Patient and physician perspectives on alopecia areata: A real‐world assessment of severity and burden in Japan

Abstract The criteria used by physicians to assess alopecia areata severity and its associated burden from the patients' point of view are not well understood. We aimed to understand physician‐assessed determinants of disease severity, factors associated with severity, patient–physician concordance, and patient‐reported burden by severity. Data were drawn from the Adelphi Alopecia Areata Disease Specific Programme™, a point‐in‐time survey of dermatologists and their alopecia areata patients in real‐world practice in Japan conducted between January and March 2021. Patients were categorized into three groups by current disease severity according to physician subjective assessment: mild, moderate, or severe. Demographics, clinical characteristics, and outcomes were described within and compared between the three patient groups. Our study of 97 dermatologists and 587 patients found overall scalp hair loss was the most important factor considered by physicians in determining disease severity. More severe disease was associated with loss of eyebrow hair, eyelashes, and hair loss from other body areas. Agreement on disease severity between physicians and patients was moderate. From the patient perspective, greater severity of alopecia areata was associated with greater anxiety and depression, with lower work productivity and worse quality of life. Our study provides insights into which factors physicians use to determine alopecia areata severity, how physician and patient severity assessments compare, and the burden of alopecia areata on patients.

587 patients found overall scalp hair loss was the most important factor considered by physicians in determining disease severity. More severe disease was associated with loss of eyebrow hair, eyelashes, and hair loss from other body areas. Agreement on disease severity between physicians and patients was moderate. From the patient perspective, greater severity of alopecia areata was associated with greater anxiety and depression, with lower work productivity and worse quality of life. Our study provides insights into which factors physicians use to determine alopecia areata severity, how physician and patient severity assessments compare, and the burden of alopecia areata on patients.

K E Y W O R D S
alopecia areata, dermatology, outcomes research, quality of life, severity of illness Alopecia areata is a multifactorial disease, thought to be caused by a combination of genetic and environmental factors. Some researchers have speculated there is a possible association between AA development and certain bacterial and viral infections, psychological stress, and even specific diets; [5][6][7][8][9] however, many of these studies had small sample sizes and produced mixed findings; therefore, further exploration of the etiology of AA is required. There have also been mixed results reported on the prevalence of AA in men and women, with some studies suggesting AA affects both to a similar extent 10 while others reported that women were more often affected than men. 11 The rapid rate of hair loss associated with AA means that patients are at risk of experiencing psychological and psychosocial symptoms, with many AA patients developing low self-esteem. 5 Previous research has shown that AA is also associated with anxiety and depression. 12,13 While AA is likely to have a negative effect on many patients' psychological well-being, there is some evidence that it may have a greater psychological impact on women, 14 leading many to have a more negative self-image, 15 possibly related to the idea of baldness in women being less acceptable in society than it is in men. 16 As a result, it is important for health-care professionals to be aware of the risk of anxiety and depression in AA 12 and that its effects on quality of life (QoL) may vary across patients.
Extensive AA poses a therapeutic challenge due to lack of efficacy and/or side-effects of available treatment options, with a lack of approved systemic therapeutics for the disease 17 and no treatments that induce and sustain remission of AA long term. 18 For adult patients with limited involvement, intralesional corticosteroids (including triamcinolone acetonide) are considered first-line therapy, and moderately potent topical steroids are also widely used. 19 In Japan, approved treatments include topical carpronium chloride hydrate, oral cepharanthine, and the oral combination monoammonium glycyrrhizinate, glycine, and DL-methionine. 20,21 The heterogenous nature of AA -with location, pattern and overall percentage hair loss and treatment outcomes often varying across patients -means that AA severity is not easily established.
We aimed, therefore, to investigate which features Japanese physicians consider important when determining whether a case of AA is mild, moderate, or severe, as well as to understand the patientreported burden of AA in each of these severity groups in real-world clinical practice in Japan. The survey captured data on patient demographics as well as current and historical disease severity, and burden and management in a real-world clinical setting. We used a combination of physicianand patient-reported questionnaires to understand how the disease presented at different degrees of severity and how this impacted QoL from the patient's perspective.

| Participants
The dermatologists recruited to participate in this survey reflected a geographically representative sample of the practicing population in Japan. To participate, physicians had to have Japanese Dermatological Association senmon-i certification (demonstrating that the physician is a specialist) and be personally responsible for treatment decisions and the management of patients with AA and consult with a minimum of three adult AA patients monthly, with at least one being currently moderate and one currently severe. We captured physician-recorded data on patient demographics and clinical characteristics including AA severity, location, time of onset, and symptoms. AA severity was rated by the physician as either mild, moderate, or severe according to their own definition of these terms based on their clinical experience together with observations, assessments, and medical history of the patient, thus reflecting how physicians classify AA severity in a real-world clinical setting. We also asked physicians to record the symptom/area affected for each patient and to define the severity of that symptom. Recruited patients were invited to complete a voluntary patient self-completion form (PSC) at the time of their consultation, independently of the dermatologist. Patients reported their current AA severity based on their own subjective perception of their disease; patient answers could then be matched with corresponding physician-rated severity to evaluate whether patients and their dermatologists were in alignment on their perception of disease severity. In addition, patients were asked about the impact that AA had on their day-to-day activities, work productivity, and emotional and psychological state.
To assess the impact of AA on QoL, the PSC included diseasespecific and general patient-reported outcome (PRO) tools. The disease-specific PRO tool used was Skindex-16 AA, which measured the psychosocial and physical effects of AA. Skindex-16 is formed of three scales covering patient symptoms (four items), emotions (seven items), and functioning (five items), 22 and patients can select one of seven answers that lie on a Likert-type scale ranging from "never bothered" to "always bothered", with scores varying from 0 (no effect) to 100 (effect experienced all the time). The Hospital Anxiety and Depression Scale (HADS) measures symptoms of generalized anxiety (seven items) and depression (seven items), 23 with each item being scored 0 to 3, with higher scores indicating greater impact. The EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) measures general health status and comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 24 The Work Productivity and Activity Index (WPAI) measures the effect of AA on work productivity during the past 7 days. It comprises questions relating to employment status, hours of work missed, hours actually worked, and productivity while working. WPAI scores range from 0 to 100, with higher scores signifying greater impact of AA on work productivity. 25 Missing data were not imputed; therefore, the base of patients varies and is thus reported separately for each analysis.

| Data analysis
Demographics, clinical/disease characteristics, and PRO were described within and compared between three groups of patients, defined by the overall physician-rated current AA severity (mild, moderate, severe) of each patient. Statistical tests were conducted to determine whether differences were observed in clinical and demographic characteristics and PRO across current severity groups, where p < 0.05 was considered significant. p-values were not multiplicity controlled. Statistical tests used were analysis of variance for numeric variables, and χ 2 -tests for categorical variables, and Kruskal-Wallis for ordinal variables. Kappa analysis was used to  All responses captured on the data collection forms were anonymized to preserve physician and patient confidentiality, and as such no personal identifiable information was requested or collected. All participating physicians and patients were assigned a study number to aid anonymous data collection, and to allow linkage of data during data collection and analysis. Using a check box, patients provided informed consent for use of their anonymized and aggregated data for research and publication in scientific journals.  Current disease progression differed significantly between severity groups, with physicians reporting a higher percentage of mild patients' AA improving compared with moderate and severe patients.

| Patient demographics/clinical characteristics
In addition, a higher proportion of patients with severe AA had uncontrolled disease (defined as changeable or worsening either slowly or rapidly; p < 0.0001; Table 1). Figure 1 shows the specific type of AA by current severity. We found that current mild disease was associated with AA monolocularis and AA multilocularis in 63% and 29% of patients, respectively.
Current moderate disease was most commonly associated with AA multilocularis (in 60% of patients), followed by AA diffuse and AA monolocularis in 23% and 12% of moderate patients, respectively.
Only 1% of moderate patients were labeled as having either AA totalis or AA universalis. Of all AA types, current severe disease was most commonly associated with diffuse (34%), totalis (22%), multilocularis (22%), and universalis (17%), with the majority of patients labeled as AA totalis or universalis being those with severe disease.
In the physician survey, 85% of dermatologists indicated that the most important factor in determining AA severity was the amount of scalp hair loss observed, and 10% reported that patient distress over hair loss was most important.

F I G U R E 1 Physician-reported alopecia areata (AA) type by current severity of patient (physician-rated)
When surveyed about the percentage of scalp hair loss that would lead them to a diagnosis of mild, moderate, or severe AA, physicians reported a mean percentage (SD) scalp hair loss of 6.9% (4.  Figure 2).
When asked to rate the severity of hair loss in each location, physicians reported that for the majority of body areas patient severity was generally aligned with the degree of hair loss in each area affected; that is, hair loss on the scalp, eyebrows, eyelashes, and body was mild in mild patients, while a greater degree of hair loss was observed in these locations in more severe patients. Regarding eyelash loss, whilst only one mild patient was reported to be experiencing this, the hair loss for this patient was classed as severe ( Figure 3).

| DISCUSS ION
Owing to limited Japan-specific information on the prevalence and burden of AA by severity, this paper fills an important gap in knowledge. We found that patients with more severe AA experienced worse  32 as well as an important driver of therapy selection. 33 We also found a greater degree of body, eyelash, and eyebrow hair loss in severe AA patients compared with moderate and mild patients.
We observed a moderate level of physician-patient alignment on disease severity; this was likely due to AA being a very visible disease, often affecting the patient's head and face, and thus allowing physicians to make a quick and accurate assessment of the locations affected and the extent of hair loss during the consultation. A previous study by Reid et al. reported lower levels of patient-physician alignment than found in our study, with some patients reporting the extent of their hair loss as more severe than that which was reported by the physician. 34 Reid et al. also found that patient-reported QoL corresponded more closely with the patient's own perception of hair loss rather than that of their physician. They suggested that the difference in physician and patient perception might be due to the negative impact the hair loss had on patients' self-image causing them to have a distorted view of how bad the hair loss was. 34 This study differed from ours in that it included only female patients. While there is evidence to suggest that women in particular experience negative psychosocial effects from hair loss, 16 it is unlikely that the mismatch between extent of hair loss and patient burden is exclusive to women; for example, a study on both male and female patients in Japan also reported that objective severity did not necessarily correlate with the effect of the disease on patient QoL. 30 Thus, it may not be sufficient to consider the psychosocial impact on the patient solely in terms of the degree of hair loss. When treating these patients, it is therefore important for physicians to be aware of the psychosocial impact associated with AA as low self-esteem and depression may negatively influence the patients' own perception of their disease. In cases of disconnect between patients and physicians, improved communication will be key as there is evidence that good patient experience can lead to better engagement with treatment 35 and promote adherence to prescribed therapies. 36 We reported that fewer patients with severe AA were improving compared with those who have mild and moderate AA and a higher percentage of patients with severe AA were uncontrolled, with changeable or worsening disease. These findings were similar to a previous study that reported unstable disease course as being associated with more severe disease. 31

ACK N OWLED G M ENTS
The authors would like to thank Victoria Davis for medical writing support and Sophie Barlow for performing all statistical analyses; both are employees of Adelphi Real World and have no conflicts of interest to report. This study was funded by Eli Lilly & Company.