Effectiveness and safety of baricitinib in patients with moderate‐to‐severe refractory alopecia areata in real world: An open‐label, single‐center study

Baricitinib is a small‐molecular drug that selectively inhibits the Janus Kinase (JAK) 1 and 2. However, it showed various efficiency and safety in treating moderate‐to‐severe alopecia areata (AA). This study was to describe the real‐world effectiveness of baricitinib in treating moderate‐to‐severe refractory AA.

5][6][7] In recent years, with the development in the pathogenesis research of AA, JAK inhibitors have demonstrated promising effectiveness in treating moderate-to-severe AA. 8 However, few previous studies have focused on the effectiveness of baricitinib in patients who react poorly to other AA therapies.In this study, we applied baricitinib, a JAK inhibitor, to treat AA patients who have received other treatments, observing its effectiveness and safety in moderate-to-severe refractory AA.

| Patients and treatment
All 32 patients were selected from the Hair Disease Clinic of our

| Assessment tools
Efficacy was assessed with the Severity of Alopecia Tool (SALT) and Investigator Global Assessment for AA (AA-IGA). 4e SALT assessed hair loss severity by following a visual approach.The total area of the scalp consists of four parts.The surface area on the left and right sides consists 18% of the total area each.
The other 64% can be divided into 40% for the surface area on the top of the scalp, and 24% for the surface area on the posterior/dorsal side.The percentage of alopecia in each part was evaluated and then multiplied by the proportion of scalp covered by that part, respectively.The SALT value is derived from the sum of the four products for each region.SALT contains only terminal hairs.Fine hairs or any fine villi were not considered in the SALT scoring process. 9,10-IGA is an overall hair loss category based on a patient's SALT value, which was determined at each visit by directly examining the patient's scalp.AA-IGA contains five categories: 0 = none (SALT value is 0%); 1 = limited (SALT value: 1%-20%); 2 = moderate (SALT value: 21%-49%); 3 = severe (SALT value 50%-94%); and 4 = very severe (SALT value 95%-100%). 11

| Statistics analysis
The distribution of data was analyzed with SPSS 22. Paired t-test.
Friedman test and X test were chosen and appropriately applied for data after analysis of data distribution.Normal distribution was analyzed through paired t-test and visualized as mean ± SE.Data distributed nonnormally were expressed as a median with an interquartile range.Column plot and box plot were used to describe the distribution of normal and nonnormal data, respectively, by GraphPad 9.0.p < 0.05 was considered statistically meaningful.

| Patients and treatment
The 32 patients included 23 females and nine males, with a median age of 30 years (range: 16-53 years) and a range of duration of AA was 3-22 years.The SALT score before baricitinib treatment was 64.45 (44.68-100).At least one treatment was used in these patients to treat AA for more than 6 months, including minoxidil, steroid, ciclosporin, or Chinese traditional medicine before the initiation of baricitinib (Table 1).However, no response was gained for 6 months of sustained medication mentioned above.
All patients had a history of other treatments before.Among them, four patients had no significant improvement in hair restoration after 12 weeks of treatment so the dose was subsequently increased to 4 mg daily in the following 12 weeks until the end of week 24.Nineteen patients were also treated with 5% minoxidil tincture externally.

| SALT score
The trend of the median SALT score is shown in Figure 1.SALT value of patients showed a significant decrease from baseline at week 12 (26.80[13.40-62.32]p < 0.0001) (Figure 1A).SALT at week 4, however, was not significantly lower than baseline.The patients in our research also had a better improvement of hair at week 24 than at week 12 Compared with that of week 4 (6.25%,0 and 0), the proportion of patients with SALT50, SALT75, and SALT90 improvement was much higher at week12 (43.75%, 21.88%, and 9.38%, respectively) and week 24 (68.75%, 59.38%, and 28.13%, respectively) (Figure 1B).
At week 12, 31.3% of patients had scalp hair covering of more than 80% (absolute SALT score ≤20), and at week 24, this proportion increased to 68.75%.

| AA-IGA score
All patients had a baseline IGA score of 2 or more.After 24 weeks of treatment, 50% of patients had an improvement of ≥2 or more points in IGA scores from the baseline and IGA scores of 68.75% of patients were less than 2 (Figure 2). Figure 3 is a photograph demonstrating a typical case.

| Hair regrowth outside of the scalp
Nine of 32 participants had an extreme form of alopecia, alopecia universalis, which manifested as not only complete hair loss but also the loss of eyebrows and eyelashes.After 12 weeks of treatment, four patients had an improvement of eyebrows and eyelashes, this number increased to 8 at week 24.At the end of the study, two patients had their eyebrows and eyelashes recovered completely.

| Safety and adverse reaction
The adverse reactions were mild, including transient platelet elevation in two cases after 4 weeks of treatment, one of which descended to normal by week 8 and 2 by week 12.Other adverse events included one case of elevated transaminase, one case of dizziness (later diagnosed as cervical spondylosis and relieved after physiotherapy), one case of tonsillitis in one case, and one case of acne.Besides, three patients had a mild increase in highdensity lipoprotein (HDL) after 12 weeks of treatment.Given the benefit of HDL on lipid metabolism, we monitored it closely but did not intervene.

| DISCUSS ION
JAKs and related signaling pathways participate in the pathogenesis of many diseases, especially in autoimmune diseases. 12Inhibitors targeting different subtypes of JAK have been developed for clinical treatment. 13,14Baricitinib is a small-molecule drug that selectively inhibits JAK1 and 2, which has been approved for treating active rheumatoid arthritis and other autoimmune disease, 15,16 including severe AA.
All patients in our study had a clear history of AA treatment, with an unsatisfying outcome though.However, baricitinib showed a valid therapeutic effect on these patients, especially after 12 and 24 weeks of treatment.This indicates that negative responses to other treatments may suggest a positive response to baricitinib therapy in clinical work.Baricitinib therapy is still worth trying even when other previous treatments such as glucocorticoids and ciclosporin had no obvious effect.
Besides, in our study, the hair restoration level observed at week 24 was superior to that of week 12 with a statistical difference.
Other researchers also observed various shrinking of the alopecia area after weeks 12 and 24 in both adult 17,18 and pediatric patients. 19wever, the SALT value at week 4 was not significantly inferior to baseline, indicating that a minimum treatment duration of more The median SALT scores (A) and proportion of patients with different SALT improvement (B).

F I G U R E 2
Patients with different AA-IGA scores at each time point.
than 12 weeks was required to determine whether a patient had a response to baricitinib.Also, baricitinib still has a positive impact on the regeneration of hair after the first 24 weeks and could be considered a solid reason for a longer period of clinical usage. 20evious phase 3 clinical trials of AA showed that baricitinib 4 mg/day was more effective than 2 mg per day. 21In our study, all patients received 2 mg of oral baricitinib until 24 weeks, except for four patients added to 4 mg after 12 weeks, and 68.75% of them reported over 80% hair covering of the scalp.Our data are not only better than expected but also better than many previous clinical studies on the efficacy of baricitinib in the treatment of AA. 22 This may be due to the fact that some of our patients had shorter, less severe disease (SALT score 25%-49%), and thus responded better to treatment, while some patients were combined with topical minoxidil, which increased the efficacy.The majority of patients in this study had been previously treated with minoxidil but with poor efficacy, suggesting that hair growth agents alone are not sufficient to stop and reverse severe AA, and intervention in immune disorders is strongly needed.
In summary, the hair situation of AA patients in our trial was improved by baricitinib without any major adverse event observed.
Our results showed that baricitinib had favorable clinical effectiveness and safety in treating patients with refractory AA at moderate to severe levels, which is worthy of attention and expectation, while Department from March 2021 to June 2022.Medical and laboratory tests were also performed for safety concerns.The patients, with alopecia severity assessment tool (SALT) score ≥25, and had received traditional treatment before, including glucocorticoids, cyclosporine, and traditional Chinese medicine, whose curative effects were not satisfactory.All patients were treated with oral baricitinib (manufactured by Eli Lilly and Company) 2 mg per day after full communication and informed consent, with contraindications excluded.The patients were followed up at 4, 12, and 24 weeks after the baricitinib treatment started.This study has obtained approval from the IRB.All patients in this study signed the informed consent before their participation.Although this study was an open-label study in the real word instead of a random control trial, it still adhered strictly to the Declaration of Helsinki to protect the interest of patients.
its long-term efficacy and safety still await further observation and study.AUTH O R CO NTR I B UTI O N S Weiling Sun (corresponding author): Conceptualization, methodology, software, investigation, formal analysis, and writing-original draft; Lingbo Bi (first author): Investigation, data curation, and writing-original draft; Chaofan Wang: Visualization and investigation; Yimei Du: Investigation and patients management; Tong Su: Investigation, patients management; Min Zhao: Software and validation; Xuewen Lin: Visualization and editing; Weixin Fan (corresponding author): Conceptualization, funding acquisition, resources, supervision, and writing.ACK N OWLED G M ENTS Funding from the National Natural Science Foundation of China is gratefully acknowledged.FU N D I N G I N FO R M ATI O N This work was supported by the National Natural Science Foundation of China (No. 81972954).