FormalPara Key Summary Points

Alopecia areata (AA) is an autoimmune hair loss disorder characterized by non-scarring hair loss and unpredictable disease course.

AA is often associated with substantial emotional and psychological distress.

This analysis of two large phase III trials aimed to report on the evolution of measures assessing health-related quality of life (HRQoL) and symptoms of anxiety and depression in patients with severe AA who achieved sustained scalp hair regrowth on continuous treatment with baricitinib.

In adults with severe AA receiving baricitinib treatment, achievement of sustained clinically meaningful scalp hair regrowth was associated with improvements in both measures of HRQoL and symptoms of anxiety and depression up to week 104.

Introduction

Alopecia areata (AA) is an autoimmune disorder characterized by non-scarring hair loss and unpredictable disease course [1]. AA can have a profound impact on patients and is often associated with impaired health-related quality of life (HRQoL) and psychological distress [2]. Evidence regarding the longitudinal effects of hair regrowth on psychological outcomes in patient with AA is limited [3,4,5,6,7]. Baricitinib, an oral selective Janus kinase (JAK) inhibitor, has demonstrated superiority versus placebo on hair regrowth over 36 weeks of treatment in two phase III trials conducted in adults with severe AA [8]. Improvements in both HRQoL and levels of anxiety and depression were also observed with baricitinib through 36 weeks, with greater benefits seen in patients achieving successful scalp hair regrowth in comparison to patients with intermediate regrowth or no to minimal hair regrowth [9, 10]. We report here the evolution of measures assessing HRQoL and symptoms of anxiety and depression up to week 104 in patients who achieved sustained scalp hair regrowth on continuous treatment with baricitinib during the BRAVE-AA phase III trials.

Methods

Study Design

This post-hoc analysis included data from the double-blind, parallel-group, randomized, placebo-controlled phase III trials BRAVE-AA1 (ClinicalTrials.gov number: NCT03570749) and BRAVE-AA2 (ClinicalTrials.gov number: NCT03899259). Both trials have identical eligibility criteria and design for the first 52 weeks. Briefly, 1200 adults with severe AA (defined as ≥ 50% scalp hair loss) were initially randomized with a 2:2:3 allocation ratio to receive placebo, baricitinib 2 mg, or baricitinib 4 mg for 36 weeks. All patients who completed the 36-week placebo-controlled period entered into a long-term extension phase. Patients initially randomized to the baricitinib arms continued without any treatment change until week 52, regardless of clinical response at week 36. Protocol-defined treatment changes, including uptitration, downtitration, and withdrawal, were planned from week 52 onwards (Electronic Supplementary Material Fig. S1). Detailed study designs for BRAVE-AA1/2 have been previously published [8]. The trials were conducted in accordance with the ethical principles of the Declaration of Helsinki of 1964 and its subsequent amendments and with Good Clinical Practice guidelines, and the research protocols were approved by each center’s institutional review board or ethics committee. All patients provided written informed consent for participation in the trials.

Outcomes

Scalp hair loss was measured by investigators using the Severity of Alopecia Tool (SALT) at baseline and at weeks 4, 8, 12, 16, 24, 36, 40, 44, 52, 56, 60, 64, 68, 76, 88, and 104. The SALT score is a weighted sum of the percentage of hair loss in the four quadrants of the scalp. Absolute SALT scores range from 0 (no hair loss) to 100 (complete hair loss) [11]. The effect of AA on HRQoL was measured using the Skindex-16 Scale for AA (Skindex-16 AA) [12], an instrument consisting of 16 items, with the aim to evaluate how much respondents have been bothered by their AA over the past week. Each item is scored on a 7-point Likert-type scale anchored by the words “Never Bothered” and “Always Bothered” at each end, with normalized scores ranging from 0 (no effect) to 100 (effect experienced all the time) [13]. Responses are aggregated in three domains: Symptoms (4 items, i.e., itching, burning, pain and irritation), Emotions (7 items, i.e., concerns about persistence/reoccurrence, evolution, appearance, frustration, embarrassment, being annoyed and feeling depressed), and Functioning (5 items, i.e., interactions with others, daily activities, work, desire to be with people, and desire to show affection) [14]. The levels of anxiety and depression were measured using the Hospital Anxiety and Depression Scales (HADS) [15], which are divided into an anxiety scale and a depression scale; each scale comprises seven items and is scored separately. HADS scores range from 0 to 21, with higher scores indicating greater levels of anxiety or depression over the past week. Skindex-16 AA and HADS were completed by patients at baseline, and then at weeks 12, 24, 36, 52, 64, 76, and 104.

Statistical Analysis

Patients randomized to baricitinib 4 mg or 2 mg at baseline in BRAVE-AA1/2 and who achieved a SALT score ≤ 20 by week 36 (primary outcome of both trials) and maintained a SALT score ≤ 20 through week 104 on the same dose of baricitinib were included in this analysis of integrated data. Physicians and patients with severe AA had previously identified a SALT score ≤ 20 as a meaningful treatment outcome for patients with AA and ≥ 50% scalp hair loss at baseline [16]. Patients on baricitinib who achieved a SALT score ≤ 20 by week 36 but who underwent a change in treatment allocation between week 36 and week 104 were excluded. Scalp hair regrowth was described using individual patient trajectories of SALT score over 104 weeks. Time to achieve a SALT score ≤ 20 was reported. Evolution of HRQoL and psychological symptoms was described in each baricitinib dose group using the change from baseline through week 104 in Skindex-16 AA and HADS domain scores. Missing data were imputed using the modified last observation carried forward (mLOCF) method. Data collected after permanent study drug discontinuation were excluded. All the analyses in the study are descriptive.

Results

Of the 515 patients initially randomized to receive baricitinib 4 mg, 193 achieved a SALT score ≤ 20 by week 36 and 88 maintained a SALT score ≤ 20 through week 104 without change in treatment regimen. In the baricitinib 2 mg arm, 72 of the 340 patients randomized to this treatment achieved a SALT score ≤ 20 by week 36 and 43 maintained a SALT score ≤ 20 through week 104 without change in treatment regimen. A total of 131 patients were included in the present analysis, and baseline characteristics are presented in Table 1. For the baricitinib 4 mg and baricitinib 2 mg groups respectively, the mean (standard deviation [SD]) duration of AA since onset was 9.9 (10.5) and 8.9 (9.2) years, the proportion of patients with a current AA episode of < 4 years was 79.5% and 83.7%, the mean SALT score was 77.3 (19.54) and 73.1 (19.06), and 33.0% and 23.3% of patients had a very severe AA (i.e., SALT score 95–100). Skindex-16 AA and HADS individual domain scores were similar across groups at baseline. The Skindex-16 AA Emotions domain score was the highest of the three Skindex-16 AA domain scores, followed by the Functioning score.

Table 1 Demographics and baseline characteristics
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The evolution of individual SALT scores over the 104-week treatment period for patients in both baricitinib groups is presented in Fig. 1. The interquartile (IQR) for time to achieve a SALT score ≤ 20 was 13.1 weeks and 19.6 weeks for patients treated with baricitinib 4 mg and baricitinib 2 mg, respectively (Table 2). With the baricitinib 4 mg dose, a SALT score ≤ 10 was achieved at week 36 and week 104 in 83.0% and 95.5% of patients, respectively (Fig. 2a). The proportion of patients treated with baricitinib 2 mg and achieving a SALT score ≤ 10 was 65.1% and 90.7% at week 36 and week 104, respectively (Fig. 2b). Overall, we observed a similar evolution of the Skindex-16 AA and HADS scores in patients treated with baricitinib 4 mg or 2 mg (Fig. 3). Improvements in Skindex-16 AA domains and HADS scores were observed for both baricitinib groups up to week 104.

Fig. 1
figure 1

Individual patient trajectories of SALT score up to week 104 for baricitinib 2 mg (a) and baricitinib 4 mg (b) treatment arms. The light-blue or red lines indicate individual patients trajectories, the thick dark-blue line is the smoothing line using local polynomial regression fitting that indicate the group trend, and the blue dashed line indicates a SALT score of 20. SALT Severity of Alopecia Tool

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Table 2 Time to achieve a Severity of Alopecia Tool score ≤ 20
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Fig. 2
figure 2

Distribution of patients by SALT score increments of 10 from week 36 through week 104 for baricitinib 2 mg (a) and baricitinib 4 mg (b) treatment arms. SALT Severity of Alopecia Tool

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Fig. 3
figure 3

Mean change from baseline to week 104 in Skindex-16 AA Symptoms domain score (a), Emotions domain score (b), Functioning domain score (c), and HADS anxiety (d) and depression (e) scores. AA Alopecia areata, HADS Hospital Anxiety and Depression Scales, Skindex-16 AA Skindex-16 Scale for AA

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Discussion

In this analysis of adults with severe AA, achievement of sustained scalp hair regrowth (SALT score ≤ 20) by patients receiving treatment with baricitinib was associated with improvements in both measures of HRQoL and symptoms of anxiety and depression up to week 104. These findings are aligned with those from a small uncontrolled trial assessing tofacitinib, another JAK inhibitor [17]. In that study, improvements in HRQoL were reported up to 30 months in 12 patients with severe AA who had experienced scalp hair regrowth (> 50% decrease from baseline in SALT score) [17].

All of the patients included in the present analysis achieved meaningful scalp hair regrowth (SALT score ≤ 20) by week 36, but the time needed to achieve this outcome was variable between individuals, ranging from 4 to 36 weeks. A previous analysis of the BRAVE-AA trials data has already shown that distinct hair-regrowth response patterns—early, gradual, and late—exist among patients with severe AA treated with baricitinib [18]. Similar findings have also been reported in studies assessing other JAK inhibitors for AA [19, 20]. The largest improvements in SALT score were seen by week 36 in both baricitinib groups. By week 36, 83.0% and 65.1% of patients in the baricitinib 4 mg and baricitinib 2 mg groups, respectively, had achieved a SALT score ≤ 10. At week 194, a SALT score ≤ 10 was achieved by > 90% of patients in both baricitinib groups. This finding suggests that many patients who achieve a SALT score ≤ 20 on baricitinib will also achieve a SALT score ≤ 10 at a later time point.

Consistent with previous results from the BRAVE-AA trials, the highest scores at baseline and the largest improvements were seen in the Functioning and Emotions domains of the Skindex-16 AA [12, 14]; conversely, the Symptoms domain scored low at baseline and improvements were more limited. AA is associated with a substantial emotional and psychological burden [2]. Patients commonly report feelings of sadness, anxiety, worry, and fear [21]; often experience inadequacy, low self-confidence, and embarrassment; and find relationships, day-to-day activities, and employment impacted by the disease [22]. On the other hand, symptoms of skin discomfort, (i.e., scalp itching, burning, pain, and irritation) are rarely reported, except when patients are experiencing active hair loss or hair regrowth [14]. The low scores observed for the Symptoms domain at baseline could therefore reflect a stable disease before enrollment in the BRAVE-AA trials [5]. A similar distribution of baseline Skindex-16 domain scores was observed in the aforementioned tofacitinib trial [17].

Previous research has shown that AA is associated with an increased risk of experiencing mental health disorders, such as anxiety and depression [2, 23]. Patients with significant uncontrolled neuropsychiatric disorders were excluded from the BRAVE-AA trials, which could be a reason for the relatively low HADS scores observed at baseline [8]. The evolution of HADS anxiety and depression scores was similar across both baricitinib groups over the 104-week period.

These findings must be interpreted in the context of the study design. First, our findings may not apply to responders who fail to maintain a SALT score ≤ 20 over time. Of note, an analysis of the BRAVE-AA trials data has shown that a SALT score ≤ 20 was maintained through week 104 in around 90% of patients treated with baricitinib who achieved this outcome by week 52 [24]. Second, it would have been relevant to evaluate the improvements in HRQoL and psychological symptoms among patients with a SALT score ≤ 10 and in those with a SALT score between 11 and 20 in whom enough hair had regrown. However, the number of patients with a SALT score between 11 and 20 was already limited at week 36 and decreased to < 10% by week 104. Analyses of BRAVE-AA trials have shown that the evolution of Skindex-16 AA and HADS scores in subgroups based on duration of current episode of hair loss was consistent with the evolution in the overall population [10]. Unfortunately, in the present work, the overall sample size was too small to conduct similar subgroup analyses on duration of disease or presence of previous episodes. Finally, we did not assess the potential contribution of hair regrowth by area of scalp involvement or on other body sites, especially eyebrows and eyelashes, to the observed improvements in HRQoL and psychological burden.

Conclusion

This analysis of adults with severe AA treated with baricitinib revealed that achievement of sustained clinically meaningful scalp hair regrowth (SALT score ≤ 20) was associated with improvements in measures of HRQoL and symptoms of anxiety and depression up to week 104. These results can help clinicians to inform treatment expectations in patients with severe AA.