tolerability of and adherence to topical treatments in

REVIEW

Tolerability of and Adherence to Topical Treatmentsin Atopic Dermatitis: A Narrative Review

Heather L. Tier . Esther A. Balogh . Arjun M. Bashyam .

Alan B. Fleischer Jr . Jonathan M. Spergel . E. J. Masicampo .

Lara K. Kammrath . Lindsay C. Strowd . Steven R. Feldman

Received: January 7, 2021 / Published online: February 18, 2021� The Author(s) 2021

ABSTRACT

Atopic dermatitis (AD) is a common, chronicinflammatory skin disease that oftentimesrequires complex therapy. Poor adherence is amajor barrier to AD treatment success. Aninterspecialty, virtual roundtable panel washeld, through which clinical dermatologists,allergists, and behavioral and social psycholo-gists discussed AD management and adherence.Relevant literature was reviewed, and the con-tent of this article was organized based on theroundtable discussion. Current guidelines forAD treatment include maintenance and acute

therapy for mild-to-severe AD. Therapy is oftencomplex and requires significant patientinvolvement, which may contribute to poortreatment adherence. Behavioral and socialpsychology strategies that may help improveadherence include scheduling timely follow-upappointments, using a clearly written eczemaaction plan (EAP), reducing perceived treatmentburden, utilizing anchoring techniques, sharinganecdotes, and rewarding children using posi-tive reinforcement and stickers. There are mul-tiple practical ways by which providers canimprove both the management and treatmentadherence of patients with AD.

H. L. Tier (&) � E. A. Balogh � A. M. Bashyam �A. B. Fleischer Jr � L. C. Strowd � S. R. FeldmanDepartment of Dermatology, Center forDermatology Research, Wake Forest School ofMedicine, Medical Center Boulevard, Winston-Salem, NC 27157-1071, USAe-mail: [email protected]

S. R. FeldmanDepartment of Pathology, Wake Forest School ofMedicine, Winston-Salem, NC, USA

S. R. FeldmanDepartment of Social Sciences and Health Policy,Wake Forest School of Medicine, Winston-Salem,NC, USA

S. R. FeldmanDepartment of Dermatology, University of SouthernDenmark, Odense, Denmark

A. B. Fleischer JrDepartment of Dermatology, University ofCincinnati College of Medicine, Cincinnati, OH,USA

J. M. SpergelDepartment of Pediatrics, Perelman School ofMedicine at the University of Pennsylvania,Philadelphia, PA, USA

J. M. SpergelDivision of Allergy and Immunology, Children’sHospital of Philadelphia, Philadelphia, PA, USA

E. J. Masicampo � L. K. KammrathDepartment of Psychology, Wake Forest University,Winston-Salem, NC, USA

Dermatol Ther (Heidelb) (2021) 11:415–431

https://doi.org/10.1007/s13555-021-00500-4

http://orcid.org/0000-0003-1036-3430

http://crossmark.crossref.org/dialog/?doi=10.1007/s13555-021-00500-4&domain=pdf

https://doi.org/10.1007/s13555-021-00500-4

Keywords: Adherence; Atopic dermatitis;Behavior; Corticosteroid; Eczema;Management; Patient; Social psychology;Tolerability; Treatment

Key Summary Points

Atopic dermatitis (AD) is a chronic,inflammatory disease that is characterizedby flares of more severe disease states.Diagnosis of AD is largely clinical, andpresenting symptoms often includespruritus, classic morphology, age-specificdisease patterns, personal or familyhistory of atopy, and associatedcomorbidities.

Treatment guidelines include routine useof emollients and trigger-avoidance,topical corticosteroids (TCS), topicalnonsteroidal antiinflammatories,humidifiers, phototherapy, and systemictreatments that depend on diseaseseverity.

Current treatment options have thepotential to be effective; however, poortreatment adherence amongst patientswith AD hinders disease outcomes.

QD and BID use of TCS yield the sametherapeutic outcomes, but QD applicationmay better improve patient adherence totreatment.

Increased frequency of follow-upappointments, clearly written EAPs, andpsychology methods such as anchoringand anecdote use can be utilized byproviders to improve treatmentadherence. The use of adherence-improving techniques may be asbeneficial as developing new drugs to treatAD.

DIGITAL FEATURES

This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.13688089.

INTRODUCTION

Atopic dermatitis (AD) is a common inflamma-tory skin disease that is characterized byeczematous lesions, erythema, and pruritus thataffects 15–20% of children and 1–3% of adultsworldwide [1, 2]. AD is the most commonpediatric inflammatory disease in the USA; it isincreasing in prevalence and is considered themost burdensome skin disease [3]. Minoritypopulations suffer from greater disease preva-lence and severity [4, 5]. Fortunately, there arenew developments in our understanding of ADand its management.

AD is often chronic, persistent, and presentsin a waxing-and-waning manner, which can befrustrating to patients, their families, andphysicians alike [6]. Current AD maintenancestrategies and treatment guidelines includeroutine use of emollients, avoiding triggers, andusing regimens that include topical corticos-teroids (TCS), nonsteroidal antiinflammatorytopicals, phototherapy, and systemic treat-ments. Although current guidelines outlinetherapy options that are potentially highlyeffective, limitations caused by application sitediscomfort, complicated treatment regimens,and poor adherence hinder AD treatment out-comes in clinical practice [1, 7].

Patients often fail to adhere to treatmentplans for various reasons including inconve-nience of treatment, concerns about sideeffects, forgetfulness, lack of understanding oftheir condition, and lack of trust in the provider[8]. The use of topical treatment for AD drops byapproximately 70% within the first few days ofbeginning a treatment regimen [9]. Variousapproaches have been developed with the goalof improving the outcome of patients with AD[10] by addressing the issue of poor treatmentadherence and proposing practical approaches

416 Dermatol Ther (Heidelb) (2021) 11:415–431

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to improve it [9, 11–14]. Physicians can usedifferent tools to enhance adherence and out-comes [15]; for example, clearly written treat-ment plans can help elucidate complex therapyinstructions for patients. Also, the use of morefrequent follow-ups is an effective motivatortowards improved adherence [16, 17]. Reducingthe amount of time between visits or betweenpatient–physician contact (via phone call, forexample) decreases the perceived burden oftreatment. Adherence depends on patientshaving a better understanding of AD and agreater perceived supportive relationship withtheir provider [8, 15, 18].

Increased holistic understanding of AD as adisease—including diagnostic criteria, mea-surement of severity, and treatment guideli-nes—as well as the use of clear treatmentdirections and the incorporation of psycholog-ical tools into providers’ clinical practice mayhelp improve both AD management and treat-ment adherence to topical AD therapies.

METHODS

An interspecialty, interactive virtualroundtable discussion was held on 19 May 2020through Wake Forest Department of Dermatol-ogy’s Annual Spring Meeting Program. Clinicaldermatologists, allergists, and behavioral andsocial psychologists discussed AD treatment,management, and adherence strategies. Theinformation presented during theroundtable was developed from a comprehen-sive foundation of research and current guide-lines that focuses on disease management andtreatment adherence of AD. Relevant literaturewas reviewed, and the content of this article wasstructured based on the roundtable discussion.

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not contain any new studieswith human participants or animals performedby any of the authors.

RESULTS

Overview of AD and Measuring Severity

Diagnosis and Assessment of ADThe diagnosis of AD is predominantly clinical.Providers observe for specific patterns andmorphology, inquire about age of disease onsetand known family history, and explore poten-tial associated symptoms. A current guidelinefor AD is the revised and adapted Hanifin andRajka criteria released by the American Acad-emy of Dermatology [2]. The guideline orga-nizes various features of AD and categorizesthem as required features, important features,and associated features necessary for an ADdiagnosis (Fig. 1).

The three required features for assessing anddiagnosing a patient with AD are pruritus,characteristic morphology and age-specific pat-terns, and chronic or relapsing history. ADmorphologies include erythema, edema,papules, excoriation, and lichenification. Typi-cal age-specific patterns seen in patients withAD include the infantile type, childhood type,and adult type. The infantile pattern of ADoften affects the face, scalp, trunk, and extensorsurfaces of extremities. The childhood patternof AD often presents on the flexural folds of

Fig. 1 Diagnosis and assessment of AD. To aid in thediagnosis of AD, the American Academy of Dermatology(AAD) published various features of AD and categorizedthem as required features needed for an AD diagnosis,important features, and associated features [2]

Dermatol Ther (Heidelb) (2021) 11:415–431 417

extensors, around the neck, and ankles. Adult-type AD most commonly affects the upperarms, back, wrists, hands and fingers, and feetand toes [19]. Due to its chronic and relapsingnature, AD often persists and presents in awaxing-and-waning manner [6].

The four important features for assessing anddiagnosing AD include early age of onset, per-sonal or family history of atopy, xerosis, and IgEreactivity. Onset of AD most commonly pre-sents by 5 years of age, with the highest inci-dence occurring between 3 and 6 months ofage. About 60% of patients who develop AD doso within the first year of life, while 90% do sowithin the first 5 years [2]. Personal or familyhistory of atopy is considered an importantfeature for the diagnosis of AD because about70% of patients with AD have a positive familyhistory of atopic diseases [2]. Consequently, theodds of developing AD are two to three timeshigher with one atopic parent, rising to a threeto five times higher likelihood with two atopicparents [2]. Atopy describes the tendency of apatient to have heightened immune response tocommon allergens and to develop allergic dis-eases, which include allergic rhinitis, asthma,and AD. IgE reactivity is considered an impor-tant diagnostic feature as AD is often associatedwith elevated serum immunoglobulin (IgE)levels. Although elevated IgE is the most com-monly associated laboratory finding of AD, suchIgE elevation is not present in approximately20% of AD-affected patients [2]. Elevated IgE isalso nonspecific, because some individualsdiagnosed with severe AD have normal IgElevels, and IgE is elevated in other nonatopicdiseases. This laboratory nonspecificity of IgE isan example of why the diagnosis of AD remainsclinical in practice.

There are many associated features of AD.Atypical vascular responses are commonlyobserved in patients with AD, including facialpallor, white dermatographism, and a delayedblanch response. Keratosis pilaris, pityriasisalba, palmar plantar hyperlinearity, and ich-thyosis are dermatologic conditions oftenfound in conjunction with AD. Regional find-ings include periorbital, perioral, and periau-ricular eczematous changes. Other findingsassociated with AD and general atopic disease

include allergic shiners, Dennie–Morgan folds,and vernal keratoconjunctivitis.

Comorbidities of ADCommon comorbidities among patients withAD include allergic rhinitis and asthma. Atopicdermatitis, allergic rhinitis, and asthma consti-tute the classic ‘‘allergic triad.’’ Although theconditions do not necessarily occur in con-junction with one another, providers may findit beneficial to ask patients about personal orfamily history of respiratory diseases likeasthma and associated symptoms, such aswheezing and rhonchi, and inquire aboutenvironmental and food allergies and associatedsymptoms including runny nose, watery eyes,itchy throat, urticaria, and anaphylaxis.

Another comorbidity often associated withAD is allergic contact dermatitis (ACD). Patientswith AD are susceptible to developing ACD athigher rates compared with patients withoutAD. Allergy or sensitivity to emollients, mois-turizers, and topical prescription medicationsshould be considered in clinical practice whentreating patients with AD [20–22].

Methods of Measuring AD SeverityAfter diagnosing a patient with AD usingassessment and diagnostic criteria guidelines,various methods can be utilized to measuredisease severity. Some of the more commonlyused methods include SCORAD, EASI, andvIGA-AD (Fig. 2).

SCORAD (or SCORing Atopic Dermatitis) is aseverity measurement method that takes intoaccount affected area, intensity, and subjectivesymptoms. Severity scores for each category aretotaled for a total SCORAD score. The first scorecategory is area, or the sites affected by AD thatare typically shaded on a drawing of generichuman body in anatomical position. Theaffected area (AA) can be calculated as a per-centage of the total body area (TBA). The per-centages of total body area for each region areadded up for a total area (A). The second scorecategory is intensity. The provider selects arepresentative area affected by AD, and theintensity of various categories is measured asnone, 0; mild, 1; moderate, 2; or severe, 3.


Intensity scores between zero and three areassigned to six different presenting morpholo-gies: erythema, edema, oozing or crusting,excoriation, lichenification, and xerosis. Theintensity score for each morphology is addedtogether for total intensity (B). The finalSCORAD category is subjective symptoms,which include pruritus and lack of sleep. Thepatient measures both pruritus and lack of sleepon a scale of 0–10, where 0 represents no itchand no sleep loss, and 10 represents worst pos-sible itch and complete sleeplessness. These twosubjective symptom scores are added together(C). The final SCORAD total is calculated asA/5 ? 7B/2 ? C, with a maximum total score of103.

Another AD severity measurement is theEczema Area and Severity Index (EASI). Underthe EASI system, there are four body regions,and each region has set percentages of totalbody regions. An area score is recorded for eachof the four body regions and comprises thepercentage of skin affected by AD in eachregion. The area score is scored 0–6, with 0being no active AD in a specific region, and 6being 90–100% of the skin affected by AD inthat region. Next, severity is scored based onintensity of erythema and inflammation,intensity of papulation, intensity of excoria-tion, and intensity of lichenification or prurigonodules. Each severity category is scored on ascale 0–3, with 0 being none or absent intensity,

and 3 being the most severe intensity. Thescores for each are added up for a total severityscore. To calculate the total EASI score, the totalseverity score is multiplied by the area score andits ‘‘multiplier’’ for each of the four bodyregions. Each body region has a unique multi-plier value, so the total EASI score is the sum ofeach multiplication score per body region. Themaximum EASI score is 72, and the minimum is0. EASI is the preferred clinimetric approach forseverity by Harmonising Outcome Measures forEczema (HOME).

The vIGA-AD is the Validated InvestigatorGlobal Assessment Scale for AD. The vIGA-AD isscored on a scale of 0–4 based on the morpho-logical descriptions including erythema, edema,papules, excoriation, and lichenification. Foreach presenting morphology: clear, or 0; almostclear, or 1; mild, or 2; moderate, or 3; and sev-ere, or 4. The scores 0–4 for each morphologyare added together for a total vIGA-AD score.

Stress and AD: A PsychoneuroimmunologicalResponseAD is often accompanied by discomfort thatstems from pruritus or pain, sleep disturbancecaused by symptoms, and complicated treat-ment regimens that oftentimes foster stress forboth the patient and their family. Stress causes apsychoneuroimmunological response, whichexacerbates AD lesions. Psychological stress—including the stress and decreased quality of life

Fig. 2 Comparing AD severity measurement tools.There are various tools that help providers assess ADdisease severity. 1SCORing Atopic Dermatitis; 2Eczema

Area and Severity Index; 3Validated Investigator GlobalAssessment Scale for Atopic Dermatitis


caused by uncomfortable symptoms of thecondition—upregulates the synthesis of stresshormones such as cortisol. Cortisol has localcutaneous effects by stimulating various proin-flammatory responses such as vasodilation andpruritus. Stress hormone mediators also activatemast cells in the skin. The mast cells respond bysynthesizing and releasing histamine andproinflammatory molecules including cytoki-nes interleukin (IL)-2, IL-8, IL-31, interferon(IFN)c, and tumor necrosis factor (TNF)-a. Theworsening inflammation and pruritus canintensify a patient’s stress, which in turn canpropagate the cycle of stress and further exac-erbate the inflammation [22, 23].

Current AD Treatment Guidelines

General Guideline Themes for AD TreatmentAD treatment regimens suggested by providersmay vary depending on the individual patient,taking into account the patient’s age, the goalbeing either maintenance or acute treatment,therapy success in the past, and conditionseverity. Despite these variations, generalthemes are shared across different guidelines.

Most treatment guidelines for AD recom-mend that patients bathe daily for 5–10 min,followed by moisturizer on both clear andaffected skin areas two or three times per day.Topical corticosteroids (TCS) are consideredmainstay treatment for AD and are prescribedfollowing the general ‘‘fingertip method’’ rule.This method emphasizes that 0.5 g of TCS isenough to cover two palm-sized surfaces on anadult body. The total amount needed per use,however, depends on the total body surface areaaffected by AD. Application of TCS is generallyrecommended once or twice per day for acuteflare-ups and two or three times per week formaintenance therapy of areas that are prone toflares. Topical calcineurin inhibitors (TCI) arecommonly recommended for sensitive areas ofthe body, including the face and genital region,and are useful if a patient is refractory to TCS orin the case of the steroid-phobic patient.Beyond topical medications, systemic treatmentis considered if AD is resistant to or poorlycontrolled by topical therapies.

AD Treatment Guidelines: Acute,Maintenance, SeverityOrganizing treatment guidelines in a clear,understandable manner for patients to followmay be beneficial to both patients and providersalike, as AD therapy is often complex andinvolved.

Guidelines are categorized by severity undernonlesional versus mild versus moderate versussevere AD, and further subcategorized as acuteflare-up treatment versus maintenance treat-ment. Information from the AD yardstick forpractical treatment recommendations [20] wasreconfigured and presented in a patient-friendlylanguage that may be valuable in clinical prac-tice (Fig. 3).

Maintenance therapy for nonlesional ADincludes a daily skin care regimen and triggeravoidance. A maintenance skin care routineconsists of liberal and frequent moisturizer use.Guidelines recommend that patients take daily,warm 5–10 min baths or showers and use non-soap cleansers, directly followed by moisturizerapplication. Moisturizer can be applied to bothproblem areas and nonlesional areas of the skin.Common allergens and irritants should beavoided; these include—but are not limited to—soaps, fragrance, wool, and temperatureextremes. Comorbidities of AD should also beconsidered, such as asthma, allergic rhinitis,and ACD.

Maintenance therapy for mild AD includesdaily, liberal moisturizing (especially afterbathing), and trigger avoidance. Antisepticmeasures and humidifier use should also beimplemented. Recommended antiseptic mea-sures include a dilute bleach bath, which con-sists of one capful of bleach into one bathtubfilled with water, one-to-two times per week.Antiseptic measures are especially useful if thepatient suffers from recurrent skin infections.Antibiotics can also be considered to treat skin

Fig. 3 Categorizing treatment regimens for AD.Managing treatment regimens for AD can be effectivelyorganized based on severity (clear or nonlesional, mild,moderate, and severe), and further categorized by main-tenance (daily regimen for clear skin) treatments and acute(flare-up) treatments in patient-friendly language [20]

c


infection, if necessary. Humidifier use is alsorecommended, especially during the dry, coldwinter months.

Maintenance therapy for moderate ADincludes daily skin moisturizing, trigger avoid-ance, antiseptic measures, and humidifier use,similar to maintenance therapy for mild AD. Inaddition to this basic management, topicalantiinflammatory medication may be intro-duced here. Maintenance low-potency TCS canbe used once or twice per day. Medium-potencyTCS for moderate AD maintenance therapy isrecommended once or twice weekly, excludingthe face. If a patient does not respond well toTCS, providers can suggest using maintenanceTCI once or twice a day, or two to three timesper week as needed. Crisaborole 2% can also beused twice daily as maintenance for moderateAD but is not considered first-line therapy.Patients with moderate AD may consider wetwrap therapy as well.

Maintenance therapy for severe AD includesdaily skin moisturizing, trigger avoidance,antiseptic measures, humidifier use, and anti-inflammatory topicals. In addition to this basicmanagement, providers may consider referringthe patient to an AD specialist. Additionalmaintenance treatment options for patientswith severe AD include phototherapy, biologicssuch as dupilumab, or systemic immunosup-pressants such as cyclosporine A, methotrexate,mycophenolate mofetil, azathioprine, and oralcorticosteroids.

In addition to maintenance therapies acrossall disease severities, AD treatment guidelinesoutline ways that can help patients gain controlduring acute flare-ups. Acute treatment fornonlesional and mild AD includes applying TCSonly to areas of inflamed skin. Low- to medium-potency TCS applied twice daily for 3–7 daysbeyond clearance is recommended for acutetherapy. Providers can also consider prescribingTCI or crisaborole for sensitive areas such as theface or genitals, or if patients are refractory totreatment using TCS.

Acute treatment for moderate-to-severe ADincludes applying a medium- to high-potencyTCS twice daily for 3–7 days beyond clearance.TCI and crisaborole can be considered for sen-sitive areas or patients who are not responsive

to TCS therapy. If the acute inflammation doesnot resolve in 7 days, providers should considerother factors including treatment nonadher-ence, infection, misdiagnosis, or developmentof contact allergy to medication. Providers mayalso consider referring to an AD specialist. First-generation oral antihistamines are recom-mended for pruritus control and associatedsleep disturbances. Other treatment optionsthat may help patients gain control of severe,acute AD flare-ups include wet wrap therapyand short-term hospitalization, especially in thecase of infection. Maintenance and acute ther-apy options across AD severities can be orga-nized and presented to patients in a clearmanner that is easy to follow (Fig. 3).

Stepping-Up AD TherapyAs AD usually presents in a waxing-and-waningpattern, it is essential for providers to under-stand when it is deemed appropriate to changetreatment regimens, assess for nonadherence,and how to step up therapy if a patient’s con-dition worsens (Fig. 4).

For patients with mild AD that has exacer-bated to a moderate degree of severity, patientsusually remain symptomatic despite low- tomedium-potency TCS use and maintenanceskin care regimens. Guideline treatment optionsfor patients stepping up from mild to moderateAD suggest increasing the TCS dose or potency,adding a TCI, or adding crisaborole 2% oint-ment. The treatment change suggested by theprovider is trialed for about 3 months, with afollow-up appointment scheduled within thefirst 1 or 2 months to assess for progress andtroubleshoot any issues such as contact allergy,application difficulty, or nonresponsiveness[20].

Patients with moderate AD who worsen tosevere disease may have issues with mentalhealth, lower quality of life, and impaired dailyactivities. Guidelines suggest alternative treat-ment options including phototherapy, dupilu-mab, or systemic therapies such as cyclosporine,methotrexate, mycophenolate mofetil, aza-thioprine, or oral corticosteroids. Providers mayalso suggest that patients see an AD specialist[20].


Before initiating new treatment regimens,however, it may be beneficial to consider thepatient’s adherence to treatment—or lackthereof. Treatment adherence among patientswith AD is poor, and a patient’s adherence isoften an unknown factor. Most patients do notuse medications as recommended [1, 7]. With-out primarily assessing for treatment adherence,providers may be unnecessarily changing orcomplicating treatment regimens while thereason for unresponsiveness or disease exacer-bation—poor adherence—remains unresolved.Although it is possible to initiate new therapieswhen the patient is thought to be fully adherentyet fails to see improvement in their condition,it is more likely that patients are nonadherentto recommended mainstay treatment. Withoutinquiring about and working to improveadherence, patients may be at risk for unneces-sary side effects that could be avoided if main-stay topical treatments were used properly.Specific techniques that may help improve

patient adherence to AD treatment are dis-cussed in a later section.

Systemic Therapies, New Treatments,and BiologicsAlthough skin care maintenance regimens andtopical antiinflammatory medications aremainstay AD treatments, high-severity diseasemay require systemic therapies for relief.Cyclosporine, methotrexate (MTX), mycophe-nolate mofetil, and azathioprine are systemictreatment options that providers may suggest.These systemic therapies, however, pose certainrisks and side effects. Most systemic AD treat-ments are immunosuppressive and increaserisks of infection, and may cause renal andhepatic toxicity. Guidelines suggest that provi-ders increase the potency or frequency of topi-cal medications, confirm and improve patientadherence to maintenance skin care regimens,and utilize humidifiers, bleach baths, or wetwrap therapies before implementing additionalsystemic therapeutics.

Fig. 4 Step-up treatment for worsening AD. Organiza-tion of guidelines depicts when it may be appropriate tochange treatment regimens or how to step up therapy if

AD worsens [20]. Treatment adherence should beadequately assessed before initiating new therapy orintroducing systemic treatment


Novel treatment options for AD available forclinical use include crisaborole and dupilumab.Crisaborole is a topical, nonsteroidal phospho-diesterase-4 inhibitor that is approved to treatmild-to-moderate AD in patients 2 years of ageand older [24]. Dupilumab is an IL-4 receptormonoclonal antibody that binds to the alphachain of the IL-4 receptor and inhibits down-stream inflammation often seen in atopic dis-eases such as AD. Dupilumab improves lesionhealing, pruritus, and sleep quality comparedwith placebo [24], and is approved for patientsolder than 12 years of age with moderate-to-severe AD who previously failed topical thera-pies [21].

Techniques to Improve TreatmentAdherence

The Downward Trend of AD TreatmentAdherencePatient adherence to topical treatment is poor,and reasons for nonadherence include lack ofunderstanding of the condition, inconvenienceof treatment, forgetfulness, concerns about side

effects, and lack of trust in the provider [8]. Ifpatients are not responding to treatment, pooradherence should be considered and appropri-ate adherence-promoting measures can beinstituted.

Adherence to topical treatment for AD dropsby approximately 70% within the first week ofstarting a treatment regimen [9]. The rates ofadherence continue to drop with time (Fig. 5).The timing of follow-up appointments can beused to improve adherence [16, 17]. Whiletreatment adherence generally decreases withtime, anticipation of a scheduled follow-upincreases adherence rates before the scheduledappointment (Fig. 5). After a follow-upappointment, adherence decreases again.Anticipation of visits or other forms ofpatient–physician contact may increase apatient’s sense of accountability and, conse-quently, treatment adherence.

Adherence Intervention PyramidThe adherence intervention pyramid [10] orga-nizes techniques that can be utilized by provi-ders to help improve treatment adherence

Fig. 5 Average rate of adherence versus time afterstarting topical treatment. Adherence to topical treat-ment is poor, and average rates of adherence decline astime passes after the initial appointment and start of

treatment. Adherence tends to increase just before ascheduled follow-up appointment (*), but then declinesagain. More frequent follow-ups may be beneficial inhelping to improve adherence to therapy in AD [9]


among patients with AD (Fig. 6). The founda-tion of the pyramid encompasses trust andaccountability. The next level of the pyramidfocuses on common, recommended ways toimprove adherence such as giving patientssimple treatment plans with clear, writtendirection, motivating patients, and consideringcosts of treatment. The top of the pyramidconsists of advanced psychological techniquessuch as anchoring, the use of anecdotes, andutilizing rewards and praise.

Trust and AccountabilityEstablishing a trusting physician–patient rela-tionship is essential, as treatment adherenceimproves with an increase in perceived supportfrom the prescribing provider [8, 15, 18]. Theimportance of establishing accountability iseasily understood via a piano lesson analogy: apiano teacher gives music sheets to a student onthe first day and instructs the student to prac-tice every day for a recital that will take place ina few months. In one scenario, the sheet music

is given on day one, and the teacher has weeklypiano lessons with the student in preparationfor the upcoming recital. The recital is a successbecause the students practiced weekly at thelessons. In an opposing scenario, the sheetmusic is given on the first day, but there are noweekly piano lessons with the piano teacher.The student arrives at the recital unprepared,and the recital is a disaster. The idea that thelatter approach would be successful is laugh-able; only in medicine do we give peopleinstructions to do something every day and notcheck in on them for months thereafter [24].

Approaches for Improving AdherenceThe middle of the pyramid focuses on standard,commonly recommended approaches toimprove adherence including simple treatmentplans, written instruction, affordable medica-tions, motivational interviewing, and patienteducation. Patient education and clear, writteninstruction are essential for improving treat-ment adherence. An eczema action plan (EAP) is

Fig. 6 Adherence intervention pyramid. The ground-work for helping to improve patient treatment adherencestarts with establishing a trusting physician–patient rela-tionship and scheduling more frequent follow-up appoint-ments. These follow-ups and more frequent interactionswith the patient will not only help to deepen the

physician–patient relationship but also improve patientaccountability. Another step to improving treatmentadherence is to provide clear, written instruction forpatients in the form of an EAP. Psychological techniquescan also be employed, including the use of anchoring,providing anecdotes, and using rewards and praise [10]


a written instruction of a patient’s treatmentregimen put together by the provider, whichhelps to elucidate complex instructions andorganizes the use of the products and tech-niques that typically compose complicated,multistep AD therapy [25].

A step beyond a generic EAP is the ‘‘pseudo-tailored’’ EAP. Since AD treatment outcomes areoften limited by poor adherence to topicaltreatments and maintenance recommenda-tions, ‘‘pseudotailoring’’ techniques can helpincrease a patient’s attention to their treatmentplan, with the goal of improving overalladherence. Through the utilization of pseudo-tailored EAPs, expectations of customizationcan be raised without actually providing indi-vidualized content [26]. Although the treat-ment plan is not truly personalized, the patientoften perceives that it is. A survey study ana-lyzed the effect of pseudotailored AD treatmentplans on overall patient satisfaction, confidencein their treatment plan, and trust in their pro-vider. One group received a generic EAP (Fig. 7),while the other group received a pseudotailoredEAP with circled treatment selections amongdecoy options (Fig. 8). Pseudotailoringimproved overall patient satisfaction in thetreatment plan, perception of personalization,

and willingness to adhere to the recommendedtreatment regimen [26].

More Advanced Psychological TechniquesThe top of the pyramid focuses on implement-ing psychological techniques such as anchor-ing, anecdotes, and rewards and praise.

Anchoring is a psychological technique thatutilizes cognitive bias in decision-making. Itdescribes the human tendency to rely on—or‘‘anchor’’—on a specific piece of information asa reference or starting point. This technique isbetter comprehended through the use ofexamples; regarding improving AD treatmentadherence, a provider may begin by explainingto a patient that a topical medication needs tobe applied four times daily. The provider then‘‘compromises’’ with the patient and instructsthem to only apply the topical twice daily. Thisperceived smaller burden due to the use ofanchoring increases adherence and willingnessto properly follow treatment instructions.

Another example of anchoring is askingpatients how willing they are to inject a sub-cutaneous medication indicated once monthly.A provider can start by first asking how willingthe patient is to inject once a day, and once theanchor is in place, the provider asks how willing

Fig. 7 Generic treatment plan. An example of a generic EAP, which provides written instruction for a patient’s treatmentregimen to clarify complex directions and organize products and techniques used in typical, multistep AD therapy [26]


the patient would be to inject once per monthinstead. Willingness to adhere to treatment wasapproximately four times higher in patientswho were anchored than those who were not(Fig. 9) [27].

Another example of anchoring in combina-tion with the ability to simultaneously lowerthe perceived burden of treatment is byexplaining to patients how moisturizers alonewill take up to 6 weeks to see improvement. It isthen explained that, with the addition of TCS,the patient may see improvement in only 1 or 2weeks. This technique may be more effectivethan simply describing how TCS takes 1 or 2weeks to see improvement alone. One or 2weeks may be perceived as a long time for apatient without context. An anchor providescontext that makes those 1 or 2 weeks seemmuch shorter, thus decreasing the burden oftreatment and increasing adherence.

Another psychological technique that mayhelp improve treatment adherence whilesimultaneously improving the physician–pa-tient relationship is the use of anecdotes in

clinical practice. Human beings are more influ-enced by things they can imagine and picture asreality. Numbers and data alone are less influ-ential and less effective than personal storiesand examples [28]. Stories make patients feelmore comfortable than data. Providers whoshare personal experiences or previous patientsuccess stories with their patients—i.e., ‘‘I had apatient with a very similar case to yours who didvery well on this treatment’’—are more likely toinstill trust and confidence into their patients,and improve treatment adherence to the pre-scribed regimen.

Another psychological technique that can beused to improve treatment adherence is theimplementation of rewards and praise, espe-cially amongst pediatric patients. Positive rein-forcement and the use of stickers or stickercharts to track a patient’s treatment progress isan effective way to instill enthusiasm in chil-dren regarding treatment adherence and lowerthe burden for parents or family members [10].

The adherence intervention pyramid incor-porates a range of valuable methods and tools

Fig. 8 Pseudotailored treatment plan. An example of apseudotailored EAP, which provides the experience ofcustomization without actually providing individualized

content. The treatment plan is perceived as personalized bythe patient. Treatment options are circled among decoyoptions [26]


that can be utilized to help improve treatmentadherence and benefit patients with AD.

DISCUSSION

Promising New Therapies

Although the mainstay treatment for AD ismaintenance therapy, there are novel drugs indevelopment that may be promising newoptions for patients with AD. Treatments cur-rently undergoing clinical trials, but that arenot yet on the market for clinical use, includeanti-leukin-31 receptor antagonists, IL-13monoclonal antibody drugs, histamine-4receptor (H4R) antagonists, and systemic andtopical Janus kinase (JAK) inhibitors.

Anti-interleukin-31 receptor antagonistsinclude nemolizumab (CIM331), a humanized

monoclonal antibody against IL-31 receptor A.The antibody binds to IL-31 receptor A toinhibit IL-31 signaling. IL-31 receptors arecommonly found on neurons, and nemolizu-mab helps alleviate pruritus [29].

Tralokinumab and lebrikizumab are novel,monoclonal antibody drugs that bind IL-13 toprevent the formation of the IL-13Ra1/IL-4Racomplex and downstream signaling, thusblocking the inflammatory effects of IL-13 seenin atopic conditions such as AD.

Histamine-4 receptor antagonists includepyrido[2,3-e]tetrazolo[1,5-a]pyrazine analogue48, a selective H4R antagonist. Orally adminis-tered, it is antipruritic and antiinflammatory,which is promising for clinical treatmentamong patients with AD [30, 31].

JAK inhibitors include baricitinib, an oralJAK inhibitor that is highly selective for JAK1and JAK2. Treatment with baricitinib improvedthe signs and symptoms of moderate-to-severeAD compared with placebo [32]. Other novelsystemic, JAK-targeting agents include abroci-tinib and upadacitinib, which are both oralJAK1-selective inhibitors. Novel topical JAK-targeting therapies include ruxolitinib and del-gocitinib. Ruxolitinib is a selective inhibitor ofJAK1 and JAK2 that suppresses the signaling ofcytokines involved in AD. Delgocitinib is a pan-JAK inhibitor that blocks JAK1, JAK2, JAK3, andtyrosine kinase 2 signaling pathways, thusinhibiting the inflammation seen in AD.

Improving Treatment Adherence:Understanding the Value

AD can detrimentally impact quality of life forpatients and their families. Pruritus and exco-riation often lead to sleep disturbances; emo-tional detriments include irritability, behavioralissues, embarrassment, and social isolation [7].Physical, emotional, and social detrimentsincrease stress levels, which, in turn, furtherexacerbate AD.

AD treatments can also be cost-prohibitivefor patients, especially newer treatment optionsthat have recently appeared on the market.General disease costs include prescriptions,over-the-counter products, physician

Fig. 9 Effect of anchoring on patient treatmentwillingness. Patients were split into two groups and askedabout their willingness to inject a subcutaneous medicationindicated once monthly. The first group was not anchored,and was only asked about their willingness to inject oncemonthly. The second group was anchored by first beingasked how willing they were to inject daily. After beingasked about once daily injections, the anchor group wasthen asked how willing they were to inject once monthly.The willingness was scored on a scale of 1–10, with 1 beingnot at all willing, and 10 being the most willing. Averagewillingness to adhere to treatment was almost four timeshigher in patients who were anchored than those who werenot [27]


appointments, and hospitalizations. If treat-ment adherence to the more cost-effectivetreatment options—such as mainstay moistur-izers and TCS—is optimized, it may provideeconomic relief to patients and their families.Even novel, effective therapies such as dupilu-mab are only as effective as the patient isadherent.

Improving adherence is essential for opti-mizing disease outcomes, which in turnimproves quality of life and reduces economicburden. Developing and utilizing techniques toimprove adherence may be as beneficial as—andpossibly more achievable, cost-effective, andpractical than—developing new drugs to treatAD. Research that aims to elucidate the patternsof nonadherence among patients with AD andthe methods that help improve it is well docu-mented [33]. What is most needed is bettereducation amongst providers who treat AD ontreatment adherence strategies and how theycan effectively implement them into clinicalpractice.

ACKNOWLEDGEMENTS

Funding. Sponsorship for this study wasfunded by Pfizer Inc. Pfizer Inc. New York, NYUSA. The Pfizer funds awarded to the institutionincluded the funds for publication fees.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Dr. Steven Feldman hasreceived research, speaking and/or consultingsupport from a variety of companies includingGalderma, GSK/Stiefel, Almirall, Leo Pharma,Boehringer Ingelheim, Mylan, Celgene, Pfizer,Valeant, Abbvie, Samsung, Janssen, Lilly,Menlo, Merck, Novartis, Regeneron, Sanofi,Novan, Qurient, National Biological Corpora-tion, Caremark, Advance Medical, Sun Pharma,Suncare Research, Informa, UpToDate and

National Psoriasis Foundation. He is founderand majority owner of http://www.DrScore.comand founder and part owner of Causa Research,a company dedicated to enhancing patients’adherence to treatment. Dr. Alan Fleischer is aconsultant for Boerhringer-Ingelheim, Incyte,Qurient, SCM Lifescience, Syneos and Trevi. Heis an investigator for Galderma and Trevi. Theauthors otherwise declare no conflicts of inter-ests. Heather L. Tier, Esther A. Balogh, Arjun M.Bashyam, Jonathan M. Spergel, EJ Masicampo,Lara K. Kammrath and Lindsay C. Strowd havenothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.


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REFERENCES

1. Draelos ZD, et al. Tolerability of topical treatmentsfor atopic dermatitis. Dermatol Therapy. 2019;9(1):71–102.

2. Eichenfield LF, et al. Guidelines of care for themanagement of atopic dermatitis: Section 1. Diag-nosis and assessment of atopic dermatitis. J AmAcad Dermatol. 2014;70(2):338–51.

3. Hay RJ, et al. The global burden of skin disease in2010: an analysis of the prevalence and impact ofskin conditions. J Investig Dermatol. 2014;134(6):1527–34.

4. Silverberg JI. Public health burden and epidemiol-ogy of atopic dermatitis. Dermatol Clin. 2017;35(3):283–9.

5. Hsu DY, Shinkai K, Silverberg JI. Epidemiology ofeczema herpeticum in hospitalized US children:analysis of a nationwide cohort. J Investig Derma-tol. 2018;138(2):265–72.

6. Margolis JS, et al. Persistence of mild to moderateatopic dermatitis. JAMA Dermatol. 2014;150(6):593–600.

7. Feldman SR, et al. The challenge of managing ato-pic dermatitis in the United States. Am Health DrugBenefits. 2019;12(2):83.

8. Patel NU, D’Ambra V, Feldman SR. Increasingadherence with topical agents for atopic dermatitis.Am J Clin Dermatol. 2017;18(3):323–32.

9. Krejci-Manwaring J, et al. Stealth monitoring ofadherence to topical medication: adherence is verypoor in children with atopic dermatitis. J Am AcadDermatol. 2007;56(2):211–6.

10. Lewis D, Feldman S. Practical ways to improvepatient adherence. Middletown: CreateSpace Inde-pendent Publishing Platform; 2017.

11. Conde JF, et al. Adherence to clocortolone pivalatecream 0.1% in a pediatric population with atopicdermatitis. Cutis. 2008;81(5):435–41.

12. Brown KL, Krejci-Manwaring J, Tusa MG, CamachoF, Fleischer AB Jr, Balkrishnan R, Feldman SR. Poorcompliance with topical corticosteroids for atopicdermatitis despite severe disease. Dermatol OnlineJ. 2008;14(9):13.

13. Yentzer BA, et al. Good adherence and early efficacyusing desonide hydrogel for atopic dermatitis:results from a program addressing patient compli-ance. J Drugs Dermatol JDD. 2010;9(4):324–9.

14. Ou H-T, Feldman SR, Balkrishnan R. Understandingand improving treatment adherence in pediatricpatients. Semin Cutan Med Surg. 2010;29(2):137–40.

15. Feldman SR, et al. Treatment adherence interven-tion studies in dermatology and guidance on howto support adherence. Am J Clin Dermatol.2017;18(2):253–71.

16. Sagransky MJ, et al. A randomized controlled pilotstudy of the effects of an extra office visit onadherence and outcomes in atopic dermatitis. ArchDermatol. 2010;146(12):1428–31.

17. Feldman SR, et al. Adherence to topical therapyincreases around the time of office visits. J Am AcadDermatol. 2007;57(1):81–3.

18. Kim HB, et al. Survey on the management of atopicdermatitis. Korean J Asthma Allergy Clin Immunol.2012;32(1):16–20.

19. Weston W, Lane A, Morelli J. Color textbook ofpediatric dermatology. 4th ed. Philadelphia: MosbyElsevier; 2007.

20. Boguniewicz M, et al. Atopic dermatitis yardstick:practical recommendations for an evolving thera-peutic landscape. Ann Allergy Asthma Immunol.2018;120(1):10-22.e2.

21. Sastre J, Davila I. Dupilumab: a new paradigm forthe treatment of allergic diseases. J Investig AllergolClin Immunol. 2018;28(3):139–50.

22. Buddenkotte J, Steinhoff M. Pathophysiology andtherapy of pruritus in allergic and atopic diseases.Allergy. 2010;65(7):805–21.

23. Suarez AL, et al. Psychoneuroimmunology of psy-chological stress and atopic dermatitis: pathophys-iologic and therapeutic updates. Acta DermVenereol. 2012;92(1):7–15.

24. Feldman S. The parable of the piano teacher. TheDermatologist. 2007;15(8).

25. Rork JF, et al. Parental response to written eczemaaction plans in children with eczema. Arch Der-matol. 2012;148(3):391–2.

26. Bashyam AM, et al. Placebo tailoring improvespatient satisfaction of treatment plans in atopicdermatitis. J Am Acad Dermatol. 2020;83:944–6.

27. Oussedik E, et al. An anchoring-based interventionto increase patient willingness to useinjectable medication in psoriasis. JAMA Dermatol.2017;153(9):932–4.


28. Feldman SR, et al. Treatment adherence in derma-tology. Cham: Springer; 2019.

29. Ruzicka T, et al. Anti-interleukin-31 receptor AAntibody for atopic dermatitis. N Engl J Med.2017;376(9):826–35.

30. Schaper-Gerhardt K, et al. The role of the histamineH(4) receptor in atopic dermatitis and psoriasis. Br JPharmacol. 2020;177(3):490–502.

31. Ko K, et al. Discovery of a novel highly selectivehistamine H4 receptor antagonist for the treatment

of atopic dermatitis. J Med Chem. 2018;61(7):2949–61.

32. Napolitano M, et al. Profile of baricitinib and itspotential in the treatment of moderate to severeatopic dermatitis: a short review on the emergingclinical evidence. J Asthma Allergy. 2020;13:89–94.

33. Bass AM, Anderson KL, Feldman SR. Interventionsto increase treatment adherence in pediatric atopicdermatitis: a systematic review. J Clin Med.2015;4(2):231–42.


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