Health‐related quality of life in patients with alopecia areata: Results of a Japanese survey with norm‐based comparisons

Abstract Alopecia areata (AA) is a non‐scarring hair loss disorder affecting approximately 2% of the global population. AA is reported to have a significant negative impact on the emotional and psychological well‐being of the patients. This study aimed to evaluate the health‐related quality of life (HRQoL) of Japanese patients with AA in comparison to the Japanese population norms (national standard values for Japanese) using Short Form Health Survey 36 Item Version 2.0 (SF‐36v2). The study also aimed to access the negative effect of AA on patients’ daily lives and the proportion of patients having anxiety and/or depression. This cross‐sectional, non‐interventional web‐based survey study included 400 participants aged 17–84 years currently suffering from medically diagnosed AA. The assessment tools integrated in the online questionnaire included SF‐36v2, the Dermatology Life Quality Index (DLQI), and the Hospital Anxiety and Depression Scale (HADS). All outcome measures from the tools were evaluated across the study population. SF‐36v2 subscale scores for patients with AA revealed lower scores specifically for mental health (45.7 ± 10.1 points), social functioning (45.8 ± 10.9 points), vitality (46.2 ± 9.8 points), and role emotional (46.9 ± 11.6 points) as compared to the Japanese population norms of 50 ± 10 points each. The DLQI questionnaire‐based analysis indicated that 32.1% of respondents showed a moderate to extremely large effect on their lives; and HADS‐A (anxiety) and HADS‐D (depression) scores categorized 46.0% and 41.8% respondents as doubtful‐to‐definite cases, respectively. Multivariate linear regression revealed that hair loss range, age, comorbidities, and depression significantly worsened DLQI scores. In conclusion, the results of this survey demonstrated that a significant decrease in the HRQoL scores was observed in Japanese patients with AA in comparison with the national norms. Hence, emphasis on mental health is crucial for AA management.


| INTRODUC TI ON
Alopecia areata (AA) is an autoimmune-mediated nonscarring hair loss disorder 1,2 with a reported global lifetime risk of approximately 2%. 3 Approximately 14-25% of patients with AA experiencing alopecia totalis and universalis have a poor recovery rate (<10%). 4 Although AA is not a debilitating condition, it has significant impact on the psychosocial condition and health-related quality of life (HRQoL) of patients. [5][6][7] Studies have highlighted that patients with AA with both clinically noticeable and negligible hair loss have a significantly decreased HRQoL. 6,8 Hair loss may significantly impair individuals' self-esteem and emotional harmony. 9 Social stigmatization or even its perception in patients may result in shy, cautious, aggressive, retreating, evasive, or defensive behavior. 4 Lack of awareness of AA is another unmet need prevailing among individuals experiencing hair loss and they often misconstrue hair loss as just cosmetic and are negligent about it; however, this chronic disorder can lead to diverse comorbidities which may further influence HRQoL. 10 Multiple comorbid conditions associated with AA include atopic, metabolic, rheumatoid, thyroid, and psychiatric diseases. 11 Numerous studies have reported a greater risk of psychiatric disorders in patients with AA. 7,[12][13][14] Since the physical, psychological, and social well-being of patients with AA are affected to a great extent, an increased incidence of depression and anxiety are expected which may result in higher suicidal risk. 6,12 A study conducted in 2021 on an Israeli registry with 41 055 patients with AA corroborated that anxiety and depression were the positively associated disorders with AA while schizophrenia and bipolar disorder were negatively or not associated with AA. 15 According to the British Association of Dermatologists' guidelines, psychological support is recommended as an essential intervention in AA. 4 Hence, it is critical to assess the HRQoL of patients for better management of AA.
Several studies have examined the impact of AA on HRQoL worldwide through various clinical outcome assessment tools. 6,8 The Short Form Health Survey 36 Item Version 2.0 (SF-36v2) is one of the most widely used instruments for evaluating HRQoL. 16 Further, evidence from multivariate analysis adjusting for possible confounders is limited for HRQoL studies in patients with AA. 21,22 Finally, no evidence with SF-36v2 has been reported for Japanese patients with AA. Hence, this study aims to address the above limitations.
The primary objective of this study was to evaluate HRQoL in Japanese patients with AA in comparison to Japanese population norms (national standard values for Japanese) using the SF-36v2 measurement tool. Secondary objectives included: (i) evaluation of the impact of AA on HRQoL using DLQI and determination of the proportion (%) of depression and anxiety in patients with AA using HADS; and (ii) evaluation of factors (e.g., hair loss range, comorbidities) that may substantially impact HRQoL using multivariate analysis. This is the first-of-its-kind study that aimed to explore correlations among SF-36v2, DLQI, and HADS scores.

| Study design
This is a cross-sectional, non-interventional study that evaluated the impact on HRQoL of Japanese patients with AA. All alopecia patients who were registered in the Rakuten Insight Disease Panel

| Statistical analysis
The sample size was estimated with the assumption to obtain 50% of the event proportion with 10% width as a 95% confidence interval. An estimated required sample size of 384 and 400 was set as the target by multiplying by 1.05 in consideration of dropouts. Descriptive statistics (n, mean, median, standard deviation [SD], range, min and max for continuous variables; percentage for categorical variables) were used to summarize the sociodemographic and clinical characteristics. The scores for SF-36v2 were interpreted using norm-based scoring (NBS), which is the deviation scores from the Japanese population norms (national standard values for Japanese). Japanese population norms used in this study were the average data from a survey conducted in 2017. 26 The DLQI and HADS questionnaires' outcomes were evaluated and presented as percentages (number of patients) per defined category. Subpopulation analysis was performed using the descriptive statistics mentioned above for specific subgroups (sex, age, hair loss range, AA type, disease duration, relapse experience, comorbidities, current treatment, and wig usage) on all subscales of the SF-36v2, DLQI, and HADS questionnaires. Correlation coefficients were calculated to evaluate correlations among the SF-36v2, DLQI, and HADS scores. Further, multivariate linear regression analysis was performed to evaluate the effects of the characteristics in specific subgroups on the SF-36v2 and DLQI scores.

| Respondents' disposition, demographic and clinical characteristics
A total of 32 257 subjects (the total unique number of subjects who registered as an alopecia panel between 2013 and 2021 at the time of the survey) were invited to participate in this study of which 16 522 respondents gave consent. While 537 participants met the inclusion criteria for AA defined in this study, 400 completed the entire survey.
The baseline characteristics of respondents are presented in Table 1.
The mean age ± SD of the respondents was 42.9 ± 11.6 years, and the majority of respondents were female (67.3%). Clinically, 83.5%

| Analysis of SF-36v2
The  Figure S1. Based on the subgroup analysis of SF-36v2 NBS performed for sex characteristics, similar scores were observed between males and females for all eight subscales (Table S1).  Table 2). The mean (SD) DLQI score was 4.8 points (5.2).

| Analysis of DLQI
In the hair loss range subgroup analysis for DLQI scores, the proportion of respondents who reported moderate to extremely large effects on their lives is higher in the groups with 25-49% and 50-100% hair loss than those with less than 25% hair loss (66.7% and 60.6%, respectively, vs 25.7%) (Figure 2a).

| Outcome correlations
Results of the correlation analysis between SF-36v2 and HADS in-

| Multivariate linear regression
A multiple linear regression analysis for SF-36v2 revealed that higher HADS-A and HADS-D scores significantly decreased all eight subscales (p < 0.01) ( vs "no") and HADS-D scores (0.319) significantly worsen DLQI (p < 0.01) ( Table 4). Furthermore, age and presence of any comorbidity were also significantly related to DLQI (p < 0.01). In contrast to the SF-36v2 analysis, higher HADS-A scores did not significantly affect DLQI (p = 0.107).  Despite differing background demographics and disease severities assessed in other studies, the outcomes (SF-36v2 and DLQI) of our study were comparable to the study results from other countries (Table S2). The DLQI score (4.8) was similar or slightly better for patients with AA in Japan when compared to the DLQI scores in other countries (5.8-13.5). 6 The HADS-A scores in this study indicated that the anxiety score was highest for the hair loss range of 25-49% as compared to the hair loss ranges of less than 25% or 50% or more. It could be interpreted that patients with very severe AA (≥50% hair loss) may cope with their condition by using wigs, with resignation of spontaneous recovery. However, the above-mentioned pattern was not observed with HADS-D scores, indicating that anxiety and depression are quite different diseases. Although not completely understood, the relationship between AA and psychological disorders may be bidirectional as stress and anxiety are hypothesized to potentiate AA in some patients. 39,40 In this study, HRQoL was evaluated using multiple indicators