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Strategies for Successful Management of Severe Atopic Dermatitis

The Journal of Allergy and Clinical Immunology: In Practice Volume 7, Issue 1, January 2019, Pages 1-16

Patients with severe atopic dermatitis (AD) are reported to represent between 10% and 18% of all patients with AD. However, in this subgroup of patients, quality of life is significantly affected and patients may have a number of atopic and nonatopic comorbidities. Treatment of this severe population has often been reactive with inappropriate use of systemic corticosteroids and unapproved immunosuppressants. Recent insights point to the systemic nature of AD, which has important therapeutic implications. Management of severe AD requires a comprehensive approach that incorporates proper diagnosis, assessment of disease severity, and impact on patient's and caregiver's quality of life, along with education regarding the chronic relapsing nature of the disease as well as treatment options. Biologics such as dupilumab offer a novel, targeted therapeutic approach for this systemic disease.

Key words: Atopic dermatitis, Eczema, Wet wrap therapy, Biologics, Dupilumab.

Abbreviations used: AD-Atopic dermatitis, AZA-Azathioprine, CSA-Cyclosporine A, EASI-Eczema Area and Severity Index, FDA-Food and Drug Administration, HIES-Hyper-IgE syndrome, MTX-Methotrexate, MMF-Mycophenolate mofetil, SCORAD-SCORing Atopic Dermatitis, STAT3-Signal transducer and activator of transcription3, TCI-Topical calcineurin inhibitor, TCS-Topical corticosteroid, TEWL-Transepidermal water loss, WWT-Wet wrap therapy.

 

Information for Category 1 CME Credit

Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

Method of Physician Participation in Learning Process: The core 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 accompanying tests may only be submitted online at www.jaci-inpractice.org/ . Fax or other copies will not be accepted.

Date of Original Release: January 1, 2019. Credit may be obtained for these courses until December 31, 2019.

Copyright Statement: Copyright © 2019-2021. All rights reserved.

Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.

Target Audience: Physicians and researchers within the field of allergic disease.

Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for 1.00 AMA PRA Category 1 Credit ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

List of Design Committee Members: Kanwaljit K. Brar, MD, Noreen H. Nicol, PhD, RN, FNP, and Mark Boguniewicz, MD (authors); Michael Schatz, MD, MS (editor)

Learning objectives :

  • 1.

    To define criteria for diagnosis of severe atopic dermatitis (AD).

  • 2.

    To recognize the systemic nature of AD, which has important therapeutic implications.

  • 3.

    To identify components of stepwise management of severe AD following international and national guidelines of care.

  • 4.

    To discuss systemic treatment including risks versus benefits in severe AD including approved biologic therapy.

 

Recognition of Commercial Support: This CME has not received external commercial support.

Disclosure of Relevant Financial Relationships with Commercial Interests: M. Boguniewicz has served as a consultant for Regeneron and Sanofi-Genzyme. The rest of the authors declare that they have no relevant conflicts of interest. M. Schatz declares no relevant conflicts of interest.

 

Introduction

Atopic dermatitis (AD) is a common inflammatory skin disease that is increasingly recognized as a global health problem. 1 Data derived from the Global Burden of Disease Study showed that dermatitis including AD was the leading skin disease in terms of global burden of disease measured by disability-adjusted life-years. 2 Epidemiologic studies in the United States have shown a prevalence of up to 18% in school-aged children 3 and 7% in adults. 4 5 However, few studies have stratified AD by severity at the population level. This review will focus on severe AD. In one study of children and adults, 18% described their eczema as severe, 6 whereas in a study limited to adults, 9.8% rated their AD as severe. 7 In the recent Atopic Dermatitis in America survey, 8 11% of participants assessed their AD as severe using the Patient-Oriented Eczema Measure, a validated scoring tool. 9

As a chronic, relapsing pruritic disease, AD has a profound impact on the quality of life of patients and families. In a study of adults with moderate-to-severe AD, 85% reported problems with itch frequency, 41.5% reported itching for greater than or equal to 18 h/d, 55% reported AD-related sleep disturbance on more than or equal to 5 d/wk, and 21.8% reported clinically relevant anxiety or depression. 10 It is noteworthy that 100% of respondents with severe patient-reported outcome scores were found to have borderline and/or abnormal Hospital Anxiety and Depression Scale scores. 11 Although atopic comorbidities of AD including asthma and allergies are well recognized, 12 association of AD with a number of nonatopic comorbidities including neuropsychiatric and cardiovascular are only beginning to be reported. 13 14 Severe AD in adults was recently shown to be associated with long-term risk of cardiovascular disease in a population-based cohort study in the United Kingdom. 15

AD is characterized by complex immune dysregulation, as well as skin barrier abnormalities. 16 A number of insights into the pathophysiology of AD have translational implications with respect to therapy. These include recognition that nonlesional skin in patients with AD is characterized by both immune abnormalities and broad terminal differentiation defects 17 and that type 2 immune abnormalities present not only in the skin but also systemically are central to the disease process. 18 Among patients with inflammatory skin diseases, patients with AD are unique in their colonization or infection by various microbes. 19 20 Altered epidermal lipids in AD skin are associated with staphylococcal colonization 21 and have been shown to be associated with type 2 cytokine dysregulation. 22 Dysbiosis of the skin microbiome appears to contribute to the disease although this is a complex and dynamic process that we are just beginning to understand. 23 However, it will likely have important translational implications for the development of novel therapeutic targets. In considering severe AD, successful management strategies will require a comprehensive approach, understanding not only the complex pathophysiology and systemic nature of the disease 24 but the profound impact it has on the patients' and caregivers' quality of life. In this setting, shared decision making in choosing appropriate treatment should be an integral part of management. 25 26 In addition, using a multidisciplinary team approach may benefit patients by addressing more than the skin barrier and immune abnormalities. 27 In the recent past, advances in our understanding of disease mechanisms have serendipitously coincided with technological advances, ushering in a new era of targeted therapy for AD. 28 29 In this review, we will discuss our strategies for managing severe AD based on these insights.

Diagnosis of Severe AD

AD should be diagnosed by one of several criteria including Hanifin and Rajka, 30 UK Working Party, 31 or AAD Consensus criteria. 32 However, the AAD criteria have not been validated or compared with other diagnostic criteria. Subsequently, severe AD should be established by minimum involvement of 10% body surface area and regardless of body surface area, individual lesions with severe features, involvement of highly visible areas or those important for function (eg, neck, face, genitals, palms, and/or soles), and significantly impaired quality of life (adapted from Boguniewicz et al 25 ). Note that although global assessment scores including Investigator's Global Assessment have not been validated in clinical practice, classifying disease as “clear,” “almost clear,” “mild,” “moderate,” or “severe” is currently mandated as a primary outcome measure by the Food and Drug Administration (FDA) in clinical trials. In contrast, more complex validated scoring systems including SCORing Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) as well as patient-reported outcome measures have rarely been incorporated into the clinical setting ( Table I ). An additional significant confounding problem for clinicians treating patients with severe AD is that at present, no biomarker has been validated to assess disease severity.

Validated scoring systems for clinician assessment
Scoring system Description Severity rating
SCORAD 3 Components: Mild: <25
  A: Extent —Sites affected are shaded on a body drawing and scored by % (head/neck, 9%; upper and lower limbs, 9% each; anterior trunk, 18%; back, 18%) Maximum score = 100% Moderate: 25-50
Severe: >50
  B: Intensity score (0, little or none, to 3, severe) for redness, swelling, crusting/oozing, skin thickening (lichenification), dryness, scratch marks. Maximum score = 18  
  C: Subjective score (VAS, 0, none, to 10, worst imaginable) for sleeplessness and itch. Maximum score = 20  
  Calculation:  
  SCORAD (total score) = A /5 + 7 B /2 + C  
  Maximum score = 103  
EASI 2 Components: Mild: 1.1-7
  Area score (% skin affected) recorded for 4 regions (head/neck; trunk/genitals; upper limbs; lower limbs/buttocks): 0 = none; 1 = 1%-9%; 2 = 10%-29%; 3 = 30%-49%; 4 = 50%-69%; 5 = 70%-89%; 6 = 90%-100% Moderate: 7.1-21
Severe: 21.1-50
Very severe: 50.1-72
  Severity score for each region calculated on the basis of intensity (0, none, to 3, severe) of redness, thickness/swelling, scratching, lichenification. Maximum score = 12 for each region  
  Calculation:  
  Total regional scores:  
  Head and neck: severity score × area score × 0.1 (in children 0-7 y, × 0.2)  
  • Trunk: severity score × area score × 0.3  
  • Upper limbs: severity score × area score × 0.2  
  • Lower limbs: severity score × area score × 0.4 (in children 0-7 y, × 0.3)  
  EASI (total score): Sum of total regional scores, Maximum score = 72  
Validated scoring systems for patient assessment
Scoring system Description Severity rating
Patient-Oriented SCORAD Adaptation of SCORAD for patients and available as an APP online (to be shared with the clinician)—similar scoring as SCORAD: extent of affected areas, severity of dry skin outside of affected areas, symptom intensity on affected areas, severity of itching, and sleep disturbance Mild: <25
Moderate: 25-50
Severe: >50
  Shown to be correlated with SCORAD  
     
Patient-Oriented Eczema Measure 7 symptoms scored over past week: 0 = no days; 1 = 1-2 d; 2 = 3-4 d; 3 = 5-6 d; 4 = every day. (Query: Over the last week, on how many days has your skin been … Clear/almost clear = 0-2
Mild = 3-7
Moderate = 8-16
Severe = 17-24
Very severe = 25-28
  itchy, red, bleeding, weeping or oozing clear fluid, cracked, flaking, felt dry or rough … because of your eczema?). Maximum score = 28  
Dermatology Life Quality Index 10-question validated questionnaire providing patient's perception of the impact of AD on quality of life in the previous week. Questions include effect of disease and treatment on physical, psychological, and social well-being Each question is answered according to ratings: “not at all” (0), “a little” (1), “a lot” (2), “very much” (3); Maximum score = 30
Nonvalidated scoring systems
Scoring system Description Severity rating
Investigator's Global Assessment FDA categorization of AD severity based on the investigator's assessment of a representative lesion based on erythema, induration/papulation ± oozing/crusting Scale: 0 = clear to 4 = severe
VAS , Visual analogue scale.

Table IEvaluation of severity of ADAdapted from Boguniewicz et al. 26

 

Differential Diagnosis of Severe AD

A number of congenital disorders, inflammatory skin diseases, infectious diseases and infestations, immunodeficiencies, genetic disorders, as well as skin malignancies may present with signs and symptoms that can be misdiagnosed as severe AD. Table II lists some of the diseases that should be considered in the differential of AD. These should be considered when a patient first presents with an eczematous rash, but also when a patient diagnosed with AD fails to respond to appropriate therapy. Infants presenting with a generalized scaling erythematous rash along with failure to thrive, diarrhea, and recurrent cutaneous and/or systemic infections should be evaluated for severe combined immunodeficiency syndrome. Omenn syndrome is an autosomal-recessive severe combined immunodeficiency that can present with an erythrodermic rash, diarrhea, lymphadenopathy, hepatosplenomegaly, susceptibility to infections as well as elevated IgE and eosinophilia. 33 Immune dysregulation, Polyendocrinopathy, and Enteropathy X-linked syndrome can present with eczematous rash, although patients will usually have recalcitrant enteropathy and autoimmune features such as type 1 diabetes, thyroiditis, hemolytic anemia, or thrombocytopenia. 34 Wiskott-Aldrich syndrome is an X-linked recessive disorder characterized by eczematous rash, thrombocytopenia, severe bacterial infections, and variable abnormalities in humoral and cellular immunity. Hyper-IgE syndrome (HIES) due to signal transducer and activator of transcription3 ( STAT3 ) mutations is an autosomal-dominant multisystem disorder with eczematous rash, but characterized by recurrent deep-seated bacterial infections, including cutaneous cold abscesses and pneumonias often with pneumatocele formation. 35 Although Staphylococcus aureus is an important pathogen in this disorder, infection with other microbes, including invasive fungi such as Aspergillus , may occur. 36 In infancy, patients may present with a papulopustular eruption of the face and scalp. Other features of HIES include skeletal abnormalities with coarse facial features and prominent frontal bossing, dental anomalies with retained primary teeth, bone fractures, and osteoporosis. Despite elevated serum IgE levels, patients usually are not atopic. STAT3 is an essential transcription factor for T H 17 T-cell development and because T H 17 T cells play an essential role in protecting against Candida, patients with mutations in STAT3 are susceptible to chronic mucocutaneus candidiasis. Patients with mutations in dedicator of cytokinesis 8 , the gene encoding dedicator of cytokinesis 8 protein, have an immunodeficiency that accounts for most cases of autosomal-recessive HIES. 37 38 These patients have an eczematous dermatitis with recurrent viral infections, including recalcitrant warts secondary to human papilloma virus, disseminated Molluscum , or recurrent herpes simplex infections. Patients can have central nervous system involvement. 39 Of note, patients with dedicator of cytokinesis 8 immunodeficiency often have associated food allergies. Malignancies contribute to morbidity and mortality usually starting in the second decade of life. One of the current HIES panels (GeneDx) screens for mutations in dedicator of cytokinesis 8 , SPINK5 , STAT3 , and TYK2 . Of note, with next-generation sequencing technologies, new primary immunodeficiencies with eczematous rashes are being described, for example, CARD11 . 40 Contact dermatitis should be considered in the differential diagnosis of AD, but can also complicate AD and may present as an exacerbation of underlying AD. Patients may become sensitized to antibiotics, topical corticosteroids (TCSs), and various excipients applied repeatedly to a damaged skin barrier. 41 Patients with facial, hand, or foot dermatitis, as well as those whose AD appears to worsen with topicals, should be evaluated by patch testing. 42 An important differential of severe AD, especially in patients presenting with a diagnosis of adult-onset AD, is cutaneous T-cell lymphoma, and patients should have appropriate skin biopsies performed. 43 Patients may have a varied presentation, which may include a single plaque, hypopigmented macules, often on regions not exposed to the sun including buttocks, as well as generalized erythroderma. Infestations with severe pruritus include scabies, which can have an associated generalized dermatitis. Other diseases that can be confused with AD include psoriasis, ichthyoses, and seborrheic dermatitis. Seborrheic dermatitis can overlap with AD in infants and the adolescent/adult population. Psoriasis can usually be differentiated from AD on the basis of typical clinical features, although inverse or flexural psoriasis or erythrodermic psoriasis may present a diagnostic challenge that can be differentiated on skin biopsy. Zinc deficiency can present with an eczematous rash with perioral, acral, or perineal distribution as a result of dietary deficiency, excessive losses with diarrhea, chronic renal or hepatic disease as well as inadequate absorption associated with an inherited deficiency of the zinc carrier protein ZIP4. 44

Differential category Diagnostic examples
Congenital disorders Netherton syndrome
Chronic dermatoses Seborrheic dermatitis
  Contact dermatitis (allergic or irritant)
  Nummular eczema
  Psoriasis (erythrodermic and inverse)
Infections and infestations Scabies
  HIV-associated dermatitis
Malignancy Cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome)
Immunodeficiencies Wiskott-Aldrich syndrome
  Severe combined immunodeficiency
  Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome
  HIES
  Dedicator of cytokinesis 8 mutation-associated immunodeficiency
Metabolic disorders Zinc deficiency
Proliferative disorders Letterer-Siwe disease

Table IIDifferential diagnosis in patients with severe AD

 

Management of Severe AD

Most national and international AD guidelines including the Joint Taskforce Practice Parameter address AD care in a stepwise fashion. 26 45 46 47 48 49 50 51 These guidelines recommend components of basic daily AD management aimed at preventing dry skin, treating the eczematous rash, maintaining the skin barrier, improving the itch, and minimizing exposure to triggers. Treatment guidelines emphasize the following: (1) Frequent and liberal use of moisturizers in conjunction with warm baths or showers to repair the skin barrier. (2) Identification and avoidance of common irritants or infections, temperature extremes, and proven allergen triggers. (3) Appropriate to the severity of AD, maintenance with TCSs or other therapeutic agents may be initiated in a stepwise fashion. (4) During AD flares, TCSs and topical calcineurin inhibitors (TCIs) are typically prescribed and wet wrap therapy (WWT) may be used in conjunction with TCSs (but not with TCIs), oral antibiotics, and other oral agents. 52 (5) Dupilumab is now being added to these guidelines for moderate-to-severe AD failing the basic therapies. 51 In addition, we advise developing a preventive approach aimed at minimizing flares, which should be multidisciplinary incorporating the use of behavioral health strategies when appropriate. 27 Figure 1 describes with annotations our diagnostic and treatment approach to patients with severe AD.

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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 . ‡For example, clinician evaluation (Investigator's Global Assessment, SCORAD, EASI) and/or patient-reported (AD global assessment, Patient-Oriented SCORAD) (see Table I ). §Onset, course, area involved, suspected triggers, complications (eg, infections), hospitalizations, associated atopic and nonatopic comorbidities, previous treatment including What? How much? and Where? ||See 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.

 

Educational interventions have long been recommended and used as a critical adjunct at all levels of therapy for patients with AD to enhance therapy effectiveness. These interventions may be directed toward patients and caregivers. Education should be individualized and should include teaching about the chronic or relapsing nature of AD, exacerbating factors, and therapeutic options with benefits, risks, and realistic expectations. This important educational facet of care management is becoming increasingly difficult to accomplish in routine care visits and seems to be equally difficult to measure and evaluate. 53 Treatment of severe AD needs to incorporate an individualized written treatment plan based on a shared decision- making process between patient or caregiver and their clinician. Figure 2 is an example of an AD Action Plan used at the authors' institution. 25

gr2
 

Figure 2
Atopic Dermatitis Action Plan.

 

Nonpharmacologic interventions

Moisturizers

Moisturizers alone will not be effective in the treatment of severe AD; however, they may reduce the severity of AD and signs of inflammation, including pruritus, erythema, fissuring, and lichenification. 54 In a Cochrane Database Review of 77 studies of emollient and moisturizer use in eczema, moisturizer use resulted in lower SCORAD, fewer flares with prolonged time to flare, and less TCS use. There was a lower investigator-assessed disease severity with moisturizer use, which was further improved when combined with active topical treatment. 55 The components of topical moisturizers treat underlying xerosis and inflammation by maintaining skin hydration while reducing transepidermal water loss (TEWL). Emollients, such as glycol, glyceryl stearate, and soy sterols, lubricate and soften the skin, whereas occlusive agents, such as petrolatum, dimethicone, and mineral oil, help the skin to retain moisture by reducing TEWL due to evaporation. Humectants, such as glycerol, glycerin, urea, and propylene glycol, help to attract and retain water in the skin. 46 There is no convincing evidence of efficacy of one type of moisturizer over another, including prescription emollient devices, and no studies define an optimal amount or frequency of moisturizer application. 46 54 Of note, application of petrolatum has been shown to upregulate antimicrobial peptides and innate immune genes, as well as key epidermal barrier differentiation markers. 56 We recommend liberal use of moisturizers, which is most effective when combined with bathing. Selection of moisturizer should be individualized on the basis of patient preference and providers' discretion. In general, use of bland moisturizers with few irritants and sensitizers is recommended. 41

Bathing practices

Regular (daily) bathing with warm water is beneficial in moderate-to-severe AD therapy by hydrating the skin and removing potential skin-exacerbating agents including serous crusts, allergens, and irritants. 46 51 The act of bathing can have added benefit of relaxation. At the authors' center, “soak and seal” was developed over 3 decades ago as a fundamental concept to teach proper daily skin care emphasizing use of hydration, moisturizers, cleansers, and topical medications to help maintain an intact skin barrier. 57 58 The “soak and seal” or “soak and smear” technique can be beneficial in severely inflamed lesions and involves bathing in plain warm (not hot, but also not lukewarm) water for 10 to 15 minutes, followed by quick pat drying and immediate application (within 2-3 minutes) of topical medications and moisturizers as appropriate. 59 60 This helps to reduce evaporative losses and drying effect. There is no current evidenced-based standard for the frequency or duration of bathing. 61 Limited data exist on the benefit of additives to the bath, and therefore, additives are not recommended. Cleansers used should be hypoallergenic, fragrance-free, and neutral to low pH. Bathing plays an adjunctive role in the management of severe AD when combined with the use of moisturizers and pharmacologic treatment.

Bleach baths

Bleach (sodium hypochlorite) baths are an inexpensive and widely available nonpharmaologic intervention, which has likely contributed to bleach baths being frequently recommended as a low-cost adjuvant therapy in patients with AD. Current guidelines include bleach baths in their recommendations although their efficacy in treating AD has recently been questioned. The addition of dilute sodium hypochlorite in bath water, or bleach baths, has demonstrated efficacy in clinically improving moderate-to-severe AD in children. 62 63 Bleach baths are thought to reduce skin inflammation and thereby decrease colonization of S aureus bacteria on the skin. This can be beneficial, because staphylococcal exotoxins are known to exacerbate AD and severity of AD correlates with S aureus density on the skin. 64 However, a recent study noted that bleach baths did not reduce S aureus colonization/infection or improve AD. 65 The benefit of bleach baths may also be due to improvements in skin barrier function, with patients with AD reporting reduction in itch scores, as well as improved TEWL and stratum corneum cohesion after 12 weeks of twice-weekly baths. 66 Although a recent systematic review found that addition of bleach as a disinfectant did not provide further clinical benefit, 67 patients with AD whose course is complicated by recurrent skin infections can be tried on once- or twice-weekly dilute bleach baths. Common side effects of bleach baths include increased xerosis and irritation of skin and nasal passages.

Wet wrap therapy

WWT in AD treatment is generally defined as a treatment modality using layers of bandages, cotton clothing, or gauze over or together with topical medication, usually TCSs. At the authors' center, Nicol 57 published one of the first detailed descriptions of WWT in AD in 1987. This article described the technique using illustrative photos and demonstrated how WWT could be simplified by using wet clothing in place of bandages to make this treatment less time intensive and less expensive. Specialized nursing care and education are important to ensure proper use of WWT. Mechanistically, WWT increases contact time with topical therapies, allowing for better absorption, decreases pruritus as a result of the cooling effects of the wet layer, and provides a physical barrier protecting the skin from damage associated with scratching. Improvement in TEWL can be demonstrated 1 week after discontinuation. 68

In an observational cohort study of 72 children with moderate-to-severe AD referred to the Day Program at National Jewish Health, Nicol et al 52 showed a significant decrease in AD severity as measured by SCORAD following WWT therapy used on average for 7 days. Clinical benefits could still be observed 1 month later, assessed by parental Atopic Dermatitis Quickscore, despite WWT being discontinued before discharge. WWT has continued to be used to reduce disease severity in children with moderate-to-severe AD flares and/or severe refractory disease and is used with undiluted TCSs of appropriate potency. After a soaking bath, a wetted layer of bandages, gauze, or a cotton suit is applied over a layer of topical corticosteroid or emollient, followed by a dry outer layer. 69 A cotton suit, which covers hands and feet, works best as an outer layer, because this serves as a barrier, which physically prevents scratching (see Figure 3 , A - H , with annotations). 58

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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, WWT with 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, WWT with 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 warranting 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.

 

A recent systematic review revealed low evidence that WWT is more effective than conventional treatment with TCSs in AD. 70 However, the review included all ages and severities of AD (including mild) and included only 6 true randomized controlled trials while acknowledging that results were reported incompletely in some trials as well as use of WWT with diluted or low-potency corticosteroids. Future studies must carefully describe all procedure components with validated tools and outcomes to aid interpretation. WWT should be considered as a potential treatment option ahead of systemic immunosuppressive therapies for patients with moderate-to-severe AD failing conventional therapy. 52 Selected wet wraps to restricted areas of the skin can be considered for “more stubborn plaques” of AD. WWT should be used cautiously, and only in moderate to severe AD, because overuse of wraps can lead to skin occlusion with resultant associated rashes, such as folliculitis and miliaria.

Pharmacological interventions for severe AD

Topical corticosteroids

TCSs are considered to be the mainstay of AD therapy and have been used for decades with more than 110 randomized clinical trials supporting their use. 45 46 They reduce the production of proinflammatory cytokines, interfere with antigen processing, and reduce the activity of immune effector cells, with resultant reduced skin inflammation, and reduced S aureus bacterial load. 46 71 TCSs are typically administered to treat active eczematous lesions evidenced by erythema, oozing, crusting, and/or chronic cutaneous manifestations of AD including lichenification. TCSs can also be used as maintenance or prophylactic therapy for prevention of relapses. 45 46

TCS therapy including the strength and frequency of use is very provider-specific. Selection of steroid should be guided by location and extent of lesional skin, patient preference, and severity of disease. Additional consideration should be given to the vehicle and excipient, particularly in severe AD, where allergy to corticosteroid or vehicle may be contributing to severity. 41 Although TCSs have been studied in adult patients, and less so in pediatric patients, there is a paucity of long-term data. Fluticasone propionate 0.05% cream, desonide 0.05% gel and foam, and hydrocortisone butyrate 0.1% lotion are currently the only TCSs that are FDA approved for use in infants as young as 3 months, but of note for up to 3 or 4 weeks. 71 Many of the TCSs commonly used in children were developed long before pediatric trials were required.

TCSs range in potencies and are grouped accordingly into 7 classes, from very low/lowest potency (VII) to very high potency (super potent) (I). 54 TCSs can be absorbed through the skin and though complications are rare, they can occur at any age. In general, the lowest effective potency to achieve disease control should be used. Low-potency (class VI-VII) TCSs are generally applied to sensitive and thin areas, such as the face, skin folds, and genitalia. High-potency (class I-II) TCSs should not be applied to the face and other sensitive areas such as the axillae or groin. Higher potency TCSs can be used in short-term courses to rapidly control significant flares, but should be followed by a stepwise decrease in potency and then tapered to the lowest effective potency for long-term management. This minimizes the adverse effects of skin atrophy, telangiectasia, acne, hypopigmentation, and striae, which are the more common side effects of TCSs. Patients should be monitored for local and systemic adverse events as described in the guidelines, in particular children, because they have a proportionately greater body surface area to weight ratio, resulting in a higher degree of absorption of topical agents. Currently, there are no guidelines on optimal dosing and quantity of TCS application and multiple dosing recommendations are available. 46 A commonly recommended schedule for active inflammation is twice-daily application of TCSs for up to 4 weeks, but once daily may be equally sufficient. 26

Complications and side effects of TCSs may occur with inappropriate class of steroid, duration of therapy, site of application, and overuse of occlusive techniques. Long-term treatment with a potent TCS can result in development of TCS withdrawal or “steroid addiction” as it is often referred to by the lay community. 72 TCS withdrawal appears to occur more often in women and is reported primarily on the face and genital areas. Symptoms of TCS withdrawal include erythema, burning/stinging, exacerbation with heat or sun, pruritus, pain, and facial hot flashes. Two subtypes have been identified including a papulopustular variant and an erythematoedematous variant. A culture of steroid phobia has contributed to underuse and poor patient adherence. Patient and caregiver education should address this topic, because steroid phobia could be a factor when adherence is not optimal, and if not resolved by information and counseling, then other treatment options should be discussed. 26 53

Topical calcineurin inhibitors

TCIs are a class of nonsteroid anti-inflammatory agents currently approved by the FDA as second-line agents in the management of AD. Tacrolimus ointment is indicated for moderate-to-severe AD, with tacrolimus 0.03% approved for children aged 2 years and older and 0.1% ointment approved for patients older than 15 years. Although the FDA issued a boxed warning for topical calcineurin inhibitors, this was due primarily to a theoretical risk of malignancy based on cancers seen only with oral tacrolimus use in solid organ transplant patients. 73 In addition, since this warning, a number of studies have failed to demonstrate this causation, and incidence of malignancy in the treated population is similar to that in the general population. 74 However, because of this warning, significant additional time is often required of prescribing providers to educate patients and caregivers to encourage optimal use and adherence and discuss safety. Of note, in their systematic review of TCSs and TCIs, Siegfried et al 75 found that data supporting long-term use of TCIs are robust, documenting safety and efficacy, whereas data supporting long-term TCS use are limited to low- to mid-potency products. In addition, in an evaluation of a large cohort of 293,253 patients with AD, Arellano et al 76 did not find any increased risk of lymphoma in patients treated with TCIs, but reported that severity of AD was the main factor associated with increased risk of lymphoma. Of note, a recent European longitudinal study did show that TCI use was associated with an increased risk of lymphoma. 77 However, the authors stated that the low incidence rates imply that even if the increased risk is causal, it represents a small excess risk for individual patients. In addition, they pointed out that residual confounding by severity of AD, increased monitoring of severe patients, and reverse causation could have affected the results.

TCIs do not cause the telangiectasia, skin atophy, or striae, which have all been associated with inappropriate and long-term use of more potent TCSs. Because of the lack of these specific side effects, TCIs have been especially useful for AD involving the face, including periocular and perioral areas, as well as axillae and groin regions. The most common side effects are burning and stinging, which tend to be transient for most patients, although have been reported to be more persistent in a subset of patients due to neuropeptide release and can be aggravated by sweating or alcohol intake. 78 Although approved for twice-daily noncontinuous use, guidelines support 2 to 3 times weekly proactive therapy in patients who are able to achieve clear/almost clear skin, but have a relapsing course. 45 46 Another approach is to use rotational therapy, where TCI use is alternated with TCS use. This may work best in patients in whom steroid resistance is suspected. 79 80

Systemic Therapy for Severe AD

In the authors' AD Program, the decision to initiate systemic therapy for patients with severe AD involves a careful reevaluation of the patient's diagnosis, understanding of their disease including psychosocial aspects, previous treatment, adherence issues, as well as systemic treatment options with risks versus benefits ( Figure 1 ). 27 A similar approach has recently been described by the International Eczema Council. 81 Current preferred therapeutic options have been proposed in recent publications. 25 26

Dupilumab

Dupilumab is a fully human mAb developed with VelocImmune technology approved by the FDA for use in adults with moderate-to-severe AD in March 2017. By blocking IL-4 receptor alpha, it interferes with signaling by both IL-4 and IL-13, 2 key type 2 cytokines. 29 In 2 phase 3 trials, 36% to 38% of adult patients with moderate-to-severe AD inadequately controlled on topical treatment treated with dupilumab monotherapy 300 mg every other week after an initial 600 mg loading dose achieved a primary outcome of an Investigator's Global Assessment of 0 or 1 (clear or almost clear) and a reduction of 2 points or more in that score from baseline at week 16. 82 In addition, improvement of at least 75% in EASI from baseline to week 16 was reported in approximately 50% of patients on dupilumab. It is important to recognize that median disease duration in patients enrolled in the phase 3 trials was approximately 26 years, median affected body surface area was more than 50%, and median EASI was approximately 30 (≥21.1 = severe AD). In addition, approximately 33% of patients had received systemic corticosteroids and 26% to 31% had been treated with systemic immunosuppressants in the 2 trials. Importantly, patients who did not achieve “clear” or “almost clear” still had significant improvement as assessed by EASI and in peak pruritus Numerical Rating Scale score. 83 Injection-site reactions and conjunctivitis were more frequent in the dupilumab-treated patients than in the placebo groups. Although the conjunctivitis has not been fully explained, it was for the most part self-limited, and only 1 patient in the phase 3 monotherapy trials discontinued study treatment. 82 Nevertheless, this adverse event requires further elucidation. It is worth noting that this adverse event was not reported in the dupilumab trials in asthma or chronic sinusitis with nasal polyposis. 84 85 Although Wollenberg et al 86 have published their experience with dupilumab-treated patients with AD developing conjunctivitis, given the need for better understanding of this complication, the authors of this review prefer to send any patient not responding to lubricating ophthalmic drops to an ophthalmologist.

A long-term study (LIBERTY AD CHRONOS) reproduced both the efficacy and safety of the monotherapy trials. 87 In this 52-week study, patients could use concomitant TCS or TCI if TCS was not advisable as needed on the basis of disease activity. An additional trial in adults with AD with inadequate response to or intolerance of cyclosporine A (CSA), or for whom CSA treatment was medically inadvisable (LIBERY AD CAFÉ), also provided similar efficacy and safety data. 88 In a recent randomized, double-blinded, placebo-controlled study, dupilumab was shown not to affect antibody responses to vaccines in adults with AD. 89 Adults with moderate-to-severe AD on dupilumab 300 mg or placebo weekly were immunized with Tdap and quadrivalent meningococcal polysaccharide vaccine at week 12. Similar positive IgG responses to tetanus and meningococcal polysaccharide were observed with dupilumab/placebo at week 16. Importantly, in a recent multicenter randomized study, biopsies from dupilumab-treated patients (though note, not with the FDA-approved dosing regimen) improved not only markers of cutaneous and systemic type 2 inflammation but also reversed epidermal barrier abnormalities. 90

Currently, dupilumab is the only drug approved for systemic treatment of AD in adults in the United States other than systemic steroids. As discussed below, systemic steroids are not recommended for this chronic disease. Recognition of AD as a systemic disease provides a strong rationale for the treatment of appropriate patients with this biologic. The approved dosing regimen is a 600 mg loading dose subcutaneously followed by 300 mg subcutaneously every 2 weeks. Injections can be self-administered at home, and patients do not require any laboratory monitoring or need to have autoinjectable epinephrine. In the United States, trials with dupilumab in adolescents with moderate-to-severe AD ( NCT03054428 ) have been completed and studies in children aged 6 to 11 years with severe AD ( NCT03345914 ) are currently ongoing. In addition, pediatric and adolescent patients with severe AD have been effectively treated with dupilumab prescribed off-label. 91

Phototherapy

Phototherapy can be considered in older children and adults who have failed treatment with topical medications or systemic immunosuppressants. Phototherapy can be used simultaneously with topical treatment with TCSs. Caution should be exercised if a patient is using TCIs because prescribing information for these medications recommend to limit exposure to natural and artificial light. 48 Phototherapy is not approved in children younger than 12 years though there have been a few pediatric clinical trials that demonstrate improvement in pruritus and moderate improvement in the extent of AD. 26 92 93 94 Side effects include erythema, burning, stinging, and possible reactivation of herpes infection; efficacy of long-term use is not known. 48 95 There are various forms of phototherapy available, including natural sunlight, narrow-band ultraviolet light B, broad-band ultraviolet light B, ultraviolet light A, ultraviolet light A and B, and topical and systemic psoralen plus ultraviolet light A. 48 Narrow-band ultraviolet light B is the most preferred form of phototherapy due to accessibility, provider familiarity, and efficacy with minimal side-effect profile. 95 Psoralen plus ultraviolet light A is not commonly recommended because of adverse effects compared with the other forms of phototherapy, which include headaches, nausea, and vomiting, hepatotoxicity, and increased photosensitivity with oral psoralen. 48

Treatment should be individualized on the basis of minimal erythema dose, and patient's underlying Fitzpatrick skin type. 26 Use of phototherapy can be restricted because of time commitment and unavailability of specialty equipment, and may be difficult to implement in younger children. 26 94 Home phototherapy units may offer an alternative solution in these cases, but there are no studies of efficacy or safety of home phototherapy in AD. Of note, in a subset of patients with severe AD, sunlight exposure can exacerbate symptoms, so routine use of sunscreen is recommended for all patients with AD. 96 97

Systemic immunosuppressants

Systemic immunosuppressants such as cyclosporine, azathioprine (AZA), mycophenolate, and methotrexate (MTX) have been used in the management of chronic severe AD when patients have failed conventional topical treatments of AD. 26 98 Before approval of dupilumab, they had been considered a next-step option after failure of high-potency topical medications, along with phototherapy. 25 26 Of note, all the immunosuppressants are used off-label for treatment of pediatric and adult patients with AD in the United States. They are typically reserved for short-term use (under 1 year) because of associated toxicities, though a recent study suggests that MTX and AZA may be safe for long-term (up to 5 years) use. 99 They should be prescribed by an experienced specialist because there is an increased risk of infections, and need for frequent laboratory monitoring ( Table III ). They may be effective in children and adults with severe AD, in conjunction with continued use of topical treatment. 26 98

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/Mg+, K+ 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, then Q1 mo × 4 mo; then every other month and with dose increases CBC w/diff/plt Q2 wk × 1 mo; then Q1 mo × 3 mo; then Q 2-3 mo
  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/Mg+, K+ 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.

Table IIIDosing and monitoring of systemic immunosuppresants used in severe AD (adapted from Sidbury et al 48 )

 

Cyclosporine

CSA is a calcineurin inhibitor that inhibits T-cell activation and subsequent IL-2 production. CSA is the first-line immunosuppressant that is effacacious as a short-term therapy in severe AD; duration of therapy is usually restricted to 6 months to 1 year because of associated toxicities. 48 100 Dosing guidelines for CSA provide a range recommendation of 3 to 6 mg/kg/d in children and 150 to 300 mg/d in adults, typically dosed at 5 mg/kg/d in the pediatric population. 48 A retrospective trial of 15 children treated with CSA found that those children treated for a longer duration (17.7 ± 10.7 months) were less likely to relapse than those treated for a shorter duration (10.2 ± 2.7 months). Relapse was noted at follow-up of 22.7 ± 15.0 months. 101 However, longer duration of treatment is limited by the side effects of CSA, which include infection, nephrotoxicity, hypertension, tremor, hypertrichosis, headache, gingival hyperplasia, and increased risk of skin cancer and lymphoma. 48 Patients must have careful and frequent blood pressure and laboratory monitoring while on treatment. 48 One alternative to an abrupt discontinuation of therapy, which may result in relapse, is continuation of intermittent maintenance therapy. 102 This resulted in maintenance of response in a small group of patients with severe AD who had been treated for a year with CSA, which was then tapered to weekend CSA administered at 5 mg/kg/d. Notably, blood pressure and creatinine levels remained stable before and during the 2-day weekend therapy. Further randomized controlled studies are needed to determine whether this intermittent scheduling alternative is a safer long-term option with continued efficacy in those with severe AD.

Methotrexate

MTX is a folic acid antagonist that affects T-cell activities and is used routinely in the management of psoriasis in adults and children. In AD, time to maximum effect averages 10 weeks, with minimal to no further efficacy after 12 to 16 weeks with further dose escalation. 48 There are a few head-to-head trials comparing MTX to other systemic immunosuppressants. 103 In a study of children with severe AD, MTX and CSA had similar efficacy over 12 weeks of treatment. 104 There was no statistically significant difference in SCORAD reduction, and mean absolute reduction was approximately 25 to 26 in both groups. In a trial of 42 adults, MTX was compared with AZA over 12 weeks, and had similar efficacy with a 42% versus 39% improvement in mean SCORAD. 103 Efficacy was also seen in secondary parameters, though more myelosuppresion was observed in the AZA group. Adverse events included liver enzyme elevation and skin infections in the MTX group. Results were comparable between the 2 agents regardless of filaggrin mutation status.

Dosing of MTX in AD is derived from the dosing used in psoriasis. The medication is generally given once weekly and can be titrated upward until effect is reached. In adults, dosing ranges from 7.5 to 25 mg/wk, and in children it is weight based at 0.2 to 0.7 mg/kg/wk. 48 Folic acid supplementation is recommended and may be protective against hematologic and gastrointestinal toxicity. Common side effects include nausea, vomiting, and stomatitis, which can be minimized by administering medication in 3 divided doses given 12 hours apart. 105 Patients should be monitored for rare, but severe and potentially irreversible side effects, such as bone marrow suppression and pulmonary fibrosis. 48 54

Azathioprine

AZA is another systemic agent that has shown modest efficacy in both pediatric and adult AD. Its use is also limited by adverse effects. 98 106 It works as a purine analog that inhibits the cell cycle of lymphocytes, resulting in immunosuppression. AZA is metabolized by thiopurine methyltransferase enzyme, and thiopurine methyltransferase activity levels should be measured at baseline to determine appropriate dosing of the drug. It may take 4 weeks before response to treatment is seen. 107 Adverse effects of the drug include nausea, vomiting, and gastrointestinal symptoms, and more severely myelosuppression, neutropenia, lymphopenia, and hepatotoxicity. In addition, AZA has received a boxed warning regarding a rare, but potentially lethal hepatosplenic T-cell lymphoma. Pediatric dosing varies, but most studies recommend 2.5 mg/kg/d, with a maximum of 4 mg/kg/d. 48 Dosing can be initiated at 2 mg/kg/d, and then gradually titrated up to minimize nausea and vomiting, while carefully monitoring for myelosuppresion. There is only 1 long-term study of long-term AZA use in AD, which followed 43 adults in the Netherlands treated with AZA and MTX for 5 years. 99 This study suggests that with dose modifications, AZA may be safely used in the long-term management of AD with reduction in severity of AD.

Mycophenolate mofetil

Mycophenolate mofetil (MMF) is an immunosuppressant drug that inhibits both T- and B-lymphocyte proliferation via inhibition of inosine monophosphate dehydrogenase. 48 MMF has been used as monotherapy in children aged 2 years and older with severe refractory AD. 108 Initial response to treatment may take up to 8 weeks, and full efficacy may not be seen until 12 weeks. It may be considered as a successive treatment to be used in the long-term after CSA. Common side effects include nausea, vomiting, abdominal pain, headaches, and fatigue, which may be transient, and avoided with slow upward titration of enteric-coated medication. 48 More serious, but rare, adverse effects include hematologic abnormalities and genitourinary symptoms, such as urgency, frequency, and dysuria. In a trial of 14 children treated with MMF, few adverse effects were seen at dosing of 40 to 50 mg/kg/d in young children and 30 to 40 mg/kg/d in adolescents. 108 Guidelines suggest dosing ranges in adults of 0.5 to 3 g/d, which is typically divided into 2 doses, and in children dosing is based on body surface area of 600 to 1200 mg/m 2 , which can be adjusted for increased hepatic metabolism in children. 48 54 Long-term safety and efficacy are not known. MMF was used for up to 24 consecutive months in 1 study of children, and for up to 36 months in adults without significant adverse effects. 48 109

Systemic corticosteroids

Systemic corticosteroids such as prednisone, prednisolone, and methylprednisolone are the only FDA-approved treatment for inflammatory skin disease, including AD. 54 However, their routine use in moderate-to-severe AD is not recommended, because risks of treatment far outweigh the temporary benefit of use. 45 48 110 In one study comparing systemic corticosteroids with MTX for the treatment of AD in adults, only 1 out of 21 patients achieved remission in their AD, resulting in study termination due to the severe exacerbations of the other patients. 111 Once systemic corticosteroids are initiated, subsequent discontinuation is often associated with rebound flaring of disease. 26 48 Additional adverse effects include hypertension, glucose intolerance, weight gain, adrenal suppression, increased infections, decreased bone density, and decreased linear growth in children. 48 112 Corticosteroids can be used concurrently with another therapy for a short time period as a bridge therapy, because other therapeutics, such as phototherapy or MTX, may take up to several weeks before efficacy is seen. 26 Dosing is typically 0.5 to 1.0 mg/kg, and it is recommended to restrict courses to 2 to 3 weeks. 48 Pediatric patients on systemic corticosteroids should be monitored for blood pressure and growth percentiles, and receive ophthalmologic and hypothalamic-pituitary-adrenal axis suppression testing. 48 54

Other systemic off-label treatment

Omalizumab

Omalizumab, a recombinant humanized mAb that inhibits binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils, has been used in AD with variable results. A case series of 7 patients aged 6 to 19 years with severe AD demonstrated clinical improvement after 3 to 6 months of treatment. 113 However, a systematic review and meta-analysis of omalizumab in AD found that fewer than 50% of the patients treated with this biologic achieved a significant clinical improvement. 114 In addition, in the 2 randomized controlled trials in that review, patients failed to show any significant clinical improvement with omalizumab or their clinical resoponse was comparable to that of the control group. However, the authors did note that 43% of patients treated with omalizumab had a good response, suggesting that a subset of patients with AD, possibly those with an urticarial component to their disease, might still benefit from this therapy.

Recombinant IFN-γ

Recombinant human IFN-γ is a biologic response modifier that has been used in the treatment of moderate-to-severe AD with variable results. 115 Side effects included flu-like symptoms, transient transaminase elevation, and granulocyte suppression. Although defects in IFN-γ have been identified in individuals with AD complicated by disseminated herpes simplex viral infection, the authors of a small review of pediatric patients with confirmed eczema herpeticum and severe AD treated with subcutaneous IFN-γ did not observe any significant improvement in either subset. 116

Conclusions

Severe AD may present a diagnostic as well as therapeutic challenge. Patients with this degree of disease severity suffer 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 pearls may be helpful to incorporate into a successful treatment strategy ( Table IV ). In the past year, approval of dupilumab, a biologic targeting key cytokine abnormalities in AD, has transformed the therapeutic landscape, including in adults with severe AD. Given the rich pipeline of biologics, small molecules, and other drugs that are being actively evaluated in AD, 117 management of AD will need to be appropriately modified as results from clinical trials are translated into clinical practice.

Participate in shared decision making with the patient and/or caregiver
• Spend time listening to the patient and/or caregiver
• Understand the patient's goals and expectations (less itching, clearer skin, better sleep, other quality-of-life issues)
• Clarify current medications and which ones are succeeding or failing
• Give treatment options explaining the risks and benefits of these treatments
• Consider all of the patient's socioeconomic factors and ability to adhere with treatment recommendations (insurance, affordability, reimbursement, patient's daily schedule, and work/school/family obligations)
Explain the nature of the disease
• Realize that deterioration in previously stable AD may result from secondary bacterial or viral infection, development of contact allergy, poor understanding or adherence to recommended treatment
Clarify the severity of the patient's AD
• Explain how much body surface area is involved—more than 10% of the body is considered moderate-to-severe AD
• Understand the extent or significant impact on quality of life (social, emotional, school, or professional functioning)
Work to find the right treatment plan and individualize for the patient to promote adherence to agreed plan
• Explain the role of proper skin hydration and moisturizers as daily care regardless of other treatments
• Prescribe, as appropriate, TCSs and TCIs after taking into account patient's age, site to be treated, extent/severity of disease, being sure to prescribe adequate amounts
• Clarify patient's vehicle preference for moisturizers and topicals
• Demonstrate how to apply topical agents
• Address steroid phobia or underuse if appropriate
• Provide written recommendations regarding skin care including bathing and medicines including prescription and over-the-counter products including WWT
• Consider use of biologics or phototherapy if failing conventional topical treatments, as appropriate
• Consider use of other systemic therapies if failing other treatments
• Prescribe, as appropriate, oral sedating antihistamines, topical and/or oral antimicrobials
Provide patient education materials and additional support measures
• Give patient education materials that support the specific messages and recommendations you are providing—not all do!
• Consider structured educational interventions (eczema school, online programs, or patient support and advocacy groups)
• Recommend environmental measures to avoid skin irritants and proven allergens or triggers
• Recommend psychosocial support
• Review skin care and reinforce key messages at follow-up visits

Table IVPractical pearls for managing severe AD

 

Acknowledgments

We acknowledge all the members of our multidisciplinary Atopic Dermatitis Day Program team and thank Dusty Christian for help with our manuscript.

Conflicts of interest: M. Boguniewicz has served as a consultant for Regeneron and Sanofi-Genzyme. The rest of the authors declare that they have no relevant conflicts of interest.

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