FormalPara Key Summary Points

Why carry out this study?

We hypothesized that there could be a proportion of physicians and patients who were dissatisfied with treatments for alopecia areata (AA) in Japanese clinical practice, which could lead to misalignment between patient and physician on treatment satisfaction.

Therefore, we investigated the degree of patient-physician alignment on disease severity and treatment satisfaction in AA in Japan.

What was learned from the study?

The percentage of patient-physician alignment overall was 76.3% and 57.6% on disease severity and treatment satisfaction, respectively.

Physicians in misaligned pairs rated disease as more severe than patients across all severity groupings and rated their own satisfaction with treatment as lower than the patient in the most severe hair loss group, citing lack of efficacy as the main reason.

Our findings demonstrated that physicians treating patients with AA experience frustration with the lack of effective treatments available and that patient expectations of treatment are low.

Introduction

Alopecia areata (AA) is a relatively common non-scarring hair loss disease characterized by an autoimmune response [1]. The 2017 Japanese Dermatological Association (JDA) guidelines categorize patients into five groups (S1–5) according to the percentage scalp hair loss. S1 includes the least severe patients with < 25% scalp hair loss; S2, S3 and S4 include those with 25–49%, 50–74% and 75–99% scalp hair loss, respectively; and S5 includes 100% scalp hair loss [2]. Patients in groups S2–5 are considered by the JDA to have severe disease.

When assessing AA severity, factors other than scalp hair loss should also be considered, including symptoms, signs, physiologic measures and hair loss on other parts of the body [3].

AA mainly affects adults in their twenties and thirties [4, 5], and there is substantial variation in AA prevalence between countries and sexes. A recent study using data from a US employer-sponsored insured population reported that AA prevalence was 0.199–0.222% from 2016 to 2019, and was higher in adult female patients [6]. Recent data from a large claims database in Japan indicated the prevalence of AA to be between 0.16 and 0.27% from 2012 to 2019 [7]. However, as consultation rates of patients with AA could be low in Japan, the prevalence of AA may be much higher.

Despite extensive evidence that AA-related hair loss leads to lower quality of life (QoL) and negative psychological effects for patients [8,9,10,11], there are few approved treatments available to control AA, and the efficacy of many existing treatments is inconsistent [12]. Current JDA guidelines rank AA treatments from A (strongly recommended) to D (discouraged for use). Topical corticosteroids, contact immunotherapy and intralesional corticosteroid injection are ranked B (recommended), the highest ranking for any AA treatment [2]. The authors of a recent claims database study in Japan reported that topical corticosteroids were the most frequently prescribed treatment for AA (70% of patients), followed by carpronium chloride (37%) and cepharanthine (36%), with systemic corticosteroids prescribed to those with more severe AA [7]. Both carpronium chloride and cepharanthine are widely used in Japan, but studies on their use are of little relevance to global dermatology practice as they are not widely prescribed outside of Japan. However, the recent approval of Janus kinase (JAK) inhibitors, such as baricitinib, in Europe, Japan and the USA, offers a new avenue of treatment for AA [13, 14].

Given the current focus on patient-centered care, it is important to consider treatment satisfaction from the perspective of both physician and patient. A study in atopic dermatitis reported that patients who were satisfied with the level of communication between themselves and their physician were more likely to adhere to treatment [15]. Since there are limited data on patient-physician alignment on disease severity and treatment satisfaction in AA clinical practice in Japan (and globally), these data may shed light on its importance in AA management.

The aim of this study was to identify demographic and clinical characteristics of patients with AA, compare how JDA severity groupings (S1-5) match with patients’ and physicians’ own perception of AA severity and determine patient-physician alignment on severity. We also explored treatment patterns, level of treatment satisfaction, degree of alignment in treatment satisfaction between patients and their physicians and reasons for dissatisfaction in Japan.

Materials and Methods

Study Design

Data were drawn out of the Adelphi AA Disease Specific Programme (DSP)™, a real-world, cross-sectional survey of consultant physicians and their patients conducted January–March 2021. Geographically representative physicians were recruited voluntarily and received an honorarium. Physicians were JDA board-certified dermatologists and were personally responsible for the management/treatment of patients with AA, including at least one patient with mild, one with severe and one to eight patients with moderate or severe disease. Each physician provided a detailed patient record form for the next consecutive three to ten adult patients (age ≤ 15 years) consulting with AA. Using patients’ medical records and information gathered during consultation, physicians reported data on patient demographics, clinical characteristics, prescribed treatments and satisfaction with the management of AA.

Patients were then invited to complete a patient self-completion form detailing their perspective on disease severity and treatment satisfaction. Patients were recruited on a voluntary basis by their physicians, and patient self-completion forms were kept confidential. To be eligible, patients had to have a physician-confirmed diagnosis of AA and not be taking part in an AA clinical trial. The DSP methodology has been previously published and validated [16,17,18].

Study Measures

Physicians were asked to rate the AA severity of patients as mild, moderate or severe based on their own subjective perception of these terms after assessing the patient’s degree of scalp hair loss during the consultation. Based on the percentage of scalp hair loss physicians had reported, patients were categorized into the S1-5 AA severity groupings. It should be noted that while physicians were not required to understand the criteria used by the JDA to categorize patients into groups S1-5, this classification is well-known and the criteria well accepted in Japan; for example, an awareness of JDA guidelines is indispensable for board certification, and all physicians would be required to learn the classification in their dermatology training. Similarly, patients were asked to report their AA severity as either mild, moderate or severe, based on their own perception of their scalp hair loss.

To assess the impact of AA on mental health—specifically depression and anxiety—the Hospital Anxiety and Depression Scale (HADS) was used. Each item is rated on a 4-point severity scale, with a maximum score of 21 for anxiety and depression, respectively. Scores of >11 represent the presence of anxiety/depression, scores of 8–10 represent borderline presence of anxiety/depression and scores of 0–7 represent a normal range [19, 20].

Skindex-16, a validated measure of the effects of skin diseases on patients’ QoL, was used to evaluate the impact of AA on patient health-related QoL. Skindex-16 scores range from 0 to 96, with lower scores indicating higher levels of QoL [21]. The minimal clinically important difference for the Skindex-16 measure has been identified as 10 [22].

To evaluate treatment satisfaction, patients and physicians were asked to report their level of satisfaction as extremely dissatisfied, very dissatisfied, dissatisfied, neither satisfied nor dissatisfied, satisfied, very satisfied or extremely satisfied. Any level of dissatisfaction or satisfaction was classified as ‘patient dissatisfied’ or ‘patient satisfied,’ respectively, and a third group that reported neither were categorized as ‘patient neither satisfied nor dissatisfied.’ Patient data were then matched to the data of their physician to determine overall satisfaction and the degree of patient-physician alignment.

Statistical Analysis

Patient-physician alignment on disease severity and treatment satisfaction and treatment patterns were reported descriptively. Continuous variables were described as means and standard deviations (SD) and categorical variables were described as numbers and percentages.

To determine patient treatment satisfaction, a logistic regression was performed using Stata 17 [23], with adjustments for current treatment (receipt of each treatment versus not receiving that treatment) as covariates, to assess the extent of the association of each treatment with being satisfied compared with less than satisfied (including dissatisfied patients and those neither satisfied nor dissatisfied). Treatments included intravenously injected corticosteroid (pulse therapy), oral corticosteroid, intralesional corticosteroid injection, topical immunotherapy, treatments specifically local to Japan (carpronium chloride, monoammonium glycyrrhizinate, glycine, DL-methionine (glyceron) and cepharanthine) and topical corticosteroid. Odds ratios, 95% confidence intervals and p-values were reported, with an alpha level of 0.05 deemed as significant.

Missing data were not imputed; therefore, patient samples could vary from variable to variable and are reported separately for each analysis.

Ethics

Patients and physicians provided informed consent for use of their anonymized and aggregated data for research and publication in scientific journals. Data were collected anonymously; all data were aggregated and de-identified before receipt.

The DSP was performed in accordance with relevant legislation, including the US Health Insurance Portability and Accountability Act (HIPAA) 1996 [24]. It was submitted to the Western Institutional Review Board for methodological review in 2019 (study protocol no.: AG8446) and was granted an exemption.

Results

Patient Group Demographics

Overall, 85 physicians provided data on 587 patients; however, our analyses only included the 545 patients for whom data on the degree of scalp hair loss were available. In total, 260 patients provided patient self-completion forms. The mean age of patients in the study was 43.7 (SD 15.5) years; the mean body mass index was 21.8 (3.1) kg/m2, and 60.9% were female (Table 1). The total mean Skindex-16 score was 42.4 (SD 23.8) (maximum score 96), with scores of 32.2 (SD 22.9), 43.1 (SD 22.1), 46.8 (SD 22.4) and 62.9 (SD 12.7) for groups S1, S2, S3 and S4, respectively, and a score of 53.5 (SD 23.4) for group S5. The scores for the two scales of the HADS, HADS-A (anxiety) and HADS-D (depression), categorized 39.8% and 29.9% of patients as borderline abnormal-to-abnormal, respectively (Table 2). We also found that patients with eyebrow/eyelash hair loss had a mean HADS-A score of 7.2 (4.7) compared with 5.9 (4.5) in patients without eyebrow/eyelash hair loss. Similarly, mean HADS-D scores were 6.1 (4.6) and 4.9 (4.2) in patients with and without eyebrow/eyelash hair loss, respectively (Table 3). It should also be noted that eyebrow/eyelash loss tended to be more prevalent in patients with more severe AA, as suggested by the JDA classification (data not shown), so it is possible that this QoL impairment might also be associated with an increase in scalp hair loss.

Table 1 Physician-reported patient demographics and clinical characteristics stratified by the Japanese Dermatological Association hair loss groups
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Table 2 Patient-reported outcomes stratified by the Japanese Dermatological Association hair loss groups
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Table 3 Patient-reported mean Hospital Anxiety and Depression Scale anxiety and depression scores in patients with versus without eyebrow/eyelash hair loss
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Patient- and Physician-Reported Alopecia Areata Severity and Degree of Patient-Physician Alignment

We evaluated the degree of hair loss that matched the severity of AA as determined by patient-physician pairs. We found that 91.9% of patients and 98.0% of physicians reported < 25% scalp hair loss (S1) as representing non-severe disease (i.e. mild or moderate disease). Similarly, 78.2% of patients (derived from the 10.9% and 67.3% of patients reported by the physician as having mild and moderate disease, respectively) in S2 reported their AA as non-severe. Physicians recognized groups S3–5 as moderate/severe, with 43.6% of physicians and 47.3% of patients classifying S3 (hair loss of 50–74%) as severe. Similarly, 75.0% and 100.0% of patients in groups S4 and S5, respectively, described their disease as severe; for physicians, this was 96.4% and 100.0%, respectively. In total, 81.8% of physicians reported patients in S2 as having non-severe disease, whereas 21.8% of patients and 18.2% of physicians reported S2 patients having severe disease (Fig. 1a, b).

Fig. 1
figure 1

Alopecia areata (AA) severity and degree of patient-physician alignment on severity perception. a Patient-reported AA severity, b physician-reported AA severity, c patient-physician alignment on severity of patients’ AA stratified by the Japanese Dermatological Association hair loss grouping (groups S1-5). Note: data for this analysis included only data from physicians for whom matched patient data from a patient self-completion form were available; in total, 7 patients were excluded from this analysis as they did not provide data on perceived disease severity

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Although at least 69.7% of patients and physicians were aligned on the perception of disease severity across the S1–5 groups, a degree of misalignment between patient and physician existed in all the groups. The largest misalignment was observed in group S4; in 25.0% of cases physicians reported greater severity compared to patient self-reported data. In groups S1–3, physicians reported that AA was more severe compared to the severity reported by patients in 20.2%, 14.5% and 7.3% of cases, respectively. In group S5, all 16 patients and physicians were aligned on AA severity (Fig. 1c).

Physician-Reported Treatment Options and the Patterns of Treatment Selection for AA in Japan

Overall, 54.2% of patients were receiving a topical corticosteroid (59.0%, 63.7%, 45.3%, 41.1% and 29.4% in S1–5 groups, respectively). Use of cepharanthine and carpronium chloride was relatively high across all groups (37.7% and 31.3%, respectively) but particularly high in S3 (47.7% and 40.7% of patients, respectively). Across all groups, 18.4% of patients were receiving the contact immunotherapy topical squaric acid dibutyl ester (SADBE), which rose to 25.0% of S4 patients and 29.4% of S5 patients (Fig. 2a). Use of intralesional corticosteroid injection was limited to just 11.0% of patients overall and to 11.9% in S1 patients. Intravenous corticosteroid pulse therapy was prescribed for 22.1% of S3 patients and 16.1% of S4 patients, respectively; for S5 patients, use of this therapy was restricted to 8.8%. Less than 2% of S1–4 patients were not prescribed treatment at the time of data collection, increasing to 8.8% in S5 patients (Fig. 2b).

Fig. 2
figure 2

Treatment options and patterns of treatment selection for AA in Japan. a Percentage of patients on each therapy regimen at the time of data collection, b percentage of patients receiving no treatment, c physician instructions for use in patients of the most prescribed treatments for AA stratified by the Japanese Dermatological Association hair loss groups (S1-5). Note: Patients included in this analysis were not receiving treatment for AA at time of data collection but had previously been receiving treatment. Intermittent use was defined as ‘use until the current symptoms subside AND patient to use again in the future if symptoms return.’ Short term was defined as ‘use until the current symptoms subside OR until they have used up all the prescribed treatment, then stop

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For most AA treatments, patients were instructed to follow the treatment on an ongoing basis, but for other treatments, short-term or intermittent use was advised, such as for oral corticosteroids and intravenously injected corticosteroids. However, 61.5% and 26.3% of those treated with oral corticosteroids or intravenous corticosteroids, respectively, were receiving these treatments on an ongoing basis (Fig. 2c).

Patient- and Physician-Reported Satisfaction with Treatments for AA and Degree of Satisfaction Alignment

Patient dissatisfaction increased with severity of the scalp hair loss. Among S1 patients, 8.6% were dissatisfied with treatment, rising to 22.6%, 23.2%, 39.1% and 38.5% among patients in groups S2–S5, respectively (Fig. 3a). Among S5 patients, 61.5% were neither satisfied nor dissatisfied, with 38.5% reporting being dissatisfied with treatment. The percentage of satisfied patients was low in S2 (13.2%), but was 30.4% and 26.1% of patients in S3 and S4, respectively, despite S3 and S4 patients suffering from greater scalp hair loss (Fig. 3a). With greater hair loss, more physicians were dissatisfied with the AA management regimen, with physicians dissatisfied with the treatment for 7.3%, 21.0%, 30.2%, 44.6% and 70.6% of patients in groups S1–5, respectively (Fig. 3b). However, satisfaction never fell to 0 %, remaining at 21.4% for S4 patients and 5.9% for S5 patients (Fig. 3b). Overall, 42.4% of physician–patient pairs were not aligned on their level of treatment satisfaction (Fig. 3c). Based on scalp hair loss groups, 37.6%, 47.2%, 42.9% and 43.5% of patient-physician pairs were misaligned on treatment satisfaction in groups S1, S2, S3 and S4, respectively. In group S5, 53.8% were misaligned and, notably, 46.2% of patients were more satisfied than their physician (Fig. 3c). Patients were 2.4-fold more likely to be satisfied with treatment if receiving an oral corticosteroid than if receiving any other treatment (Fig. 3d). Patient- and physician-reported treatment satisfaction data are summarized for the eight most prescribed AA therapies in Table 4.

Fig. 3
figure 3

Patient- and physician-reported satisfaction with AA treatments and degree of alignment on their satisfaction. a Patient satisfaction with control of AA, b physician satisfaction with control of patients’ AA, c level of physician and patient alignment on treatment satisfaction (data from a–c stratified by the Japanese Dermatological Association hair loss groups [S1-5]), d odds ratio of patients who were satisfied with treatment (per each treatment) versus when they were not receiving the treatment Bold (d) indicates a significant difference (p < 0.05) between treatment versus no treatment

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Table 4 Patient- and physician-reported satisfaction with treatment stratified by therapy class
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Reasons for patient dissatisfaction included: treatment had not improved their condition (89.4% of patients), side effects (10.6%), reduced efficacy over time (10.6%) and disliking injections (10.6%; Fig. 4a). The most common reason for physician dissatisfaction with treatment was lack of overall efficacy (79.8%) followed by patient dissatisfaction (21.8%) and that AA was still impacting patients’ quality of life (14.3%; Fig. 4b).

Fig. 4
figure 4

Reasons for dissatisfaction with treatment: a patient, b physician. Symptoms include pain, burning sensation, itch, tingling sensation. Asterisk indicates that only data for patients for whom physicians were dissatisfied with treatment were included

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Discussion

In this study of patients with AA in Japan, we reported how patients and their physicians perceived disease severity, evaluated the degree of alignment of disease severity between patients and their physicians and compared patient- and physician-reported severity to the JDA severity groupings S1–5. We described treatment patterns at the time of data collection, treatment satisfaction, degree of physician–patient alignment on satisfaction and reasons for dissatisfaction with treatment.

Patients tended to rate their disease severity slightly lower than their physicians. This difference may be due to patients being unable to fully recognize the extent of hair loss, such as on the occipital region, and/or that they have become used to their condition and therefore perceive their disease as being less severe than they may have done previously. In contrast, physicians rating their patients’ AA condition worse than the patients themselves may be reflecting frustration over the inability to manage the condition to meet patient needs and improve their QoL. Patient and physician ratings of AA severity generally matched those identified by the JDA severity groups S1–5, with the majority of patients in S1–2 being rated by their physicians and themselves as mild and patients in S3–5 recognized as having moderate to severe disease. These results suggest that patient and physician overall perceptions of AA severity were reflected in these groupings despite there being some patient-physician differences in severity ratings.

In this study, we found that the overall Skindex-16 total score increased as the range in hair loss increased in groups S1–S4, with the maximum score of 62.9 (SD 12.7). However, the Skindex-16 score in S5 was 53.5 (SD 23.4) out of 96 and was not clearly exacerbated. A possible explanation for these findings is that Skindex-16 scores are unlikely to be directly associated with percentage scalp hair loss as the questions on the Skindex-16 questionnaire focus on itch, burning, worry over appearance, depression and anxiety and impact interactions with others. Therefore, it is possible that beyond a certain threshold of percentage scalp hair loss there is no incremental increase in Skindex-16 score. Also, some of the S5 patients might have accepted their disease status, which may have partially affected their perception of their condition and eventually such scores as Skindex-16. Finally, as sample sizes were small (n = 28 patients and n = 14 patients in S4 and S5, respectively), these results may not be caused by a true effect but rather be a result of low sample sizes.

We found that HADS-A (anxiety) and HADS-D (depression) scores categorized almost 30% of patients with some degree of depression and almost 40% with some degree of anxiety. A previous cross-sectional study that evaluated the impact on QoL of Japanese patients with AA reported anxiety and depression scores of 46.0% and 41.8%, respectively [25]. An advisory board composed of AA physicians reported that, second to degree of scalp hair loss, psychosocial symptoms such as depression are a key indicator of AA severity [26]. These study results indicated the importance of interventions to prevent the development of psychological comorbidities and thus, improving patient outcomes and the overall management of AA.

Before the approval of JAK inhibitors for the treatment of severe AA, few effective treatments were available to manage AA in Japan, and none were universally accepted to do so successfully [27]. Across scalp hair loss groups, we found that a high proportion of patients in our study were receiving topical corticosteroid or cepharanthine. The majority of the patients receiving intravenous corticosteroid pulse therapy were in groups S3–4, indicating that these types of systemic treatments are largely being received by patients with more severe disease (current JDA guidelines recommend this therapy—a JDA C-ranked therapy—as a therapeutic option for acute/rapidly progressive cases in groups S2 or above). It is recommended that patients should not be prescribed systemic corticosteroid on an ongoing basis; however, more than a quarter of patients in our study were prescribed this therapy over the long term, likely because other treatments had not worked. Also, more than half of the patients in our study were receiving a combination of therapies, demonstrating that no single treatment had been effective at managing their AA at the time of this survey. Studies show that many patients with more severe or moderate disease across numerous countries receive diphenylcyclopropenone (DPCP) [28]; however, very few patients in our sample were prescribed DPCP, just 2%. This is likely because in Japan, SADBE is more routinely used than DPCP [29], highlighting that clinical practice in Japan is in some cases different from global standards.

Nearly 10% of those with the most severe scalp hair loss (group S5) were not receiving any treatment at the time of this study, perhaps because no treatment had been effective or because patients had become frustrated with treatment not being effective, resulting in decreased adherence levels. This result indicates that while some patients with severe AA are receiving stronger treatments, many are not. Combined with a lack of improvement in disease severity among those receiving treatments, patient and physician satisfaction was low, possibly explaining the over-reliance on corticosteroids. As a therapy, systemic corticosteroids are usually prescribed for a shorter time than seen in this study due to multiple organ side effects associated with their long-term use [30]. While the proportion of physicians satisfied with AA control decreased as scalp hair loss increased, even in the most severe groups (S4-5) the proportion of satisfied physicians never fell to zero, suggesting that some physicians may be satisfied with the treatment but not the outcome. In addition, physicians may rate satisfaction based on their understanding that no one treatment works particularly well and thus may be basing their satisfaction on a different scale.

We found that patients reported being less satisfied than their physician with intralesional corticosteroid injections, one of just three available JDA B-ranked therapies. Patient satisfaction increased among those receiving oral corticosteroids. This finding may be due to injectable treatments being more invasive or inconvenient and may suggest that some patients might prioritize convenience and avoidance of pain over efficacy. This possibility was supported by findings as the second most common patient-cited reason for treatment dissatisfaction was not liking injections. A type 2 diabetes study in Japan [31] and a study of patients with rheumatoid arthritis in Europe [32] reported similar findings, with patients preferring oral over injectable treatments. Only a small proportion of physicians in our study reported that patients found treatment administration burdensome and, therefore, preference for oral treatments may be contrary to physician expectation and thus may not be taken into account by physicians at prescription. Overall, this study indicated that there is large dissatisfaction with current conventional treatments, including those ranked highly by the JDA, with the highest ranked treatment available for AA at the time of writing this article being ranked as B by JDA guidelines. In addition, better patient-physician communication could result in a better alignment of patients’ and physicians’ perception of AA severity, and increasing treatment satisfaction could also improve treatment outcomes and adherence.

There are several strengths and limitations that should be considered regarding our findings. The data collected were not based on a true random sample of physicians or patients. While minimal inclusion criteria governed the selection of the participating physicians, participation was influenced by willingness to complete the survey. Physicians were asked to provide data for a consecutive series of patients to avoid selection bias, but no formal patient selection verification procedures were in place. The cross-sectional design of this study prevents any conclusions about causal relationships; however, identification of significant associations is possible. Recall bias might also have affected the responses of both patients and physicians to the questionnaires, which is a common limitation of surveys. However, the data for these analyses were collected at the time of each patient consultation, and this was expected to reduce the likelihood of recall bias.

Conclusion

Taken together, the findings of this study showed patient and physician ratings of AA severity generally matched the severity groupings described by the JDA (S1—5), highlighted the aligned recognition of unmet needs in the treatment for severe AA by patients and their physicians and identified that physicians classified AA severity as worse than their patients. This study used patient-physician matched real-world survey data to elucidate the degree of patient-physician misalignment on disease severity and treatment satisfaction in Japan. Our results revealed a lack of satisfactory treatment options for patients with AA in Japan and demonstrated physicians’ distress and frustration with the lack of effective treatments, particularly for their patients with severe disease. Our data also show that lack of effective treatment has led to lower patient expectations of disease management and outcomes.