Why can’t you just tell yourself to stop scratching? Very simple: you never told yourself to start. Your conscious willpower self isn’t running the show.
Published On: Apr 4, 2022
Last Updated On: Apr 5, 2022
Atopic dermatitis (AD) is a chronic disease which can have periods where symptoms are milder and periods where symptoms increase in intensity. This periodic and often unpredictable worsening of symptoms that then resolve is called an acute episode and can be referred to by patients or healthcare providers as a “flare.” Despite the common use of this term, there is currently no standardized definition of an AD flare. The meaning of flare as defined by patients and healthcare providers, and even from patient to patient and healthcare provider to healthcare provider, can be very different. While there are a few proposed definitions of an AD flare in the medical literature, studies are still needed to understand the biology underlying these acute episodes and what clinical and patient-reported changes characterize flare onset, duration, healing, and resolution (or a return to “normal state”). This disease resolution or “normal state” might not be complete control of symptoms, since barrier abnormalities and inflammation will likely remain, but may feel more manageable to a patient. Understanding this key concept in disease management is critical, as the goal of many current clinical trials for new AD therapies is to reach long-term symptom control with reduced frequency and intensity of acute episodes. Further, a key question for many patients considering different therapies is the effect on disease flares.
Dr. David Margolis, PhD, of the University of Pennsylvania, has extensively studied the epidemiology of AD including what acute AD phases mean. He said, “AD is always a waxing and waning disease. Sometimes the disease gets worse and we need to help a patient get better again. People should be treated to the degree that they’re comfortable. People know themselves and what feels comfortable.” He believes that looking at the long-term course of disease is the way to approach making sure that patients are well controlled, but that there have been several practical and methodological challenges to studying both chronic AD and acute episodes that have limited really understanding the long-term course of AD.1
The most common definition of flare (or acute phase) in the scientific literature is “disease worsening, requiring escalation/intensification of treatment.”2 However, many AD patients are used to living daily with the phases of their AD and do not necessarily seek medical attention during acute episodes, while others have flares so intense that they must seek emergency medical treatment.3 To address this gap in understanding, NEA has recently been awarded a competitive grant from Pfizer to explore what flares mean from the patient perspective. Deepening knowledge of AD flares could help improve their management and provide a framework for patients and healthcare providers to align on this key treatment outcome during ongoing care decision-making conversations.
The work of NEA and others interested in AD flares builds on the efforts of others over the past several decades. In 1977, Mark V. Dahl defined the concept of “flare factors,” which meant “a biologic or environmental factor which induces exacerbation of atopic dermatitis.”4 Dahl defined flare factors broadly as dry skin, sweating, scratchy clothes, allergy, infection, scratching, allergic contact dermatitis, anxiety and co-existing disease. Research since then has confirmed many of these flare factors, or disease and itch “triggers” that can lead to seasonal, episodic, or continuous acute AD episodes.5 Importantly, this early work also put forth the concept that there would not be one treatment regimen of topical or systemic AD treatment ideal for all AD patients, or even for one AD patient over time. He also thought that paying attention to flare factors and acute symptoms could help guide treatment planning.4
In 2006, Langan et al reviewed the available literature to make recommendations for a standardized definition of AD flares in clinical research.6 From 16 papers the themes that emerged were symptoms, severity, duration, treatment, changes in severity scores and behavioral definitions. They concluded that the concept of an AD flare was complex yet proposed to define a flare as “an episode requiring escalation of treatment or seeking additional medical advice.”6 The authors also looked at other recurring, chronic diseases like asthma and proposed using “totally controlled weeks” and “well-controlled weeks” as terms to monitor the long-term course of the disease.
In 2014, Langan et al returned to defining flare in relationship to evaluating treatment success, noting that flares had still not been well described in the scientific literature.7 With now 26 papers referring to or describing an AD flare they found 22 different flare definitions, and importantly, only four studies had used a patient-reported flare definition. This large number of definitions made it difficult to compare findings across studies and the author team urged more research to make a standardized, measurable definition. A year later the same group published a definition of flares as “treatment escalation.”8 They also worked to define long-term AD control and validated the concept of using the term “well controlled weeks,” similar to the scale used in asthma but not yet defined for AD at the time.9 One of the most recently proposed definitions of flare is “acute, clinically significant worsening of signs and symptoms of AD requiring therapeutic intervention.”10
The Harmonising Outcome Measures for Eczema (HOME) group has also been involved in this area of research. The overall goal of this multi-stakeholder group is focused on defining and standardizing outcomes measures to allow comparisons of clinical trials.11-16 One of the HOME working groups has focused on developing consensus and methodology to measure long-term AD control.12,17 Professor Hywel Williams, MSc, PhD, FRCP, of the University of Nottingham in the UK and previous Chair of the HOME initiatives shared his perspective, “The concept of a flare is a change in state from ‘normal,’ living comfortably with the disease, to something that really begins to interfere with daily activities and quality of life. It cannot be defined in absolute terms. Flare is a dynamic concept of change of state, so in that sense it can only be defined by the patient. The other point to remember is that for some people with severe eczema, their eczema is there all the time and may or may not worsen or improve. Even with mild eczema, the condition may be fairly continuous with little fluctuation – so the concept of flare is less useful. Flares in mild disease may be very infrequent (once a year), which makes studies in the community that attempt to find treatments to prevent flares challenging.” The HOME effort has recommended different tools and instruments to quantify AD signs and symptoms (EASI [Eczema Area and Severity Index] and POEM [Patient-Oriented Eczema Measure]).18 The HOME effort also has tested two instruments to measure long-term control (RECAP – a seven item questionnaire to capture eczema control via self or caregiver report) and ADCT (Atopic dermatitis control tool).19-21
Despite these important efforts, there is no patient-informed consensus on what a flare means from the patient perspective and which aspects of AD worsening are most important. This is the aim of the grant NEA received from Pfizer to ask these very questions. NEA’s study will engage a diverse group of adult patients to help identify what constitutes a ‘flare’ from the patient perspective including identifying domains/characteristics such as disease signs and symptoms, amount of disease increase, treatment and/or behavioral alterations, and duration of these characteristics relative to their ‘normal’ daily AD status. NEA plans to develop a consensus-based, patient-centered conceptual understanding an AD flare that can enhance understanding of treatment effectiveness and help with long-term disease control.
Dr. Aaron Drucker of Women’s College in Toronto and part of the research team for the NEA grant said, “The funded NEA study will take an agnostic approach. We are not satisfied with what’s out there in the literature to date. It could be that everything published is right on, but we just don’t know. Do patients find the word flare helpful or not? How many flares did they have over time? Is it meaningful to them? We still need ways to approach good eczema management.”
Wendy Smith Begolka, NEA’s Senior Vice President for Scientific and Clinical Affairs, and the principal investigator for the grant shared that, “NEA’s research will help identify how unified or diverse the patient perspective is related to their description and ‘definition’ of AD flares. The outcome of this research will be an important step toward helping patients, healthcare providers, and researchers align on how patients perceive this key aspect of disease management, and hopefully provide new ways to talk about and align on care approaches and needs.” Dr. Drucker follows this up by saying, “Assessing treatment function means assessing whether a patient is happy. Some patients may have one acute episode per month but it impacts their life so much that they are not happy with it while others may have learned to live with four flares a month and just gotten used to it. We may assess that neither of these patients is well controlled, but it is hard to know what each patient considers ‘controlled.’ Getting patients controlled and happy is the most important.”
There is some general guidance from the scientific literature for patients to both proactively work on the factors that may lead to a flare and manage worsening symptoms on their own such as using moisturizers and emollients, avoiding irritants and employing specific bathing rituals.22 The goal of these strategies is to reduce the number and intensity of flares. As AD can vary between individuals, the approaches that work best may vary. At first sign of an acute episode patients may switch to a more clinical approach to aggressively manage even the initial symptoms. A shared understanding between a patient and a healthcare provider of what constitutes a flare is an important step toward developing and revising this management framework as needed.
Dr. Drucker said, “If someone’s eczema is worsening then that’s something every person with eczema should have a plan for. It could be to use a certain cream or ointment and to contact their doctor to get advice on what to do next based on their care plan. If an acute episode management plan is not in place, patients should raise that at one of their visits to a healthcare provider. Whether an acute phase can be anticipated is an interesting concept. Is there a trigger that can be avoided? Is there a proactive treatment approach that could stop an acute phase before it starts? As a physician we think about increasing topical therapies and if those aren’t working, we will start something systemic, but those cannot be as quickly or easily changed as topicals. We are constantly thinking about body surface area when deciding between topical and systemic treatments.”
Dr. Margolis said, “Some of the new therapeutics may increase the time between one worsening symptom phase and the next, but they can be difficult to stop and start depending on what is going on with the patient. Topicals are all about cyclical treatment. Systemic therapeutics such as a biologic can’t really be easily stopped and started. A physician has to take into account how long treatments take to work in the first place. If patients have their own solutions they should be encouraged to use them as well. For example, if symptoms get worse in winter or when a patient sweats or when there is a lot of stress, patients should be encouraged to manage that with both medical approaches and their own management systems.”
Tracking eczema signs and symptoms can be very helpful and, according to Dr. Williams, “tracking may provide insights that are hidden from normal recall and reveal patterns that are helpful to see.” NEA has developed EczemaWise specifically for this purpose. This may help patients self-manage flares better and also talk to healthcare providers about long-term control of the disease. Dr. Margolis also weighed in on this and said, “While I wish patients would contact me earlier when their symptoms worsen, so far I have no proof that contacting me earlier might work. I do know that the sooner a patient can stop itching and not break down skin further the better.” Right now, tracking tools are in the early stages of being piloted and validated, but Dr. Margolis believed it “would be nice to have that kind of info when a patient comes to see you as opposed to them trying to remember what happened to them two or three months ago. Sometimes it’s nice to know what’s really been going on the last few months.”
Looking to the future, technology is being created that may help make defining flares less subjective and more quantifiable. Scientists have been working to identify skin changes that indicate symptoms are worsening or help patients and physicians understand faster whether a treatment plan is working. For example, a wireless sensor that can fit on skin has recently been tested to objectively monitor itch in 11 pediatric patients with moderate to severe atopic dermatitis.23 Dr. Shuai (Steve) Xu, Msc of Northwestern University, and lead author of the study said, “I think digital technologies are going to be able to do so much for our patients with atopic dermatitis. Right now, everything we have to evaluate flares only gives us data after the flare symptoms are already well underway. Skin being in a full-on flare means we lost the chance to intervene earlier. New advanced wearables and non-contact sensors in development may change this completely.”
Work has been ongoing for decades to try to define flare for the purpose of comparing clinical trials and for the purpose of determining how well a treatment is working, but patients themselves have not been widely involved in these efforts to provide their opinions and input. NEA has an exciting opportunity to develop a patient-defined consensus understanding of an AD flare to help facilitate shared decision making and long-term control of AD.
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