bouyssounouse from Pierre Fabre Dermo-Cosmétique R&D department and Fabienne Carballido from A-DERMA Medical Direction for their contribution in this trial. The trial was designed by A-DERMA, Pierre Fabre Dermo-Cosmétique, Lavaur, France and carried out by Roman J. Nowicki, Magdalena Trzeciak and Magdalena Czarnecka- Operacz in Poland and by and Blanka Pinkova in Czech Republic.

Conflict of Interest

MSA is the medical director of A-DERMA and an employee of Pierre-Fabre Dermo-Cosmétique, which sponsored the clinical trial. TA and DK are employees of Pierre-Fabre Dermo-Cosmétique. RN, MT, MOC and BP were the principal investigators of this study.

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