Brar, Nicol, Boguniewicz - 2019 - Strategies For Successful Management of Severe Atopic Dermatitis
Brar, Nicol, Boguniewicz - 2019 - Strategies For Successful Management of Severe Atopic Dermatitis
INFORMATION FOR CATEGORY 1 CME CREDIT AMA PRA Category 1 CreditÔ. Physicians should claim only the credit
commensurate with the extent of their participation in the activity.
Credit can now be obtained, free for a limited time, by reading the
review articles in this issue. Please note the following instructions. List of Design Committee Members: Kanwaljit K. Brar, MD, Noreen
H. Nicol, PhD, RN, FNP, and Mark Boguniewicz, MD (authors);
Method of Physician Participation in Learning Process: The core Michael Schatz, MD, MS (editor)
material for these activities can be read in this issue of the Journal or
online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The Learning objectives:
accompanying tests may only be submitted online at www.jaci-
inpractice.org/. Fax or other copies will not be accepted. 1. To define criteria for diagnosis of severe atopic dermatitis (AD).
Date of Original Release: January 1, 2019. Credit may be obtained for 2. To recognize the systemic nature of AD, which has important
these courses until December 31, 2019. therapeutic implications.
Copyright Statement: Copyright Ó 2019-2021. All rights reserved. 3. To identify components of stepwise management of severe AD
following international and national guidelines of care.
Overall Purpose/Goal: To provide excellent reviews on key aspects of
allergic disease to those who research, treat, or manage allergic disease. 4. To discuss systemic treatment including risks versus benefits in se-
vere AD including approved biologic therapy.
Target Audience: Physicians and researchers within the field of
allergic disease. Recognition of Commercial Support: This CME has not received
external commercial support.
Accreditation/Provider Statements and Credit Designation: The
Disclosure of Relevant Financial Relationships with Commercial
American Academy of Allergy, Asthma & Immunology (AAAAI) is
accredited by the Accreditation Council for Continuing Medical Edu- Interests: M. Boguniewicz has served as a consultant for Regeneron and
cation (ACCME) to provide continuing medical education for physi- Sanofi-Genzyme. The rest of the authors declare that they have no relevant
cians. The AAAAI designates this journal-based CME activity for 1.00 conflicts of interest. M. Schatz declares no relevant conflicts of interest.
Patients with severe atopic dermatitis (AD) are reported to diagnosis, assessment of disease severity, and impact on patient’s
represent between 10% and 18% of all patients with AD. and caregiver’s quality of life, along with education regarding the
However, in this subgroup of patients, quality of life is chronic relapsing nature of the disease as well as treatment
significantly affected and patients may have a number of atopic options. Biologics such as dupilumab offer a novel, targeted
and nonatopic comorbidities. Treatment of this severe therapeutic approach for this systemic disease. Ó 2019
population has often been reactive with inappropriate use of Published by Elsevier Inc. on behalf of the American Academy of
systemic corticosteroids and unapproved immunosuppressants. Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract
Recent insights point to the systemic nature of AD, which has 2019;7:1-16)
important therapeutic implications. Management of severe AD
requires a comprehensive approach that incorporates proper Key words: Atopic dermatitis; Eczema; Wet wrap therapy;
Biologics; Dupilumab
a
Division of Allergy-Immunology, Department of Pediatrics, National Jewish
Health, Denver, Colo
b
University of Colorado College of Nursing, Denver, Colo
INTRODUCTION
Conflicts of interest: M. Boguniewicz has served as a consultant for Regeneron and Atopic dermatitis (AD) is a common inflammatory skin disease
Sanofi-Genzyme. The rest of the authors declare that they have no relevant con- that is increasingly recognized as a global health problem.1 Data
flicts of interest. derived from the Global Burden of Disease Study showed that
Received for publication September 11, 2018; revised October 18, 2018; accepted
dermatitis including AD was the leading skin disease in terms of
for publication October 22, 2018.
Corresponding author: Mark Boguniewicz, MD, Division of Allergy-Immunology, global burden of disease measured by disability-adjusted life-
Department of Pediatrics, National Jewish Health and University of Colorado years.2 Epidemiologic studies in the United States have shown a
School of Medicine, 1400 Jackson St, J310, Denver, CO 80206. E-mail: prevalence of up to 18% in school-aged children3 and 7% in
[email protected]. adults.4,5 However, few studies have stratified AD by severity at the
2213-2198
Ó 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy,
population level. This review will focus on severe AD. In one study
Asthma & Immunology of children and adults, 18% described their eczema as severe,6
https://doi.org/10.1016/j.jaip.2018.10.021 whereas in a study limited to adults, 9.8% rated their AD as
1
2 BRAR ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
Patient-Oriented SCORAD Adaptation of SCORAD for patients and available as an Mild: <25
APP online (to be shared with the clinician)—similar Moderate: 25-50
scoring as SCORAD: extent of affected areas, severity of Severe: >50
dry skin outside of affected areas, symptom intensity on
affected areas, severity of itching, and sleep disturbance
Shown to be correlated with SCORAD
Patient-Oriented Eczema Measure 7 symptoms scored over past week: 0 ¼ no days; 1 ¼ 1-2 d; Clear/almost clear ¼ 0-2
2 ¼ 3-4 d; 3 ¼ 5-6 d; 4 ¼ every day. (Query: Over the last Mild ¼ 3-7
week, on how many days has your skin been . Moderate ¼ 8-16
Severe ¼ 17-24
Very severe ¼ 25-28
itchy, red, bleeding, weeping or oozing clear fluid, cracked,
flaking, felt dry or rough . because of your eczema?).
Maximum score ¼ 28
Dermatology Life Quality Index 10-question validated questionnaire providing patient’s Each question is answered according to ratings: “not
perception of the impact of AD on quality of life in the at all” (0), “a little” (1), “a lot” (2), “very much”
previous week. Questions include effect of disease and (3); Maximum score ¼ 30
treatment on physical, psychological, and social well-
being
Nonvalidated scoring systems
Scoring system Description Severity rating
Investigator’s Global Assessment FDA categorization of AD severity based on the investigator’s Scale: 0 ¼ clear to 4 ¼ severe
assessment of a representative lesion based on erythema, induration/
papulation oozing/crusting
TABLE II. Differential diagnosis in patients with severe AD Patients may have a varied presentation, which may include a
Differential category Diagnostic examples single plaque, hypopigmented macules, often on regions not
exposed to the sun including buttocks, as well as generalized
Congenital disorders Netherton syndrome
erythroderma. Infestations with severe pruritus include scabies,
Chronic dermatoses Seborrheic dermatitis
which can have an associated generalized dermatitis. Other diseases
Contact dermatitis (allergic or irritant) that can be confused with AD include psoriasis, ichthyoses, and
Nummular eczema seborrheic dermatitis. Seborrheic dermatitis can overlap with AD
Psoriasis (erythrodermic and inverse) in infants and the adolescent/adult population. Psoriasis can
Infections and infestations Scabies usually be differentiated from AD on the basis of typical clinical
HIV-associated dermatitis features, although inverse or flexural psoriasis or erythrodermic
Malignancy Cutaneous T-cell lymphoma (mycosis psoriasis may present a diagnostic challenge that can be differen-
fungoides/Sézary syndrome) tiated on skin biopsy. Zinc deficiency can present with an
Immunodeficiencies Wiskott-Aldrich syndrome eczematous rash with perioral, acral, or perineal distribution as a
Severe combined immunodeficiency result of dietary deficiency, excessive losses with diarrhea, chronic
Immune dysregulation, Polyendocrinopathy, renal or hepatic disease as well as inadequate absorption associated
Enteropathy, X-linked syndrome with an inherited deficiency of the zinc carrier protein ZIP4.44
HIES
Dedicator of cytokinesis 8 mutation-
associated immunodeficiency MANAGEMENT OF SEVERE AD
Metabolic disorders Zinc deficiency Most national and international AD guidelines including the
Proliferative disorders Letterer-Siwe disease Joint Taskforce Practice Parameter address AD care in a stepwise
fashion.26,45-51 These guidelines recommend components of
basic daily AD management aimed at preventing dry skin,
treating the eczematous rash, maintaining the skin barrier,
formation.35 Although Staphylococcus aureus is an important improving the itch, and minimizing exposure to triggers.
pathogen in this disorder, infection with other microbes, including Treatment guidelines emphasize the following: (1) Frequent and
invasive fungi such as Aspergillus, may occur.36 In infancy, patients liberal use of moisturizers in conjunction with warm baths or
may present with a papulopustular eruption of the face and scalp. showers to repair the skin barrier. (2) Identification and avoid-
Other features of HIES include skeletal abnormalities with coarse ance of common irritants or infections, temperature extremes,
facial features and prominent frontal bossing, dental anomalies and proven allergen triggers. (3) Appropriate to the severity of
with retained primary teeth, bone fractures, and osteoporosis. AD, maintenance with TCSs or other therapeutic agents may be
Despite elevated serum IgE levels, patients usually are not atopic. initiated in a stepwise fashion. (4) During AD flares, TCSs and
STAT3 is an essential transcription factor for TH17 T-cell devel- topical calcineurin inhibitors (TCIs) are typically prescribed and
opment and because TH17 T cells play an essential role in pro- wet wrap therapy (WWT) may be used in conjunction with
tecting against Candida, patients with mutations in STAT3 are TCSs (but not with TCIs), oral antibiotics, and other oral
susceptible to chronic mucocutaneus candidiasis. Patients with agents.52 (5) Dupilumab is now being added to these guidelines
mutations in dedicator of cytokinesis 8, the gene encoding dedicator for moderate-to-severe AD failing the basic therapies.51 In
of cytokinesis 8 protein, have an immunodeficiency that accounts addition, we advise developing a preventive approach aimed at
for most cases of autosomal-recessive HIES.37,38 These patients minimizing flares, which should be multidisciplinary incorpo-
have an eczematous dermatitis with recurrent viral infections, rating the use of behavioral health strategies when appropriate.27
including recalcitrant warts secondary to human papilloma virus, Figure 1 describes with annotations our diagnostic and treatment
disseminated Molluscum, or recurrent herpes simplex infections. approach to patients with severe AD.
Patients can have central nervous system involvement.39 Of note, Educational interventions have long been recommended and
patients with dedicator of cytokinesis 8 immunodeficiency often used as a critical adjunct at all levels of therapy for patients with
have associated food allergies. Malignancies contribute to AD to enhance therapy effectiveness. These interventions may be
morbidity and mortality usually starting in the second decade of directed toward patients and caregivers. Education should be
life. One of the current HIES panels (GeneDx) screens for mu- individualized and should include teaching about the chronic or
tations in dedicator of cytokinesis 8, SPINK5, STAT3, and TYK2. relapsing nature of AD, exacerbating factors, and therapeutic
Of note, with next-generation sequencing technologies, new pri- options with benefits, risks, and realistic expectations. This
mary immunodeficiencies with eczematous rashes are being important educational facet of care management is becoming
described, for example, CARD11.40 Contact dermatitis should be increasingly difficult to accomplish in routine care visits and
considered in the differential diagnosis of AD, but can also seems to be equally difficult to measure and evaluate.53 Treat-
complicate AD and may present as an exacerbation of underlying ment of severe AD needs to incorporate an individualized written
AD. Patients may become sensitized to antibiotics, topical corti- treatment plan based on a shared decision- making process be-
costeroids (TCSs), and various excipients applied repeatedly to a tween patient or caregiver and their clinician. Figure 2 is an
damaged skin barrier.41 Patients with facial, hand, or foot example of an AD Action Plan used at the authors’ institution.25
dermatitis, as well as those whose AD appears to worsen with
topicals, should be evaluated by patch testing.42 An important Nonpharmacologic interventions
differential of severe AD, especially in patients presenting with a Moisturizers. Moisturizers alone will not be effective in the
diagnosis of adult-onset AD, is cutaneous T-cell lymphoma, and treatment of severe AD; however, they may reduce the severity of
patients should have appropriate skin biopsies performed.43 AD and signs of inflammation, including pruritus, erythema,
J ALLERGY CLIN IMMUNOL PRACT BRAR ET AL 5
VOLUME 7, NUMBER 1
No
Yes
Classify severity of AD
Add
A
Address
dd
d d b
basics
i off A
AD
D care:
• Appropriate skin hydration and u s e of moisturizers or skin Not
barrier repair measures improved
• Avoidance of irritants Reassess diagnosis of AD ,
• Identification and avoidance of proven allergens Reassess triggers
• Antiinflammatory therapy with topical steroids or topical Reassess patient/caregiver
calcineurin inhibitor(tacrolimus) understanding of disease and
• Antipruritic
A ti iti interventions
i t ti ( d ti
(sedating tihi t i
antihistamines, shared
h d AD treatment
t t t plan
l as
behavioral modification) well as adherence to plan
• Identification and treatment of complicating bacterial, viral, or
fungal infections (+/- role for 2x/week dilute bleach baths) Not
• Treatment of psychosocial aspe cts of diseas e improved
• Education including developing a shared written AD action plan
Improved
FIGURE 1. Annotated approach to the patient with severe AD. *For example, Hanifin and Rajka, UK Working Party, American Academy of
Dermatology Consensus. †See Table II. zFor example, clinician evaluation (Investigator’s Global Assessment, SCORAD, EASI) and/or
patient-reported (AD global assessment, Patient-Oriented SCORAD) (see Table I). xOnset, course, area involved, suspected triggers,
complications (eg, infections), hospitalizations, associated atopic and nonatopic comorbidities, previous treatment including What? How
much? and Where? jjSee Fig. 2. (National Jewish Health Atopic Dermatitis Action Plan). {Consider biopsy, patch testing, genetic testing.
#FDA approved for patients 18 years or older with moderate-to-severe AD not adequately controlled with topical steroid or when topical
steroid not indicated. Document severe AD, body surface area greater than 10%, previous therapies. **CSA, MTX, MMF, AZA. ††While
FDA approved, systemic corticosteroids should be avoided or used for shortest course possible, usually while transitioning to a systemic
therapy with slower onset of action.
fissuring, and lichenification.54 In a Cochrane Database Review glycerin, urea, and propylene glycol, help to attract and retain
of 77 studies of emollient and moisturizer use in eczema, water in the skin.46 There is no convincing evidence of efficacy of
moisturizer use resulted in lower SCORAD, fewer flares with one type of moisturizer over another, including prescription
prolonged time to flare, and less TCS use. There was a lower emollient devices, and no studies define an optimal amount or
investigator-assessed disease severity with moisturizer use, which frequency of moisturizer application.46,54 Of note, application of
was further improved when combined with active topical treat- petrolatum has been shown to upregulate antimicrobial peptides
ment.55 The components of topical moisturizers treat underlying and innate immune genes, as well as key epidermal barrier dif-
xerosis and inflammation by maintaining skin hydration while ferentiation markers.56 We recommend liberal use of moistur-
reducing transepidermal water loss (TEWL). Emollients, such as izers, which is most effective when combined with bathing.
glycol, glyceryl stearate, and soy sterols, lubricate and soften the Selection of moisturizer should be individualized on the basis of
skin, whereas occlusive agents, such as petrolatum, dimethicone, patient preference and providers’ discretion. In general, use of
and mineral oil, help the skin to retain moisture by reducing bland moisturizers with few irritants and sensitizers is
TEWL due to evaporation. Humectants, such as glycerol, recommended.41
6 BRAR ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
Bathing practices. Regular (daily) bathing with warm water used should be hypoallergenic, fragrance-free, and neutral to low
is beneficial in moderate-to-severe AD therapy by hydrating the pH. Bathing plays an adjunctive role in the management of
skin and removing potential skin-exacerbating agents including severe AD when combined with the use of moisturizers and
serous crusts, allergens, and irritants.46,51 The act of bathing can pharmacologic treatment.
have added benefit of relaxation. At the authors’ center, “soak
and seal” was developed over 3 decades ago as a fundamental Bleach baths. Bleach (sodium hypochlorite) baths are an
concept to teach proper daily skin care emphasizing use of hy- inexpensive and widely available nonpharmaologic intervention,
dration, moisturizers, cleansers, and topical medications to help which has likely contributed to bleach baths being frequently
maintain an intact skin barrier.57,58 The “soak and seal” or “soak recommended as a low-cost adjuvant therapy in patients with
and smear” technique can be beneficial in severely inflamed AD. Current guidelines include bleach baths in their recom-
lesions and involves bathing in plain warm (not hot, but also not mendations although their efficacy in treating AD has recently
lukewarm) water for 10 to 15 minutes, followed by quick pat been questioned. The addition of dilute sodium hypochlorite in
drying and immediate application (within 2-3 minutes) of topical bath water, or bleach baths, has demonstrated efficacy in clini-
medications and moisturizers as appropriate.59,60 This helps to cally improving moderate-to-severe AD in children.62,63 Bleach
reduce evaporative losses and drying effect. There is no current baths are thought to reduce skin inflammation and thereby
evidenced-based standard for the frequency or duration of decrease colonization of S aureus bacteria on the skin. This can
bathing.61 Limited data exist on the benefit of additives to the be beneficial, because staphylococcal exotoxins are known to
bath, and therefore, additives are not recommended. Cleansers exacerbate AD and severity of AD correlates with S aureus
J ALLERGY CLIN IMMUNOL PRACT BRAR ET AL 7
VOLUME 7, NUMBER 1
FIGURE 3. WWT. A, Bathing of child with AD and head involvement. Have the patient take a warm soaking bath for 10 to 15 minutes
before this procedure or soak the area to receive wraps. B, Pat away excess water. Immediately apply the prescribed undiluted topical
corticosteroid to affected areas and fragrance-free moisturizing cream or ointment to nonlesional skin. Use clean plastic spoons, tongue
depressor, or creams with pump dispenser to access products to avoid contamination. If wraps are to be applied to a large portion of the
body or used on small children, work with 2 people if possible. It is necessary to work rapidly to prevent chilling. C, WWTwith application
of first wet layer. Have the dressings soaking in very warm water. Squeeze out excess water. Dressing should be warm and wet, but not
dripping. In infants and small children, place wet tube socks first over the hands. Then, start at the feet and move upward. Cover the feet
with wet tube socks as well and then place first wet layer of thinner cotton or cotton-blend pajamas on next. D, WWTwith application of
second dry layer. Place second layer of dry tube socks over the wet layer on hands, then place the heavier dry pajamas over the entire
body (footed pajamas in children are preferred or sweat suits for older individuals). E, Wrap head only when affected to a degree war-
ranting the wrap. In small children, this is much easier to accomplish with 2 individuals. First apply warm, wet gauze usually wrapping 2
or 3 times to cover adequately. F, Wrap the same area with dry gauze in approximately an equal amount. Twist the dry gauze over the
bridge of the nose. G, Place an expandable surgical netting or very flexible bandage over the wet gauze to hold in place. H, Full-body WWT
of child with severe generalized AD. Ensure that the patient is able to move and see properly. WWT is not only accepted but can be
enjoyed with proper education and age-appropriate explanation. Take steps to avoid chilling. Comforting a small child with a warm blanket
just removed from the dryer and cuddling helps pass the time. Wraps are generally removed after 1 to 3 hours or can be re-wet. These
figures and procedure information are reprinted with permission from Nicol and Boguniewicz.58 Please refer to the original article for
comprehensive WWT procedure and practical information.
8 BRAR ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
density on the skin.64 However, a recent study noted that bleach Pharmacological interventions for severe AD
baths did not reduce S aureus colonization/infection or improve Topical corticosteroids. TCSs are considered to be the
AD.65 The benefit of bleach baths may also be due to im- mainstay of AD therapy and have been used for decades with
provements in skin barrier function, with patients with AD more than 110 randomized clinical trials supporting their
reporting reduction in itch scores, as well as improved TEWL use.45,46 They reduce the production of proinflammatory cyto-
and stratum corneum cohesion after 12 weeks of twice-weekly kines, interfere with antigen processing, and reduce the activity
baths.66 Although a recent systematic review found that addi- of immune effector cells, with resultant reduced skin inflam-
tion of bleach as a disinfectant did not provide further clinical mation, and reduced S aureus bacterial load.46,71 TCSs are
benefit,67 patients with AD whose course is complicated by typically administered to treat active eczematous lesions evi-
recurrent skin infections can be tried on once- or twice-weekly denced by erythema, oozing, crusting, and/or chronic cutaneous
dilute bleach baths. Common side effects of bleach baths manifestations of AD including lichenification. TCSs can also be
include increased xerosis and irritation of skin and nasal passages. used as maintenance or prophylactic therapy for prevention of
relapses.45,46
Wet wrap therapy. WWT in AD treatment is generally TCS therapy including the strength and frequency of use is
defined as a treatment modality using layers of bandages, cotton very provider-specific. Selection of steroid should be guided by
clothing, or gauze over or together with topical medication, location and extent of lesional skin, patient preference, and
usually TCSs. At the authors’ center, Nicol57 published one of severity of disease. Additional consideration should be given to
the first detailed descriptions of WWT in AD in 1987. This the vehicle and excipient, particularly in severe AD, where allergy
article described the technique using illustrative photos and to corticosteroid or vehicle may be contributing to severity.41
demonstrated how WWT could be simplified by using wet Although TCSs have been studied in adult patients, and less so
clothing in place of bandages to make this treatment less time in pediatric patients, there is a paucity of long-term data. Fluti-
intensive and less expensive. Specialized nursing care and edu- casone propionate 0.05% cream, desonide 0.05% gel and foam,
cation are important to ensure proper use of WWT. Mecha- and hydrocortisone butyrate 0.1% lotion are currently the only
nistically, WWT increases contact time with topical therapies, TCSs that are FDA approved for use in infants as young as 3
allowing for better absorption, decreases pruritus as a result of the months, but of note for up to 3 or 4 weeks.71 Many of the TCSs
cooling effects of the wet layer, and provides a physical barrier commonly used in children were developed long before pediatric
protecting the skin from damage associated with scratching. trials were required.
Improvement in TEWL can be demonstrated 1 week after TCSs range in potencies and are grouped accordingly into 7
discontinuation.68 classes, from very low/lowest potency (VII) to very high potency
In an observational cohort study of 72 children with (super potent) (I).54 TCSs can be absorbed through the skin and
moderate-to-severe AD referred to the Day Program at National though complications are rare, they can occur at any age. In
Jewish Health, Nicol et al52 showed a significant decrease in AD general, the lowest effective potency to achieve disease control
severity as measured by SCORAD following WWT therapy used should be used. Low-potency (class VI-VII) TCSs are generally
on average for 7 days. Clinical benefits could still be observed 1 applied to sensitive and thin areas, such as the face, skin folds,
month later, assessed by parental Atopic Dermatitis Quickscore, and genitalia. High-potency (class I-II) TCSs should not be
despite WWT being discontinued before discharge. WWT has applied to the face and other sensitive areas such as the axillae or
continued to be used to reduce disease severity in children with groin. Higher potency TCSs can be used in short-term courses to
moderate-to-severe AD flares and/or severe refractory disease and rapidly control significant flares, but should be followed by a
is used with undiluted TCSs of appropriate potency. After a stepwise decrease in potency and then tapered to the lowest
soaking bath, a wetted layer of bandages, gauze, or a cotton suit is effective potency for long-term management. This minimizes the
applied over a layer of topical corticosteroid or emollient, fol- adverse effects of skin atrophy, telangiectasia, acne, hypo-
lowed by a dry outer layer.69 A cotton suit, which covers hands pigmentation, and striae, which are the more common side
and feet, works best as an outer layer, because this serves as a effects of TCSs. Patients should be monitored for local and
barrier, which physically prevents scratching (see Figure 3, A-H, systemic adverse events as described in the guidelines, in
with annotations).58 particular children, because they have a proportionately greater
A recent systematic review revealed low evidence that WWT is body surface area to weight ratio, resulting in a higher degree of
more effective than conventional treatment with TCSs in AD.70 absorption of topical agents. Currently, there are no guidelines
However, the review included all ages and severities of AD on optimal dosing and quantity of TCS application and multiple
(including mild) and included only 6 true randomized controlled dosing recommendations are available.46 A commonly recom-
trials while acknowledging that results were reported incompletely mended schedule for active inflammation is twice-daily applica-
in some trials as well as use of WWT with diluted or low-potency tion of TCSs for up to 4 weeks, but once daily may be equally
corticosteroids. Future studies must carefully describe all proced- sufficient.26
ure components with validated tools and outcomes to aid inter- Complications and side effects of TCSs may occur with
pretation. WWT should be considered as a potential treatment inappropriate class of steroid, duration of therapy, site of
option ahead of systemic immunosuppressive therapies for pa- application, and overuse of occlusive techniques. Long-term
tients with moderate-to-severe AD failing conventional therapy.52 treatment with a potent TCS can result in development of
Selected wet wraps to restricted areas of the skin can be considered TCS withdrawal or “steroid addiction” as it is often referred to
for “more stubborn plaques” of AD. WWT should be used by the lay community.72 TCS withdrawal appears to occur
cautiously, and only in moderate to severe AD, because overuse of more often in women and is reported primarily on the face and
wraps can lead to skin occlusion with resultant associated rashes, genital areas. Symptoms of TCS withdrawal include erythema,
such as folliculitis and miliaria.
VOLUME 7, NUMBER 1
J ALLERGY CLIN IMMUNOL PRACT
TABLE III. Dosing and monitoring of systemic immunosuppresants used in severe AD (adapted from Sidbury et al48)
Dosing Cyclosporine MTX AZA MMF
Adult dosing 150-300 mg/d 7.5-25 mg/wk 1-3 m/kg/d 1-1.5 g PO BID
Pediatric dosing 3-6 mg/kg/d 0.2-0.7 mg/kg/wk 1-4 mg/kg/d 30-50 mg/kg/d
Time to response (wk) 2 8-12 8-12 8-12
Baseline monitoring BP 2 measurements CBC w/diff/plt TPMT CBC w/diff/plt
CMP w/Mgþ, Kþ CMP CBC w/diff/plt CMP
Uric acid Hep B/C CMP TB
U/A with micro TB Hep B/C HIV if indicated
Fasting lipids HIV if indicated TB HCG if indicated
TB HCG if indicated HIV if indicated
HIV if indicated PFTs if indicated HCG if indicated
HCG if indicated
Follow-up monitoring BP every visit CBC w/diff/plt CBC w/diff/plt, CMP Q2 wk 2 mo, CBC w/diff/plt Q2 wk 1 mo; then
then Q1 mo 4 mo; then every other Q1 mo 3 mo; then Q 2-3 mo
month and with dose increases
CBC w/diff/plt LFTs Q 1 wk 2-4 wk and 1 wk after each
major dose increase, then Q 2 wk 1 mo,
then Q 2-3 mo on stable doses
CMP w/Mgþ, Kþ Renal function Q 6-12 mo
Uric acid Annual TB Annual TB Annual TB
U/A with micro HCG as indicated HCG as indicated HCG as indicated
Fasting lipids
Q 2 wk 2-3 mo and 2-4
wk after dose increases
Annual TB
HCG as indicated
Maximum length of treatment 6 mo to 1 y May be safe up to 5 y May be safe up to 5 y Up to 24 mo in children
(limited data) (limited data) Up to 36 mo in adults
(limited data)
BID, Twice a day; BP, blood pressure; CBC, complete blood cell count; CMP, comprehensive metabolic panel; diff, differential; HCG, human chorionic gonadotropin; Hep, hepatitis; LFT, liver function test; PFT, pulmonary function test;
plt, platelet; PO, per os (by mouth); Q, every; TB, tuberculosis; TPMT, thiopurine methyltransferase; U/A, urinalysis; w/, with.
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burning/stinging, exacerbation with heat or sun, pruritus, pain, of the patient’s diagnosis, understanding of their disease including
and facial hot flashes. Two subtypes have been identified psychosocial aspects, previous treatment, adherence issues, as well
including a papulopustular variant and an eryth- as systemic treatment options with risks versus benefits
ematoedematous variant. A culture of steroid phobia has (Figure 1).27 A similar approach has recently been described by the
contributed to underuse and poor patient adherence. Patient International Eczema Council.81 Current preferred therapeutic
and caregiver education should address this topic, because ste- options have been proposed in recent publications.25,26
roid phobia could be a factor when adherence is not optimal,
and if not resolved by information and counseling, then other Dupilumab
treatment options should be discussed.26,53 Dupilumab is a fully human mAb developed with Veloc-
Immune technology approved by the FDA for use in adults with
Topical calcineurin inhibitors. TCIs are a class of nonste- moderate-to-severe AD in March 2017. By blocking IL-4 re-
roid anti-inflammatory agents currently approved by the FDA as ceptor alpha, it interferes with signaling by both IL-4 and IL-13,
second-line agents in the management of AD. Tacrolimus oint- 2 key type 2 cytokines.29 In 2 phase 3 trials, 36% to 38% of
ment is indicated for moderate-to-severe AD, with tacrolimus adult patients with moderate-to-severe AD inadequately
0.03% approved for children aged 2 years and older and 0.1% controlled on topical treatment treated with dupilumab mono-
ointment approved for patients older than 15 years. Although the therapy 300 mg every other week after an initial 600 mg loading
FDA issued a boxed warning for topical calcineurin inhibitors, this dose achieved a primary outcome of an Investigator’s Global
was due primarily to a theoretical risk of malignancy based on Assessment of 0 or 1 (clear or almost clear) and a reduction of 2
cancers seen only with oral tacrolimus use in solid organ transplant points or more in that score from baseline at week 16.82 In
patients.73 In addition, since this warning, a number of studies addition, improvement of at least 75% in EASI from baseline to
have failed to demonstrate this causation, and incidence of ma- week 16 was reported in approximately 50% of patients on
lignancy in the treated population is similar to that in the general dupilumab. It is important to recognize that median disease
population.74 However, because of this warning, significant duration in patients enrolled in the phase 3 trials was approxi-
additional time is often required of prescribing providers to educate mately 26 years, median affected body surface area was more
patients and caregivers to encourage optimal use and adherence than 50%, and median EASI was approximately 30 (21.1 ¼
and discuss safety. Of note, in their systematic review of TCSs and severe AD). In addition, approximately 33% of patients had
TCIs, Siegfried et al75 found that data supporting long-term use of received systemic corticosteroids and 26% to 31% had been
TCIs are robust, documenting safety and efficacy, whereas data treated with systemic immunosuppressants in the 2 trials.
supporting long-term TCS use are limited to low- to mid-potency Importantly, patients who did not achieve “clear” or “almost
products. In addition, in an evaluation of a large cohort of 293,253 clear” still had significant improvement as assessed by EASI and
patients with AD, Arellano et al76 did not find any increased risk of in peak pruritus Numerical Rating Scale score.83 Injection-site
lymphoma in patients treated with TCIs, but reported that severity reactions and conjunctivitis were more frequent in the
of AD was the main factor associated with increased risk of lym- dupilumab-treated patients than in the placebo groups. Although
phoma. Of note, a recent European longitudinal study did show the conjunctivitis has not been fully explained, it was for the
that TCI use was associated with an increased risk of lymphoma.77 most part self-limited, and only 1 patient in the phase 3 mon-
However, the authors stated that the low incidence rates imply that otherapy trials discontinued study treatment.82 Nevertheless, this
even if the increased risk is causal, it represents a small excess risk for adverse event requires further elucidation. It is worth noting that
individual patients. In addition, they pointed out that residual this adverse event was not reported in the dupilumab trials in
confounding by severity of AD, increased monitoring of severe asthma or chronic sinusitis with nasal polyposis.84,85 Although
patients, and reverse causation could have affected the results. Wollenberg et al86 have published their experience with
TCIs do not cause the telangiectasia, skin atophy, or striae, dupilumab-treated patients with AD developing conjunctivitis,
which have all been associated with inappropriate and long-term given the need for better understanding of this complication, the
use of more potent TCSs. Because of the lack of these specific authors of this review prefer to send any patient not responding
side effects, TCIs have been especially useful for AD involving to lubricating ophthalmic drops to an ophthalmologist.
the face, including periocular and perioral areas, as well as axillae A long-term study (LIBERTY AD CHRONOS) reproduced
and groin regions. The most common side effects are burning both the efficacy and safety of the monotherapy trials.87 In this
and stinging, which tend to be transient for most patients, 52-week study, patients could use concomitant TCS or TCI if
although have been reported to be more persistent in a subset of TCS was not advisable as needed on the basis of disease activity.
patients due to neuropeptide release and can be aggravated by An additional trial in adults with AD with inadequate response to
sweating or alcohol intake.78 Although approved for twice-daily or intolerance of cyclosporine A (CSA), or for whom CSA
noncontinuous use, guidelines support 2 to 3 times weekly treatment was medically inadvisable (LIBERY AD CAFÉ), also
proactive therapy in patients who are able to achieve clear/almost provided similar efficacy and safety data.88 In a recent random-
clear skin, but have a relapsing course.45,46 Another approach is ized, double-blinded, placebo-controlled study, dupilumab was
to use rotational therapy, where TCI use is alternated with TCS shown not to affect antibody responses to vaccines in adults with
use. This may work best in patients in whom steroid resistance is AD.89 Adults with moderate-to-severe AD on dupilumab 300
suspected.79,80 mg or placebo weekly were immunized with Tdap and quadri-
valent meningococcal polysaccharide vaccine at week 12. Similar
positive IgG responses to tetanus and meningococcal poly-
SYSTEMIC THERAPY FOR SEVERE AD saccharide were observed with dupilumab/placebo at week 16.
In the authors’ AD Program, the decision to initiate systemic Importantly, in a recent multicenter randomized study, biopsies
therapy for patients with severe AD involves a careful reevaluation from dupilumab-treated patients (though note, not with the
J ALLERGY CLIN IMMUNOL PRACT BRAR ET AL 11
VOLUME 7, NUMBER 1
FDA-approved dosing regimen) improved not only markers of medications recommend to limit exposure to natural and artifi-
cutaneous and systemic type 2 inflammation but also reversed cial light.48 Phototherapy is not approved in children younger
epidermal barrier abnormalities.90 than 12 years though there have been a few pediatric clinical
Currently, dupilumab is the only drug approved for systemic trials that demonstrate improvement in pruritus and moderate
treatment of AD in adults in the United States other than sys- improvement in the extent of AD.26,92-94 Side effects include
temic steroids. As discussed below, systemic steroids are not erythema, burning, stinging, and possible reactivation of herpes
recommended for this chronic disease. Recognition of AD as a infection; efficacy of long-term use is not known.48,95 There are
systemic disease provides a strong rationale for the treatment of various forms of phototherapy available, including natural sun-
appropriate patients with this biologic. The approved dosing light, narrow-band ultraviolet light B, broad-band ultraviolet
regimen is a 600 mg loading dose subcutaneously followed by light B, ultraviolet light A, ultraviolet light A and B, and topical
300 mg subcutaneously every 2 weeks. Injections can be self- and systemic psoralen plus ultraviolet light A.48 Narrow-band
administered at home, and patients do not require any labora- ultraviolet light B is the most preferred form of phototherapy
tory monitoring or need to have autoinjectable epinephrine. In due to accessibility, provider familiarity, and efficacy with min-
the United States, trials with dupilumab in adolescents with imal side-effect profile.95 Psoralen plus ultraviolet light A is not
moderate-to-severe AD (NCT03054428) have been completed commonly recommended because of adverse effects compared
and studies in children aged 6 to 11 years with severe AD with the other forms of phototherapy, which include headaches,
(NCT03345914) are currently ongoing. In addition, pediatric nausea, and vomiting, hepatotoxicity, and increased photosen-
and adolescent patients with severe AD have been effectively sitivity with oral psoralen.48
treated with dupilumab prescribed off-label.91 Treatment should be individualized on the basis of minimal
erythema dose, and patient’s underlying Fitzpatrick skin type.26
Phototherapy Use of phototherapy can be restricted because of time commit-
Phototherapy can be considered in older children and adults ment and unavailability of specialty equipment, and may be
who have failed treatment with topical medications or systemic difficult to implement in younger children.26,94 Home photo-
immunosuppressants. Phototherapy can be used simultaneously therapy units may offer an alternative solution in these cases, but
with topical treatment with TCSs. Caution should be exercised if there are no studies of efficacy or safety of home phototherapy in
a patient is using TCIs because prescribing information for these AD. Of note, in a subset of patients with severe AD, sunlight
12 BRAR ET AL J ALLERGY CLIN IMMUNOL PRACT
JANUARY 2019
exposure can exacerbate symptoms, so routine use of sunscreen is reduction was approximately 25 to 26 in both groups. In a trial
recommended for all patients with AD.96,97 of 42 adults, MTX was compared with AZA over 12 weeks, and
had similar efficacy with a 42% versus 39% improvement in
Systemic immunosuppressants mean SCORAD.103 Efficacy was also seen in secondary param-
Systemic immunosuppressants such as cyclosporine, azathio- eters, though more myelosuppresion was observed in the AZA
prine (AZA), mycophenolate, and methotrexate (MTX) have group. Adverse events included liver enzyme elevation and skin
been used in the management of chronic severe AD when pa- infections in the MTX group. Results were comparable between
tients have failed conventional topical treatments of AD.26,98 the 2 agents regardless of filaggrin mutation status.
Before approval of dupilumab, they had been considered a Dosing of MTX in AD is derived from the dosing used in
next-step option after failure of high-potency topical medica- psoriasis. The medication is generally given once weekly and can
tions, along with phototherapy.25,26 Of note, all the immuno- be titrated upward until effect is reached. In adults, dosing ranges
suppressants are used off-label for treatment of pediatric and from 7.5 to 25 mg/wk, and in children it is weight based at 0.2
adult patients with AD in the United States. They are typically to 0.7 mg/kg/wk.48 Folic acid supplementation is recommended
reserved for short-term use (under 1 year) because of associated and may be protective against hematologic and gastrointestinal
toxicities, though a recent study suggests that MTX and AZA toxicity. Common side effects include nausea, vomiting, and
may be safe for long-term (up to 5 years) use.99 They should be stomatitis, which can be minimized by administering medication
prescribed by an experienced specialist because there is an in 3 divided doses given 12 hours apart.105 Patients should be
increased risk of infections, and need for frequent laboratory monitored for rare, but severe and potentially irreversible side
monitoring (Table III). They may be effective in children and effects, such as bone marrow suppression and pulmonary
adults with severe AD, in conjunction with continued use of fibrosis.48,54
topical treatment.26,98
Cyclosporine Azathioprine
CSA is a calcineurin inhibitor that inhibits T-cell activation AZA is another systemic agent that has shown modest efficacy
and subsequent IL-2 production. CSA is the first-line immu- in both pediatric and adult AD. Its use is also limited by adverse
nosuppressant that is effacacious as a short-term therapy in severe effects.98,106 It works as a purine analog that inhibits the cell
AD; duration of therapy is usually restricted to 6 months to 1 cycle of lymphocytes, resulting in immunosuppression. AZA is
year because of associated toxicities.48,100 Dosing guidelines for metabolized by thiopurine methyltransferase enzyme, and thio-
CSA provide a range recommendation of 3 to 6 mg/kg/d in purine methyltransferase activity levels should be measured at
children and 150 to 300 mg/d in adults, typically dosed at baseline to determine appropriate dosing of the drug. It may take
5 mg/kg/d in the pediatric population.48 A retrospective trial of 4 weeks before response to treatment is seen.107 Adverse effects
15 children treated with CSA found that those children treated of the drug include nausea, vomiting, and gastrointestinal
for a longer duration (17.7 10.7 months) were less likely to symptoms, and more severely myelosuppression, neutropenia,
relapse than those treated for a shorter duration (10.2 2.7 lymphopenia, and hepatotoxicity. In addition, AZA has received
months). Relapse was noted at follow-up of 22.7 15.0 a boxed warning regarding a rare, but potentially lethal hep-
months.101 However, longer duration of treatment is limited by atosplenic T-cell lymphoma. Pediatric dosing varies, but most
the side effects of CSA, which include infection, nephrotoxicity, studies recommend 2.5 mg/kg/d, with a maximum of 4 mg/kg/
hypertension, tremor, hypertrichosis, headache, gingival hyper- d.48 Dosing can be initiated at 2 mg/kg/d, and then gradually
plasia, and increased risk of skin cancer and lymphoma.48 Pa- titrated up to minimize nausea and vomiting, while carefully
tients must have careful and frequent blood pressure and monitoring for myelosuppresion. There is only 1 long-term
laboratory monitoring while on treatment.48 One alternative to study of long-term AZA use in AD, which followed 43 adults
an abrupt discontinuation of therapy, which may result in in the Netherlands treated with AZA and MTX for 5 years.99
relapse, is continuation of intermittent maintenance therapy.102 This study suggests that with dose modifications, AZA may be
This resulted in maintenance of response in a small group of safely used in the long-term management of AD with reduction
patients with severe AD who had been treated for a year with in severity of AD.
CSA, which was then tapered to weekend CSA administered at 5
mg/kg/d. Notably, blood pressure and creatinine levels remained Mycophenolate mofetil
stable before and during the 2-day weekend therapy. Further Mycophenolate mofetil (MMF) is an immunosuppressant
randomized controlled studies are needed to determine whether drug that inhibits both T- and B-lymphocyte proliferation via
this intermittent scheduling alternative is a safer long-term inhibition of inosine monophosphate dehydrogenase.48 MMF
option with continued efficacy in those with severe AD. has been used as monotherapy in children aged 2 years and older
with severe refractory AD.108 Initial response to treatment may
Methotrexate take up to 8 weeks, and full efficacy may not be seen until 12
MTX is a folic acid antagonist that affects T-cell activities and weeks. It may be considered as a successive treatment to be used
is used routinely in the management of psoriasis in adults and in the long-term after CSA. Common side effects include nausea,
children. In AD, time to maximum effect averages 10 weeks, vomiting, abdominal pain, headaches, and fatigue, which may be
with minimal to no further efficacy after 12 to 16 weeks with transient, and avoided with slow upward titration of enteric-
further dose escalation.48 There are a few head-to-head trials coated medication.48 More serious, but rare, adverse effects
comparing MTX to other systemic immunosuppressants.103 In a include hematologic abnormalities and genitourinary symptoms,
study of children with severe AD, MTX and CSA had similar such as urgency, frequency, and dysuria. In a trial of 14 children
efficacy over 12 weeks of treatment.104 There was no statistically treated with MMF, few adverse effects were seen at dosing of 40
significant difference in SCORAD reduction, and mean absolute to 50 mg/kg/d in young children and 30 to 40 mg/kg/d in
J ALLERGY CLIN IMMUNOL PRACT BRAR ET AL 13
VOLUME 7, NUMBER 1
adolescents.108 Guidelines suggest dosing ranges in adults of 0.5 severe AD treated with subcutaneous IFN-g did not observe any
to 3 g/d, which is typically divided into 2 doses, and in children significant improvement in either subset.116
dosing is based on body surface area of 600 to 1200 mg/m2,
which can be adjusted for increased hepatic metabolism in
children.48,54 Long-term safety and efficacy are not known. CONCLUSIONS
MMF was used for up to 24 consecutive months in 1 study of Severe AD may present a diagnostic as well as therapeutic
children, and for up to 36 months in adults without significant challenge. Patients with this degree of disease severity suffer
adverse effects.48,109 disproportionately as reflected by patient-reported outcome
scores. Thus, clinicians need to approach the management of
severe disease in a comprehensive manner. A number of practical
Systemic corticosteroids pearls may be helpful to incorporate into a successful treatment
Systemic corticosteroids such as prednisone, prednisolone, and strategy (Table IV). In the past year, approval of dupilumab, a
methylprednisolone are the only FDA-approved treatment for biologic targeting key cytokine abnormalities in AD, has trans-
inflammatory skin disease, including AD.54 However, their formed the therapeutic landscape, including in adults with severe
routine use in moderate-to-severe AD is not recommended, AD. Given the rich pipeline of biologics, small molecules, and
because risks of treatment far outweigh the temporary benefit of other drugs that are being actively evaluated in AD,117 man-
use.45,48,110 In one study comparing systemic corticosteroids agement of AD will need to be appropriately modified as results
with MTX for the treatment of AD in adults, only 1 out of 21 from clinical trials are translated into clinical practice.
patients achieved remission in their AD, resulting in study
termination due to the severe exacerbations of the other pa-
tients.111 Once systemic corticosteroids are initiated, subsequent
discontinuation is often associated with rebound flaring of dis- Acknowledgments
ease.26,48 Additional adverse effects include hypertension, glucose We acknowledge all the members of our multidisciplinary
intolerance, weight gain, adrenal suppression, increased in- Atopic Dermatitis Day Program team and thank Dusty Christian
fections, decreased bone density, and decreased linear growth in for help with our manuscript.
children.48,112 Corticosteroids can be used concurrently with
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