A VIRTUAL DERMATOLOGY CLINIC: CAN YOU HELP THESE

PATIENTS CONTROL THEIR ATOPIC DERMATITIS?

LITERATURE REVIEW

Atopic dermatitis (AD), also called atopic eczema or childhood eczema, is a chronic pruritic
inflammatory skin disorder that often follows a relapsing-remitting course. AD is the most common
inflammatory skin condition in the developed world, with increasing incidence in many regions. AD is a
significant cause of morbidity worldwide and can drastically reduce the quality of life of those affected.

Epidemiology

Most cases of AD first manifest during early childhood, with 80% of individuals developing AD before
the age of 6 years. The Global Burden of Disease Study estimated the global 1-year prevalence of AD
to be 230 million people, or 3.5% of the world's population, with the highest prevalence in affluent
countries.1

Genetic Risk Factors

The single greatest risk factor for AD is a family history of atopic disease. Twin studies suggest that
AD has a heritability as high as 75%, indicating a substantial genetic component to the disease.2 The
genetic variation most strongly associated with AD is a semi-dominant null mutation in the FLG gene,
which leads to reduced expression of the epidermal protein filaggrin.3 Genetic variants in the region
encoding the interleukin-4 (IL-4), IL-13, and RAD50 proteins believed to influence the expression of
the type 2 cytokines IL-4 and IL-13 have been strongly associated with AD.2,3

Comorbidities

AD is commonly associated with other atopic diseases such as food allergies, allergic rhinitis, and
asthma.5,2 AD often manifests early in childhood, followed sequentially by food allergies, allergic
rhinitis, and asthma. This characteristic progression has been termed the atopic (or allergic) march, and
there is evidence that, in some patients, disruption of the epidermal barrier, the initiating event for AD,
allows for increased entry of allergens that promote the activation of inflammatory pathways that lead
to allergic rhinitis and asthma phenotypes.5

CLINICAL PRESENTATION

Pathophysiology

AD is thought to be triggered by environmental factors in individuals with a susceptible genetic

background. AD is caused by a combination of dysfunction of the epidermal barrier and a chronic T

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cell-mediated inflammatory response believed to result both from tissue damage itself and
environmental irritants that can penetrate the dysfunctional epidermal layer. Skin lesions show
increased expression of cytokines associated with the activation of TH2 cells (IL-4, IL-10, and IL-13).2

Signs and Symptoms

The characteristic symptoms of AD are pruritus and eczematous lesions with either a chronic or
relapsing-remitting disease pattern. Pruritus is typically worse in the evening and at night and can cause
sleep problems when severe. AD commonly presents with generalised skin dryness and antigen-specific
IgE reactivity (80% of patients). Areas of involvement are characterized by erythema, excoriation,
scaling and lichenification. Two less common AD subtypes are follicular and prurigo type AD.
Follicular type AD is characterised by dense regions of follicular papules and is most frequent in people
of Asian origin and dark-skinned individuals. Prurigo type AD is most frequently seen in individuals
with a long history of AD; it is characterised by erythematous papules and hardened nodules.2

DIAGNOSIS AND DISEASE ASSESSMENT

Diagnostic Criteria

The diagnosis of AD is based on patient history, clinical features, and the exclusion of other diagnoses.
There are no reliable biomarkers capable of distinguishing it from other inflammatory skin disorders.7,8
The most commonly tested biomarker, elevated total and/or allergen-specific serum IgE, is absent in
approximately 20% of affected individuals but found in 55% of the US general population, resulting in
underdiagnosis of the affected population and overdiagnosis of the unaffected when it is used as part of
diagnostic criteria.9

The consensus-based EDF, EADV, EAACI, ETFAD, EFA, ESDaP, ESPD, GA2LEN, and UEMS 2018
guidelines (European guidelines) for management of AD do not discuss the diagnostic criteria for AD.
10,11 The 2014 American Academy of Dermatology (AAD) guidelines and 2012 Joint Task Force (JTF)
Practice Parameter Update representing the American Academy of Allergy, Asthma & Immunology
(AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council
of Allergy, Asthma and Immunology (JCAAI) both require following features for a diagnosis of AD9,12
:

● Pruritus
● Eczematous lesions (acute, subacute, chronic)
● Chronic or relapsing-remitting disease history
● Typical morphology and age-specific patterns
● Involvement of the face, neck, and extensor regions in infants and children
● Current or previous flexural lesions in any age group
● Sparing of the groin and axillary regions

The AAD guidelines further specify that the following features are seen in most cases and support a
diagnosis based on the previously mentioned clinical features9:

● Early onset (< 1 year old)

● Atopy

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 ● Personal and/or family history of atopic disease
● IgE reactivity
● Xerosis

The differential diagnoses include scabies, seborrheic dermatitis, contact dermatitis (irritant or allergic),
ichthyoses, cutaneous T-cell lymphoma, psoriasis, photosensitivity dermatoses, immune deficiency
diseases, and erythroderma of other causes.9

Disease Assessment and Staging

Following diagnosis, disease severity must be assessed to determine an appropriate treatment plan.
Multiple scoring systems exist based on objective physical signs, subjective patient-reported symptoms,
or a combination of the two. The Eczema Area and Severity Score (EASI) is a signs-only, objective
physician score based on visible lesions, the Patient-Oriented Eczema Measures (POEM) score is based
on patient-reported symptoms using 7 questions regarding symptoms and their frequency, and the
Scoring of Atopic Dermatitis (SCORAD) index is based on both physical signs and patient-reported
symptoms.

The European guidelines for management of AD recommend the SCORAD index for clinical use due
to its encapsulation of both clinical signs of disease and important patient quality-of-life issues such as
sleep disturbance and severity of pruritus. The SCORAD index is based on patient-reported severity of
pruritus and sleep disturbance as well as physician evaluation of 6 clinical features of the patient
(erythema, oedema/papulation, oozing/crusts, excoriation, lichenification, and dryness) for both
severity and extent of distribution.13 A SCORAD index of ≥ 50 is considered severe AD, a score of
25–50 is considered moderate AD, and a score of ≤ 25 mild AD. The majority of patients with AD
have mild disease, while fewer than 10% of patients suffer from severe disease.10

The validated investigator global assessment (vIGA) scale is a simple scale from 0 (clear) to 4 (severe)
that describes the overall appearance of an AD patient's lesions and is frequently used to evaluate
endpoints in controlled clinical trials, with ease of use outweighing a lack of standardised criteria.14

PATIENT MANAGEMENT

Treatment Goals

The goals of AD therapy are to improve pruritus and skin lesions, establish long-term disease control,
and restore patient quality of life to a level that allows individuals with AD to perform normal daily
activities. Disease management generally relies on a multistep approach combining patient and
caregiver education, and pharmacologic and nonpharmacologic treatments tailored to disease severity.4,
9,15

AAD, JTF, and European guidelines recommend that patients and caretakers remove sources of
aeroallergens and indoor allergens such as house dust mites. AD patients should avoid clothing with
fabric and fibres likely to cause skin irritation, which may exacerbate inflammation and damage the
epidermal barrier.8,9,10 European guidelines emphasise that children with AD should not deviate from
their normal vaccination schedule, although no vaccines should be administered during acute AD flares.

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10

Nonpharmacologic Treatments

Bathing and Emollient Use

Frequent bathing and emollient use are suggested by European guidelines as part of treatment and
maintenance in patients with AD. Bathing and emollient use help relieve the chronic dry skin
characteristic of AD as well as eliminate residual crusting, bacteria, and irritants. Alkaline, drying soaps
should be avoided and nonsoap cleaners with neutral to low pH that are hypoallergenic and
fragrance-free are recommended. Emollients should be applied soon after bathing to avoid exacerbating
chronic dry skin via evaporative water loss. Emollient use on AD lesions can exacerbate their severity,
but they should be used approximately twice weekly to maintain remission of AD. Antimicrobial bleach
baths are recommended in the context of active skin infections. 10

Patient and Caregiver Education

The complex pathogenesis and multiple therapies required for successful management of AD require
extensive teaching of both patients and caregivers to ensure optimal care. Formal, structured
educational programs for children and adults, often led by nurses and other healthcare providers, have
been found to improve disease severity as measured by SCORAD as well as patient-reported symptoms
and the ability to cope in groups. European guidelines recommend formal educational programs for
both patients and caregivers when available.10

Psychological Interventions

Psychological interventions such as autogenic training, biofeedback, brief dynamic psychotherapy,

cognitive-behavioural therapy, habit-reversal behavioural therapy, and stress management programs
have been shown to improve patient coping mechanisms in managing the symptoms of AD. European
guidelines recommend psychological interventions when practical.11

First-Line Treatments

Treatment with topical pharmacotherapy is indicated in patients whose symptoms do not respond to
recommended skin care treatment and emollients. The major recommended classes of topical
medications are corticosteroids and calcineurin inhibitors. The use of topical antihistamines is not
recommended in AD due to the risk of absorption and contact dermatitis.10

Topical Corticosteroids

Topical corticosteroids (TCS) relieve AD symptoms by inhibiting pro-inflammatory signalling; they are
a first-line therapy in AD and the standard of care for pharmacotherapy in AD against which other
treatments are typically compared.8 A mainstay of AD treatment, TCS have been in use for > 60 years,

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and their efficacy has been demonstrated in > 100 different randomised, controlled trials.15 TCS are
most often used to treat active lesions or chronic AD symptoms, although they can also be used
prophylactically to prevent relapses. In the US system, TCS are grouped into 7 classes, from low
potency (VII) to high potency (I).16 The German Niedner classification system reverses this schema,
with group I agents being mildly potent and group IV super potent. Specific potency and dosing
schedule are provider specific, but European guidelines recommend diluted TCS under wet wraps for
short-term periods for acute lesions and twice-weekly application for long-term prophylactic use to
reduce relapses. High-potency TCS should be used only in the short term, with a stepwise decrease in
potency for longer-term use. Itch is the key symptom for evaluating response to treatment, with
tapering introduced when it is largely controlled. High-potency TCS should not be applied to sensitive
areas such as the face, neck, or groin.10 Common side effects associated with TCS use include skin
atrophy, acne, hypopigmentation, and telangiectasia, while hypothalamic-pituitary-adrenal axis
suppression is a rare but serious systemic side effect that becomes more likely with prolonged use.16,15

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors (TCIs) relieve AD symptoms by inhibiting T-cell activation, attenuating
the TH2-mediated inflammation responsible for AD symptoms.8 TCIs, most commonly tacrolimus and
the less potent pimecrolimus, are recommended as a first-line therapy in AD for both children and
adults. TCIs have been shown to be safe and effective for long-term use as well as in the treatment of
acute lesions and disease flares. Both tacrolimus and pimecrolimus were shown to be more effective
than placebo in short-term (up to 12 weeks) and long-term (up to 12 months) studies in children and
adults with active AD.15 TCIs are preferred to TCS for long-term, uninterrupted use, when TCS are not
tolerated, and to treat lesions of the face, neck, and other sensitive areas. They may also be used under
wet wraps for acute lesions. The most frequent side effect associated with TCI use is a local tingling,
stinging, or burning sensation at the application site during the first several days of use.10,9 Rare cases
of malignancy have been reported in patients treated with TCIs; therefore, the boxed warning should be
discussed with patients. However, ongoing 10-year studies have found no evidence of increased
malignancy rates.15

Other Topical Treatments

The phosphodiesterase-4 (PDE-4) inhibitor crisaborole, which blocks inflammatory cytokine release
mediated by cAMP signalling, was approved in the United States in 2016 as a treatment for
mild-to-moderate AD in patients over the age of 2 years.17 It is not licensed in Europe. Crisaborole's
efficacy has not been directly compared to TCS or TCIs in controlled clinical trials.18 Crisaborole was
evaluated in 2 randomised, double-blind, vehicle-controlled trials where the primary efficacy endpoint
was the proportion of subjects at Day 29 who achieved an Investigator's Static Global Assessment
(ISGA) grade of clear or almost clear skin with a 2-grade or greater improvement from baseline. In
both trials, more crisaborole-treated patients achieved the primary endpoint than vehicle-treated
patients (in trial 1, 32.8% vs 25.4%, respectively, and in trial 2, 31.4% vs 18.0%, respectively).17 The
trial was limited by its short duration.

Many topical treatments are used in a limited capacity or have been investigated for use in AD
including coal tar treatments, cannabinoid receptor agonists, opioid receptor antagonists, anaesthetics,
and capsaicin. None of these treatments are recommended over TCS or TCIs due to a lack of
high-quality data regarding their safety and efficacy.11,15

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Antimicrobial Treatment

Individuals with AD typically demonstrate an increased susceptibility to skin infections as well as

extensive colonisation by Staphylococcus aureus of both lesions and healthy skin. However, AAD and
European guidelines do not recommend the prophylactic use of topical or oral antibiotics due to a lack
of clinical evidence of their benefit and the increased risk of antibiotic resistance from their overuse.
Instead, antibiotic treatment with a first-generation cephalosporin is recommended only in the case of
apparent and extensive bacterial superinfection. TCS or TCI treatment should not be discontinued
during antibiotic treatment.11,19

Second-Line Treatments

Phototherapy

Phototherapy is recommended as a second-line treatment among both paediatric and adult patients who
do not respond to emollients or topical anti-inflammatory therapies in both AAD and European
guidelines.19,10 European guidelines further recommend the use of medium-dose, narrowband-UVB or
UVA1 over broadband UVB based on the safety profile.10 Common adverse reactions include local
erythema, tenderness, actinic damage, changes in skin pigmentation, and, more rarely, increased risk of
cutaneous malignancies and cataract formation.8

Systemic Agents

European, AAD, and JTF guidelines recommend systemic treatments in patients with severe AD that
fails to respond to topical treatments or phototherapy or when quality of life is severely impacted by
AD.11,19,8 Commonly used systemic agents include corticosteroids, systemic immunosuppressants, and
immunomodulatory biologics.

Systemic Corticosteroids

Systemic corticosteroids, most commonly prednisone, prednisolone, and triamcinolone acetonide, are
sometimes used to manage AD symptoms due to their anti-inflammatory properties, fast time to action,
and perceived efficacy. European guidelines recommend only short-term use (< 1 week) in adult
patients with severe AD experiencing acute disease flares.11

A meta-analysis of the clinical trial literature about systemic corticosteroid use in AD determined that
there is a body of anecdotal evidence that oral corticosteroids are effective in the relief of AD
symptoms, but their extensive side-effect profile limits their utility in the long-term management of
AD. However, there are relatively few controlled clinical trials that examine the efficacy of systemic
corticosteroid use in AD, and none of sufficient statistical power to demonstrate superiority when
comparing systemic corticosteroids to standard-of-care therapies.20

Immunomodulatory Agents

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Systemic immunosuppressants such as cyclosporine, methotrexate, mycophenolate, interferon-gamma,
and azathioprine are frequently used off-label treatments in patients with moderate-to-severe AD that is
refractory to treatment with topical agents. Although their precise mechanisms of action vary, all of
these agents relieve symptoms of AD by suppressing the activity of the patient's immune system.
European and AAD guidelines recommend cyclosporine as the nonbiologic immunosuppressant of
choice in patients who require systemic agents based on the available clinical evidence. Cyclosporine
can be used for up to 1 year for management of AD in adult and paediatric patients. Although they are
effective, all of the commonly used nonbiologic immunosuppressants demonstrate significant
side-effect profiles that must be closely monitored.11,19,21

Biologics

The only monoclonal antibody currently approved for treatment of moderate-to-severe AD is

dupilumab. Dupilumab targets the shared IL-4Rα subunit of IL-4 and IL-13, inhibiting TH2-mediated
pro-inflammatory cytokine and IgE release.22,28 Dupilumab was initially approved in 2017 in Europe
and the United States only for patients aged 18 and over based on the results of the SOLO 1 and 2,
CHRONOS, and CAFÉ studies.23,24,25 These indications were recently expanded (see below).

The phase 3, randomised, double-blind, placebo-controlled SOLO trials enrolled 1379 adults with
moderate-to-severe AD who received either subcutaneous dupilumab 300 mg (weekly or biweekly) or
placebo over 16 weeks. The primary outcome measured was the proportion of patients with an
Investigator Global Assessment (IGA) score of 0 or 1 at 16 weeks. Patients given dupilumab at any
dosing frequency were significantly more likely than those given placebo to meet the endpoint goal in
both trials (SOLO 1: 37% weekly dupilumab, 38% biweekly dupilumab, 10% placebo, P < 0.001;
SOLO 2: 36% weekly dupilumab, 36% biweekly dupilumab, 8% placebo, P < 0.001). The overall
incidence of adverse events was similar between the drug and placebo groups, although patients
receiving dupilumab experienced a higher incidence of injection-site reactions and conjunctivitis.
Limitations of the SOLO studies include a relatively short 16-week timeline, exclusion of concomitant
TCS or TCIs for study participants, and evaluation of only adults, who represent a minority of
individuals affected by AD.23

The phase 3, randomised, double-blind, placebo-controlled CHRONOS trial enrolled 740 adults with
moderate-to-severe AD who received low-potency TCS and either subcutaneous dupilumab 300 mg
(weekly or biweekly) or placebo over 52 weeks. The primary outcome measured was the proportion of
patients with an IGA score of 0 or 1 at 52 weeks. Patients given dupilumab at any dosing frequency
were significantly more likely than those given placebo to meet the endpoint goal (39% weekly
dupilumab, 39% biweekly dupilumab, 12% placebo, P < 0.0001 for both comparisons). The overall
incidence of adverse events was similar between the drug and placebo groups, although patients
receiving dupilumab experienced a higher incidence of injection-site reactions and conjunctivitis.
Major limitations of the study include the difficulty of accurately quantifying patient TCS use and large
variability in the outcome range of the patient cohort receiving biweekly dupilumab.24

The phase 3, randomised, double-blind, placebo-controlled CAFE trial enrolled 325 adults with
moderate-to-severe AD with inadequate response to cyclosporine, intolerance of cyclosporine, or for
whom cyclosporine was medically inadvisable. Patients received low-potency TCS and either
subcutaneous dupilumab 300 mg (weekly or biweekly) or placebo over 16 weeks. The primary outcome
measured was the proportion of patients with an improved score at 16 weeks. Patients given dupilumab
at any dosing frequency were significantly more likely than those given placebo to meet the endpoint

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goal (59.1% weekly dupilumab, 62.6% biweekly dupilumab, 29.6% placebo, P < 0.001 for both
comparisons). The overall incidence of adverse events was similar between the drug and placebo
groups, although patients receiving dupilumab experienced a higher incidence of conjunctivitis, and
skin infections were more frequent with placebo. Major limitations of the study include the inability to
compare the efficacy of weekly and biweekly dupilumab or differences between cyclosporine-treated
and -naïve patients.25

In August 2019, the indication for dupilumab in Europe was expanded to patients with
moderate-to-severe atopic dermatitis in adults and adolescents 12 years and older who are candidates
for systemic therapy.22 In 2020, it was approved in the United States for AD patients with
moderate-to-severe AD ages 6 and over. The EMA for ages 12 and older label expansion was based in
part on the results of a phase 3, randomised, double-blind, placebo-controlled, parallel-group trial in
patients aged 12–17 (AD ADOL) with moderate-to-severe AD; 251 patients were enrolled and treated
with either subcutaneous dupilumab 300 mg every 4 weeks, dupilumab 200 mg (body weight < 60 kg)
or 300 mg every 2 weeks, or placebo over 16 weeks. The primary outcomes measured were the
proportion of patients with an IGA score of 0 or 1 and the proportion of patients with 75%
improvement of EASI score at 16 weeks. Patients receiving dupilumab were significantly more likely to
meet either of the primary outcomes, regardless of dosing schedule (IGA 0 or 1: 24.4% dupilumab
every 2 weeks, 17.9% dupilumab every 4 weeks, 2.4% placebo, P < 0.0001; EASI-75: 41.5%
dupilumab every 2 weeks, 38.1% dupilumab every 4 weeks, 8.2% placebo, P < 0.0001). The overall
incidence of adverse events was similar between the drug and placebo groups, with conjunctivitis and
injection-site reactions higher with dupilumab and AD exacerbation and nonherpetic skin infection
higher with placebo. Safety and efficacy in adolescents were similar to those observed in adults. The
study is limited by its relatively short duration.26

An analysis of data from 1505 participants in the SOLO 1 and 2, CHRONOS, and AD ADOL trials
evaluated the effect of dupilumab treatment on itch. Treatment resulted in significant rapid
improvements from baseline in daily Peak Pruritus Numerical Rating Scale (PP-NRS) scores vs
placebo, by day 2 in adults and day 5 in adolescents. At the end of treatment, dupilumab yielded a
greater least-squares mean percent change from baseline vs placebo/control treatment in the weekly
average of PP-NRS scores: SOLO, -47.5% vs -20.5%; AD-ADOL, -47.9% vs -19.0%; CHRONOS,
-57.3% vs -30.9% (P < 0.0001 for all).27

The European guidelines recommend dupilumab as a disease-modifying drug for patients with
moderate-to-severe AE in whom topical treatment is not sufficient and other systemic treatment is not
advisable. The drug should be combined with daily emollients and may be combined with topical
anti-inflammatory agents as needed.11 The UK National Institute for Health and Care Excellence
(NICE) guidelines recommended dupilumab in combination with TCS for the treatment of atopic
dermatitis in adults who have not responded to at least 1 other systemic therapy or when these are
contraindicated or not tolerated. Dupilumab treatment should be stopped at 16 weeks if a 50%
reduction in EASI (EASI-50) and a 4-point reduction in the Dermatology Life Quality Index (DLQI)
have not been reached.28 A survey of a group of AD experts from the International Eczema Council
achieved consensus on several statements concerning dupilumab: specifically, that while conjunctivitis
is a common adverse event in patients receiving the drug, treatment may be continued despite previous
or current conjunctivitis, and in cases of new-onset conjunctivitis, treatment should be continued when
possible, with appropriate referral to an ophthalmologist.29

Treatment of Comorbidities

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The common co-occurrence of AD with other atopic conditions such as food allergies, allergic rhinitis,
and asthma necessitates a treatment strategy capable of managing these common comorbidities of AD.

Management of food allergies is based on avoidance and does not affect management strategies for AD.
30 Asthma and allergic rhinitis should be managed according to treatment guidelines when they are
present alongside AD, with alterations made to treatment regimens to avoid comorbidity-based
contraindications.31,32

Dupilumab is approved in Europe as add-on maintenance treatment for severe eosinophilic asthma and
for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP).22 Treatment of multiple atopic
comorbidities with a single biologic is an attractive option in appropriate patient populations.

Although they are commonly used to treat asthma, there is limited evidence that the IgE inhibitor
omalizumab or the IL-5 inhibitors mepolizumab, reslizumab, and benralizumab are effective in the
treatment of AD. A review of the clinical literature describing the use of omalizumab to treat AD
describes a number of case reports and small clinical studies in which omalizumab appears to be
effective and well-tolerated. However, no large, placebo-controlled studies have been conducted to
assess its efficacy in AD.34 A small phase 2 trial to evaluate the efficacy of mepolizumab in AD was
terminated early after reaching pre-determined futility criteria, and a phase 2 study to evaluate
benralizumab in AD is currently recruiting patients.35,36 No controlled clinical trials have been
conducted to study the efficacy of reslizumab in the treatment of AD.37 The European guidelines state
that mepolizumab may be tried in selected cases of AD unresponsive to standard therapy.11

INVESTIGATIONAL AGENTS

An improved understanding of the immune mechanisms underlying the symptoms of AD have led to
the development of a number of small molecule and biologic therapies targeted toward the immune
signals that mediate AD.

Small Molecules

JAK 1/2 Inhibitors

The kinases JAK 1 and JAK 2 are important regulators of immune cell differentiation and a number of
JAK1/2 inhibitors are currently being investigated in AD. Abrocitinib, upadacitinib, ruxolitinib, and
baracitinib are currently in phase 3 trials and tofacitinib, delgocitinib, and ASN002 have completed or
are currently being investigated in phase 2 trials.38,39,40,41,42,43,44,45

PDE-4 Inhibitors

Apremilast, an oral PDE-4 inhibitor for systemic treatment of AD, was evaluated in a phase 2 trial in
which 2 doses were compared to placebo: apremilast 30 mg twice daily (APR30) and apremilast 40 mg
twice daily (APR40). Patients in the APR40 group demonstrated significantly greater reduction in
EASI than the placebo group while patients in the APR30 group did not. However, an independent

9
safety monitoring committee determined that the adverse event profile of diarrhoea, nausea, headache,
and nasopharyngitis experienced by the APR40 group outweighed therapeutic benefit and discontinued
the APR40 dosage arm of the trial. Further development of apremilast for the treatment of AD is
uncertain due to the unacceptably severe adverse event profile of the dosage found to be effective.46
The European guidelines state that apremilast may be used in selected cases of AD that are
unresponsive to standard therapy.11

Leukotriene Receptor Antagonists

Leukotriene receptor antagonists such as montelukast and zafirlukast are frequently used in the
treatment of asthma, where they serve as both bronchodilators and anti-inflammatory agents. Their
anti-inflammatory properties have led to their occasional off-label use in the treatment of AD. Several
small clinical trials have been performed to determine the efficacy of montelukast in the treatment of
children and adults with AD with inconsistent results.47 No controlled clinical trials have been reported
for the use of zafirlukast in AD; however, there have been case reports of its efficacy in the treatment
of refractory AD in adults.48 Despite anecdotal evidence of their efficacy in AD, there have been
contradictory results in small-scale clinical trials. There is currently no major ongoing clinical program
to evaluate the use of leukotriene receptor antagonists in AD, and their use is not recommended in the
European guidelines.11

Biologics

A number of biologics targeting a variety of immune signalling molecules are currently being
investigated for use in AD. The IL-31R inhibitor nemolizumab and the IL-13 inhibitor tralokinumab
are currently in phase 3 trials for AD.49,50 The OX40 inhibitor ISB 830, the IL-33 inhibitor etokimab,
the CRTH2 inhibitor timapiprant, the IL-13 inhibitor lebrikizumab, the IL-22 inhibitor fezakinumab,
the IgE inhibitor QGE031, the IL-12/23 inhibitor ustekinumab, the IL-17C inhibitor MOR106, the
IL-17A inhibitor secukinumab, and the TSLP inhibitor tezepelumab are currently in or have completed
phase 2 trials for AD.51,52,53,54,55,56,57,58,59,60

Conclusion

Atopic dermatitis is a common skin disorder characterised by pruritus and eczematous lesions that
follow a chronic or relapsing-remitting course. AD occurs most often in childhood, although some cases
persist to adulthood or first manifest in adults. AD causes significant physical discomfort and affects
quality of life of those affected, with many sufferers experiencing social problems because of their
disease. Research into the mechanistic basis of AD has advanced in the last decade, and AD has come
to be understood as an inflammatory condition mediated by TH2-dependent signalling. Despite these
advances in the mechanistic understanding of AD, no reliable biomarkers exist to identify AD, which
still must be diagnosed based on clinical features and the exclusion of other conditions. However, a
number of targeted therapies have been developed based on improved understanding of the mechanisms
of AD, and their efficacy is currently under investigation. One of these therapies, the IL-4Rα inhibitor
dupilumab, has been approved for the treatment of AD and other atopic diseases and has become the
systemic therapy of choice in patients who are refractory to topical therapy and/or phototherapy.

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