Immunopharmacology and Immunotoxicology

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iipi20

Atopic dermatitis: new insight into the etiology,

pathogenesis, diagnosis and novel treatment
strategies

Deepa S. Mandlik & Satish K. Mandlik

To cite this article: Deepa S. Mandlik & Satish K. Mandlik (2021) Atopic dermatitis: new insight
into the etiology, pathogenesis, diagnosis and novel treatment strategies, Immunopharmacology
and Immunotoxicology, 43:2, 105-125, DOI: 10.1080/08923973.2021.1889583

To link to this article: https://doi.org/10.1080/08923973.2021.1889583

Published online: 28 Feb 2021.

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IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
2021, VOL. 43, NO. 2, 105–125
https://doi.org/10.1080/08923973.2021.1889583

REVIEW

Atopic dermatitis: new insight into the etiology, pathogenesis, diagnosis and
novel treatment strategies
Deepa S. Mandlika and Satish K. Mandlikb
a
Bharat Vidyapeeth, Deemed to be University, Poona College of Pharmacy, Pune, India; bSinhgad College of Pharmacy, Vadgaon,
Pune, India

ABSTRACT ARTICLE HISTORY

Atopic dermatitis (AD) is the long-lasting chronic inflammatory skin condition associated with cutane- Received 14 August 2020
ous hyper-reactivity and triggered by environmental factors. The attributes of AD include dry skin, Accepted 5 February 2021
pruritus, lichenification and frequent eczematous abrasions. This has a strong heritable aspect and typ-
KEYWORDS
ically occurs with asthma and allergic rhinitis. The complex pathological mechanism behind AD eti-
Atopic dermatitis;
ology is epidermal barrier destruction resulting in the lack of filaggrin protein that can induce pathogenesis; glucocorticos-
inflammation and T-cell infiltration. T-helper 2 cell-mediated pathways also bear the responsibility of teroids; systemic therapy;
damage to the epidermal barrier. Certain causative factors for AD include microbial imbalance of skin phototherapy; adjuvant
microbiota, immunoglobulin-E-induced sensitization and neuro-inflammation. Numerous beneficial top- treatment; natural products;
ical and oral treatments have been available to patients and there are even more drugs in the pipeline nonadherence
for the treatment of AD. Topical moisturizers, corticosteroids, anti-inflammatory agents such as calci-
neurin inhibitors, phototherapy, cAMP-specific 3, 5 half-cyclic phosphodiesterase 4 inhibitors and sys-
temic immunosuppressants are widely available for AD treatments. Different positions and pathways
inside the immune system including JAK-STAT, phosphodiesterase 4, aryl hydrocarbon receptor and T-
helper 2 cytokines are targeted by above-mentioned drug treatments. Instead of the severe side
effects of topical steroids and oral antihistamines, herbal plants and their derived phytoconstituents
are commonly used for the treatment of AD. A clear understanding of AD’s cellular and molecular
pathogenesis through substantial advancement in genetics, skin immunology and psychological fac-
tors resulted in advancement of AD management. Therefore, the review highlights the recent advance-
ments in the understanding of clinical features, etiology, pathogenesis, treatment and management
and non-adherence to AD treatment.

Introduction as per the various clinical measurement scales, the most

Scientists, Wise and Sulzberger first invented the word AD to
explain puzzling kinds of local or general skin lichenification
[1]. AD is a long-lasting, inflammatory and pruritus skin dis-
ease generally observed in early childhood but may also con-
tinue in adulthood [2]. AD is distinguished by a hyperactive
immune reaction to environmental influences that results in
dry, itchy skin. Skin lesions can cause significant emotional
stress and a vivid burden on the quality of life of patients.
Patients are not only impacted by the common perception
of a prominent skin disorder, but the extreme scratching
characteristic of the diseases also contributes to skin discom-
fort and severe sleep disruptions. Skin lesions may be caused
by stress, interaction with allergens, scrabbling and many
other reasons [3]. The incidence of AD is projected to be 10
to 15 percent in children and two to 10 percent in adults in
the Western population. Two forms of AD were primarily
established, the extrinsic form linked to IgE intermediate sen-
sitization and the intrinsic form without IgE intermediate sen-
sitization [4]. AD is characterized for its variations, potential
reversibility and irregular progression in the patient life.
Twenty percent cases of AD will be graded as mild to severe
commonly employed of which are the Investigator Global
Evaluation (IGA), the Eczema Region and Frequency Rating
(EASI) and the SCORing Atopic Dermatitis (SCORAD) scale [5].
AD shows a varied range of clinical skin features. The clinical
features of AD are given in Table 1. Present research indi-
cates that AD is a key skin barrier deficiency that causes cer-
tain atopic disorders to evolve [6]. Also, AD is always the first
stage in the ‘atopic march’ (the concurrent progression of
symptoms of allergic infection in infancy), developing bron-
chial asthma and/or allergic rhinitis in most affected patients
[7]. Interestingly, initial AD might be an etiological factor in
food allergy progression [8]. New findings into AD indicate
that both skin structure defects and immune dysregulation
play significant roles in the disease’s pathophysiology. Of this
cause, effective treatment of AD involves a multidimensional
approach to repair and maintain the skin barrier and resolv-
ing the multifarious immunopathogenesis of the diseases [9].
A breakthrough in translational science in recent years has
broadened understanding of AD pathogenesis and contrib-
uted to the creation of novel molecules that target core
inflammatory features of the disease. The review article offers

CONTACT Deepa S. Mandlik deepa_ingawale@yahoo.com Department of Pharmacology, Poona College of Pharmacy, Pune, India
ß 2021 Informa UK Limited, trading as Taylor & Francis Group
106 D. S. MANDLIK AND S. K. MANDLIK

Table 1. Clinical features of AD.

Clinical sign Description
Pruritus The unpleasant sensation of the skin that provokes the urge to scratch
Xerosis Dry skin in areas without clinically apparent inflammation
Ichthyosis vulgaris Fish-like dry scales that can often look extremely thick and dry
Keratosis pilaris Appearance of thick scale and redness around the hair follicles that may be
surrounded by a patchy erythema
Follicular prominence Follicles have a goose-bump appearance
Palmar & plantar hyperlinearity Patients more often have exaggerated palmar hand creases than
plantar creases.
Dennie-Morgan lines Dark, symmetric, double horizontal folds below the lower eyelids
Periorbital darkening Gray to violet-brown discoloration and swelling around the eyes
Anterior neck folds Horizontal folds or lines across the middle of the anterior neck
Hertoghe sign Loss of the lateral third of the eyebrows because of constant scratching
White dermatographism Blanching response as a result of stroking of the skin with the back of a
fingernail that leads to white streaks
Pityriasis alba Consists of multiple ill-defined light (hypopigmented) patches with fine
scaling that are often located on the face and neck and occasionally
appear on the shoulders and arms

a summary of existing research on etiology, disease patho- Environment

physiology with possible use for therapeutic targets, diagno-
sis and effective treatment of AD.
Etiology of AD
In those family whose members are affected, the risk of
developing AD is substantially greater. For example, in
monozygotic twins, the concordance rate of AD is about 75
percent, which means that if the cotwin is infected, the risk
of disease in the twin sibling is 75 percent [10]. The risk in
dizygotic twins, on the other hand, is just 30%. It indicates
that genetic factors play a part in AD vulnerability. Because
there is no full agreement between monozygotic twins, how-
ever, who share all of their genes, environmental and devel-
opmental factors may also play a role. As such, AD is a
complex genetic disorder that results from many interactions
between the gene-gene and gene-environment.
Genetics
Several genes have been linked to AD, mainly genes that
encode epidermal structural proteins and genes that encode
the main elements of the immune system. The reported
strong association between AD and mutations in the filag-
grin gene (a genetic risk factor for AD), located on chromo-
some 1 is a recent and important genetic discovery [11].
Approximately 10 percent of people from western cultures
have mutations in the filaggrin gene, while about 50 percent
of all patients with AD have those mutations. Mutations of
the filaggrin gene cause functional impairments in the filag-
grin protein and thus weaken the skin barrier. The clinical
manifestation of these impairments is dry skin and an ele-
vated risk of eczema. Not all patients with AD have these
mutations, and there have also been other genetic variations
incriminated. This is the cumulative action of both of these
genetic variations along with AD causing environmental and
developmental risk factors [12].
Several different environmental risk factors for AD have been
considered potentially causative, only a few are widely recog-
nized. There is significant evidence, for example, that our
western lifestyle has contributed to some of the recorded
rise in the incidence of eczema over the past few years but
this did not point to particular environmental risk factors or
explicitly translate into functional preventive measures [13].
Some support the hygiene hypothesis when describing the
dramatic rise in the prevalence of eczema [14]. This hypoth-
esis notes that decreased early childhood exposure to proto-
typical infections like hepatitis A and tuberculosis has
enhanced atopic disease susceptibility [15]. The theory is
backed by the findings that the youngest sibling has the
lowest risk of AD and that children growing up in a typical
agricultural community where they are exposed to a range
of microflora, such as unpasteurized cow’s milk, livestock and
poultry, are to some degree shielded against disease devel-
opment and allergic disease [16]. Conversely, the incidence
of the disease is likely to be positively associated with the
period of breastfeeding [17], although several studies have
linked the parents’ high social status to an enhanced risk of
AD in the infant. While these findings are not easy to under-
stand, they may also support the hygiene hypothesis or at
least the widely established theory that eczema arises in
genetically susceptible individuals that are subjected to a
certain detrimental climate [18].
Pathophysiology of AD
AD’s pathophysiology is dynamic and multifactorial, contain-
ing aspects of barrier failure, shifts in cell-mediated immune
responses, IgE-induced hypersensitivity and environmental
influences. It also occurs due to a complicated interface
between accountable genes, a climate of the host, pharma-
cological abnormalities and immunological factors [19].
Skin barrier dysfunction
The skin serves as a physicochemical shield to numerous
physical, chemical and biological influences that are

Table 2. Elements of skin barrier dysfunction in AD.
Component
Filaggrin gene expression
Skin Ceramide
Epidermal proteases
responsible for causing AD. Proksch et al., have examined
core facets of skin barrier failure in AD [20]. A variety of gen-
etic vulnerability loci responsible for skin barrier activity is
noted by genome-wide linkage studies [21]. The role of these
individual genes in AD pathogenesis requires additional
exploration but at best three main motives for barrier dys-
function have been identified in AD patients: (a) reduced
gene expression of filaggrin, (b) deficiency of ceramides and
(c) over manifestation of epidermal proteases (Table 2).
Immunological factors
There has been much discussion in the literature about the
pathophysiology of IgE mediated or extrinsic AD. The pri-
mary passageway leading to the inflammation of the skin is
still not clear. This may occur due to scratching of the skin
that induces the keratinocytes to stimulate pro-inflammatory
cytokines or may trigger due to contact between T-cell and
infiltrated allergens from interrupted skin barrier [24].
Togetherly adaptive and non-adaptive immunity have an
important role in the pathophysiology of AD. The adaptive
immune responses are greatly specific to a precise antigen
while non-adaptive immune responses are unspecific. For
any repeated antigen exposure, the adaptive immune
responses get stronger [25]. Multiple cells which reside in
the skin like dendritic cells (DCs), keratinocytes, macro-
phages, mast cells (MCs), and innate lymphoid cells (ILCs)
play a significant part in skin inflammation of AD patients
[26]. Rather than skin resident cells, T cells, granulocytes,
monocytes, and plasmacytoid dendritic (pDCs) from blood
circulation, also play an imperative role in the progress of
AD skin lesions [27]. After the presentation of antigen from
DCs into the skin, the naive T cell is divided into T helper
(Th) 1 and Th2-cells. It is commonly believed that, regardless
of the relative disruption in the equilibrium between Th1/
Th2 cells, AD occurs, with total Th2 cell superiority [28]. The
inflammatory reaction is a two-step process, original, acute,
Th2 dominant process accompanied by a chronic Th1 like
profile. In the acute AD stage, allergens through disrupted
skin barrier stimulate the degranulation of mast cells (MC)
triggering the release of histamine, interleukin (IL)-6, IL-8,
prostaglandins D2 and tumor necrosis factor (TNF)-a along
with IL-23 and IL-31. Along with these mediators, damaged
epithelial cells release thymic stromal lymphopoietin (TSLP)
which results in increased Th2 type inflammatory response.
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 107
Description
Filaggrin is an essential skin protein that is responsible for cross-linkage of
keratin filaments into tight bundles and stratum corneum hydration.
Around 50 percent of AD patients display mutation in the filaggrin
gene [11].
Phospholipid is essential for preservation of water in the outermost layer of
the skin (stratum corneum). In the stratum corneum of AD patient, there
is an inverse relationship between the ceramide levels and the
transepidermal water loss [22].
The proteases responsible for desquamation of corneal desmosomes are
Kallikrein (KLK)-5, KLK-7, and KLK-14. Lymphoepithelial Kazal-type 5 serine
protease inhibitor is expressed by serine protease inhibitor Kazal type 5
genes. The mutation in SPINK5 was related to the exacerbation of AD
symptoms [23].
In response to allergens invasion, skin-inhabitant keratino-
cytes and Langerhans cells (LCs) produce cytokines like IL-10,
IL-12, IL-18 and chemokines that cause stimulation of other
inflammatory cells like neutrophils, eosinophils, basophils
and T cells. Cytokines, such as IL-10 and IL-23, respectively,
stimulate differentiation of naïve T cells into Th2 and Th17.
The Th17 cells stimulate the release of IL-17A, IL-17E and IL-
22 cytokines. The change from an acute to a chronic inflam-
matory phase is triggered by intensified IL-12 and IL-18 pro-
duced from inflammatory epidermal dendritic cells (IDECs) or
eosinophils or both. During chronic AD, dendritic cells
release IL-12 and IL-18 lead to activation of the Th1 cells.
IFN- c released from Th1 cells induces keratinocyte apoptosis
while IL-22 promotes skin modification and chronic AD skin
thickness. A recent study further concludes that stimulation
of Toll-like receptors 2 (TLR2) on DCs converts Th2 dermatitis
to chronic skin inflammation in mouse models [29]. Both the
stages of AD have been reported to contain a substantial
level of Th2 cytokines compared to normal skin; however,
chronic skin lesions are associated to improved IL-5 and IL-
12 and decreased IL-4 and IL-13 release [30].
Environmental and microbial factors
AD occurs due to the interaction between hereditary and
environmental influences. Many environmental factors like
bacteria, viruses, airborne allergens, food, smoking, soaps
and detergents can trigger the inflammatory pathway in AD
and cause the interruption of the epidermal barrier. The
essential environmental factors have been mentioned in
Figure 1 and Table 3.
Diagnosis of AD
There are no screening measures to identify AD. Disorder
evaluation is based upon the patient history and clinical
symptoms of the disease’s condition [38]. Figure 2 discusses
the diagnostic criteria of AD. Through these benchmarks, the
finding of AD includes the existence of a scratchy skin dis-
order or report of itching or rubbing of the skin by the par-
ental/caregiver in a child plus three or more minor criteria,
which differ based on the age of the patient. Irrespective of
age, the scratching associated with AD usually persists dur-
ing the day and worsens at night, contributing to lack of
sleep and severe impairments in quality of life.
108 D. S. MANDLIK AND S. K. MANDLIK

Differentiating AD from certain skin disorders such as contact Prevention of AD

dermatitis, seborrheic dermatitis, scabies and psoriasis is
often difficult; nevertheless, in certain instances, a familial
history of atopy and lesions scattering is beneficial in deter-
mining the diagnosis. Nutritional abnormalities, malignancies
and keratinization or immunodeficiency diseases correlated
with skin symptoms are other factors that need to be
addressed in the differential diagnosis of AD [9].
Though there are currently no proven primary preventive
methods for AD, the efficacy of early, reliable application of
emollients to infants at elevated risk has been shown in
recent clinical trial studies. This quick and cost-effective
method has culminated in a decrease of 30–50 percent of
AD diagnosis at 6 months [39].

Figure 1. Different risk factors affecting on AD.
Treatments of AD
AD treatment should be aimed at repairing the skin barrier
that involves moisturizing and maintenance of the skin, pre-
venting scratching, and reducing inflammation when needed.
Hence, proper treatment of AD includes a multidimensional
strategy including patient and caregiver awareness, appropri-
ate skin maintenance procedures, treatment with anti-inflam-
matory drugs like topical corticosteroids (first-line) and/or
topical calcineurin inhibitors (TCIs) and skin infection man-
agement [40]. For extreme situations, systemic immunosup-
pressive agents can also be used that cannot be managed
with adequate skincare and topical therapy. Though first-
generation antihistamines are not widely prescribed for AD
treatment due to their sedative and damaging side effects,
acute usage of such drugs can be beneficial in certain per-
sons with serious AD flares, mainly if such flares are corre-
lated with major sleep disorders [41]. Physicians will
routinely track patient improvement and progression of the
illness, and assess treatment efficacy and tolerability. The
treatment pattern of AD and treatment in adult and children
are mentioned in Figure 3 and Table 4.

Table 3. Environmental factors in AD.

Factors Description
Airborne allergens The inflammatory reaction in sensitized atopic skin can be triggered by
airborne allergens. House dust mites (HDM) obtained from the species
Dermatophagoides pteronyssinus and D. farina are the commonest source
of airborne allergens. The HDM can destroy the skin barrier by abolishing
the tight epithelial junctions by enzymatic activity [31].
Food Food allergy in children is well recognized in around one-third of cases of
AD. Milk, fish, for example, protein, soya, peanut and nuts are mostly seen
among food allergens to exacerbate AD conditions.
Microbial exposure S. aureus colonization of the atopic skin influenced by dysfunction of the skin
barrier, elevated skin pH, elevated content of fibronectin, and reduced
ceramides and low antimicrobial peptide levels [32]. S. aureus also
documented to secrets enterotoxin A and B and toxin-1, playing a major
function in aggravating AD [33]. In addition, S. aureus secretes proteinases
capable of breaking down corneodesmosomes [34]. AD patients are more
prone to skin infections like Verruca vulgaris, Molluscum contagiosum and
Herpes simplex than non-AD patients.
Soap and Detergents The acidic pH of human skin greatly leads to barrier activity against multiple
antigens. This serves as an antibacterial agent that regulates desquamation
of corneodesmosomes. The change in skin pH to greater side can
aggravate lesions of AD skin. Soaps induce skin pH rise, lipid
emulsification on skin surface, skin protease enhancement and subsequent
thinning of stratum corneum [35].
Weather factor and Smoking Humidity, temperature and UV sensitivity affect the production of AD skin
lesions. In AD incidence, the combination of high UV intensity and
temperature tends to have a shielding effect, while high humidity and
precipitation are correlated with progressive impact on AD [36]. Active
smoking behavior was not considered as a risk in AD but maternal
smoking was identified as a danger in children with AD [37].

Figure 2. Diagnostic criteria for AD.
Figure 3. Treatment pattern of AD.
Table 4. Treatment of AD in adults and children [5].
Severity of AD
Baseline AD
Mild AD
Moderate AD
Severe AD
Education
Patients and/or their carers should be informed regarding
the progressive existence of the disease’s condition, the
necessity for consistent commitment to appropriate skincare
procedures, and the correct usage of topical treatments for
effective disease control. Poor care results are also correlated
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 109
AD management in adult and children
Educational program, Avoidance of allergens, Emollients, Bath oils
Topical glucocorticosteroids, Topical calcineurin inhibitors, Antiseptics
containing silver
Tacrolimus or Class II or Class III topical glucocorticosteroids, UV therapy, Wet
wrap therapy, Psychosomatic counseling
Hospitalization, Systemic immunosuppressive agents like Oral
glucocorticosteroids, Cyclosporine A, Mycophenolate mofetil, Duplimab,
Methotrexate, Azathioprin
with inadequate adherence, in particular with topical treat-
ments, arising from unreasonable concerns about the side
effects and inadequate diseases knowledge [9]. This has
been found that time invested in discussing these concerns
and training patients and carers have a significant impact on
the outcomes of the disease. For better understanding,
110 D. S. MANDLIK AND S. K. MANDLIK

Table 5. Skin care in AD.

Methods Recommendations
Cleansing and bathing Smooth and thorough cleaning is done to avoid surface microbial contamination.
Nonirritating cleansers like syndets, aqueous solutions can be used with or without antiseptics.
In case of infants bathing, use of baby oil is advised in the last stage of bathing.
For antibacterial action, sodium hypochlorite (0.005 %) may be used as an antiseptic in bathwater [44].
Emollient treatment It is recommended to apply the emollients twice a day.
Tannins and ichthammol emollients are advised for the treatment of AD.
Emollient formulations without protein allergens and haptens can be used.
Non-medicated emollients containing riboflavins, flavonoids and saponins were suggested for the AD treatment [45].

Topical anti-inflammatory therapy

Figure 4. Examples of flare factors in AD.
patients may also provide with detailed instructions/informa-
tion on proper drug usage, skincare, and flare prevention.
Skin care
Good routine skincare is a crucial function in AD manage-
ment. While bathing the frequency is a little uncertain, most
experts recommend bathing every day [42]. Bathing in warm
water one or two times in a day (based on the intensity of
AD) for ten minutes is advised to help hydrate and cleaning
of the skin, help debride diseased skin and increase the per-
meation of topical drugs. Moisturizing cleansing agents are
advised whereas avoiding heavily fragrant soaps because
they can irritate the skin. The skin of the patient should be
patted dry with a towel after bathing and moisturizers
should be used to avoid further loss of moisture and drying
of the skin. In the treatment of AD creams and ointments
are more powerful than lotions for nourishing the skin [43]
(Table 5).
Identification and elimination of flare factor
Possible flare factors of AD may be recognized depending
on the background and detailed allergy testing. The sensitiv-
ity should be documented by in vivo tests (skin prick test
and prick-prick test) and in vitro tests (serum specific IgE).
Food sensitivity can be tested by in vitro allergy studies, such
as double-blind placebo-controlled food challenges, avoid-
ance of diets or patch checks for atopy. In nonspecific and
specific flare factors are distinguished from each other and
examples are mentioned in Figure 4.
Topical anti-inflammatory AD therapy relies on three funda-
mental principles; appropriate dose, sufficient intensity and
proper usage. There are currently three types of topical anti-
inflammatory drug therapy approved by USFDA for the treat-
ment of AD. Those involve topical corticosteroids, calcineurin
inhibitors and phosphodiesterase 4-inhibitor (PDE4 inhibitor).
Topical anti-inflammatory treatment is usually performed
only on skin lesions and minimized as the flares are
decreased. Nowadays, this type of therapy is more structured
and recognized as preventive therapy that is triggered by a
systemic anti-inflammatory treatment after the effective heal-
ing of lesions [46]. Regardless of advancements in the pro-
duction of systemic medications, topical therapies appear to
be important for both the renovation and distribution of
anti-inflammatory drugs in barrier functions. Furthermore,
ointments, calcineurin inhibitors and corticosteroids newer
drugs have been established for the topical use. Various top-
ical drugs under different phases of clinical trials are men-
tioned in Table 6.
Glucocorticosteroids
Topical glucocorticosteroids are the first alternative for the
treatment of inflammatory skin in AD. In case of moderate
AD, topical applications of corticosteroids two or three times
in a week following the usage of emollients aids ineffective
treatment. The corticosteroids were categorized into a cat-
egory I (mild) to group IV (super potent) by Niedner based
on their potency [47] (Figure 5). Super potent corticosteroids
are not recommended to babies and children. The adrenal
gland functions are usually suppressed by group III (Potent)
and group IV (super potent) than group I and group II corti-
costeroids, but their systemic effects will reduce rapidly due
to immediate repair of the skin barrier [48]. Group I and II
corticosteroids would be used for the treatment of face
lesions, particularly the eyelid area. According to the US-
American classification, the corticosteroids are classified from
group VII (mild) to the group I (super potent). The long term
use of glucocorticosteroids produces numerous adverse
effects include skin atrophy, spontaneous scars, ecchymosis,
stretch marks, dirty neck, hypertrichosis and perioral derma-
titis [49]. In children, chronic topical usage of corticosteroids
in the diaper area may induce granuloma gluteale infantum
or even iatrogenic Cushing ’s disease. Ocular adverse effects
like cataract or glaucoma have been identified after systemic
glucocorticosteroids treatment [50].
 IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 111

Table 6. New topical treatments under development for the treatment of AD.
Biological agent Therapeutic target Severity Phase Status
Tofacitinib JAK 1, JAK 3 Mild to moderate II Completed
Ruxolitinib JAK 1, JAK 2 Mild to moderate II Completed
Delgocitinib PAN- JAK Mild to moderate II Completed
Crisaborol PDE4 Mild to moderate III Completed
MM36 PDE4 Mild to moderate II Completed
III Active
AN2898 PDE4 Mild to moderate II Completed
Rofiumilast PDE4 Mild to moderate IIa Completed
E6005 PDE4 Mild to moderate II Completed
Tapinarof Aryl hydrocarbon receptor agonist Mild to moderate II Completed
Omiganan Anti-microbial peptide Mild to moderate II Completed
VTP-38543 Liver X receptors receptor Mild to moderate I/II Completed
Q301/Zyleuton PG 2 trans-membrane receptor Mild to moderate II Completed
PR022 Hypochlorous acid Mild to moderate II Active
SP14019/Cyclato Ciclosporin Mild to moderate II Completed
JAK: Janus kinase; PDE4: Phosphodiesterase-4; PG: Prostaglandin.

not account for an elevated lymphoma hazard in a newly

released article [54].

Figure 5. Examples of common topical corticosteroid therapies.
Topical calcineurin inhibitors
In the year 2000 and 2001, the FDA approved the topical cal-
cineurin inhibitors, that is, tacrolimus and pimecrolimus cor-
respondingly [51]. Both the drugs act by inhibiting the
calcineurin phosphatase enzyme thus; impeding the activa-
tion of T cells and mast cells with the secretion of cytokines.
Additionally, both medications have been documented to
have an increased impact on the skin AD. Kyllonen et al.
found that the application of 0.1% tacrolimus exhibited a sig-
nificant improvement in collagen production resulting in
increased skin thickness and reversal of skin atrophy from
the usage of corticosteroids [52]. Murrell and colleagues
stated that pimecrolimus therapy results in substantial
changes in AD lesions, skin thickening of the neck and the
head area along with the eyelids [53]. Topical calcineurin
inhibitors offer a healthy substitute to corticosteroids for
treating vulnerable areas of the face and back skin. In March
2006, the FDA issued both pimecrolimus and tacrolimus a
blanket black box warning over an elevated incidence of
malignancies like lymphoma with topical calcineurin inhibi-
tors. A meta-analysis of preclinical and clinical evidence does
Phosphodiesterase 4-inhibitors
In 2016, the FDA licensed a new topical anti-inflammatory
drug category that inhibits the cAMP-specific 3, 5-cyclic
phosphodiesterase 4 (PDE4) enzyme. Crisaborole ointment is
licensed by USFDA for the care of patients aged up to
2 years with mild to moderate AD. By inhibiting PDE4, crisa-
borole promotes second messenger cAMP activity, contribu-
ting to a decrease in pro-inflammatory cytokine production.
The reason for this therapy emerged from multiple experi-
ments that have shown that leukocytes from AD patients
had a blunted reaction to cAMP owing to elevated PDE4
activity [51]. Many investigational PDE4 antagonists are OPA-
15406 and E6005. In phase III trials, two years age patients
with mild to moderate AD, 32% of patients treated with cri-
saborole displayed nearly clear skin as compared to patients
treated with the vehicle no severe adverse effects have been
reported, and the main adverse effect at the application site
was burning or stinging [55]. Crisaborole crucial role in AD
management is yet to be decided; however, it can provide
another topical non-steroidal alternative for use in individuals
with mild to severe AD [56].
Tapinarof. It is a nonsteroidal anti-inflammatory drug that
functions as an aryl hydrocarbon receptor agonist, an activity
that may boost the barrier role and reduce the Th2 immune
response. The usage of one per cent tapinarof two times in a
daily in a phase-II trial demonstrated substantial improve-
ments in investigator global assessment score 0–1 and
reduction of eczematous area and severity index, scoring AD
and body surface area relative to vehicle control [57].
Cyclatop (SP14019). It is a topical medication developed as
a five percent spray of cyclosporine under investigation in
patients over 2 years of age in phase-II randomized clinical
trial (NCT02865356). The findings, reported at the 2018
European dermatology congress, revealed substantial advan-
tages of strong tolerability and minimal systemic absorption
in eczematous area, severity index and investigator’s global
112 D. S. MANDLIK AND S. K. MANDLIK
assessment scale as compared to vehicles for four
weeks [58].
Hypochlorous acid (PR022). Study of AD patients resulted
in a reduction of pruritus was correlated with the usage of
hypochlorous acid (0.008 and 0.002 per cent) topically in a
hydrogel formulation. Hypochlorous acid is believed to
reduce the concentrations of various like TNF-a, histamine,
interferon (IFN) - c, IL-2 [59].
Ominagan. It is a gel formulation of an antimicrobial pep-
tide that is being tested in phase-II randomized clinical trial;
while there are no efficacy results, good tolerability was
documented. The reduced antimicrobial peptide develop-
ment in AD promotes microbial invasion and infection and
enhances inflammatory response [59].
Janus associated kinase-signal transducer and activator
of transcription (JAK-STAT) inhibitors
Most of the signaling cytokines in AD utilizes the JAK path-
way. Tofacitinib, a JAK inhibitor, has been shown to decrease
inflammation in AD due to inhibition of interleukin-4 [60].
Already there are pending trials on its usage in AD, psoriasis
and alopecia areata. A Phase-IIa clinical trial found that two
percent tofacitinib topical administration two times a daily
had substantial-effectiveness when match with vehicle con-
trol ointment [61]. Currently, topical JAK/STAT receptor inhib-
itors are reportedly under review. These involve 2% topical
tofacitinib and 1.5% ruxolitinib, which tend to be effective in
minimizing EASI and pruritus [62]. A PAN-JAK inhibitor in a
Japanese RCT also demonstrated EASI gains that were
greater than with the vehicle alone, but no major harmful
effects [63]. Four orally administered JAK inhibitors are cur-
rently under investigation. Baricitinib antagonizes JAK 1 and
JAK2 that is linked to modulation of different cytokines. In
phase-II clinical trial, oral administration of 4 mg/day bariciti-
nib in patients with moderate to extreme AD was associated
with a higher proportion of patients attaining Eczema Area
and Severity Index (EASI-50) compared to placebo with bet-
ter tolerability. The reported adverse effects included asymp-
tomatic creatine kinase elevation but no cases of thrombosis
or herpes zoster were recorded [64]. The active inhibitors of
JAK1 are Upadacitinib (ABT-494) and Abrocitinib (PF-
04965842) and show early progress with these medications.
A phase-IIb randomized clinical trial assessed the usage of
Upadacitinib for 16 weeks at doses of 7.5, 15 and 30 mg
when compared with placebo. Several phase-III randomized
clinical trial are underway with Abrocitinib at doses of 100
and 200 mg compared to placebo and a phase-III RCT as a
comparator with Dupilumab. In addition, ASN002 is a dual
inhibitor of JAK and spleen tyrosine kinase (SYK) pathways.
Inhibition of PAN-JAK inhibits the expression of several AD-
implied cytokines such as IL-4, IL-13, IL-31 and IL-33, whereas
inhibition of SYK suppresses the signals of proinflammatory
cytokines such as IL-1b, IL-10 and IL-17. In the first phase-Ib
randomized clinical trial with ASN002 the number of patients
who reached EASI-50 at 28 days was higher than in placebo
with 40 and 80 mg doses [65]. Topically administered JAK
inhibitors are a successful treatment but additional clinical
trials are required in patients with AD.
Phototherapy
Artificial UV radiation revelation has been documented as an
effective treatment for atopic skin improvement. A new
study found that mild to moderate AD was entirely resolved
in 74 percent of patients, 16 percent showed marginal
improvement and nine percent showed no change in AD at
all. This concludes the infection’s seasonal variability, with
improvement during summer season and degradation in the
other season. Furthermore, seaside holidays in sunshine
exhibited substantial change relative to holidays spent in
mountain regions, with considerable reversal of AD situations
[66]. These findings do not fully explain the function of ultra-
violet (UV) exposure in AD but they encourage the medical
group to further investigate the effect of UV radiation on AD.
Phototherapy enhances the atopic skin circumstances by
modifying the immune system by inflammatory cell apop-
tosis, inhibition of LCs and variability in cytokine production
[67]. Additionally, UV radiations act as antimicrobials and
lessen staphylococcus aureus colonization on atopic skin.
UVA1 treatment has also revealed the immunosuppression of
IL-5, IL-13 and IL-31 [68]. Recent research supports the
importance of vitamin-D during phototherapy in healing
atopic lesions [69]. Phototherapy for two weeks exhibited a
marked change in the balance of vitamin D with an enlarged
level of serum calcidiol contributing to an effective cure of
AD lesions. Reduction and functional loss of DCs in the skin’s
epidermal and dermal regions help immunosuppression
through the source of UV light [70]. Narrowband UVB (311-
313 nm) performs more efficiently than UVB broadband.
Medium UVA1 dose (340-400 nm) affects close to that of UVB
narrowband. It is possible to use a combination of UVA and
UVB for the treatment of AD lesions. Photochemotherapy
was also prescribed in conjunction with a photosensitizing
drug given orally, that is, psoralens (PUVA: psoralen and
ultraviolet A). Chronic use of all UV treatments, particularly in
PUVA, poses the risk of skin aging and cancer. Blue visible
light has also been observed in AD for some promising
results and is being investigated as other phototherapy
modes [71]. Photopheresis in selected cases of extreme
refractory AD has also shown a positive response. Other
excimer-308 nm laser monochromatic tools extend the thera-
peutic options in patients with localized and therapy-resist-
ant AD [72]. Pulsed-dye lasers are currently under rigorous
review for the treatment of chronic AD [73].
Systemic therapy
Numerous types of medications, that is, antihistamines, cyclo-
sporine A, mycophenolate mofetil, selective serotonin
reuptake inhibitor and opioid receptor antagonists have
been systemically approved for immunosuppression.
Different proof exists as to the effectiveness of antihist-
amines (H1 antagonists) for pruritus treatment in AD, since

most investigations exhibited a poor or no response to prur-
itus [74]. The naltrexone opioid receptor antagonists have
been found to alleviate pruritus in AD patients which can
have frequent side effects such as dizziness, headache, vom-
iting, weakness, agitation, arthralgia and sleepiness [75]. The
drugs from selective serotonin reuptake inhibitors category
like paroxetine and fluvoxamine may be effective for the
management of pruritus but are associated with several side
effects such as dizziness, diarrhea, insomnia, constipation,
erectile and ejaculatory dysfunction and diminished libido
[76]. Cyclosporine suppresses cytokine-stimulating transcrip-
tion of T cells. The drug interacts with intracellular cyclophi-
lin and thus acts in a similar way as tacrolimus and
pimecrolimus. Short duration cyclosporine with an enhanced
quality of life can support conventional drug therapy for AD
patients [77]. Furthermore, termination of treatment typically
occurs in periods of relapse. The treatment of cyclosporine
associated with specific side effects like hypertension and
renal inefficiency. For the treatment of refractory inflamma-
tory skin diseases, mycophenolate mofetil, an antimetabolite
that inhibits biosynthesis of purine has been recommended
[78]. The daily dose of two gram has cleansed the adult AD
lesions that were resistant to steroid or PUVA therapy.
Suppression of bone marrow was the main side effect identi-
fied with the mycophenolate mofetil treatment. Various sys-
temic drugs under different phases of clinical trials are
mentioned in Table 7. Many emerging types of medications
are under review for the management of acute AD.
Duplimab
In 2017, the FDA has approved Duplimab to treat mild to
severe AD. Duplimab is a fully humanized, monoclonal anti-
body that affects the IL-4 receptor alpha subunit and thus
inhibits IL-4 and IL-13 signaling [51]. Duplimab obstructs the
mRNA expression that activates T cells, inflammatory cas-
cade, eosinophils, dendritic cells, Th2 cytokines and sup-
presses epidermal hyperplasia in AD [79]. It has also been
proposed that inhibition of IL-4 and IL-13 can not only min-
imize skin lesion severity but may also restore skin barrier
function due to increased levels of claudine, loricrin, filaggrin
and lipid products. The suggested dose of duplimab is
300 mg two times in a day followed subcutaneously by
300 mg every other week. Duplimab has less reported serious
adverse reactions such as conjunctivitis, upper respiratory
tract infection, injection-site reactions and nasopharyngi-
tis [80].
Lebrikizumab and tralokinumab
Lebrikizumab and Tralokinumab are the human monoclonal
antibody was stated to have substantial efficacy in moderate
to severe AD due to the blockade of IL-13 [81]. However,
outcomes for both medications were deemed questionable
because results were obtained in the clinical trials with sig-
nificant use of topical corticosteroids. The drugs are under
phase II clinical trial, for regulatory approval [82].
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 113
Apremilast
It is an oral PDE4 inhibitor approved for obstructive pulmon-
ary disease, psoriatic arthritis and plaque psoriasis. Its safety
and efficacy investigation in adult AD patients in an open-
label pilot study revealed a substantial reduction in itching
and enhancement in quality of life [83]. Then, its beneficial
use has been documented in AD and other inflammatory
skin conditions but more comprehensive randomized con-
trolled trials are needed [84].
Nemolizumab
It is a monoclonal antibody that affects the IL-31 receptor. A
phase II, placebo-controlled trial assessing safety and efficacy
in patients with mild to serious AD reported a substantial
enhancement in AD conditions. Treatment in a dose-depend-
ent manner provided noticeable relief in itching [85].
Therefore, further work is needed to better understand the
therapeutic impact of skin lesions and the history of the
adverse effects.
Omalizumab
It is a recombinant humanized monoclonal antibody that
affects the IgE antibodies and has been approved by USFDA
for allergic asthma and urticaria treatment [86]. It is a deriva-
tive of a monoclonal murine antibody, which is humanized
to produce omalizumab [87]. Several reported studies sug-
gest that the omalizumab is effective in atopic dermatitis
and is well tolerated too. In a case study conducted by Holm
and colleagues, out of nine omalizumab-treated AD patients,
50% of the patient’s revealed excellent response, 12.5% dis-
played moderate response, and 37.5% presented no effect to
the treatment. Researchers also carried out a systematic
review of 26 separate studies conducted to assess the thera-
peutic effectiveness of omalizumab in AD [88]. The research
focused on large scale randomized clinical trials is still
awaited to support its clinical application in AD.
Rituximab
It is an anti-CD20 antibody that causes reduction of circulat-
ing B cells. Rituximab therapy enhanced skin signs in
severely AD patients, indicating its possible function on B
cells in the AD pathogenesis [89].
Pitrakinra
It is an inhibitor of IL-4 receptor signaling that obstructs the
binding of IL-4 and IL-13 to IL-4 a receptor complexes. It has
been proposed that the biologic material enhances the
asthma symptoms [90].
Infliximab
It is a TNF antagonist was tested in a pilot study containing
nine patients with moderate to extreme AD. The treatment
with infliximab has enhanced the signs but the effect
through maintenance therapy was not maintained [91].
114 D. S. MANDLIK AND S. K. MANDLIK

Table 7. New systemic treatments under development for the treatment of AD.
Biological agent Therapeutic target Route of administration Severity Phase Status
Dupilumab IL-4, IL-13 SC Moderate to severe III Completed
Mepolizumab IL-5 SC Moderate to severe II Discontinued
Lebrikizumab IL-13 SC Moderate to severe II Completed
Tralokinumab IL-13 SC Moderate to severe IIb Completed
III
KHK4083 OX40 IV Moderate to severe I Completed
II
GBR 830 OX40 IV Moderate to severe IIa Completed
SC IIb
Tezepelumab TSLP SC Moderate to severe IIa Completed
IIb
MK-8226 TSLP -R IV Moderate to severe I Discontinued
Secukinumab IL-17A SC Moderate to severe II Completed
MOR106 IL-17C IV Moderate to severe II Completed
Fezakinumab IL-22 IV Moderate to severe II Completed
Ustekinumab IL-12, SC Moderate to severe II Completed
IL-23
BMS-981164 IL-31 SC Moderate to severe I Discontinued
Nemolizumab IL-31RA SC Moderate to severe II Completed
Etokinab IL-33 SC Moderate to severe II Active
Omalizumab IL-E IV Moderate to severe II Completed
Ligelizumab IL-E SC Moderate to severe II Completed
KPL-716 OSMRb IV Moderate to severe Ia Completed
SC
Upadacitinib JAK 1 Oral Moderate to severe IIb Completed
III Active
Baricitinib JAK 1, JAK 2 Oral Moderate to severe I Completed
III Active
Abrocitinib JAK 1 Oral Moderate to severe IIb Completed
III Active
ASN002 JAK 1, JAK 2, JAK 3; SYK Oral Moderate to severe I Completed
II
Apremilast PDE 4 Oral Moderate to severe II Completed
ZPL389 HT 4 receptor Oral Moderate II Completed
JNJ-39758979 HT 4 receptor Oral Moderate II Discontinued
Tradipitant NK-1receptor Oral Mild, moderate or severe II Completed
II Completed
III Active
Serlopitant NK-1receptor Oral Mild, moderate or severe II Completed
DS107 Dihomo-c-linoleic acid Oral Moderate to severe II Completed
Asimadolin Kappa opioid receptor agonist Oral Mild, moderate or severe II Completed
IL: Interleukin; TSLP: Thymic stromal lymphopoietin; OSMRb: Deficiency of oncostatin M receptor b; SYK: Spleen tyrosine kinase; PDE 4: Phosphodiesterase-4;
HT4: Histamine 4; NK-1: Neurokinin 1 receptor.

Mepolizumab inflammation of all kinds. AMG 157 is a human anti-TSLP

It is a humanized monoclonal antibody binding to the IL-5
receptor, did not cause clinical progress in AD patients follow-
ing a substantial reduction in serum eosinophilic count [92].
Furthermore, a recent double-blind study found that, in patients
with extreme eosinophilic asthma, mepolizumab had a major
glucocorticoid-sparing effect [93]. Additional research is needed
to decide whether anti-IL5 therapy can be used to treat AD.
monoclonal immunoglobulin which binds to human TSLP
and prevents interaction between receptors. Treatment with
anti-TSLP antibody in patients with mild allergic asthma with
elevated allergen-induced early and late asthma responses
[95]. Phase-I clinical trial was conducted with an anti-TSLP
antibody in a healthy individual and moderate to severe AD
patients [96].

Tocilizumab
It is an IL-6 receptor humanized monoclonal antibody used
for the management of rheumatoid arthritis. Current research
demonstrated the possible efficacy of disturbing activation of
IL-6-receptors in AD patients [94]. Nevertheless, the correl-
ation of bacterial superinfections with the therapy was also
identified. More research is required to examine the effi-
ciency and safety of IL-6 receptor antagonists.
Anti-TSLP
It is a cytokine obtained from epithelial cells that performs
the main part in the maturation of T-cell by activating anti-
gen-presenting cells. Production of TSLP can cause
Treatment of skin infections
The skin of AD patient gets severely populated with the S.
Aureus bacterial infection. Short duration topical and oral
antibiotic treatment is required when there is an apparent
bacterial infection. Suitable systemic antibiotics are recom-
mended for extensive secondary infections. First- or second-
generation cephalosporin or anti-staphylococcal penicillin for
seven to 10 days are usually efficacious in controlling the
bacterial infection. Macrolides antibiotics are less effective
alternatives for erythromycin-resistant organism’s infection in
AD patients. Often, AD patients are vulnerable to recurrent
viral infections. Eczema herpeticum (a serious disseminated

herpes infection that typically occurs at skin damage sites), is
a significant risk in patients with widespread AD and can be
certainly misdiagnosed as a bacterial infection, requiring sys-
temic antiviral treatment with acyclovir or other antiviral
agents [97]. Among children with AD, molluscum contagio-
sum (a serious viral cutaneous infection caused by
Molluscipox genus poxvirus) is repeatedly seen. Although the
infection is typically self-limited, the lesions also gradually
resolve and continue to spread in AD patients. Severe, per-
sistent infection with the molluscum contagiosum can require
laser and/or antiviral therapy. It is also recommended that
diluted baths with bleach help raising the amount of S. aur-
eus skin infections, and the necessity for systemic antibiotics
is highly colonized skin patients. Diluted bleach baths require
soaking the patient in a tub full of lukewarm water for
around ten minutes, combined with 60–120 ml of chlorine
bleach. The patient is then exhaustively washed with fresh
water and immediate application of a moisturizer or emolli-
ent to avoid dehydration and dryness of the skin. Several
authors have suggested diluted bleach baths for three
months for two times in a week [98].
Anti-histamines
Even though antihistamines of the first generation such as
chlorpheniramine, hydroxyzine, diphenhydramine do not spe-
cifically affect AD-related itching, the sedative effects of these
drugs have been shown to enhance sleep pattern in AD
patients. Furthermore, these drugs lessen rapid eye movement
sleep, diminish work performance, and impair learning, there-
fore are not regularly recommended for AD patients. They can
be recommended for the acute adjuvant care of serious AD
patients who have trouble sleeping or frequently scratch dur-
ing sleep. Due to their sedative effects, chronic and daytime
use of first-generation antihistamines should be circumvented.
Among AD patients with allergic causes, nonsedating second-
generation antihistamines tend to be of moderate benefit,
and thus, a therapeutic trial of these agents could be sug-
gested in some clinical circumstances [99]. The histamine 4
receptor (H4R) antihistamines are other long-acting, oral, small
molecules which represent an added auspicious treatment
option for AD. In comparison to the H1R-blocking antihist-
amines traditionally used as antipruritic agents, the effects in
patients with AD are primarily based on their sedative proper-
ties. H4R antihistamines have effects related to the pathogen-
esis of AD. H4R is vastly expressed on keratinocytes in AD
patients with lesional skin, and its activation encourages the
proliferation of keratinocytes and prevents their differentiation,
impairs the skin barrier and causes pruritus [100,101]. ZPL-
3893787, an H4R antagonist, is an ongoing phase II clinical
trial (NCT02424253).
Adjuvant treatment
Adjuvant therapy should be provided in situations where AD
symptoms are unrestrained without sufficient
basic treatment.
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 115
Evening primrose oil, black currant seed oil and borage oil:
Due to its gamma-linoleic acid content, primrose oil at night
was thought to be helpful in AD patients. Even though a cur-
rent meta-analysis has revealed that primrose oil has unsuc-
cessful to substantially recover AD, it is nevertheless utilized
as an adjuvant treatment in AD with a limited danger of side
effects [102].
Sunflower seed oil: Both anti-inflammatory and membrane
restorative properties have been reported with the sunflower
seed oil. Its main lipid is linoleic acid that is supposed to
reduce skin inflammation by stimulating the peroxisome pro-
liferative-activated receptor-alpha. The oleodistillate form of
the sunflower seed oil is believed to strengthen the skin bar-
rier [103]. Sunflower seed oil was shown to be equivalent to
Aquaphor in decreasing child mortality and sepsis levels by
growing the skin barrier recovery [104].
Olive oil: It was found to be toxic to the skin barrier, while
sunflower oleodistillate maintained the integrity of stratum
corneum, did not lead to erythema and increased skin hydra-
tion than the olive oil [105].
Virgin coconut oil: It has demonstrated benefits in animal
models of both acute and chronic inflammation as an out-
standing emollient, natural antibacterial and anti-inflamma-
tory agent [106]. A latest randomized double-blind study in
117 pediatric AD patients tested the impact of virgin coconut
oil on SCORAD index and transepidermal water loss for
eight-weeks as compared to mineral oil. Mean SCORAD indi-
ces in the virgin coconut oil decreased from baseline to the
mineral oil, and it was found to be superior to mineral
oil [107].
Honey: It has customarily been used in the diagnosis of
inflammatory skin disorders like psoriasis and AD. Fingleton
et al. performed an open-label, single-blind, randomized clin-
ical study of 15 adults who had bilateral lesions identified
with AD on their limbs [108]. Some patients were treated
with Kanuka honey added topically. Honey’s clinical efficacy
was evaluated by measuring AD scores and severity of skin
lesions. Honey has also been demonstrated to be therapeut-
ically beneficial when used in adult patients with AD in con-
junction with beeswax and olive oil [109].
Omega-3 fatty acid: Currently, it has been proposed that
the increased frequency of AD could be linked with improve-
ments in the Western diet (decreased consumption of
omega-3 polyunsaturated fatty acids and improved intake of
omega-3 polyunsaturated fatty acids. A pilot study found
that dietary consumption of omega-3 polyunsaturated fatty
acids may have a beneficial impact on the AD symp-
toms [110].
Probiotics: These are live microbial foods additives that are
indigestible carbohydrates that promote the production of
probiotic bacteria in the intestine. These act as an immuno-
modulator by acting on T-helper cell cytokine activation
[111]. Recently, Baquerizo et al., reported that probiotics and
prebiotics tend to be effective in decreasing AD incidence in
the infant [112]. Yet their role in treating AD remains debat-
able. More studies are required to determine if, by modulat-
ing immunological dysfunction of AD, these agents may play
a role in AD treatment.
116 D. S. MANDLIK AND S. K. MANDLIK
Adherence to treatment as a hurdle in AD
Since AD is a long-lasting skin illness, treatment schedules
that are often formed precisely for individual patients require
regular management. It can be a daunting hurdle to sustain
strong adherence over long periods of time. It is assessed
that 30% to 40% of all drugs used for chronic conditions are
not taken as prescribed [113]. Electronic surveillance of der-
matologic patients indicates that patients are frequently
poorly adherent to topical therapy and that their use of
medication in care logs could be overestimated by patients
[114]. Numerous studies have demonstrated varying grades
of nonadherence directly to AD care. Primary nonadherence
defines the first stage of a patient’s nonadherence when
their original prescription at a pharmacy is not redeemed. If
the patient does not adequately obey their care plan or use
their medicine as prescribed, secondary nonadherence hap-
pens at home. In Denmark, the primary adherence activity of
322 patients with outpatient dermatology was examined by
means of a national pharmacy registry, showing that pre-
scriptions were redeemed within four weeks of their appoint-
ment for consultation. 31.8% of patients with AD did not
receive their medications within 4 weeks, which indicates
that nearly one-third of such patients showed primary non-
adherence [115]. While the emphasis on enhancing second-
ary non-adherence is often greater, primary nonadherence is
just as significant and should not be discounted. It is not
likely to be successful if the drug is not filled in.
If the drugs are filled out by patients, secondary adher-
ence can still be poor. In research secondary adherence has
been assessed in which patients are given medication using
electronic monitors. Sometimes, patients exaggerate their
use of therapy. For 5 days of treatment with fluocinonide
cream (0.1 percent), the median daily adherence was 40 per-
cent per electronic monitoring, whereas subjects reported
100 percent adherence to drug diaries. On day 1 of treat-
ment, adherence was higher in six out of nine patients using
their treatment regimen, while on day 5, only 1 out of 9
patients was adherent [116]. Mean adherence to twice-daily
desonide hydrogel decreased from 81 percent adherence on
day 1 to 50 percent by day 27 over a 4-week period out of
41 adult patients with mild to moderate AD [117].
At the end of 8 weeks of treatment, electronic monitoring
of 26 pediatric AD patients showed that average adherence
to topical triamcinolone was 32 percent. At the date of the
initial visit, adherence was highest, then fell steadily, dou-
bling before the date of the return visit and declining again
subsequently. In Japan, adherence was usually lower in AD
patients compared to psoriasis or tinea patients [118]. In a
small pilot study of 25 patients, 92% of patients indicated
that they often failed to use their drugs, 88 percent stated
that they sometimes stopped their AD treatment when their
skin indications upgraded, and 33.3 percent described that
when their skin signs deteriorated, they stopped their AD
treatment [119].
There may be several explanations for the diminished
commitment to care seen in AD. For parents of children with
skin disorders, the utmost common reasons identified for
nonadherence were the cost of drug and unease about
adverse effects. In AD trials in which patients were given the
drug and decided to contribute, however, adherence was
low, indicating that costs and worries about side effects are
not the only significant restrictions to adherence in AD.
Other explanations include oblivion, confusing orders, and
difficulty of time for medication, corticosteroid phobia, or
lack of knowledge of the disease or treatment [120].
Assistance between parents, disapproval of treatment,
inability to bathe, late bedtime, absence of social support,
concern about eczema, feelings of discrimination and per-
ceived seriousness of the disease were factors linked to
adherence in a group of parents of children specifically with
AD [121]. Factors such as patient preferences, past experi-
ence with interventions, and mode of drug administration
can also influence adherence, as topical procedures may be
more problematic for patients [122]. Even short-term use of
topical fluorescent test cream applications is difficult [123].
Topical drug adherence can also be affected by the preferen-
ces of patients for particular formulations of vehicles
to others.
Although there are a multitude of treatments for AD and
more are being developed, topical therapies for AD, such as
corticosteroids, remain the first-line treatment. Adherence to
these therapies can vary, with anxiety regarding the use of
corticosteroids, also called as ‘steroid phobia,’ playing a role
in the use of these drugs by patients. Despite their safety
and effectiveness in treating AD, patients often show fright
and worry about topical steroid usage [124]. Topical cortico-
steroids may also be confused with anabolic steroids by
patients or caregivers, causing more misunderstandings
about the usage of these drugs. The social media may also
spread this steroid phobia, along with the popular miscon-
ception that topical steroids may have the similar side effects
as oral or systemic steroids [125]. In France, 80.7 percent of
208 patients or parents of AD patients reported fears of top-
ical steroids and 36 percent admitted that they did nonad-
herence to their medication. 47.8 percent of those surveyed
were not aware of the adverse effects of specific drugs, but
also showed fear of using these drugs. Fear of topical corti-
costeroids was substantially associated with the belief in 300
Italian patients with AD that treatment benefits do not over-
weigh the drawbacks and the belief that TCS could be risky
regardless of the specific side effect [126]. Likewise, 72.5 per-
cent of the 200 AD patients surveyed in the UK expressed
concern about topical steroids, and 24 percent registered
failure to comply with their care because of these concerns
[127]. The perceived thinning of the skin, systemic absorp-
tion, skin inflammation, nonspecific long-term effects and a
negative influence on growth and development are the most
common concerns among patients [128].
Role of natural products in the treatment of AD
Natural products extracted from medicinal plants have been
used since ancient times for the management of various dis-
eases. The earliest use in Mesopotamia of natural resources
as medicine dates back to 2600 BC. Also, the ‘Ebers Papyrus’
records of over 700 drugs back in 1550 BC are well kept

[129]. Similarly, the Indian Ayurveda philosophy was intro-
duced after the first century BC [130]. The production of
drugs based on natural products is fraught with certain prob-
lems, such as consistency, identification of bioactive substan-
ces, difficulties in obtaining wild samples and unsuitability
with high-performance screening of natural products [131].
To further establish the detailed mechanism of action of nat-
ural products is a challenging task. The pharmaceutical firms
have shifted their prime focus on new product innovations
to synthetic substances because of these challenges. Yet the
results recorded from the recently launched synthetic medi-
cines during the 1990s do not satisfy expectations [132].
USFDA approval levels have been poor for such medicines.
Given these reasons, it has revived the trust in the develop-
ment of medicines depending on natural ingredients. For
drug development and study, many natural phytoconstitu-
ents used for the management of a number of diseases,
including AD, are becoming important [133]. A significant
number of herbs and phytoconstituents are used for the
treatment of chronic hepatic disorders worldwide due to
budget effectiveness, high protection constraints, long-term
beneficial action and less side effects (Figure 6).
For thousands of years, herbal medicine for skin condi-
tions has been used. The great apes, and our biologically
close relatives, use herbal self-medication [134]. Regional pro-
duction of specific herbs and their uses, based on locally
available plants, and through the trade in ethnobotanical
Figure 6. Mechanism of action of herbal plants and phytoconstituents in the management of AD.
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 117
remedies. In Europe, the Middle East [135], Africa, India (Behl
and Srivastava 2002), China, Japan, Australia, and the
Americas, herbal usage systems have evolved regionally.
Ayurvedic herbs in India [136] and herb combinations, devel-
oped as part of traditional Chinese medicine (TCM) in China,
are two well-known systems still in use [137]. For the follow-
ing reasons, the use of herbs has become resurgent in recent
years: the side effects of chemical medicines have become
evident, there has been a demand for a return to nature,
natural remedies have become part of the green revolution,
and there has been a return to organic produce. Herbal rem-
edies are currently gaining popularity among patients and to
a lesser degree among doctors, including those for
skin disorders.
Natural drugs from plant origin are getting more accept-
ance due to many benefits such as having fewer side effects,
improved patient tolerance, being comparatively less costly
and appropriate due to a long history of use. Besides herbal
medicines, other diseases which are obstinate and incurable
in other medicine systems are treated rationally. Given the
profound side effects caused by topical steroids and oral
antihistamines, herbal medicines and their derived phytocon-
stituents are widely used for treating AD [138]. Therefore,
efforts have been made to identify safer and more powerful
plant-derived compounds that can modulate AD’s patho-
logical mechanism(s) such as antihistaminic effects, inhibition
of Th2 responses and production of IgE [139]. The review
118 D. S. MANDLIK AND S. K. MANDLIK

Table 8. The effect of various plants on AD with respect to their mechanism of action.
No. Plant name & Family Nature of Extract Inducing agent Mechanism of action References
1 Actinidia arguta Water DNCB Decrease inflammatory cells, lymphocyte, [140]
Actinidiaceae elevate Treg-related & Foxp3 expression
2 Amomum xanthioides Water DNCB Reduce immunoglobulin E (IgE), CCL-17, [141]
Zingiberaceae CCL22, pro-inflammatory cytokines levels
3 Angelicae Water DNCB Reduce pro-inflammatory cytokines levels, [142]
dahuricae Apiaceae decrease inflammatory cells, mast cells &
CD4þ cells
4 Artemisia argyi Ethanol DNCB Reduce IgE, histamine, pro-inflammatory [143]
Asteraceae cytokines; Inhibit IjBa & PI3K/Akt
phosphorylation
5 Artemisia argyi Methyl alcohol DNFB Inhibit the release of NO & PGE2 in [144]
Asteraceae macrophages, pro-inflammatory cytokines
6 Artemisia scoparia Butanol DNFB Inhibit TSLP, histamine, IgE, pro-inflammatory [145]
Asteraceae cytokines levels & suppress caspase-1
7 Bambusae caulis Ethanol D. farina Reduce TEWL, inhibit IgE, eosinophil, pro- [146]
Poaceae inflammatory cytokines levels
8 Bambusae caulis Bamboo stem 2,4-DNFB Suppression of IgE, IL-4, IL-13 & TNF-a levels [146]
Poaceae
9 Betula Aqueous Picryl chloride Suppresses T-helper 2 cell response & serum [147]
platyphylla Betulaceae IgE level
10 Broussonetia kazinoki Ethanol D. farina Reduce IgE, IL-4 & skin mast cells levels [148]
Moraceae
11 Calophyllum inophyllum Methanol DNCB Decrease in pro-inflammatory cytokines and [149]
Calophyllaceae scratch behavior
12 Cervus Nippon Water DNCB Reduce mast cells, CD4 þ T, downregulate IgE, [150]
Cervidae pro-inflammatory cytokines levels
13 Cinnamomum cassia Ethanol HDM antigen Reduce IgE, histamine, pro-inflammatory [151]
Lauraceae cytokines & TARC mRNA expressions
14 Cordyceps bassiana Butanol DNFB Inhibition of release of histamine, IgE, IL-4 & [152]
Cordycipitaceae IFN-c production
15 Cynanchum atratum Water DNCB Ameliorate total IgE; reduce mast cell & pro- [153]
Apocynaceae inflammatory cytokines levels
16 Dictamnus dasycarpus Methyl alcohol Oxazolone Reduction of pro-inflammatory cytokines [154]
Rutaceae
17 Forsythia suspense Ethanol HDM antigen Suppression of expression of chemokines, [155]
Oleaceae cytokines & adhesion molecules in
keratinocytes
18 Gardenia jasminoides Water DNCB Suppressed COX-2, TNF-a expression, NF-jB [156]
Rubiaceae activation, IgE level & pro-
inflammatory cytokines
19 Hypsizigus marmoreus Ethanol 1-chloro 2, 4, 6- Decrease in dermatitis score, thickness of [157]
Tricholomataceae trinitrobenzene epidermis & proinflammatory cytokines
expressions
20 Morus alba Ethanol Biostir-AD Decrease PGE2 & NO production; suppress IgE, [158]
Moraceae TARC & histamine levels
21 Panax ginseng Water TNCB Decrease IFN-c, TNF-a, IgE, substance P, TSLP [159]
Araliaceae & TNF-a levels
22 Perilla frutescens Water DNFB Alleviating expressions of MMP-9 and IL-31 [160]
23 Platycodon grandiflorum Water DNFB Downregulation of IgE levels through [161]
Campanulaceae modulation of TH1 & TH2 immune
responses, decrease in TH2-
mediated cytokines
24 Pseudostellaria Water DNCB Suppress mast cells, IgE, pro-inflammatory [162]
heterophylla cytokines, MAPKs & NF-jB expression
Caryophyllaceae
25 Pyrus ussuriensis Ethanol DNCB Reduce IgE, pro-inflammatory cytokines; [163]
Rosaceae Reduction of scratching tendency &
erythema; Improved skin hydration
26 Rheum tanguticum Ethanol Hapten Decrease WBC, IgE & 5-LOX levels [164]
Polygonaceae
27 Saussurea lappa Methanol Biostir-AD Downregulate MDC, IL-8, IgE, TARC, RANTES, [165]
Asteraceae histamine & TARC levels
28 Schizandra chinensis Water DNCB Inhibit histamine, IgE, IgM, mast cell, IL-4, IL- [166]
Schisandraceae 5 expression
29 Scutellariae radix Aqueous Environmental stimuli Decrease IL-5 expression [167]
Lamiaceae
30 Tribulus terrestris Ethanol Oxazolone Reduce transepidermal water loss (TEWL), [168]
Zygophyllaceae Orai-1 & TRPV3 activation, inhibit
inflammatory cell
 IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 119

Table 9. The effect of phytoconstituents on AD with respect to their mechanism of action.

No. Phytoconstituents Plant source Inducing agent Mechanism of action Reference
1 7, 8, 40 - Glycine max DNCB Decrease eosinophils count, lower pro- [169]
trihydroxyisoflavone inflammatory cytokines levels
2 Capsaicin Capsicum annuum DNFB Suppressed activation of CD4þ T cells & mast [170]
cells, expression of pro-
inflammatory cytokines
3 Chlorogenic acid Artemisia capilliaris D. farina Reduce histamine, NO & IgE levels [171]
4 Chrysophanol Rumex crispus DNFB Reduce histamine, IgE, TSLP, ICAM-1, IL-4, IL-6 [172]
Cordyceps militaris & TNF-a, MIP-2
5 Cordycepic acid Cordyceps sinensis DNFB Inhibit IL-4, INF-c, histamine & IgE [152]
6 Crocin Gardenia jasminoides D. farina Inhibit activation of IL-4, IL-13, [173]
STAT6 & NF-jB
7 Cupressuflavone Juniperus rigida OXA/DNCB Inhibit IL-4, IgE & b-hexosaminidase release [174]
8 Daidzein, Genistein Glycine max Merr D. farina Reduce IL-12, TNF-a, IL-4, PKC, MMP-9, IL-4, [175]
substance P, iNOS & p-IjB levels
9 Decursin Angelica sinensis DNCB Reduce pro-inflammatory cytokines, NF-jB, [176]
IgE, MAPKs levels
10 Ergosterol Poria cocos DNCB Increase aryl hydrocarbon receptor expression [177]
11 Forsythiaside, Phillyrin, Forsythia suspensa D. farina Reduce VCAM-1, ICAM-1, IgE, histamine, mast [155]
Phylligenin Pinoresinol cell, TARC, MDC, RANTES, IL-4 levels
12 Gallic acid Cortex Moutan OXA Suppress pro-inflammatory cytokine, CCL7 [178]
& CCL8
13 Geniposide Gardenia jasminoides D. farina Reduce INF-c, IgE, histamine, mast cells, IL-4, [179]
IL-6 & TNF-a levels
14 GinsenosideRh2 Panax ginseng DNCB Inhibit TARC, TAR, TSLP, IL-4, IL-10, IL-6, TNF- [180,181]
Ginsenoside Rg3 a & MAPKs
15 Gintonin Panax ginseng DNFB Inhibit microglial activation & reduce IL-4, IgE, [182]
histamine, ]INF-c levels
16 Indirubin Polygonum tinctorium DNFB Inhibit TSLP, IgE, IL-4, IL-6, caspase-1 & [183]
histamine level
17 Lancerin Polygala tenuifolia Trimellitic anhydride Reduce IgE & histamine levels, Inhibit [184]
degranulation of tryptase, HMC-1 cells
& PKA
18 Linolenic acid Coriandrum sativum DNCB Reduce Th-1 & Th2-mediated cytokines [185]
19 Liquiritigenin, Liquritin Coptidis Rhizoma DNFB Inhibit Substance P, MMP-9; reduce COX-2, [186]
Glycyrrhiza uralensis TNF-a, p-IjB, iNOS & levels
20 Momordin Kochia scoparia DNCB Reduce expression of NF-jB, IL-1b, TNF-a [187]
& MAPKs
21 Naringenin Citrus fruits, tomatoes, DNFB Suppressed IFN-c, serum IgE levels, Reduced [188]
cherries, grapefruit infiltration of infiltration of eosinophils,
mast cells
22 Naringin Drynaria fortune D. farina Decrease IgG, IgE, IL-4, IL-6 & TNF-a [189]
expressions
23 Oregonin Alnus japonica Biostir AD Decrease the eosinophil count; Reduce IgE, IL- [190]
4, IL-5, IL-13 levels
24 Polysaccharide Ericerus pela DNCB Decrease IgE & mast cell; Inhibit Th1, Th17 [191]
activation, IL-6, IL-17A & INF-c
25 Quercetin Dendrobium tosaense TNCB Upregulate INF-c; Downregulate IgG, IL-4 [192]
& IgE,
26 Resveratrol Skin of red grapes DNFB Inhibition of proinflammatory cytokines [193]
27 Rutin Broussonetia kazinoki D. farina Inhibit TARC, MDC & RANTES production; [194]
Reduce IgE, IL-4, IL-5, IL-13
28 Valencene Cyperus rotundus DNCB Inhibit TARC, GM-CSF & I-CAM levels; Reduce [195]
IgE, IL-1b, IL-6, IL-13 levels
29 Ziyuglycoside I Sanguisorba officinalis DNCB Reduce IgE & b-HEX levels [196]
30 b-pinene Alpinia intermedia HDM Inhibit mast cell & TLSP expression [197]

paper presents the study findings of the anti-inflammatory
role of the medicinal plants and phytoconstituents used in
the treatment of AD (Tables 8 and 9). Table 10 depict the
available marketed products (like cream, ointment, lotion)
used in the management of atopic dermatitis. Table 11 illus-
trate the list of patented drug along with mechanism of
action and patent number for the treatment of AD.
Conclusion
In conclusion, AD is a complex, multifactorial disorder with a
substantial effect on the quality of life of affected patients
and their families. The elevated incidence of AD in develop-
ing countries has been a major public health problem as it
substantially reduces the patient’s quality of life. It also leads
to hereditary allergy and asthma if not treated properly. AD
may be triggered by genetic conditions and can be affected
by environmental factors. Optimum skin care activities and
topical corticosteroids treatment remains the keystone of the
disease. Topical calcineurin inhibitors in suitable patients vul-
nerable to regular flare-ups are an efficient, alternative treat-
ment to topical corticosteroids. In severe cases, systemic
immunosuppressive agents may also be considered for the
treatment of AD. Enhanced knowledge of physiology and
120 D. S. MANDLIK AND S. K. MANDLIK

immunoregulatory pathway can contribute to effective drug appear to be implemented as step-up medication in the pro-
discovery and management therapy reducing flares recur- tocols for the treatment of AD. Since the introduction of
rence and increased quality of life. Monoclonal antibodies dupilumab several other monoclonal antibodies is currently
being explored as possible therapeutic alternatives for AD,
Table 10. Marketed products for the treatment of AD [198]. albeit with conflicting outcomes. Also, detailed clinical trials
No. Brand name Generic name Dosage form are needed to establish a successful treatment regimen. As a
1 Cortizone Hydrocortisone Cream/Ointment chronic disease, long-term adherence, a long-term care bur-
2 Kenalog Triamcinolone Aerosol den for the patient, is expected for AD. By enhancing adher-
solution
3 Vanos Fluocinonide Cream ence to treatment regimens through instructional
4 Protopic Tacrolimus Ointment approaches, earlier follow-up visits and better contact with
5 Verdeso Desonide Foam patients and their caregivers, clinicians may enhance patient
6 Elidel Pimecrolimus Cream
7 Elocon Mometasone Cream outcomes. Natural herbal remedies and active constituents
8 Cutivate Fluticasone Cream extracted from plants have been commonly used for the pre-
9 Diprolene Betamethasone Cream
dipropionate
vention, remedy or diagnosis of different forms of acute,
10 Embeline and Temovate/Clobex Clobetasol Cream/Lotion chronic moderate to serious atopic diseases for several deca-
11 Topicort and Topicort LP Desoximetasone Cream des. Literature survey has reported that the usage of natural
12 No brand Fluocinolone Cream
herbal medicinal in the management of AD is safe, cost-

Table 11. List of patented drug for the treatment of AD [199].

No. Category Drug Mechanism of action Patent No.
1 GPR142 agonists N-quinolylbenzamide Filaggrin production promoters WO2014017319
2 GPR142 agonists phenylalanine amide derivatives Filaggrin production promoters WO2014017319
3 Tomethamol-based pseudoceramide Pseudoceramides Accelerated barrier repair WO2014084676
4 Ceramide and sphingosine kinase inhibitor Guanidino- sphingosine or ceramide Inhibitory effects on ceramidases & sphingosine kinases US20120035268
5 PDE4/PDE7 inhibitors Pyrazolol [3,4-b] pyridnes Suppress release of inflammatory mediators US8420666
6 PDE4/PDE7 inhibitors 1-oxa-2-azaspirocycles Suppress release of inflammatory mediators US20110021473
7 PDE4 inhibitors Isoxazoline spirocycles Suppress release of inflammatory mediators US20090048247
8 PDE4 inhibitors Benzo [4, 5] furo [3,2-c] pyridines Suppress release of inflammatory mediators US7943634
9 PDE4 inhibitors Dibenzofuranederivatives Suppress release of inflammatory mediators WO2009115874
10 CRTH2 inhibitors Phenoxy acetic acid derivatives Anti-inflammatory activity WO2010092043
11 CRTH2 inhibitors Indol-1-yl acetic acid derivatives Anti-inflammatory activity WO2011006936
12 CRTH2 inhibitors Indol-1-yl acetic acid derivatives Anti-inflammatory activity EP2492268
13 CRTH2 inhibitors OC000459 (Indol-1-yl acetic acid) Anti-inflammatory activity US20110124683
US20130052190
14 CRTH2 inhibitors Indol-1-yl acetic acid derivatives Anti-inflammatory activity US20140039012
15 CRTH2 inhibitors Quinazoline derivatives Anti-inflammatory activity WO201205036
16 CRTH2 inhibitors Pyrazol-4-yl acetic acid derivatives Anti-inflammatory activity WO2012101043
17 CRTH2 inhibitors Pyrazol-4-yl acetic acid derivatives Anti-inflammatory activity WO2012069175
18 CRTH2 inhibitors Pyrimidine-5-yl acetic acid derivatives Anti-inflammatory activity WO2012013566
19 CCR3 antagonists Benzenesulfonamides Anti-inflammatory activity US20140005176
20 CCR3 antagonists Arylsulfonamides Anti-inflammatory activity US20100204213
21 CCR3 antagonists Arylsulfonamides Anti-inflammatory activity NZ620092
22 CCR3 antagonists 2,5-disubstituted arylsulfonamides Anti-inflammatory activity NZ620048
23 CCR2 antagonists Piperazinyl 3-aminopyrrolidines Anti-inflammatory activity US8575173
24 CCR5 antagonists Bipiperidinyl derivatives Anti-inflammatory activity US7652142
25 CCR2 and CCR5 agonists 3-aminocyclopentanecarboxamides Anti-inflammatory activity US8293903
26 CCR2 modulators 3-aminocyclopentane derivatives Anti-inflammatory activity US20100234409
27 CCR3 antagonists Substituted piperazines Anti-inflammatory activity WO2009020534
28 Chymase inhibitors Imidazopyridines Anti-inflammatory and anti-pruritic activity US20120094944
29 Chymase inhibitors Diazepane derivatives Anti-inflammatory and anti-pruritic activity US8846660
30 TLR7 agonists 2, 4-diaminopyrimidines Immune response modifiers WO2009067081
31 TLR7 agonists Pidotimod Immunomodulators WO2014094839
32 Raft modulator Miltefosine Anti-inflammatory activity US20110263531
33 Vitamin D receptor antagonist ZK 168281 US2010144683
34 SYK inhibitors Pyrimidine-5-carboxamides Anti-inflammatory US2015232470
35 TRPV1 channel agonist Palvanil Antipruritic US20140066399
36 TRPM8 agonist Menthoxypropanediol Antipruritic WO2014060150
37 Opioid antagonist Nalmefene salts Antipruritic US20090093509
38 5-HT7 receptor antagonist SB-269970 Antipruritic WO2013154513
39 H4 receptor antagonist Tricyclic heterocycles Antipruritic US20140315888
40 H1, H2 and H4 receptor antagonist Alcaftadin Antipruritic WO2014130526
GPR142 agonists: Agonists of G protein-coupled receptor 142; CRTH2: Chemoattractant receptor-homologous molecule expressed on Th2 cells; PDE4:
Phosphodiesterase-4; PDE7: Phosphodiesterase-7; TLR7: Toll-like receptor 7; SYK: spleen tyrosine kinase; TRPV1: Transient receptor potential cation channel sub-
family V member 1; TRPM8: Transient receptor potential cation channel subfamily M (melastatin) member 8; 5HT7: 5-hydroxytryptamine 7; H1 receptor:
Histamine 1 receptor; H2: Histamine 2 receptor; H4: Histamine 4 receptor.

efficient, systemically nontoxic, patient-compliant and effi-
cient following traditional therapeutic protocols.
Declaration
The work is original and has not been submitted for publica-
tion elsewhere in the journal.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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