Effectiveness of oral tofacitinib treatment on patients with moderate‐to‐severe alopecia areata in Iran

Alopecia areata is an inflammatory hair loss and a common autoimmune disease. Conducting treatment studies on alopecia areata is difficult due to unpredictable periods and even spontaneous recovery from the disease. In this study, the effectiveness of tofacitinib in treating alopecia areata was investigated.

response to treatment among patients, each of these drugs, especially systemic drugs, has side effects. 4,5[15][16][17][18] It is worth noting alopecia areata is prevalent in Iran, 19 and tofacitinib has been recently available as a treatment in the country. 13fore the widespread use of this drug in the Iranian population, it is necessary to conduct studies to understand its effectiveness.On the other hand, considering the side effects of previous drugs such as prednisolone as well as lack of insufficient response to treatment or the instability of the treatment effect, 20,21 the use of tofacitinib as an almost new treatment is effective and promising for alopecia areata treatment.

| MATERIAL S AND ME THODS
All the methods used in this research follow the regulations of the medical ethics committee of Isfahan University of Medical Sciences.
This study was semi-experimental.The target population was patients with alopecia areata older than 18 years old who were referred to Sedigeh Tahereh Skin and Hair Clinic (affiliated with the Isfahan University of Medical Sciences, Isfahan, Iran) and were under treatment with oral tofacitinib.In the treatment center, there were contact details of 134 AA patients who had visited the center within 3 years, and among them, 73 patients were treated with tofacitinib.
After reviewing their records, there were 47 patients who had complete medical records and were willing to participate in this study.
The criteria for inclusion of the patients included being over 18 years of age with no current treatments of alopecia areata or with previous ineffective treatment or associated with side effects.Complete clinical and laboratory history including complete metabolic and lipid profile, HIV, hepatitis, and PPD tests were recorded for these patients before starting the treatment.Patients who refused to participate for any reason or with incomplete medical record were excluded. 22In addition, only patients with moderate and severe hair loss were included in the study.
In the treatment center, medical history, time and dose of the drug initiation, clinical tests, treatment process, and follow-ups were recorded and given to the patients in each treatment session.After obtaining verbal consent from those with their contact details in the registration center, they were asked to bring their medical history.

| Treatment method
The initial drug regimen was 5 mg tofacitinib tablets twice a day, and the duration of usage lasted at least 6 months. 23After the complete response to the treatment, the dose was tapered to control the disease with the minimum maintenance drug dose.In cases where the patient's condition could be controlled with the minimum maintenance dose without disease recurrence, the drug was discontinued.In this study, the minimum follow-up period was 18 months.In addition, a questionnaire was prepared and filled with information such as age, gender, concomitant autoimmune disease, age at the disease onset, duration of the disease, and duration of the treatment with tofacitinib for this disease and other conditions associated with this disease.The latest photo of the patient was also recorded.It should be noted that possible complications due to drug use were also recorded and investigated. 24Disease severity was assessed using the Alopecia Severity Tool (SALT score) (Table 1) (Figure 1).Information including photos before and during treatment and other medical documents related to the disease were extracted from each patient's medical records.Based on the medical history and photos, the score before and after the treatment was determined for each patient. 24

| Statistical analysis
In this study, general linear models were used for analyzing data using SPSS software version 26.

| RE SULTS
In total, 47 patients with an average age of 30 years participated in the study, of which 47.1% and 52.9% were female and male, respectively.

TA B L E 1
Alopecia Severity Tool score.
Our findings show that the frequency of hair loss in people suffering from vitiligo and alopecia areata was 56%, and the difference was statistically significant (p < 0.05).The frequency of hair loss in patients with hypothyroidism in addition to alopecia areata was 1.8 times higher than in those with only alopecia areata (p < 0.05).Nail involvement in cases with vitiligo and alopecia areata was 2.7 times more than in patients with only alopecia areata (p < 0.05).Among The effects of the tofacitinib were followed up in two intervals of 6 months and 18 months after the treatment.After 6 months of treatment (taking 5 mg of tofacitinib twice a day), all the patients except for three of them who had stable treatment were prescribed maintenance dose (average daily intake of 7 mg of tofacitinib) to prevent recurrent hair loss.Hair loss decreased by 6.45 times after 18 months compared to the start of treatment and 0.5 times after the end of 6 months which shows that the treatment had a positive effect (p < 0.05).The detailed examination of the changes in hair loss because of the therapeutic effect of tofacitinib in two-time intervals of 6 and 18 months is included in Table 2. Photos of a patient with complete hair regrowth after 6 months are shown in Figure 2.
Body hair loss decreased four times after 18 months compared to the start of treatment and 0.6 times compared to the end of 6 months which shows the treatment had positive effect (p < 0.05).
Detailed changes in body hair loss were also investigated at twotime intervals of 6 and 18 months after treatment and recorded in Table 3.After 18 months of treatment, the reduction in nail involvement was 1.2 times and compared to 6 months of treatment was 0.6 (p < 0.05).Table 4 shows the detailed changes in nail involvement.

| DISCUSS ION
Alopecia areata is a common autoimmune disease, and the degree of alopecia varies from mild hair loss, including patchy hair loss, to complete hair loss on the head and body. 1,2This disease is highly prevalent in the United States, and its risk is 1.7%. 2 Similar to other countries in the world, it is prevalent in Iran. 19Nevertheless, alopecia areata is a significant unmet need in dermatology, and there is no definitive treatment for it.Cytotoxic CD8+ T cells cause hair follicle inflammation that leads to this disease.It functions through IFN-γ and IL-15, 3 and JAK/STAT pathways are downstream of these cytokine pathways.[8][9] In this study, it was observed that the percentage of hair loss on the head, body, and nail involvement was significantly higher in cases with alopecia areata and other autoimmune diseases such as vitiligo and hypothyroidism (p < 0.05).Therefore, it is useful to prescribe tofacitinib F I G U R E 1 The method for determining hair loss percentage.for the treatment of this disease, especially because, like the study conducted by Dai et al. 25 on Asian patients, in most of the patients under treatment, the side effects of the drug were very minor and reversible.
Although in the study of Cheng et al., 26 use of 5 mg of tofacitinib twice a day had complications such as hyperlipidemia and weight gain in some patients, adding exercise and proper diet to their lifestyle resolved the complications.In addition, in the study by Yichu Liu et al., 27 using the same dosage had very mild side effects in the upper respiratory tract and urinary tract, and there was no need to stop the medication.In another study by Ibrahim et al., 18 after observing three types of side effects caused by tofacitinib use, the dosage was reduced, and the side effects completely disappeared.According to our study and other studies, the use of tofacitinib is recommended for the treatment of alopecia areata due to the absence of serious side effects.
In this study, as in the most studies, cases treated with a dosage of 5 mg twice a day of tofacitinib were followed after 6 month. 18,28,29e average maintenance dose of the drug in our study was 7 mg daily, which reduced the risk of any side effects caused by increasing the dose of the drug.In studies conducted by Steves et al. 29 and Ibrahim et al., 18 10 mg of tofacitinib was prescribed after 4-5 months follow-up for treatment stability.In the study by Yichu Liu et al. 27 and Hogan et al., 22 the average maintenance dose was 15 mg and 20 mg, respectively.
The limitation of our study was that we conducted a retrospective study to have a larger statistical population for investigating tofacitinib effects.However, it is suggested to conduct a randomized controlled clinical trial to determine the drug effectiveness, side effects, and the necessary dose for treatment and prevention of relapse with minimal side effects for patients.

| CON CLUS ION
The prescription and treatment of alopecia areata with the tofacitinib in Iran is recommended due to the insignificant and reversible side effects of the drug, as well as its positive effects in reducing hair loss on the head, body, and nail involvement.
47 patients under treatment with tofacitinib, only one case was excluded from the study after 6 months due to sensory-peripheral neuropathy, and the patient recovered from all symptoms two months after treatment cessation.No abnormal signs or complications due to tofacitinib use were observed in other subjects.In addition, during the 6-month treatment and follow-up period, there were no changes in laboratory tests in the patients.

2
The percentage of detailed comparative changes in hair loss according to Alopecia Severity Tool score.

3 4
The percentage of detailed comparative changes in body hair loss according to Alopecia Severity Tool score.The percentage of detailed comparative changes in nail involvement according to Alopecia Severity Tool score.F I G U R E 2A woman with alopecia areata (A) before treatment, (B) 6 months after treatment with tofacitinib, and (C) 18 months after treatment.