INTRODUCTION:

Atopic dermatitis (AD) is a chronic, inflammatory skin condition and has a variable natural course. This disorder falls under the group of atopic diseases and is characterized by itchy, red, dry, and irritated skin symptoms. AD can affect a person in their childhood before they seem to "grow out of it" but later in life they could develop sensitive skin^1–3.

AD is a major health issue. Its recurrence and chronicity may influence a person's quality of life, economics, social relationships, and career. It can also have an impact on a person's mind and lead to mental health issues in both children and adults³.

With a prevalence of 10–20% in children and 3% in adults, AD is a global public health issue. As many as 50% of AD cases start during the first year of life. In Southeast Asia, the prevalence of AD varies from 1.1% at the age of 13–14 in Indonesia to 17.9% at the age of 12 in Singapore. Between 2009 and 2011, 353 AD patients visited Dermatology and Venereology Outpatient Clinic at Dr.Soetomo General Academic Hospital Surabaya⁴.

Steroids, antihistamines, and immunosuppressive drugs have been considered as the first-line therapy for the treatment of AD even though varying degrees of side effects have been recorded for long-term use. Therefore, a potential treatment approach for AD is to seek out alternative antiinflammatory agents that are more efficient⁵. Several active substances with antiinflammatory properties such as aloe vera, bisabolol, and shea butter for example, are also included in moisturizers that claim that they are beneficial for atopic skin. The negative effects of topical corticosteroids may be reduced or even eliminated with the use of these antiinflammatory medications. An eight-week twice-daily application of a formulation including heparin and levomenol (α-bisabolol) was found to significantly reduce pruritus and disease symptoms, according to a randomized, double-blind clinical investigation involving 278 AD patients (Ancova, p<7x10^-8). Although the combination of these two medications demonstrated higher effectiveness, using a single agent to treat itchy and irritated skin was still possible⁶. Moisturizers containing anti-inflammatory agents are anticipated to decrease the reliance on corticosteroids as anti-inflammatory treatments, given the well-established adverse effects associated with long-term steroid consumption.

There is currently limited data available on the use of antiinflammatory agents in moisturizers. The purpose of this study was to analyze the role of an antiinflammatory moisturizer containing anti-inflammatory agent in the clinical improvement of atopic dermatitis patients, especially mild-moderate AD, using SCORAD evaluation.The hypothesis of this study is that use of moisturizers containing anti-inflammatory agent reduce SCORAD scores compared to moisturizers without anti-inflammatory agent.

MATERIALS AND METHODS:

This study was a double-blind randomized clinical trial, involving 32 patients mild-moderate AD who came to the Dermatology and Venereology Outpatient Clinic at Dr.Soetomo General Academic Hospital Surabaya. The inclusion criteria were mild-moderate AD patients aged 18-64 years old, who met the criteria diagnosis of AD according to the Hanifin-Rajka criteria, the general condition of the patient is good, and willing to participate in the study.

Subjects were then randomly divided into two groups, 16 people in the control group received moisturizer that contains occlusive (dimethicone), humectants (glycerine, saccharide, butylene glycol, hyaluronic acid), emollients (shea butter, squalane) without antiinflammatory ingredients, while 16 people in the intervention groups received moisturizer containing occlusive (dimethicone), humectant (glycerine, saccharide, butylene glycol, hyaluronic acid), emollients (shea butter, squalane) with antiinflammatory ingredients (shea butter, bacterial lysate, allantoin, bisabolol, Phragmites kharka extract, Poria cocos, and Mirabilis jalapa). The labelling and formulation process of the control group and intervention group were carried out by Paragon Technology and Innovation Co., Ltd. The administration of moisturizers in both groups of patients was carried out on both upper limbs and both lower limbs both on the areas with lesions and areas without lesions for 14 days twice a day. The twice-daily administration regimen was chosen based on recommendations for emollient administration in atopic dermatitis patients⁷. Evaluation was conducted on days 0, 7, and 14 after moisturizer application because based on the time required for skin desquamation, previous studies observed the effects of moisturizers at various times, namely on day 14 or day 28 by measuring atopic dermatitis parameters, namely erythema, desquamation, lichenification, excoriation, itching, stinging, burning sensation, and general severity^8–10.

The evaluation of SCORAD consists of three components, namely: the extent of the lesion by percentage (head and neck 9%, upper and lower extremities 9% each, the anterior side of the body 18%, back 18%, maximum 100%); Intensity score for redness, swelling, crusting, pus, skin thickening, dry skin, scars scratching (maximum 18); and subjective score for complaints of not being able to sleep and itching. The maximal total SCORAD was 103. The scores are categorized as follows mild (score <25), moderate (score 25 - 50), and severe (score >50). Evaluation of SCORAD was performed thrice during the study, namely at baseline, one week after treatment and two weeks after treatment. This study was approved by the ethical committee of Dr.Soetomo General Academic Hospital Surabaya (No.0356/KEPK/I/2022).

RESULT:

The mean baseline SCORAD in the intervention group and the control group were 21.51±3.42 and 19.96±2.08, respectively. There was no significant difference in SCORAD between both groups at baseline (p>0.05) (Table 1) which shows the homogenity of the two groups. Based on the analysis conducted, there was a significant difference of SCORAD at baseline and on day 14, on both groups (p<0.001) (Table 2). After analyzing the improvement in SCORAD outcome between both groups, it was discovered that the intervention group had a significant difference (Table 3).

Table 1. Baseline SCORAD

	Baseline	p-value
Intervention group	21.51±3.42	0.153**
Control group	19.96±2.08	0.153**

**no significant difference (p>0.05)

Table 2. SCORAD before and after treatment

	Baseline	Day 14	p-value
Intervention group	21.51±3.42	16.25±3.35	0.000*
Control group	19.96±2.08	17.02±2.04	0.007*

*significant difference (p<0.05)

Table 3. The improvement in SCORAD Outcome

	d	p-value
Intervention group	5.27±0.06	0.000*
Control group	3.44±0.11	0.000*

*significant difference (p<0.05)

d = delta of SCORAD (improvement in SCORAD outcome)

DISCUSSION:

Strengthening and maintaining the skin barrier function are the aims of moisturizing as a treatment for atopic dermatitis. Every stage of the disease course, from those with an atopic genetic predisposition to those who have developed AD, requires moisturizers. Those who develop flare-ups are given anti-inflammatory medication or topical corticosteroids^11,12. Similarly, consensus recommendations have been published with a specific focus on AD in the Asia-Pacific area, that moisturizers should be used frequently as maintenance therapy and as an addition to other treatments already in use, such as topical steroids^13,14. The side effects of topical corticosteroids are something to be aware of, the most prevalent ones include purpura, rosacea, perioral dermatitis, striae, atrophy, and rosacea. Topical corticosteroid use for an extended period of time may impair the skin barrier. Therefore, numerous non-steroidal topical anti-inflammatory agents have been developed and incorporated into moisturizer formulations recently^14–16.

Based on the analysis conducted, it is known that there were significant differences of SCORAD (p<0.05) between baseline and day 14 in the intervention group and control group, respectively. The decrease in SCORAD in the intervention group is 21.51±3.42 to 16.25±3.35 and in the control group is 19.96±2.08 to 17.02±2.04. This research is in line with research previously in atopic dermatitis patients, which found that local SCORAD values (median and interquartile range) in the test area (elbow fold) decreased significantly (p<0.001) from 7.0 (5.0-8.0) to 3.5(1.5-6.5) on day 7 and 4.0 (2.0-6.5) on day 28 in the group of non-antiinflammatory moisturizers containing only emollients (decanediol, menthoxypropanediol, omega-6-fatty acid, and licochalcone)¹⁷. Gueniche et al. (2008) found that the SCORAD decreased significantly (p<0.001) on day 14 and day 29 in the moisturizing group with the antiinflammatory lysate V. filiformis bacteria, and the difference in the SCORAD achieved between the control group that was given placebo and the moisturizer group with antiinflammatoryV. filiformis achieved a significant result (p=0.004) on day 29¹⁸.

The moisturizer given to both groups both contained occlusives, humectants, and emollients. Occlusives are oil substance that creates an exterior hydrophobic layer on the skin's surface, humectants are defined as low-molecular-weight compounds that have the ability to draw water, while emollients are substances that have the capacity to deliver tiny oil droplets into the spaces between desquamating corneocytes in dry skin^6,16,19.

The moisturizer used in the intervention groupwere added antiinflammatory agent. In this study, both moisturizers provide a significant value in reducing SCORAD from baseline to posttherapy. The reason was both moisturizers contained moisturizing ingredients: 1) Dimethicone (3.125%), which belongs to the occlusive class; 2) Gliserin (3.000%), saccharide (1.000%), butylene glycol (4.000%), and hyaluronic acid (0.050%), these ingredients falls under the humectants class; 3) Shea butter (3.150%) and squalane (1.000%) belong to the emollients class. Because of the occlusive, humectant, and emollient ingredients that may cause decreased transepidermal water loss (TEWL) and increased hydration, the severity of atopic dermatitis reflected in SCORAD will also decrease²⁰. However, some of the ingredients in both moisturizers given can be classified as antiinflammatory agents, such as hyaluronic acid in the humectant content and shea butter and squalane in the emollient content^17,18,21,22.

Presumably, the results of this study where both groups experienced a significant decrease in SCORAD (<0.001) were influenced by the moisturizing content which also has additional beneficial properties as an anti-inflammatory. Hyaluronic acid is a humectant that had a significant antiinflammatory benefit, it may decrease the production of inflammatory cytokines. Specific cytokines and hyaluronic acid interactions can influence the activity of immune cells. One such is interleukin (IL)-8, which is secreted during an inflammatory response by fibroblasts, monocytes/macrophages, endothelial, and epithelial cells. Since hyaluronic acid is known to have weak binding to IL-8, its usage as a coating component was useful in preventing unwanted immunological responses^22,23.

The antiinflamatory effect from shea butter was due to lupeol, a dominating triterpene found in shea butter. Studies show that lupeol modulates the expression of a number of molecules, including the proteases, α-glucosidase, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (cFLIP), B-cell lymphoma-2 (Bcl-2), Nuclear factor kappa B (NF-kB), and cytokines IL-2, IL-4, IL-5 and IL-1β. Particularly, it has been found to considerably lower levels of IL-1b and IL-12, Tumour Necrosis Factor- α (TNF-α), and lipopolysaccharide (LPS)-induced nitric oxide. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression of pro-inflammatory enzymes was also suppressed. These anti-inflammatory effects resulted from lupeol's inhibition of COX-2, TNF-α, IL-1b, IL-12 mRNA, and LPS-induced iNOS. Lupeol also prevented LPS-induced NF-kB nuclear translocation and IkB phosphorylation. These discoveries clarify the molecular foundation of the bioactivity of shea butter against numerous inflammatory diseases²⁴.

Squalane is an emollient, saturated form of squalene that had been proven to have anti-inflammatory effects by immunomodulating macrophages, the primary innate cells involved in wound healing. Squalene enhanced IL-10 production, an anti-inflammatory cytokine that reduced proinflammatory cytokines and antigen presentation. Squalene increased the levels of IL-4 and IL-13, two other important cytokines that aid in the M2 anti-inflammatory polarization of macrophages together with IL-10. In order to control the wound-healing process, the Th2 cytokines IL-13 and IL-4 balance the M1 response during the anti-inflammatory process^25,26.

This study showed that intervention group gave better result in the improvement in SCORAD outcome (p<0.05). The antiinflamatory agents contained in the intervention group moisturizer were shea butter (3.150%), lysate bacterium (1.000%), allantoin (0.500%), bisabolol (0.500%), Phragmites kharka and Poria cocos extract (3.000%), Mirabilis jalapa (3.000%). Shea butter is an emollient made up of five main fatty acids: palmitic, stearic, oleic, linoleic, and arachidic acids. Eighty five until 90% of which were steric and oleic acids. Additionally, it has been demonstrated that the triterpene acetate and cinnamate esters in shea butter have anti-inflammatory and tumor-promoting properties⁶. At low dosages, specifically 100–500 ppm, anti-inflammatory actions of shea butter are already possible. Epidermal thickness increased by 84% as a result of the use of shea butter. At concentrations of 300 ppm and 600 ppm, shea butter can also result in keratinocytes matrix metalloproteinase-3 (MMP-3) expression declining by >50% and >60%, respectively. The dermal papillae collagen level increased by 6% after 0.5% shea butter extract was applied to the skin. Shea butter may reduce the release of cytokine IL-1α intracellular pro-inflammatory mediators to 25%, thereby reducing inflammation²⁴.

Vitreoscilla filiformis extract (Vfe) activates preferentially by attaching to Toll Like Receptor (TLR2), which is found on the surface of all skin cells, including keratinocytes, melanocytes, sensitive neurons, Langerhans cells, and dendritic cells. Vfe has an ideal bio-affinity with the skin and mimics the actions of helpful skin bacteria due to its composition, which is rich in key ingredients required for the support of the skin and the microbiome. It also stimulates cells via the TLRs. In addition, it has been demonstrated in vitro that Vfe specifically works to increase skin resistance, induce natural defence mechanisms, and modulate immunity. Moreover, topical applications of Vfe in vivo were demonstrated to have a direct impact on the skin to alleviate the signs and symptoms of atopic eczema and seborrheic dermatitis by calming the skin, repairing the skin barrier, boosting adenosine monophosphate (AMP), and rebalancing the skin microbiota^27–29.

Allantoin has been demonstrated to have antioxidant and antiinflammatory properties, direct antibacterial effects, and keratolytic activity that aids in wound healing. By encouraging cell growth and the production of extracellular matrix, allantoin has been found to aid in the growth of healthy tissue. There is evidence that allantoin reduces hyperkeratotic alterations, erythema, infiltration, and the subjective feelings of itching and burning in individuals with psoriasis^30,31.

German chamomile (Matricaria recutita) can be used to extract bisabolol, it contains anti-inflammatory and anti-spasmodic activities. Sesquiterpene alcohol, chamazulene, and flavonoids are additional components of German chamomile that possess these qualities. The anti-inflammatory action of bisabolol was caused by the inhibition of cyclooxygenase and lipoxygenase. Bisabolol was also believed to encourage granulation tissues in the healing of wounds^6,32.

Poria cocos are said to have immunological, anti-inflammatory, and anti-tumor effects. The administration of a combination of Phragmites kharka and Poria cocos was reported to reduce TEWL, reduce irritation, erythema, and pruritus. In addition, Phragmites kharka and Poria cocos also reduce the production of TNF-α and IL-8 which are pro-inflammatory mediators that cause skin irritation^33–36.

According to reports, Mirabilis jalapa reduces the production of mucopolysaccharides, collagen, and fibroblasts when granuloma tissue develops in the course of chronic inflammation. Along with these additional benefits, Mirabilis jalapa can prevent mast cell granulation, decrease eosinophilia, and reduce albumin-induced edema^37,38.

A moisturizer's main purpose is to prevent moisture loss. To repair the skin barrier once it has been compromised, it is first necessary to prevent water loss. A moisturizer adds moisture to rough, flaky skin that is dry and may be impacted by the environment's dryness and other external factors. A moisturizer also encourages even shedding of old dead skin cells to retain a healthy skin surface and helps to preserve and restore skin elasticity by preventing moisture evaporation. The skin helps regulate when the moisturizer works effectively in the skin, allowing the stratum corneum to remain appropriately hydrated regardless of alterations in the environment outside^39,40.

The skin barrier is rebuilt over the course of the next four steps once a moisturizer has been applied to injured skin. The oily component of the moisturizer forms a thin film on the skin, starting the process of barrier repair, then changes in the skin moisture distribution coefficient. After that, water diffuses from the dermis to the epidermis, and the production of skin lipids and intercellular lipid secretion regulate water distribution to the epidermis^39,40.

That is, the emollient component of the moisturizer regulates the exfoliation of dead skin cells to restore the skin barrier, the humectant component directly supplies moisture to the epidermis and dermis, and the oily element of the moisturizer forms a film on the skin to prevent the evaporation of moisture. Additionally, when moisturizers contain ingredients that are comparable to the lipids in the stratum corneum of the skin, the lipid component is delivered to the keratinocytes of the epidermis to reorganize the intercellular lipids, preserving the moisture content in the epidermis and enhancing the performance of the skin barrier. Applying a moisturizer properly not only reduces dryness but also strengthens the skin's natural defenses against external and internal aggressors, maintaining the skin's health. Excellent moisturizing agents also act as adjuvants in the treatment and prevention of diseases as well as the relief of the symptoms of skin diseases like itching and stinging since numerous skin diseases are accompanied by irregularities in the skin barrier function^39,40.

CONCLUSION:

Moisturizer administration in mild-moderate AD was able to improve the clinical manifestations in both groups. Furthermore, moisturizers containing anti-inflammatory agents (shea butter, lysate bacterium, allantoin, bisabolol, Phragmites kharka and Poria cocos extract, Mirabilis jalapa) improved the SCORAD outcome significantly more than moisturizers without anti-inflammatory agents. Future suggestions include conducting research on moisturizers that contain other anti-inflammatory agents, outside those examined in this study, as an alternative approach for treating atopic dermatitis.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

We are immensely grateful to PT Paragon Technology and Innovation, Dr. Soetomo General Academic Hospital, and all the other entities that supported this research.

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Received on 07.09.2023 Modified on 01.03.2024

Research J. Pharm. and Tech 2024; 17(11):5183-5188.

DOI: 10.52711/0974-360X.2024.00793