Evaluating the Longitudinal Course of Atopic Dermatitis: Implications for Clinical Practice

Abstract

Atopic dermatitis (AD) is characterized by a heterogenous longitudinal course with varying severity, flares, and persistence. However, AD course is not routinely assessed in clinical practice or controlled trials. To review the longitudinal course of AD in children and adults and discuss implications for routine practice and clinical trials. We conducted a focused review of the published literature, including retrospective, prospective, and interventional studies, clinical trials, and consensus guidelines. Estimates of AD persistence vary widely across studies but suggest that AD can indeed persist through childhood and into adulthood. Predictors of persistence are broad and include both disease-intrinsic and -extrinsic (i.e. environmental) factors. In real-world practice, most individuals with AD show fluctuation of signs and symptoms over time and are unable to achieve persistent clearance of skin lesions. Clinical trials utilize mainly static measurements which don’t take into account fluctuations in course, which may confound treatment effects. The heterogenous temporal pattern of AD can be incorporated into routine practice to better set expectations and offer realistic prognosis. AD course should be routinely incorporated into clinical decision-making. Future studies are needed to develop a standardized approach to AD assessment and treatment that includes longitudinal course.

1. Introduction

Atopic dermatitis (AD) is associated with heterogeneous intensity and distribution of skin lesions,[1] symptoms (itch, skin pain,[2] sleep disruption,[3] and mental health disturbances),[4, 5] and numerous atopic and non-atopic comorbid health conditions.[6–13] AD is associated with impaired quality of life (QOL),[14, 15] increased healthcare resource utilization,[16, 17] morbidity and patient-burden.[14, 18]

AD also has a heterogenous longitudinal course consisting of variable persistence (i.e., continued AD activity over time), fluctuating severity, dynamic flares, and periods of disease quiescence (i.e., dormancy of AD activity) or remission (i.e., long-term resolution of AD activity). However, the longitudinal course of AD is not routinely incorporated into clinical management. AD practice guidelines, e.g. European Task Force on AD,[19, 20] and virtually all clinical trials utilize static, cross-sectional, and/or short-term assessments of AD signs, symptoms, or quality of life. While these assessments are valid and reliable in AD[21–26] they do not reflect the longitudinal course of AD.

Understanding of the longitudinal course of AD and its predictors has the potential to improve phenotyping, prognostication, and personalization of care. Recently, studies addressed the temporal course of AD and revealed key associations and predictors that can be used guide long-term management. Herein, we perform a narrative review of studies about the longitudinal course of AD in children and adults and discuss their implications for clinical practice.

2. AD course in children

AD is commonly regarded as a disease that starts early in childhood, follows a waxing and waning course, and “burns out” by adulthood. These ideas were based on anecdotal clinical experience, largely cross-sectional studies and importantly, studies that did not consider the heterogeneity of AD’s natural course. One of the first large-scale, prospective studies to suggest that AD commonly persists beyond childhood originated from the Pediatric Eczema Elective Registry (PEER). PEER is a phase IV, post-marketing study of children (ages 2-17 years) with mild-to-moderate AD to examine a potential link between pimecrolimus use and malignancy over a 10-year observation period. The study was repurposed to examine longitudinal epidemiology of AD and found that >80% of children had persistent AD, i.e. continued symptoms and/or medication use.[27] During the first five years of follow-up, 64% never achieved a six-month period free of AD symptoms or medications. Only by age 20 did 50% of children achieve at least one six-month disease-free period. Atopic comorbidities, environmental exposures, race/ethnicity, and household income <$50,000 were all associated with more persistent AD, and models incorporating these sociodemographic factors showed fair to good prognostic ability. Previous studies also showed association of similar factors with AD prevalence and flares in childhood.[28–30]

The persistence of childhood AD in the PEER study was markedly higher than estimates from other long-term follow-up studies. For example, a review of longitudinal studies from the second half of the 20^th century showed that children with AD evaluated in university hospitals or outpatient clinics showed persistence of only 40-60% after puberty (Table 1).[31] A multicenter German birth cohort following children from birth until the age of 7 demonstrated that 43% of children with early-onset AD were in remission by age 3, while 38% had intermittent AD and 19% had disease symptoms every year.[32] Similarly, retrospective studies from Thailand and Italy showed that 50% of children showed remission between the ages of 3-4 and 6-7, respectively.[33, 34] The high-degree of persistence observed in PEER may be due to enrolled children having AD that was more severe, refractory to topical corticosteroids, and more chronically persistent thereby warranting long-term treatment with a non-steroidal agent such as pimecrolimus. Regardless, estimates of persistence vary widely across studies (Table 1). Interpretation of persistence across studies is challenging, given non-uniform methods of data collection (retrospective, prospective; questionnaire, examination), cohorts (inpatient, outpatient; homogenous, heterogenous), AD diagnosis, use of AD severity scales for stratification, and overall length of the studies themselves.[35–37]

Table 1.

Selected studies examining AD persistence

Author and year	Study component(s)	Sample size	Baseline or recruitment age (years)	Follow-up (years)	Rate(s) of AD Persistence
Osborne and Murray 1953[91]	• Retrospective cohort with clinic exam	98	≤2	≥5	• 80%
Purdy 1953[92]	• Retrospective cohort with questionnaire	93	≤1	15-21	• 25%
Finn 1955[93]	• Retrospective cohort with questionnaire	37	≤1	15-22	• 41%
Vowles et al. 1955[94]	• Retrospective cohort with questionnaire	78	Infants, children	13-22	• 18-55%
Meenan 1959[95]	• Retrospective cohort with questionnaire	48	≤1	13-27	• 31%
Burrows and Penman 1960[96]	• Retrospective cohort with questionnaire and clinic exam	38	≤1	9-12	• 83%
Roth and Kierland 1964[66]	• Retrospective cohort with questionnaire	221	22-44	20	• 60% (baseline mild disease) • 71% (baseline severe disease)
Stifler 1966[97]	• Retrospective cohort with questionnaire	40	≤1	22-25	• 35% (baseline severe disease)
Musgrove and Morgan 1976[98]	• Retrospective cohort with clinic exam	99	≤5	15-17	• 58%
Vickers 1980[99]	• Prospective cohort with questionnaire	2,000	2-21	5-20	• 8-13%
Vanhecke and Leys 1981[100]	• Retrospective cohort with questionnaire	50	≤5	20	• 62%
Queille-Roussel et al 1985[101]	• Prospective cohort with questionnaire and clinic exam	200	≤1	2-8	• 74%
Rystedt 1985[67]	• Retrospective cohort with questionnaire and clinic exam	955	≤14	22-44	• 40% (baseline evaluation as outpatient) • 62% (baseline evaluation as inpatient)
Schudel and Wuthrich 1985[102]	• Retrospective cohort with questionnaire and clinic exam	227	≤2	15	• 58% (based on questionnaire) • 62% (based on exam)
Podmore et al. 1986[103]	• Retrospective cohort with questionnaire and clinic exam	62	≤2	10-14	• 45%
Businco et al. 1989[104]	• Prospective cohort with clinic exam	68	<11	5	• 43%
Linna et al. 1992[105]	• Retrospective cohort with clinic exam	40	≤2	10	• 83%
Kissling and Wuthrich 1993[106]	• Retrospective cohort with questionnaire and clinic exam	106	≤2	20	• 61%
Illi et al. 2004[32] (Multicenter Allergy Study [MAS])	• Prospective birth cohort with questionnaire and clinic exam	1,314	Birth	7	• 19%
• Belgrave et al. 2014[107] (Manchester Asthma and Allergy Study [MAAS])	Prospective birth cohort with questionnaire and clinic exam	1,184	Birth	11	• 8.6% (early-onset AD with subsequent “atopic march”) • 4.5% (persistent AD and wheeze) • 4.5% (persistent AD with later-onset rhinitis) • 14.5% (persistent AD only)
Margolis et al. 2014[27] (Pediatric Eczema Elective Registry [PEER])	• Prospective cohort with questionnaire	7,157	2-17	10	• >80%
Ricci et al. 2014 (AllerGene2)[33]	• Prospective cohort with clinic exam	184	≤5	10	• 67% (non-IgE-associated) • 20% (IgE-associated)
Wanankul et al. 2014[34]	• Retrospective cohort with questionnaire and clinic exam	205	≤15	3-8	• 50%
Mortz et al. 2015[45] (The Odense Adolescence Cohort Study [TOACS])	• Prospective cohort with questionnaire and clinic exam	1,271	8th grade	15	• 17% (based on questionnaire) • 10% (based on exam)
Paternoster et al. 2017[48] (Avon Longitudinal Study of Parents and Children [ALSPAC])	• Prospective birth cohort with questionnaire and clinic exam	9,894	Birth	16	• 7.3% (early-onset, persistent) • 7.0% (early-onset, late-resolving)
Paternoster et al. 2017[48] (Prevention and Incidence of Asthma and Mite Allergy [PIAMA])	• Prospective birth cohort with questionnaire	3,652	Birth	11	• 4.9% (early-onset, persistent) • 3.8% (early-onset, late-resolving)
Roduit et al. 2017 (Protection Against Allergy Study in Rural Environments [PASTURE])[47]	• Prospective birth cohort with questionnaire	1,038	Birth	6	• 6% (early-onset, persistent)
McKenzie and Silverberg 2019[43] (Fragile Families and Child Wellbeing Study [FFCWS])	• Prospective birth cohort with questionnaire	4,898	Birth	15	• 13% (early-onset, persistent) • 7% (intermediate-onset, persistent)
Thorsteindottir et al. 2019 (Copenhagen Prospective Study on Asthma in Childhood 2000 [COPSAC2000])[46]	• Prospective birth cohort with questionnaire and clinic exam	411	Birth	13	• 24%

Given conflicting results, a systematic review and meta-analysis was performed to determine rates and associations of persistent AD.[38] Across 46 studies identified, 80% of childhood AD had ≥1 observed period of disease clearance, i.e. did not persist, by 8 years. Less than 5% persisted 20 years after diagnosis. More severe, already persistent disease at baseline, and female sex were all associated with greater AD persistence. Among three studies that stratified AD persistence by severity, a large subset of patients with even mild or moderate AD had persistent disease.[32, 39, 40] Interestingly, patient-reported assessment of severity was associated with higher persistence compared to clinician-assessed severity, likely reflecting the dynamic course of AD that may not be appreciated by cross-sectional clinician assessments. AD flares or recurrence were not assessed beyond the initial period of disease clearance, likely underestimating longer term persistence. Nevertheless, a substantial subset of AD patients appear to experience improvement by adulthood. Persistence may be an intrinsic feature of AD that has its own risk factors and occurs even in milder disease.

A more recent evaluation of the PEER study described patterns of persistent AD and utilized latent class analysis to identify predictors of longitudinal AD control.[41] Two distinct subgroups with distinct patterns of disease control were identified: resolving (i.e., more likely to report complete control with no treatment) and persistently active (i.e., continued AD activity beyond childhood). Predictors of persistently active AD included non-white race, household income <$50,000 per year, female sex, personal history of atopy (including food and animal allergies), earlier-onset AD, and frequent use of AD medications at younger ages. Notably, black race and lower household income were associated with the highest odds of persistently active AD. When stratified by age of onset, early-onset AD (age ≤2) was associated with poorer disease control and increased persistence over time when compared to mid- (ages 3–7) and late-onset (ages 8–17) AD, and this association was independent of atopic comorbidities and sociodemographic factors.[42] Differences in control and persistence became most clearly differentiated starting in early adolescence and extending into adulthood.

A prospective birth cohort study following nearly 5,000 women and their children in large urban cities across the U.S. revealed additional associations with childhood AD persistence.[43] Female, black and multiracial children had more persistent AD, which was considered as a major driver of increased AD prevalence in these groups. Persistent AD was also associated with increased odds of asthma and poorer health status, highlighting the known associations between AD severity, persistence, and atopic comorbidities with poor health outcomes in children,[10, 44, 45] and raising important questions about the interaction of AD severity with persistence and impact on HRQOL.

The findings from US-based studies mirror those of several international birth cohort studies. The Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC₂₀₀₀), a Danish birth cohort that followed children born to mothers with asthma until age 13, showed that predictors of AD persistence in early adolescence included AD genetic risk score (i.e., heritability, including common Filaggrin mutations), family atopic history, elevated social circumstance (i.e., household income, parental education), signs and symptoms at time of presentation (including several Hanifin-Rajka minor criteria, e.g., Dennie-Morgan folds, white dermographism, intolerance to wool, food allergy, and recurrent skin infections), and increased severity.[46] Protection Against Allergy Study in Rural Environments (PASTURE), a European rural birth cohort, identified history of allergies in both parents as the strongest predictor of an early-persistent AD phenotype.[47] Avon Longitudinal Study of Parents and Children (ALSPAC), an English longitudinal population-based birth cohort study, and Prevention and Incidence of Asthma and Mite Allergy (PIAMA), a Dutch multicenter birth cohort of children from allergic and non-allergic mothers, also identified family history of atopic disease as a strong predictor of persistence, along with AD genetic risk score and personal history of atopic disease.[48] Across these and other international, longitudinal, birth cohort studies, the most important predictors of AD persistence beyond childhood were earlier age of onset, disease severity, allergic multimorbidity, family history of atopy, filaggrin gene mutations, and urban environment.[35] Despite differing methodologies, children with AD across prospective cohort studies showed fairly similar patterns of progression and could generally be categorized as early-onset resolving, late-onset resolving, early-onset persistent, and unaffected/transient courses.[35]

Though the prevalence and severity of AD is increased among non-white children.[29, 49], few studies examined the role of race or ethnicity as predictors of AD persistence. Given that the previously highlighted studies suggested a relationship with AD course, Kim et al. studied the association of race/ethnicity with persistence of AD in mid-childhood using a prospective, pre-birth cohort originally designed to study the effect of environmental exposures on maternal and child health.[50] Non-Hispanic black children and children of other non-Hispanic race were most likely to develop AD in early childhood when compared to non-Hispanic white children, and children of black race and those of Hispanic ethnicity had the highest odds of persistent disease in mid-childhood, an association that was further strengthened after adjusting for sociodemographic factors. A hypothesis-independent, unsupervised cluster analysis of the PEER study revealed unique phenotypes defined in part by race and variable long-term outcomes.[51] Notably, black individuals with minimal AD clearance prior to study enrollment, few medication allergies, and little maternal history of AD had the lowest odds of AD clearance over time. Among black children, increased AD persistence is another element of a unique disease burden, which alongside increased prevalence and severity[9, 29, 49, 52, 53] includes higher likelihood of AD diagnosis during an office visit[54] and overall incident AD,[29] low rates of overall healthcare utilization,[55] more ambulatory visits and prescriptions,[55] increased rates of allergic comorbidities,[56] more treatment-resistant disease,[57] and greater HRQOL impact.[58] Racial/ethnic disparities in AD persistence may be driven in part by disease-intrinsic factors. Filaggrin-2 mutations are associated with more persistent AD in black individuals.[59] Dysregulated innate and adaptive immune signaling underlying AD appear to vary across racial groups.[57, 60, 61] Extrinsic factors likely also influence disparities in persistence, including geographic location, environment/climate, socio-economic status, access to and utilization of preventive and medical care. The predictors of AD persistence in and beyond childhood appear to be unique and warrant additional study.

3. AD Course in Adults

Most studies of adult AD, including prospective studies and randomized clinical trials, employed static assessments of signs, symptoms, and HRQOL without addressing their persistence and longitudinal course. Inconsistent terminology describing the dynamic nature of AD (“long-term”, “flare”, “remission”) and analytical approaches to model longitudinal data make direct comparison between studies difficult.[62–64] This is further complicated by absence of consistent repeated measures of AD severity or activity and the possibility of unobserved AD recurrences in those thought to have remittance within a study.[65]

Despite these limitations, early studies showed that baseline AD severity was strongly associated with persistence. Among patients with baseline severe vs. mild disease evaluated at a single, tertiary-care, academic medical center in the US in 1940s, 29% vs. 40% had completely cleared when surveyed about their AD two decades later (Table 1).[66] The median age of onset and clearance was 4 months and 21 years, respectively. Mean AD duration was higher in those with severe (32 years) vs. mild (27 years) disease. Those with persistent disease noted classic flexural involvement (82%), followed by hand eczema (11%) and localized neurodermatitis (3%). Among inpatients and outpatients with AD who were originally evaluated in a single Swedish academic medical center in 1950s, long-term follow-up (>24 years) revealed commonly persistent and/or recurrent AD in previous inpatients (62%) and outpatients (40%).[67, 68] Among those with persistent disease, the most common site of eczema was hands. Hand involvement was the strongest predictor of persistent disease in children. Predictors of active AD later in adulthood included severe AD in childhood, early-onset disease, family history of AD, and comorbid allergic rhinitis and/or bronchial asthma. In a Turkish academic medical center, persistent AD was observed in 77-91% of adults who with moderate-severe AD as adolescents in 1960s and 1970s.[69] Most AD observed at follow-up was mild or moderate and typically presented on face or hands.

A survey of Swedish adults in the fourth to eighth decade of life who were initially evaluated for AD as young adults at a university hospital outpatient clinic revealed persistent AD in 59% of respondents, with a mean clearance rate of 18% per person-year.[70] Predictors of persistence based on the initial encounter in young adulthood included head and neck dermatitis, early-onset, family history of atopic disease, allergy to furry animals or pollen, oral allergy syndrome (OAS), and nickel sensitivity. Among those with persistent AD, sun-sensitive skin types (Fitzpatrick 1 and 2), dry skin, pruritus, personal history of atopic comorbidities were more significantly more common. These findings were similar to a subsequent retrospective study of German adolescents and adults with AD that showed that chronic persistent AD patients had increased history of head and neck lesions, concomitant respiratory disease, and earlier-onset AD.[71]

To better understand the real-world longitudinal course of AD lesional severity and extent, a prospective clinical cohort followed 400 adults with mild-severe AD undergoing standard-of-care treatment over a two year period.[72] While most patients with mild AD had persistently mild disease, those with moderate-severe AD were more likely to have fluctuating or persistent improvement in severity over time. Erythema and edema/papulation showed greatest fluctuation over time (subacute signs of AD that may be more responsive to treatment) while xerosis and lichenification were the most stable (chronic signs of AD that may be less responsive to treatment). The main baseline predictors of increased eczema area and severity index (EASI) and objective-Scoring AD (SCORAD) scores over time were body surface area (BSA) and edema/papulation. Elevated BSA was speculated to contribute toward more severe AD over time due to difficulty with widespread application of topical anti-inflammatory therapy. Edematous skin may impede cutaneous penetration of topical therapy. Patients with severe cutaneous inflammation may be refractory to topical treatment. Male sex, age, and public insurance were also associated with increased EASI and objective-SCORAD scores. The relationship with public insurance likely reflects the complex, overlapping health care disparities associated with more severe AD.[49, 73, 74]

Itch is a multidimensional symptom associated with varying intensity, frequency, and HRQOL impact.[75] Itch is the most prevalent and burdensome symptom of AD,[14, 76, 77] and the itch-scratch cycle contributes to AD chronicity.[78, 79] A prospective clinical cohort (n=399 adults) with mild-severe AD found that most patients had fluctuating itch and scratching/excoriation. Few had persistent or improved scratching/excoriation over the observation period.[80] Those with baseline mild excoriations had high probability of persistent mild excoriations. Those with moderate-severe excoriations had more fluctuation or sustained improvement over time. Those with no excoriations continued to have no itch or excoriations at follow-up, likely reflecting periods of disease quiescence in patients with intermittent disease activity. Those with severe excoriations had a more fluctuating course but were more likely to have sustained improvement of excoriations, suggesting that even partial improvement of itch can lead to more profound improvements of excoriations over time. Predictors of increased scratching/excoriations over time included baseline scratching severity, EASI score, public insurance, and atopic comorbidities. Scratching severity was only moderately correlated with itch.

AD is associated with heterogeneous itch triggers, including stress, sweat, weather change, dry air, and heat.[81] More than one-third of AD patients identified ≥3 itch triggers, and the number of triggers was associated with ≤3 months of AD remission during the year, ≥2 flares per year, and worsening of AD during certain seasons.[81]

Skin-pain is a multifactorial symptom in AD, with heterogenous intensity, frequency, etiology, and HRQOL impact.[2, 77, 82] A prospective study (n=572 adults) with mild-severe AD showed that skin-pain had only weak-moderate correlation to itch and lesional severity at baseline and throughout the observation period.[83] The weaker correlation with itch is intriguing and suggests that skin-pain is not caused solely by itching and scratching. The time course of skin-pain was also distinct from that of itch. Only one-third experienced fluctuating or persistent skin-pain over time; nearly all experienced fluctuating or persistent itch. Patients were more likely to experience sustained improvement of skin-pain than itch. Baseline predictors of persistently severe skin-pain over time included skin-pain severity and no/self-pay insurance, but surprisingly no association with lesional severity. These findings suggest that skin-pain is a distinct symptom from itch in AD.

Previous studies found that AD signs and symptoms are only moderately correlated with each other. A prospective real-world study (n=592 adults) characterized the proportion and longitudinal course of AD patients using novel subsets defined by combined itch and lesional severity: mild-moderate itch and lesions (MI-ML), mild-moderate itch and severe lesions (MI-SL), severe itch and mild-moderate lesions (SI-ML), and severe itch and lesions (SI-SL).[84] Patients with SI-SL, SI-ML, and MI-SL had increased flares (about 5-10 per 6 months) compared with MI-ML, with the SI-SL and SI-ML groups also having a higher proportion with ≤3 months of disease remission. Most patients with baseline MI-ML continued to have MI-ML, while patients with SI-ML, SI-SL, and MI-SL had more substantial fluctuation across subsets over time. High flare frequency, limited time spent in remission, and fluctuating course underscore a need for better longitudinal control with step-up therapies (systemic, biological, phototherapy), particularly among those with SI-ML. Though, less than one-third of SI-ML patients initiated step-up therapy compared to most SI-SL patients.

Taken together, most individuals with moderate-to-severe AD have fluctuating signs and symptoms and are unable to achieve persistent clearance of skin lesions, highlighting unmet needs in these patients.

4. Evaluating AD course in clinical practice

Recognition of the heterogenous temporal pattern of AD (fluctuation, persistence, improvement) is highly clinically relevant. Consideration of these factors may improve clinical decision-making and set realistic expectations for patients.

AD is usually classified using non-standardized cross-sectional assessments during patient encounters that may not appreciate longitudinal course and potentially lead to inadequate treatment recommendations. For example, a patient may have almost clear disease during their encounter, after having a severe flare 3 weeks earlier and being prescribed a course of oral steroids and antibiotics in an emergency department visit.

Each combination of AD severity and persistence warrants specific treatment consideration. Treatment of flares requires agents with rapid-onset and robust efficacy. Maintenance treatment requires agents that can be used safely long-term for flare prevention. For example, long-term treatment of persistent mild-moderate AD should incorporate both reactive treatment of flares and proactive therapy to prevent flares with topical anti-inflammatory agents. Whereas, long-term treatment of persistent moderate-severe AD may warrant step-up therapy with non-steroidal systemic or biologic therapies.[63, 85]

To better visualize the variability of AD course over time, the authors summarized their expert clinical opinion into a graphical depiction of several common phenotypes of AD course (Figure 1)[86] which is further explained in the following section.

Figure 1.

AD course in clinical practice.

AD with good control is relatively stable over time with transient mild worsening of AD but no major disease fluctuation. Such patients can be controlled with optimized basic skin care, e.g., bathing, emollients, itch trigger avoidance, and intermittent reactive use of topical anti-inflammatory medications.

Seasonally moderate-severe AD may manifest with only one or two major flares per year in a particular season or with change of seasons but is otherwise well-controlled. This AD subset would benefit most from short-term topical and systemic treatment with rapid-onset and robust efficacy that can be used intermittently, e.g., topical corticosteroids or Janus kinase (JAK) inhibitors, oral corticosteroids, cyclosporine A or JAK inhibitors. Narrowband ultraviolet B phototherapy, oral methotrexate or biologics likely would not work fast enough in such patients. Proactive maintenance therapy may not be needed in this patient subset.

In patients with frequent, moderate flares, multiple courses of topical or lower dose oral systemic immunomodulators may be needed to reactively treat flares. Alternatively, chronic treatment with biologic, phototherapy, or lower dose oral systemic immunomodulators may be used to prevent flares and achieve long-term disease control.

Patients with baseline moderate AD with severe flares are difficult to manage longitudinally, given the persistent high level of disease activity. Oral cyclosporine A or Janus kinase inhibitors may be used with flexible dosing in these patients, with high dose to treat severe flares and low dose to treat baseline moderate disease and prevent subsequent severe flares. Alternatively, continuous therapy with a biologic may be used to achieve long-term disease control.

Patients with chronic severe disease are typically most difficult to manage longitudinally. Oral Cyclosporine A or Janus kinase inhibitors may be required at continuous high doses, or biologic or phototherapy, to achieve long-term control. Combination approaches are often needed to optimize disease control.

We propose that AD be classified using a combination of severity and disease persistence similar to asthma.[87] Asthma is most commonly classified as (1) intermittent, (2) mild persistent, (3) moderate persistent, (4) and severe persistent. This classification is conceptually relevant to AD as intermittent disease should primarily be treated reactively, whereas persistent disease also requires proactive treatment. For AD, we propose the following classification: (1) mild intermittent, (2) mild persistent, (3) moderate-severe intermittent, and (4) moderate-severe persistent AD.

Incorporating AD course in clinical trials

Currently, RCTs in AD utilize validated measures of AD signs (investigator’s global assessment [IGA], EASI) and symptoms (NRS-itch) as inclusion criteria and measures of efficacy. These static assessments do not account for the fluctuating course of AD, which may confound treatment-effects. For example, patients with seasonally severe AD (Figure 1B) who are enrolled in a study during a flare may naturally experience disease clearance 8-16 weeks later. Such patients may result in inflated placebo-responses. Disease flares prior to or during a RCT may result in underestimation of treatment-effects. However, baseline AD course is generally not assessed in RCTs.

Most studies assess disease improvement at pre-specified time points, e.g. after 4 or 16 weeks of therapy. These are somewhat arbitrary time-points in the context of different disease subsets (Figure 1). A patient may achieve clear skin at weeks 2-14 and then flare by week 16 and be considered a treatment non-responder. Another patient may not achieve clear skin until week 16 and be considered a treatment responder. Studies should additionally examine aggregate measures of long-term disease control, e.g. number of itch-free days, weeks with clear skin, or flares experienced. Post-hoc analyses of previous RCT suggested that treatment escalation and days of topical anti-inflammatory use are valid and feasible proxy measures of AD flares.[88]

Harmonizing Outcomes Measures in Eczema (HOME) designed a theoretical framework to define eczema control from the patient and caregiver perspective.[89] They described eczema control as a multi-layered construct involving changes in AD activity, treatment/management of AD, and physical, psychological, and social function, and favored patient/caregiver measurement over clinician assessment for more frequent and personal accounts of control. HOME agreed by consensus that a long-term control assessment in RCTs should include signs, symptoms (including itch intensity and frequency), HRQOL, and a patient global domain.[90] We propose that baseline and endpoint measures of the longitudinal AD course are also incorporated in future RCTs to better define disease subsets and understand long-term response to different classes of therapy.

5. Conclusion

The longitudinal course of AD is not routinely assessed in clinical practice or trials. We recommend that the longitudinal course of AD be routinely assessed in clinical practice and trials and considered in combination with AD severity for disease classification, treatment selection and patient counseling regarding prognosis.

Key Points.

• Most assessments of atopic dermatitis signs and symptoms in clinical practice and research are cross-sectional and fail to account for the longitudinal disease course.

• Atopic dermatitis is characterized by a heterogenous longitudinal course with varying severity, flares, and persistence.

• The heterogenous temporal pattern of atopic dermatitis should routinely be assessed into clinical practice and trials.

Availability of data and material:

not applicable