Atopic Dermatitis Across the Lifespan: Understanding, Measuring and Minimizing Cumulative Life Course Impairment.

To minimize CLCI, the impact of AD on patients’ life courses needs to be assessed to identify when intervention is needed. Incorporation of CLCI measurement in routine clinical practice may advance understanding of the long-term impact of untreated or undertreated AD and help identify the type and timing of interventions that would best reduce CLCI. To do so, it is necessary to develop tools to evaluate both existing CLCI and patients at risk, and to assess the predictive value of CLCI for disease outcomes. The only available CLCI instruments for chronic skin diseases, including AD, are 2 questionnaires ( Fig. 4 ) that have recently been developed for adults that focus on quality of life, psychosocial impacts and comorbidities. The DermCLCI-r is a retrospective tool for assessing CLCI and the DermCLCI-p is a predictive tool that assesses current CLCI status and future risk ( 65 ). Patients are asked to rate how burdensome they find various disease-related problems, such as feeling stressed by their disease or negative financial impacts. While the DermCLCI-r asks respondents to rate each item since the onset of the first symptoms of the disease and to state whether each problem is ongoing or has been life changing, the DermCLCI-p asks for rating of the past 2 weeks. The print version of these tools has been validated, but the electronic version has not. It may be used in clinical practice using electronic documentation. More education about the CLCI concept is likely to accelerate their adoption. One study using these questionnaires determined that CLCI-p has good internal consistency with the Patient-Oriented Eczema Measure (POEM) and the Dermatology Life Quality Index (DLQI), and both tools had excellent reliability, with Cronbach’s alpha scores of >0.96 ( 66 ). Importantly, these available measures have not been adapted for use in paediatric patients. An ideal CLCI measure would be a digital, brief, structured questionnaire that is validated to address age-specific considerations. Both predictive and retrospective measures would be valuable, but predictive ones are needed more in practice for measures to avoid CLCI. A new CLCI tool is likely to have broader clinical adoption if it is in a familiar format that integrates into electronic health records and augments existing scoring systems with CLCI-specific questions. For example, established metrics like the DLQI ( 67 ), Eczema Area and Severity Index (EASI) ( 68 ), or POEM ( 69 ) may be used as foundational elements that are combined with items that capture cumulative life impacts. Actionable outputs, such as a treat-to-target approach if defined thresholds for CLCI and severity measures are crossed, would help with usability. Given that important life events change over time, independent tools for paediatric and adult patients are needed. Questions related to educational or social impairment could provide valuable information about paediatric patients, while indicators of employment or relationship stability may be more relevant for adult patients. Family impact metrics and proxy instruments would also be important for paediatric patients because young children cannot fully articulate their experiences and parents and caregivers often have secondary burdens, including sleep disruption, additional caregiving tasks and emotional distress ( 42 ). The different components affecting CLCI can interact to make an individual vulnerable to life course impairment ( 3 , 6 ). While disease severity, chronic course, early onset and comorbidities are among the more easily assessed factors that place patients at risk, clinicians also need to recognize and evaluate more complex factors, such as each patient’s perception of stigmatization, level of social support, personality traits, coping strategies and behaviours that affect health ( 70 ). Validated screening tools to measure anxiety and depression, health-related quality of life, social support and coping behaviours have been developed and can be used as a starting point ( 70 ). Notably, the impact of CLCI on patient outcomes is intertwined with cultural and societal expectations, and personal definitions of success or impairment can vary significantly. These differences require sensitivity to each patient’s life context. Rather than imposing standard outcomes, a CLCI measure should be framed in a positive, patient-centred way to accommodate individual life paths, personal aspirations and potential, reducing stigma and fostering engagement with quality-of-life improvement strategies. Therefore, language that could be perceived as negative or limiting should be avoided. For example, a question on the degree of physical limitations would be reworded to ask about the degree of physical capabilities. Ideally, this tool would help with shared decision-making by empowering the patient and facilitating treatment conversations. The most useful information may be collected if patients can complete the measure at home, which would streamline clinical workflows and provide more accurate responses, as patients have more time to reflect when outside the clinical setting. Given that both patients and providers are often hesitant to escalate treatment, even when warranted ( 71 ), the measure could show everyone involved when a patient may face significant risks if more effective therapy is not initiated, helping to overcome reluctance and leading to better outcomes. Once a CLCI assessment tool has been developed, additional steps will be needed prior to implementation ( Fig. 5 ). The critical first steps for integrating CLCI metrics are for healthcare professionals to appreciate the concept of CLCI and understand that they can intervene to minimize it. Empirical research will be needed to validate the tool’s relevance and positive impact on outcomes. The development framework will be based on the current evidence for child developmental research in AD and follow the COSMIN criteria (COnsensus-based Standards for the selection of health Measurement INstruments). Validation will require a multinational, multilanguage development and validation study. Multiple specialties and professions will be included, and patient and parent involvement will be a special focus. Additionally, robust training resources will be needed to support dermatologists and other practitioners in applying CLCI as part of routine care. Moreover, methods to facilitate the implementation of these tools are needed to minimize their impact on outpatient visits (e.g., length of visit, reducing patient-doctor interactions). Public awareness initiatives to introduce the concept of CLCI in an accessible way could also increase recognition and empower patients to understand and address their own life course impacts. Finally, advocacy by dermatologic societies and patient organizations could be instrumental in expanding awareness and encouraging further adoption.

AD is characterized by recurrent, itchy, painful skin inflammation, often beginning in infancy ( 8 , 13 ). Eczematous plaques present on the face, trunk and extensor extremities in infants and on flexural surfaces in older patients ( 8 ). While some children experience improvement, severity remains the same or worsens in many children after they transition to adolescence ( 14 ). Although itch and pain are more well-known components of disease burden ( 15 – 17 ), overall health effects have been noted on growth, development and social connections. Patient- and caregiver-reported measures have found a negative impact of AD on quality of life in patients as young as age 6 months ( 13, 15–17 ). Greater disease severity also increases costs, both the direct financial burden of health care as well as indirect costs such as loss of productivity both in patients and employed caregivers of paediatric patients ( 13 , 15 , 18 ), for example, through effects on career choice and education ( 19 ). Sleep . AD is associated with impaired sleep quality, and sleep disturbance is among the most reported and problematic symptoms both in childhood and throughout life, affecting patients, caregivers and partners ( 13 , 16 , 17 , 20 ). Itch can drive disrupted sleep, but the relationship between sleep and inflammation may be bidirectional ( 21 , 22 ). Lack of sleep and resultant biological and psychological stress may impair cognition, increase inflammatory biomarkers and lower the itch threshold ( 22 ). Sleep disturbance is also likely to influence other aspects of health, including neurocognitive processing, mood and even growth ( 21 , 22 ). Although AD has not been associated with short stature overall, bone mineral density is decreased in children and adolescents with AD, and an analysis of multiple population-based studies found that a subset of children with severe disease and insufficient sleep are at increased risk of short stature in early adolescence ( 23 , 24 ). Attention-deficit/hyperactivity disorder (ADHD ). An association between AD and the diagnosis of ADHD is also modified by sleep ( 25 , 26 ). However, factors other than sleep disturbance are likely to mediate the impact of AD on development as well. The presence of an atopic disease increases the risk of developing ADHD by 30% to 50%, possibly because of hypersensitivity to environmental stimuli, effects of inflammatory cytokines or other pathways ( 27 ). ADHD may be misdiagnosed in children with AD as they may lack the ability to sit still due to itch and scratching. Notably, cognitive impairment associated with AD is primarily limited to children with concomitant ADHD or learning disabilities, so these patients are at highest risk ( 28 ). Atopic comorbidities . Multiple atopic conditions are associated with AD, including asthma, rhinitis, eosinophilic oesophagitis and food allergies ( 29 , 30 ). In one international survey, at least 1 atopic comorbidity was present in 92% of paediatric patients with AD ( 17 ). Longitudinal studies have shown that the presence of AD increases the likelihood of developing other atopic diseases, in a relationship referred to as the “atopic march” ( 31 ) ( Fig. 2 ). Infants diagnosed with AD have a 2–8 fold higher risk of developing other atopic diseases over the 8 years after diagnosis than children who do not develop AD before age 1 year ( 32 ). Additionally, the severity of AD is directly correlated with the severity of the associated atopic comorbidities ( 33 ). It has been hypothesized that a dysfunctional skin barrier leads to allergic sensitization, inducing systemic type 2 immunity that predisposes patients to other atopic diseases ( 31 ). Together, these conditions contribute to limitations in daily activities and negative effects on quality of life in paediatric patients ( 34 ). Avoidance of allergens or triggers from food, sports or other activities can be limiting and decrease life satisfaction ( 35 , 36 ). Indeed, the presence of multiple allergic diseases at age 4 years is significantly associated with increased risk for internalizing behaviours and anxiety at age 7 years ( 37 ). Depression and anxiety . The burden of AD is high, and the development of other diseases multiplies that burden, so it is unsurprising that depression and anxiety are among the most frequently reported burdens of AD in adolescents and adults ( 13 ). Multiple studies have found associations between AD and depression, anxiety and suicidal ideation ( 38 – 41 ). Notably, there is an age-dependent pattern for psychological comorbidities. One study in children aged 2–17 years found that while emotional and behavioural difficulties peaked during early adolescence, depression, worry and prevalence of multiple psychological comorbidities increased throughout adolescence ( 41 ). A longitudinal cohort study evaluating mental health outcomes in patients with AD aged 4–18 years found increased risk of internalizing behaviours as early as age 4 years and remaining similar across ages, while symptoms of depression increased from 6% at age 10 years (earliest age evaluated) to 22% at age 18 years ( 39 ). Stigmatization and social isolation . Stigmatization and social isolation associated with AD are likely to play a role in these negative outcomes and affect development over time. According to one survey, children aged 6–11 years with AD were more frequently bullied compared with a control group (20% vs 9%) ( 42 ). Another survey found that 52% of children aged 12–15 years with AD had been the target of AD-related bullying ( 16 ). This age group was also most likely to report that they felt embarrassed because of AD, that AD interfered with relationships with friends or classmates, and that they self-isolated because of AD ( 16 ). Absenteeism (being absent from school or work because of the disease) and presenteeism (e.g., difficulty remaining focused and concentrated at school or while doing homework) resulted in 37.8 days of study impairment per student aged 6–11 years over the previous 12 months ( 42 ). Similarly, in students overall, 17.1 days of absenteeism and 19.5 days of presenteeism per student per year were reported ( 16 ). Again, absenteeism was more pronounced in the 12–15 year-old group. In adults, social isolation may be evident because people with AD are less likely to be living with a partner and have higher rates of separation and divorce than are those without AD. ( 43 ). Nonatopic comorbidities . An increased risk of nonatopic comorbidities, such as infections, autoimmune conditions, lymphoid/haematologic malignancies, ocular disorders, metabolic syndrome and obesity, has also been identified in paediatric and adult patients with AD ( 29 , 30 ). In a study comparing children with AD with a non-AD reference cohort, having AD increased the likelihood of developing infections and neurological, immunological/inflammatory, endocrine/metabolic and ocular disorders over a mean follow-up of 5.7 person-years ( 44 ). The factors predisposing patients to nonatopic conditions are being investigated; for example, skin barrier defects, suppression of cutaneous innate immunity by type 2 inflammation, Staphylococcus aureus colonization and cutaneous dysbiosis contribute to increased infections in patients with AD ( 45 ). Importantly, each of these comorbidities has its own burden that is likely to worsen over time, supporting the need to treat early to avoid a cumulative burden. Work productivity . Although developmental concerns no longer exist in adults, impacts on quality of life and health can persist and accumulate, affecting productivity. As found in paediatric patients, sleep disturbance remains a mediator of impaired overall health. AD in adults is associated with fatigue, daytime sleepiness and insomnia. However, adults with AD are more likely to report fair/poor rather than good/very good/excellent overall health, even without fatigue or sleep disturbances ( 46 ). Associations between AD and poorer health outcomes, such as higher numbers of missed workdays, days in bed and doctor visits, are only partially explained by fatigue and/or sleep disturbance ( 46 ). Depression and anxiety are also observed in a majority of adults with moderate-to-severe AD and are associated with work-related impairment and decreased health-related quality of life, leading to substantial direct and indirect costs ( 47 ). For example, one survey estimated AD-related absenteeism to be 10.9 days/year and presenteeism to be 13.1 days/year, with 67.8% of respondents having had negative professional implications in the previous year because of AD ( 16 ). Another study quantified the mean indirect costs of an incapacity to work at €589 /year ( 48 ). Older adult health concerns . Additional health concerns may also develop in adults with AD that are not present in childhood. AD of any severity has been associated with an increased risk of type 2 diabetes, dyslipidaemia, cerebrovascular accident and deep vein thrombosis in adults ( 49 ). Another study found that adult patients newly diagnosed with AD were at a significantly increased risk of subsequently developing cardiovascular diseases, including angina pectoris, myocardial infarction, ischaemic stroke and haemorrhagic stroke within a mean follow-up period of 5 years ( 50 ). However, other large European claims database studies found no increased levels of obesity, cardiovascular risk or type 2 diabetes ( 51 , 52 ). Overall, the many components of disease burden need to be identified in practice and translated to patient needs and treatment goals. Patients with AD have been shown to have a particularly broad spectrum of treatment needs, ranging from itch relief and skin clearance to improvements in emotions, social relationships and participation, everyday life, treatment facilitation and overall disease control ( 53 ). Because AD typically starts in early childhood and early onset is a risk factor for disease persistence and the development of AD comorbidities, the combined burden over time is likely to cause CLCI ( 54 ). Treating patients with AD early and with the most effective available therapies can impede this trajectory of increasing impairment, meet patients’ needs and avoid accumulation of risk factors and possible comorbid conditions. In effect, treatment should “flatten the curve” of accumulating CLCI over time ( Fig. 3 ). Ideally, early intervention would minimize CLCI by controlling or stopping the underlying disease. The concept of disease modification has been introduced in other chronic inflammatory diseases, such as rheumatoid arthritis and Crohn’s disease, where earlier intervention has resulted in higher remission rates ( 55 ), and has been hypothesized in other skin diseases, such as psoriasis ( 56 ). Like these diseases, moderate-to-severe AD is believed to be systemic and, recently, disease modification in AD has been discussed as a novel treatment outcome ( 57 ). It is hypothesized that epidermal barrier dysfunction allows the penetration of allergens that increase sensitivity and lead to inflammation, including the generation of type 2 helper T cells, production of allergen-specific immunoglobulin E (IgE), which can lead to food allergy and asthma, and release of cytokines and chemokines that affect other organs involved in atopic disorders ( 57 ). Therefore, influencing the natural course of AD through treatment is likely to affect overall health. Definitions of disease modification vary, referring to attenuation of disease progression, full regression or prevention of the development or progression of comorbidities ( 55 , 57 ). For AD, early intervention may lead to remission, reduced disease severity and/or reduced risk of comorbidities. Some early intervention trials targeting the skin barrier to prevent the atopic march have found that proactive use of topical steroids in patients with AD reduced later incidence of food allergy or aeroallergen IgE sensitization ( 55 ). However, patients receiving topical treatment alone, especially those with severe AD, report low effectiveness and overall satisfaction ( 58 , 59 ). In a multinational study, 27.6% of adult patients and 12.9% of adolescents reported inadequately controlled disease ( 60 ). Systemic treatment options may be underused ( 61 ) and even patients on systemic corticosteroids and older nonsteroidal systemic immunosuppressants, such as cyclosporine, can experience treatment failure ( 62 ). Newer systemic agents may be better suited to influence AD disease course and reduce the development of comorbidities and CLCI. For example, one cohort study of paediatric patients with AD found that treatment with dupilumab, a human monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signalling, resulted in a significantly lower incidence of asthma and allergic rhinitis after 3 years than treatment with conventional systemic therapies. The greatest reductions occurred in the youngest age group ( 63 ). Similarly, a cohort study in adults found that dupilumab treatment was associated with statistically significant improvements on all patient-reported outcomes, including disease control, flares, skin symptoms and treatment satisfaction ( 64 ). Importantly, patients also reported improved sleep and health-related quality of life and reduced work and activity impairment, suggesting the positive impact of treatment on multiple aspects of life.

The concept of CLCI is particularly relevant to patients with AD, who are often diagnosed in infancy or childhood and have symptoms and comorbidities that affect overall health, growth and development. Routine assessment of CLCI would help to identify opportunities when intervention could minimize or prevent impairment. Development of a validated CLCI measure for paediatric and adult patients, and collaboration between dermatologists, paediatricians, primary care providers, patients and advocacy groups is needed to improve awareness of CLCI, lessen the overall negative impacts of AD and increase the quality of life and well-being of patients and the people important to them.