Understanding the Challenges of Atopic Dermatitis: The Urgent Need for Improved Clinical Trials

Atopic dermatitis (AD) is more than just a skin condition. This chronic, inflammatory disease is fundamentally rooted in the immune system [1], manifesting itself through an array of physical symptoms including persistent itching, redness, and skin lesions. Yet, its impact extends far beyond these visible signs. From sleep disturbances to psychological distress, AD can drastically impair a patient's quality of life [2].

The prevalence of AD has steadily risen over the years, making it a pressing public health issue. In the United States alone, an estimated 16.5 million adults are affected by AD, with around one in four being classified as moderate-to-severe cases [3]. Globally, the prevalence is estimated to be around 230 million, making it one of the most common skin conditions worldwide [4].

Despite its prevalence and debilitating impact, there remains a significant unmet need for effective treatments. The pathophysiology of AD is complex, and the disease itself is known for its diverse clinical presentation and variable response to treatments, thereby making it challenging to manage [1].

These challenges underscore the necessity to conduct robust clinical trials to uncover new, more effective treatments for AD. The financial burden on healthcare systems and society as a whole is substantial. In the US, the annual cost related to AD was estimated to be 5.3 billion dollars in 2015 [5]. This cost, coupled with the personal and societal burdens of living with AD, underscores the urgency for continued research and therapeutic development.

Additionally, AD is not a stand-alone disease but is often accompanied by other comorbidities, including asthma, hay fever, food allergies, obesity, and cardiovascular disease [6]. This complexity further magnifies the urgent need for continued research and more comprehensive clinical trials to address the multifaceted challenges that AD presents.

The psychosocial impact of atopic dermatitis should not be understated. The visibility of the condition, coupled with its persistent itch and the resulting sleep disturbance, can result in significant psychological stress and stigma. Studies have shown that people living with AD often report feelings of embarrassment, frustration, and even depression. The psychosocial distress may also extend to family members, particularly parents of children with the condition [7].

Moreover, the perceived severity of AD can significantly vary depending on the location of the lesions. For example, lesions on the face or hands, which are often visible to others, can lead to greater psychological distress compared to lesions hidden under clothing. This heightened distress can, in turn, exacerbate the physical symptoms, creating a vicious cycle of inflammation and stress [8].

Therefore, addressing both the physical and psychological components of the disease is critical in managing AD and improving the patients' quality of life. As we proceed, this article will explore the mechanisms employed in clinical trials to measure the effectiveness of potential treatments for AD.

Understanding Clinical Scales and Measures in Atopic Dermatitis Research

As we delve into the realm of clinical research for atopic dermatitis, it is crucial to comprehend the diverse array of tools that researchers employ to measure the efficacy of potential treatments. Here we describe 20 such clinical scales and measures, each playing a unique role in evaluating different facets of the disease - from physical symptoms to quality of life impacts.

1. Eczema Area and Severity Index (EASI): EASI provides a quantitative measure of the extent and severity of atopic dermatitis by focusing on the physical manifestations of the condition across different regions of the body.

2. SCORAD Index (SCORing Atopic Dermatitis): This comprehensive tool enables clinicians to assess the extent and severity of atopic dermatitis by considering the affected body area, intensity of symptoms, and subjective symptoms such as itching and sleep loss.

3. Investigator's Global Assessment (IGA): This tool provides an overall assessment of the disease severity, considering the size, redness, swelling, and other clinical manifestations of the disease.

4. Pruritus Numeric Rating Scale (NRS) and Visual Analogue Scale (VAS) for pruritus: Both scales provide a simple and efficient means of quantifying itch intensity, one of the most bothersome symptoms of atopic dermatitis.

5. Self-Assessed Eczema Area and Severity Index (SA-EASI): A patient-reported version of the EASI, allowing for self-assessment of disease severity and extent.

6. Atopic Dermatitis Severity Index (ADSI): ADSI is another clinical scale to quantify disease severity, focusing on five clinical signs: erythema, excoriation, oozing/crusting, edema/papulation, and lichenification.

7. Body Surface Area (BSA): This tool measures the percentage of the patient's body that is affected by atopic dermatitis, aiding in determining the extent of the disease.

8. Atopic Dermatitis Control Tool (ADCT): A patient-friendly tool that allows individuals to self-assess their disease control over the past week.

9. Atopic Dermatitis Quickscore (ADQ): This tool gauges disease severity over the previous week, providing a quick snapshot of the patient's current condition.

10. Skin Pain Numeric Rating Scale (NRS): This scale allows for the quantitative assessment of the level of skin pain experienced by the patient, another common symptom of atopic dermatitis.

11. Patient-Oriented Eczema Measure (POEM): A patient-centric tool that measures the impact of the disease on patients' lives, considering factors like itch, sleep disturbance, and impact on daily activities.

12. Dermatology Life Quality Index (DLQI) and Children's Dermatology Life Quality Index (CDLQI): These questionnaires measure the impact of skin disease on the quality of life of adults and children, respectively.

13. Pediatric Eczema Elective Course (PEEC): This tool gauges the impact of pediatric atopic dermatitis on quality of life, with a particular focus on the domains most affected in children.

14. Pruritus/Itch Questionnaire: This tool helps clinicians understand and quantify the presence and severity of itching, a key symptom of atopic dermatitis.

15. EuroQol-5 Dimension (EQ-5D): A standardized measure of health status, EQ-5D evaluates five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.

16. Hospital Anxiety and Depression Scale (HADS): This psychological tool measures the levels of anxiety and depression, addressing the significant psychological burden often associated with atopic dermatitis.

17. Treatment Satisfaction Questionnaire for Medication (TSQM): This questionnaire assesses patient satisfaction with their medication, an important factor in long-term treatment adherence and success.

18. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): While not specific to atopic dermatitis, this tool can assess cognitive function, which might be indirectly affected by chronic conditions like atopic dermatitis due to factors like chronic itch and sleep disturbance.

We will not cover all of these scales in the following chapters but specific highlight will be provided for the most commonly used as primary endpoints in the clinical trials assessing the efficacy of a new treatment.

The Eczema Area and Severity Index (EASI)

1) Advantages

The Eczema Area and Severity Index (EASI) is widely used in clinical trials for atopic dermatitis for several reasons:

  1. Detailed Assessment: EASI provides a thorough evaluation of the extent and severity of the disease by assessing four clinical signs (erythema, induration, excoriation, and lichenification) in four body regions (head/neck, trunk, upper limbs, and lower limbs). This detailed assessment allows a more granular understanding of the disease's presentation and progression [9].

  2. Sensitivity to Change: EASI is sensitive to changes over time, making it particularly useful in clinical trials to monitor disease progression and response to treatment [10].

  3. Scientific Rigor and Acceptance: The EASI has been extensively validated for its reliability and has become a standard measure for clinical research in atopic dermatitis. Regulatory authorities such as the FDA and EMA recognize the EASI as a key efficacy endpoint in clinical trials [11].

  4. Useful for Moderate to Severe Cases: The EASI is particularly beneficial in moderate to severe atopic dermatitis, where its sensitivity can fully come into play [12].

  5. Comparison Across Studies: Since EASI is so widely used, it allows for comparison across different studies and different patient populations [13].

EASI remains an essential tool in atopic dermatitis clinical trials due to these strengths. It provides a comprehensive and sensitive measure of disease severity and treatment response, making it an invaluable resource in the development and assessment of new therapies for atopic dermatitis.

2) Limitations

Like any assessment tool, the Eczema Area and Severity Index (EASI) has its strengths and limitations. Here are some commonly discussed critiques:

  1. Complexity: EASI is often considered more complicated than some of the other assessment tools because it requires an estimation of the percentage of involvement in four body regions and grading of four clinical signs. This can lead to inter-rater variability and might affect the accuracy and consistency of the scores [14].

  2. Subjectivity: Despite being more objective than some other measures, EASI still contains subjective elements such as the assessment of redness and thickness of the skin, which can vary between observers [15].

  3. Lack of Patient Input: EASI is an investigator-based scoring system that does not include patient-reported outcomes. As such, it does not capture how patients perceive their symptoms, which is a significant part of disease impact [16].

  4. Ignores Certain Body Areas: The EASI score neglects certain parts of the body such as the face and scalp, which are significant areas of involvement for some patients [17].

  5. No Assessment of Quality of Life: EASI focuses solely on the physical symptoms of atopic dermatitis and does not consider the impact of the condition on a patient's quality of life. Therefore, it might not fully capture the patient's overall disease burden [18].

SCORAD Index (SCORing Atopic Dermatitis)

1) Advantages

  1. Comprehensive Scoring: SCORAD provides a comprehensive evaluation of the severity and extent of atopic dermatitis, as it includes both objective measures (extent and intensity) and subjective symptoms (pruritus and sleep loss) [19].

  2. Broad Consideration of Symptoms: The SCORAD index considers a wide range of symptoms, including redness, swelling, oozing/crusting, scratch marks, skin thickening, dryness, and lichenification, which are typical manifestations of atopic dermatitis [20].

  3. Inclusion of Patient Symptoms: Unlike some other scales, SCORAD includes patient-reported symptoms such as itching and sleep loss, which are major factors impacting patients' quality of life [21].

  4. Consistent Use in Clinical Trials: The SCORAD index has been used in numerous clinical trials since its introduction, leading to a consistency that allows results to be compared across different studies [22].

  5. Validation: The SCORAD Index has been validated in various settings and populations, ensuring its reliability and consistency [23].

2) Limitations

The SCORAD (SCORing Atopic Dermatitis) Index, despite its wide use, also has certain limitations:

  1. Complexity: The SCORAD Index is fairly complex to implement, which may make it less practical in routine clinical settings [24].

  2. Subjectivity: While it incorporates subjective symptoms from patients, it also includes subjective elements in its objective part. The scoring of redness, swelling, oozing/crusting, scratch marks, skin thickening, and dryness may vary between observers [25].

  3. Time-Consuming: Due to the detailed evaluation it involves, using the SCORAD Index can be time-consuming, which can be a challenge in busy clinical settings [26].

  4. Non-Linear: The score is non-linear in the sense that a change from a high score to a medium score may not reflect the same change in severity as a shift from a medium to a low score [27].

  5. Learning Curve: Proper application of the SCORAD Index requires a learning curve, further limiting its routine use, especially among non-dermatologists [20].

The Investigator's Global Assessment (IGA)

It is a commonly used tool to evaluate the severity of atopic dermatitis in clinical trials.

1) Advantages:

1. Simplicity: The IGA is a simple and straightforward scale, usually consisting of a 5-point grading system. This makes it easy to use in clinical trials [28].

2. Common Use: It's often used as a primary endpoint in clinical trials for atopic dermatitis treatments, making it a standard tool for assessing the overall efficacy of a treatment [29].

3. Quick to Implement: Because of its simplicity, the IGA can be quickly implemented, making it practical in a busy clinical setting or in large-scale studies [30].

2) Limitations:

1. Subjectivity: It's a highly subjective scale, and the assessment can vary depending on the evaluator. This can lead to inconsistencies in the scoring [31].

2. Limited Details: The IGA provides a global assessment, and therefore, may not capture all aspects of the disease such as specific symptoms or the impact on quality of life [32].

3. Lack of Patient Input: The IGA is investigator-based and doesn't include patient-reported outcomes. This may result in an incomplete understanding of the disease impact as perceived by patients [33].

4. No Standardization: There is a lack of standardization in the IGA among different clinical trials or even between different sites in the same trial, making it challenging to compare outcomes across studies [34].

The Pruritus Numeric Rating Scale (NRS) or Visual Analogue Scale (VAS) for pruritus

Both are interchangeable and are widely used to evaluate itch intensity in clinical trials for atopic dermatitis.

1) Advantages:

1. Simplicity: Both scales are simple to use, requiring patients to indicate the intensity of their itch on a scale [35].

2. Patient-Reported Outcome: Both the NRS and VAS directly record patient's perception of itch, capturing an essential aspect of atopic dermatitis from the patient's perspective [36].

3. Validation: These scales have been validated for their reliability and sensitivity to change, making them appropriate for use in clinical trials [37].

4. Quick to Implement: Because of their simplicity, these scales can be quickly implemented, which is practical in a busy clinical setting or in large-scale studies.

2) Limitations:

1. Subjectivity: Both NRS and VAS rely on patient self-report, which can be influenced by factors other than pruritus intensity, such as mood, sleep quality, and other discomforts [38].

2. Variability in Perception: Perception of itch intensity can vary greatly between individuals and may be influenced by cultural, psychological, and individual factors [39].

3. Limited Dimension: These scales mainly evaluate the intensity of itch but may not fully capture other dimensions such as the frequency, duration, and distribution of pruritus [40].

3) Complementarity:

Eczema Area and Severity Index (EASI) and SCORing Atopic Dermatitis (SCORAD) are both clinical tools used to assess the extent and severity of atopic dermatitis, largely focusing on the observable and measurable aspects of the condition such as redness, inflammation, and surface area affected. These scales provide a clinician-based perspective on the physical state of the disease, factoring in both objective signs and subjective symptoms to varying degrees. SCORAD, in particular, includes an evaluation of itch and sleep loss, based on the patient's statements.

The Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS), on the other hand, specifically address the patient's subjective experience of pruritus or itch, which is a key symptom of atopic dermatitis and a significant factor affecting quality of life. These scales are patient-reported, providing a direct measure of the patient's perception of their itch intensity.

Therefore, EASI, SCORAD, VAS, and NRS can be seen as complementary tools. EASI and SCORAD provide a more holistic, clinical evaluation of disease severity, while VAS and NRS allow for a focused assessment of the patient's personal experience of itch. Together, they offer a comprehensive view of atopic dermatitis, combining the objectivity of clinical assessments with the subjective experience of the patient, which can provide a more complete understanding of the patient's condition and the impact of treatment interventions. Patient-reported outcomes are are often used as secondary endpoint because they lack standardization, however we believe that they should enter in a composite endpoint to measure the effectiveness of a treatment.

The Self-Assessed Eczema Area and Severity Index (SA-EASI)

This is a patient-reported version of the Eczema Area and Severity Index (EASI).

1) Advantages:

1. Patient-Centered: SA-EASI directly records patients' perception of their disease, capturing essential aspects of atopic dermatitis from the patient's perspective [9].

2. Flexibility: SA-EASI can be completed by the patient at home, allowing for more frequent assessments without the need for clinic visits [41].

3. Consistency with EASI: SA-EASI has been shown to correlate well with physician-assessed EASI scores, indicating its reliability as a self-assessment tool [14].

2) Limitations:

1. Subjectivity: Like all patient-reported outcomes, SA-EASI is subjective and can be influenced by factors other than disease severity, such as mood and perception [42].

2. Training Requirement: Accurate use of SA-EASI requires patient education and understanding of the scoring system [43].

3. Potential Misjudgment: Areas of the body that are difficult for the patient to see or evaluate, like the back, may be assessed inaccurately [44].

3) Comparing SA-EASI with physician-assessed EASI:

- Consistency: Studies show that SA-EASI scores align well with physician-assessed EASI scores, providing consistency between the two measures [45].

- Differences in Assessment: However, there can be discrepancies, as patients might judge severity differently from healthcare professionals. Patients may give more weight to symptoms such as pruritus, while physicians may focus more on visible signs such as redness or scaling [46].

The Patient-Oriented Eczema Measure (POEM)

It is a patient-reported measure of atopic dermatitis severity.

1) Advantages:

1. Patient-Centered: POEM prioritizes the patient's perspective, capturing the impact and severity of symptoms as experienced by the patient [24].

2. Comprehensive: POEM covers a wide range of symptoms including redness, itching, scratching, bleeding, weeping, cracking, flaking, and sleep disturbance, providing a comprehensive view of the disease's impact [47].

3. Validated and Reliable: The tool has been extensively validated and proven to be reliable and sensitive to change over time [27].

4. Ease of Use: POEM is simple and quick to use, making it convenient for both patients and researchers [48].

2) Limitations:

1. Subjectivity: Like all patient-reported outcomes, responses can be influenced by factors other than disease severity, such as mood, sleep quality, or other discomforts [14].

2. Lack of Clinical Signs: POEM does not account for clinical signs of disease that a patient may not notice, such as subclinical inflammation [49].

3. No Assessment of Body Surface Area Affected: Unlike EASI or SCORAD, POEM does not assess the proportion of the body surface area affected by atopic dermatitis.

The Dermatology Life Quality Index (DLQI)

It is a 10-item questionnaire developed to measure the impact of skin disease on the quality of life of an affected individual. It covers six domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Here are the questions asked [50]:

1. Over the last week, how itchy, sore, painful, or stinging has your skin been?
2. Over the last week, how embarrassed or self-conscious have you been because of your skin?
3. Over the last week, how much has your skin interfered with you going shopping or looking after your home or garden?
4. Over the last week, how much has your skin influenced the clothes you wear?
5. Over the last week, how much has your skin affected any social or leisure activities?
6. Over the last week, has your skin prevented you from working or studying?
7. Over the last week, how much has your skin created problems with your partner or any of your close friends or relatives?
8. Over the last week, how much has your skin caused any sexual difficulties?
9. Over the last week, how much of a problem has the treatment for your skin been, for example by making your home messy, or by taking up time?
10. Over the last week, how much has your skin been a problem in any way, like this?

While the EASI and SCORAD scales provide a comprehensive assessment of the physical severity and extent of atopic dermatitis, they don't fully capture the disease's impact on patients' daily life, psychosocial wellbeing, and quality of life. Here's where DLQI comes into play.

DLQI is designed to measure the impact of skin conditions on various aspects of life quality, from feelings about appearance to interference with daily activities, work, school, relationships, and treatment burden. By using DLQI in conjunction with EASI or SCORAD, researchers and clinicians can obtain a more holistic understanding of the disease impact and treatment effectiveness from both a clinical and a patient-centered perspective.

The Hospital Anxiety and Depression Scale (HADS)

This is a widely used self-report questionnaire designed to screen for the presence and severity of symptoms of anxiety and depression in medically ill patients. It consists of 14 items, 7 each for anxiety (HADS-A) and depression (HADS-D). Each item is scored from 0 to 3, resulting in a maximum score of 21 for each subscale, with higher scores indicating greater symptom severity [51].

HADS has been shown to be a valid and reliable tool for detecting states of anxiety and depression in various medical settings and differentiating them from general distress, and it has been widely translated and validated in many languages [52].

Now, why is HADS useful in clinical trials for atopic dermatitis?

Atopic dermatitis is a chronic, relapsing skin condition that can cause significant psychological distress due to its symptoms (itch, pain), impact on appearance, and the need for ongoing management. Studies have shown that patients with atopic dermatitis have higher rates of anxiety and depression compared to the general population [53].

Using HADS in clinical trials for atopic dermatitis can therefore help researchers to understand the psychological impact of the disease and treatment interventions. By incorporating HADS scores, researchers can gain insights into whether a treatment not only improves physical symptoms but also alleviates anxiety or depression associated with the disease. This is especially relevant given the growing recognition of the importance of a holistic approach to patient health, including mental and emotional wellbeing, in addition to physical health.

Conclusion

In conclusion, the evaluation of atopic dermatitis in clinical studies is a complex process that benefits from a multi-dimensional approach. Each of the scales we have explored - EASI, SCORAD, IGA, VAS and NRS for pruritus, SA-EASI, POEM, DLQI, and HADS - has its unique strengths and limitations, and no single instrument can capture all relevant aspects of this multifaceted disease.

Clinical scales like EASI, SCORAD, and IGA provide objective assessments of disease severity based on the extent, intensity, and characteristics of skin lesions. However, their main limitation resides in the fact they may miss subtler fluctuations in symptoms and fail to capture the patients' subjective experiences. Patient-reported outcomes such as the VAS, NRS, POEM, and SA-EASI offer a valuable counterpoint by focusing on the patients' personal perception of their symptoms and disease impact.

DLQI and HADS, on the other hand, address the wider psychosocial impact of atopic dermatitis, including the effects on quality of life and mental health. This is particularly crucial, given that atopic dermatitis is a chronic disease with a significant psychological burden.

The complementarity of these various tools underscores the necessity of a holistic approach to atopic dermatitis assessment in clinical studies. In this context, a tailored selection of instruments that best fit the trial design, objectives, and population can provide a comprehensive, nuanced picture of treatment efficacy. It is not merely about symptom reduction but also about improving patients' quality of life and psychological wellbeing.

As an actor of clinical trials and innovator in virtual/decentralised trials, Healint would advocate for continued efforts towards refining these tools and developing new ones that can even more accurately capture the complex reality of living with atopic dermatitis. Perhaps a future direction lies in integrating digital technologies to provide real-time monitoring of both subjective symptoms and objective signs, providing a truly comprehensive, dynamic perspective on disease activity and treatment response.

Remember, the ultimate goal of clinical trials and research in atopic dermatitis, or any disease for that matter, should not be restricted to merely treating a disease. It should extend to enhancing the overall wellbeing of the individuals living with the condition. Each of these scales and measures, despite their individual limitations, contributes to achieving that goal.

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