Adult patients with alopecia areata report a significantly better medication adherence compared to those with atopic dermatitis: Results from a large cross-sectional cohort study

Background Alopecia areata (AA) and atopic dermatitis (AD) are chronic skin diseases where the suboptimal medication adherence (MA) may result in poor clinical outcomes. Objective To assess the impact of AA on MA among adults compared to AD. Methods Patient reported MA of adults with AA were compared with AD. Patients were identified from the Danish Skin Cohort, a nationwide prospective cohort of dermatological patients in Denmark. We used the Medication Adherence Report Scale- 5, a self-reporting questionnaire, to assess MA. Demographic and disease characteristics were collected. Logistic regression was conducted. Results Patients with AA reported higher MA than AD (mean 21.81 vs 18.29). Logistic regression analyses showed AA diagnosis had a statistically significant positive effect on MA (odds ratio = 3.94, 95% CI 2.01-8.89). Men reported significantly higher MA (odds ratio = 1.49, 95% CI 1.14-1.94). Current disease severity did not impact MA. Limitations Data were self-reported by patients. Data regarding the specific treatment undergone by patients were not available. Conclusion Patients with AA have significantly higher MA compared to patients with AD. The stability of AA patients’ symptoms may lead to higher MA due to a desire for disease control. Conversely, the sporadicity of AD symptoms could negatively affect adherence, causing fluctuations in medication use.


INTRODUCTION
Chronic skin disorders are among leading causes of nonfatal disease burden worldwide, 1 and account for a significant proportion of total healthcare utilization.The optimal therapeutic management of chronic skin disorders depends critically on medication adherence (MA).Poor MA among chronic diseases is a complex and critical challenge in today's health care system.While poor MA poses a significant financial burden, it may furthermore have consequences on the care management of patients, with unnecessary switch of treatments and dose escalations. 2he main factors impacting MA among patients with dermatological disorders include lack of patient training about the disease or the treatment, lack of belief in the treatment, poor prior experience, side effects or fear of it, and cost of medication among others. 3n managing patient care, it is important to understand how different chronic skin conditions affect MA.Alopecia areata (AA) and atopic dermatitis (AD) are common immune-mediated skin diseases which affect nearly 2% and 10% of the general population at some point in their lifetime, respectively. 4,55][6] Both diseases are associated with a profound negative impact on quality of life, [7][8][9][10][11] and a successful treatment management of AA and AD has been shown to significantly improve quality of life. 12,13To achieve optimal outcomes for patients, a better understanding of how factors such as disease burden and patient characteristics in specific patient populations can impact the individual patients' MA is warranted.
The aim of the current study was to assess the impact of adult AA vs AD on MA.Also, we aimed to identify demographic and disease characteristics that may play a role in MA among adults with AA.

MATERIALS AND METHODS
All study participants provided a written informed consent before participating.The study was registered according to the Danish Data-protection Agency (Videncenter for Dataanmeldelser, ref.P-2021-386).
This constitutes the necessary legal requirements, and ethical approval is not required for this type of study in Denmark.

Data sources and study population
The Danish Skin Cohort served as the data source for the 2 patient cohorts included in this study.The data collection method and the initial characterization of the patient populations are previously described in detail. 14Briefly, the Danish Skin Cohort was established in 2018 as a prospective inception cohort of dermatological patients in Denmark and follow-up data were collected and added in 2020, 2022, and at least once a year hereafter. 14atients with at least 1 diagnostic code for AA verified by a dermatologist after their 18th birthday were identified as the primary study population.Patients with AD (at least 1 dermatologist-verified diagnostic code for AD after their 18th birthday) served as the control group, as both patient groups suffer from chronic skin diseases and were most comparable in terms of patient characteristics.All identified patients received an invitation by secure electronic governmental mail and answered the survey electronically.Study data were collected and managed using REDCap (Research Electronic Data Capture) 15,16 a secure, web-based software platform designed to support data capture for research studies.

Outcome measure
As the primary outcome measure, we used the Medication Adherence Report Scale (MARS-5), a validated measure for MA. 17 Here the patients were asked how often they do 5 different behaviors toward their treatment utilization, for example, ''I take less than instructed'' and have the answers: ''Very often,'' ''Often,'' ''Sometimes,'' ''Rarely,'' and ''Never''.The answers ''Rarely'' and ''Never'' were seen as high adherence.

Covariates
We collected information regarding participants' age, gender, height, weight, ethnicity, Fitzpatrick skin type, 18 and natural hair color.Additionally, we asked participants to answer questions regarding levels of physical activity and a rating of general health on a scale from 0 to 100, where 0 is worst CAPSULE SUMMARY d Medical adherence is vital to disease management of skin disorders.We provide insight by observing 2 common dermatological diseases and their associations with medical adherence.
The results indicate the different nature of alopecia areata and atopic dermatitis, and a need for unique approaches when tackling treatment management for each diseases.
possible health and 100 is best possible health.Furthermore, disease specific data regarding onset of disease, disease activity and severity, prescribed treatment and Dermatology Life Quality Index, 19 were collected.

Statistical analysis
The patient populations with AD and AA were characterized using descriptive statistics including mean, standard deviation, median, and interquartile ranges, according to data distribution.Frequencies were calculated for categorical variables including percentages of the primary endpoints.Odds ratios (ORs) for the primary outcome were estimated using logistic regression models.The selected covariates in the adjusted models were gender, age and disease severity.Disease severity was defined as current severity rated on a numeric rating scale from 0 to 10 where 10 was ''worst possible AA.''Predictors for MA were further estimated in multiple regression models.Statistical analyses were conducted using RProject software, version 4. The overall baseline characteristics of groups are presented in Table I.At time of the present survey, patients with AD were younger than those with AA, (mean 47.0 vs 54.6 years old).In general, [70% of the patients, in either group, were females.Both groups reported similar levels of physical activity (Table I).
Table II provides an overview of patients reported disease characteristics.Additionally, a total of 766 patients (N = 125 with AA, N = 641 with AD) who did not actively confirm their skin disease diagnosis were included in the analysis.
As expected, most adults with AD had an onset of their disease at a younger age (84.4% with an onset \18 years old) with a median (interquartile range) age of 46 (37-56) years, compared to adults with AA (83.6% reported an onset [18 years old) with a median (interquartile range) age of 55 (46-65) years.Therefore, patients with AD reported longer disease duration.A higher percentage of patients with AD reported receiving current treatment (62.5%) or previously received treatment   [4.6]).The comparison analysis between AA and AD showed a statistically significant difference and a higher level of MA among adults with AA.The adjusted OR showed almost 4 times higher MA among adults with AA compared to those with AD (OR = 3.94, 95% CI 2.01-8.89,P \.001).Surprisingly men reported a significantly higher MA than women (OR = 1.49, 95% CI 1.14-1.94,P \ .005).Also, unexpectedly, disease severity did not impact the MA (P = .63).
The analysis was also done for only patients with AA and AD currently receiving treatment and the results were similar regarding MARS-5 (data not shown).

DISCUSSION
The aim of this study was to investigate the impact of AA on MA of adults in comparison to MA of patients with AD.Indeed, this study supports the notion that different skin diseases have a different impact on MA of patients, as previously described by Feldman et al in patients with AD compared to those with psoriasis or hand dermatitis (reference).Additionally, the study results indicate that patients with AA have a significantly higher MA than patients with AD, regardless of disease severity.
Previous studies have compared the burden of illness and the prescription usage of patients with AA and those with AD, 20 yet no study has investigated the impact of AA vs AD on the MA in adults. 21nterestingly, patients with AA showed a tendency of better adherence to prescribed therapies than patients with AD, despite the lack of effective treatments for AA until very recently.This finding possibly reflects the significant burden of disease and high desire to achieve improvement in symptoms among patients with AA.It is well established that AA may significantly affect patients' selfesteem and quality of life and the unpredictable disease course and fear of relapse may lead to a stronger motivation to follow therapies as prescribed.On the other hand, patients with AD may experience frequent fluctuations in their symptoms, leading to periods with alternating good and bad adherence.
To our surprise, women were found to have a significantly lower MA than men.While studies assessing the impact of sex on MA among dermatological disorders are scarce, aligned with our empirical expectation, female patients with dermatitis herpetiformis had a better MA to a gluten-free diet compared to men. 22There could be several potential root causes for this finding, as demonstrated by studies in other therapeutic areas and regions reporting an association with gender differences in MA.One study conducted in the US adult population showed a lower MA among women due to costs related to medical care. 23While Denmark offers a tax-supported national medical coverage which includes largely free primary and specialist care, a capped copayment for drugs filled at community pharmacies is applied, which may contribute to a lower MA among women aligned with findings in the above-mentioned report. 24It is conceivable that cost of copayment of medications might have influenced the MA leading to the observed gender differences, as previously shown in a Japanese study. 25Indeed, we found significant socioeconomic difference between male and female patients with AD (data not shown).However, we did not find significant differences in personal income between male and female patients with AA in our cohort, indicating that the difference is not explained by financial factors alone.Other factors that have been discussed in the literature are fear of transmission of medicines to the breast milk while women are pregnant or nursing. 26Again, we have not studied this factor as a potential bias in our population.Furthermore, it is unclear if social desirability bias could have influenced men to self-report a better MA pattern than women.Nevertheless, independent of the root causes, the results highlight a need for dermatologists to consider gender differences in MA in their efforts to enable patients to effectively adhere to their treatment.In disease management, understanding the nature of chronic skin diseases and their impact on MA is critical for patient care.While we have not studied how to overcome these differences, other studies have shown and recommended how to improve the MA in patients with AD 3,27,28 ; whereas such studies and recommendations are lacking in AA care management.It would be interesting to evaluate if there is an increased use of these tools to enhance adherence and outcome for patients with AA in general compared to patients with AD.In this context, prior studies suggested the development of clearly written treatment plans to help simplify the treatment regiments for the patients with AD will increase the MA. 3 Additional tactics included reducing the time intervals between the follow-up visits by increasing patients and health care provider remote/virtual contacts 21,29 as well as increasing the level of patient's understanding of their condition, by strengthening patient education. 3Others have demonstrated an increased MA by using digital interventions including using mobile app, treatment reminders, and lifestyle coaching. 30hile, in the current study, we tried to limit biases through adjustment for some baseline characteristics, factors including use of tactics to enhance MA, as mentioned above, and differences in socioeconomic status and social support that could impact MA, were not adjusted for.Therefore, further studies controlling for these factors/biases are necessary to fully understand and verify the true MA differences between these 2 patient groups.The ultimate assessment would be in the form of a longitudinal prospective study to determine whether the MA of patients with AA and AD increase or decrease as disease management continues over time.

CONCLUSION
In this cross-sectional survey, we observed that patients with AA have a higher MA than patients with AD, possibly reflecting an unrecognized burden of disease or unmet medical needs in patients with AA.Individual patient characteristics should be incorporated in clinical decision making and assessment of therapeutic goals.

Conflicts of interest
1.2 (R Foundation for Statistical Computing) with packages ''Tableone.''RESULTS In total, 3331 adult patients ($18 years) with confirmed skin diagnosis were identified from Danish Skin Cohort with either a diagnosis of AA (N = 459) or AD (N = 2872).The patient selection process is visualized in the flowchart in Fig 1.

Fig 1 .
Fig 1. Flowchart for the patient selection process.