Evaluation of the Efficacy and Safety of Oral Tofacitinib for the Treatment of Alopecia Areata in Children
Abstract
Alopecia areata (AA) is a common chronic relapsing nonscarring alopecia. Severe forms of AA commonly manifest during childhood. Treatment of AA is challenging due to the variability of the disease course as well as unpredictable responses to treatment. There is no uniform approved treatment for cure or sustained remission in children till now. Tofacitinib emerged as a novel drug in the treatment of AA, but few studies have been conducted on its safety and efficacy in children. Limitation of this study includes retrospective nature, small sample size, and lack of prolonged follow-up. Aim. This retrospective study aimed to assess the efficacy and safety of oral tofacitinib in children with AA. Method. In this retrospective study, we included patients aged 18 years or younger with AA. The scalp blandness of included patients was greater than 20% and they were on oral tofacitinib for at least two months. The demographic data, clinical characteristics, tofacitinib efficacy, and adverse effects were recorded. The primary endpoint was the last recorded percent change in the Severity of Alopecia Tool (SALT) score during treatment. Results. We included 26 patients (12 males and 14 females) with AA with a mean age of 11.6 ± 4.42 (3–18) years. Eighteen of them were in the alopecia areata (AA) group, whereas eight patients had alopecia totalis (AT) or alopecia universalis (AU). The mean disease duration before starting treatment with tofacitinib was 3.9 ± 3.3 years. Most of the patients were on a tofacitinib daily dose of 5 mg (53.85%) and 10 mg (38.46%). Patients were on tofacitinib for 6.73 ± 3.79 months. The patients’ baseline SALT score was recorded as 68.58 ± 32.65 and the final SALT score was 17.65 ± 23.88. Thus, the patients achieved a 50.92% reduction in the SALT score. Interestingly, there were no statistically significant differences in clinical efficacy between subtypes of AA and AT/AU. Conclusion. Tofacitinib was significantly effective in treating AA and AT/AU in children, with mild tolerable adverse effects, although relapse during treatment and tapering was recorded. Future randomized clinical trials with longer follow-up periods are needed to evaluate the safety of oral tofacitinib in children.
1. Introduction
Alopecia areata (AA) is a common autoimmune disorder. It causes inflammatory nonscarring alopecia in adults and children. The prevalence of AA is estimated to be 2% in the general population. AA usually affects the scalp, although any hair-bearing site of the body could be involved and the disease might progress to alopecia totalis (AT) or even alopecia universalis (AU). Severe forms start during childhood. Thus, it can influence patients’ self-esteem, psychological well-being, and quality of life [1–3].
The pathophysiology of AA is triggered by infiltration of CD8 T cells, CD4 T cells, and natural killer group 2D T cells, which promotes INF gamma production, leading to IL-15 secretion through the Janus kinase 1/2 pathway. In a vicious cycle, IL-15 stimulation leads to more production of INF gamma in the hair follicle via the Janus kinase1/3 pathway causing a prompt inflammatory response, damage to the hair follicle, and hair loss [1, 2].
Several traditional therapies are used to manage the condition such as topical, intralesional, and systemic steroids; topical minoxidil; contact immune-chemotherapy; photo-chemotherapy; and systemic cytotoxic agents. However, there is no cure and the treatment is usually ineffective and not satisfactory [4, 5].
Recently Janus kinase inhibitors (tofacitinib, ruxolitinib, and baricitinib) have emerged as potentially effective treatments for AA to downstream its pathophysiology. Baricitinib was the only FDA-approved systemic medication for AA until June 2023 [5, 6]. Recently, ritlecitinib was approved for individuals older than 12 years [7].
Since severe AA usually affects the patients since childhood, it may cause significant psychological distress and lead to functional impairment in affected individuals. Thus, it is crucial to investigate any effective systemic medication for treating children especially for severe and refractory cases. Hence, in this study, we aimed to assess the efficacy and safety of oral tofacitinib in children suffering from AA.
2. Materials and Methods
2.1. Study Design
This is a retrospective cohort study approved by the Ethics Committee of Tehran University of Medical Science (IR.TUMS.MEDICINE.REC.1400.1027).
2.2. Participants
In this study, we reviewed the records of all children with AA on oral tofacitinib from January 2020 to February 2023. We obtained written and verbal informed consent from their parents before inclusion in the study. Inclusion criteria were as follows: (1) age less than 18, (2) patients who were on oral tofacitinib at least for 2 months, and (3) clinically confirmed AA with a SALT score equal to or more than 20. Patients were categorized into 2 groups: (1) AA and (2) AT/AU. The following data were extracted: (1) age, (2) sex, (3) age of disease onset, (4) family history of AA and autoimmune disorder, (5) dose of oral tofacitinib, (6) SALT score assessing alopecia severity, (7) concurrent medications, and (8) drug side effects. In case of incomplete records, exclusion was performed.
2.3. Methods
Before starting oral tofacitinib, laboratory evaluation such as complete blood count with differential, fasting lipid profile, comprehensive metabolic panel, QuantiFERON-TB Gold (Cellestis Limited, Melbourne, Australia), and screening for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) were requested. Initial SALT score and then follow-up every month at visit were recorded by a dermatologist. A SALT score of 100 represents a total loss of scalp hair, whereas a SALT score of 0 shows no hair loss. The absolute change in SALT score was evaluated by the following formula: (initial SALT score-last SALT score)/initial SALT score. A 100% change in the SALT score indicates complete hair growth, although a 0% change points to no hair growth. Greater than 5% change in the SALT score is regarded as a clinical response. The safety profile was assessed through a serial review of the medical history, physical examination, and recording of laboratory metabolic panel.
2.4. Statistical Analysis
Continuous quantitative variables were described as mean with standard deviation (SD) as well as median with interquartile ranges. Qualitative variables were described as frequencies. Clinical response was assessed by SALT score percent change rather than absolute difference. The Pearson correlation coefficient was used to show the correlation between patients’ clinical and demographic variables and clinical response. p < 0.05 was considered statistically significant. All data were analyzed by IBM SPSS statistical software version 23.
3. Results
3.1. Patient Characteristics
A total of 26 patients with a mean age of 11.6 ± 4.42 (3–18 years) were included in the study. There were 12 (46.2%) males and 14 (53.8%) females with mean disease duration before starting treatment with tofacitinib as 3.923 ± 3.37 years. Eighteen of them were clinically diagnosed with AA, while eight patients suffered from AT or AU. Family history was positive for AA in 9 (34.6%) patients and other disorders such as atopic dermatitis, hypothyroidism, and asthma in 17 (65.38%) patients. Patient demographic and clinical characteristics are presented in Table 1.
| Mean ± SD | Median (Q1–Q3) | |
|---|---|---|
| N | 26 | |
| Age (years) | 11.6 ± 4.42 (3–18) yrs | |
| Male/female | 12 (46.2%)/14 (53.8%) | |
| Disease duration (years) | 3.923 ± 3.37 | 2 (2–5) |
| Baseline SALT score | 68.58 ± 32.65 | 78.5 (43.5–100) |
| Final SALT score | 17.65 ± 23.88 | 9 (2.25–21.5) |
| AA | 18 (69.23%) | |
| AT | 3 (11.54%) | |
| AU | 5 (19.23%) | |
| Eyebrow involvement | ||
| No | 15 | |
| Yes | 11 | |
| Family history of AA | ||
| No | 17 (65.38%) | |
| Yes | 9 (34.6%) | |
| Family history of other disorders | ||
| No | 9 (34.6%) | |
| Yes | 17 (65.38%) |
3.2. Treatment Protocol and Efficacy
All of the patients included in the study tolerated oral tofacitinib well and continued with the treatment. The initial dose was determined based on the patient’s body weight; in case of body weight of more than 40 kg, a dose of 5 mg twice per day was started. If the body weight was less than 40 kg, 5 mg daily or 2.5 mg daily was advised. Initiation of the response was considered as a 5% decrease in the SALT score. If no response was observed after three months, the tofacitinib dosage was increased or adjuvant therapy was added. The only adjuvant therapy was topical corticosteroid in the initial few weeks of starting therapy with tofacitinib. It was applied to the scalp once per day for the first two weeks and then tapered to every day and then for another two weeks and finally discontinued in most of the cases.
The mean duration of tofacitinib therapy was 6.73 ± 3.79 months. Most of the patients were on tofacitinib daily dose of 5 mg (53.85%) and 10 mg (38.46%). Interestingly, the mean starting effect time was 7.2 ± 4.4 weeks. The patients’ baseline SALT score was regarded as 68.58 ± 32.65 and the final SALT score was 17.65 ± 23.88. Spontaneous relapse on oral tofacitinib was noticed in 9 (34.6%) patients. Tapering the dosage was performed in only 5 patients due to complete hair regrowth, but relapse occurred in 4 of them (80%). Thus, the drug dosage was increased to the previous dose. Table 2 shows oral tofacitinib’s prescription, efficacy, and safety features in included patients.
| Mean ± SD | Median (Q1–Q3) | |
|---|---|---|
| Duration of tofacitinib therapy (month) | 6.731 ± 3.79 | 6 (3.25–9) |
| Tofacitinib daily dosage | N | |
| 2.5 mg | 1 (3.85) | |
| 5 mg | 14 (53.85) | |
| 10 mg | 10 (38.46) | |
| 15 mg | 1 (3.85) | |
| Effect time (month) | 1.692 ± 1.05 | 2 (1–2) |
| Absolute SALT score changes in the AA group | 61.74 ± 57.89 | 84.11 |
| AT/AU group | 79.68 ± 33.6 | 93.22 |
| Adjuvant therapy (N) | ||
| No | 17 | |
| Yes | 9 | |
| Spontaneous relapse (N) | 9 (34.6%) | |
| Relapse while tapering the dose (N) | 4/5 (80%) | |
| Adverse effect (N) | ||
| Loss of appetite | 1 | |
| Headache | 1 | |
| Rise of LDL | 1 | |
| Rise of liver enzymes | 2 | |
| URI symptoms | 1 |
No association was found between the patients’ age, the duration of their most recent hair loss episode, the dosage of oral tofacitinib, the severity of AA (AA or AT/AU), and absolute SALT score change (p > 0.05).
3.3. Treatment Safety
Only mild adverse effect was reported such as loss of appetite and headache in two patients. An abnormal lipid profile was found in another patient that was corrected by exercise and lifestyle changes. Two patient laboratory data exhibited a moderate rise in liver enzymes which were corrected after 2 weeks of discontinuation of the medication. Treatment with the previous dose was reinstituted for both patients with subsequent normal liver enzymes on follow-up. In addition, mild temporary upper respiratory tract infection and coryza symptoms were recorded in one patient.
4. Discussion
AA is a common chronic autoimmune disorder with a variable response to nonspecific traditional medications including immune-suppressive agents. Severe forms of AA commonly manifest during childhood. Children as psychologically vulnerable patients could be affected adversely. Consequently, the deterioration of spiritual health and social performance may occur. Oral tofacitinib as a targeted immune-suppressive drug has promising efficacy in treating AA [8].
Our study shows that oral tofacitinib can significantly reduce the SALT score (50.92%) in children with AA independent of the severity of the disease within about 6 months.
This result is compatible with previous studies that showed the effectiveness of oral tofacitinib in the treatment of AA. Craiglow and colleagues presented 4 children with recalcitrant AT and AU aged 8–10 years. After 6 months of initiation of oral tofacitinib, they reported complete hair regrowth in half of them, 62% regrowth in one patient, and only scant hair regrowth in the other patient [9]. Another study was performed by Castelo-Soccio et al. on 8 adolescent AU patients who failed to respond to traditional systemic and topical agents. They received oral tofacitinib, and all patients showed significant hair growth; also, there was noticeable eyebrow, eyelash, and body hair growth of more than 50% [10]. In another survey reported by Craiglow et al. on 13 patients with AA aged 12–17 years, tofacitinib induced hair regrowth in 70% of the patients. They tolerated the drug with mild adverse effects. The median SALT score change was 93% during 6.5 months [11]. Jundong at el, in their retrospective study of 11 preschool children on treatment with tofacitinib 5 mg once or twice daily, aged 6–12 years, demonstrated that 82% of them experienced hair regrowth and 64% had a SALT score change of more than 50%, which is close to the result of this study [12]. In a recent study, Hussein et al, in a nearly 3-year duration retrospective, single-center cohort study, demonstrated that patients with AT were less responsive to treatment with oral tofacitinib, and 12 of 47 patients with AA did not respond to oral tofacitinib, and they were mostly patients with alopecia universalis, unlike our study in which 8 patients with AT/AU responded well and statistically, there were no difference in response between subtypes of alopecia areata [13]. Dai suggested tofacitinib as a therapeutic option for severe and recalcitrant AA in children. They reported the median SALT score change of 98.2% in 7 patients with AA aged 12–18 years for a median of 10 months [14]. In a case series of 3 children aged 5 years or less receiving tofacitinib, one patient achieved more than 90% response after 12 months, while the other experienced greater than 50% improvement for 6 and 21 months [1]. In another retrospective study on fourteen children aged 7–11 years, the median SALT score change was 67.7%; however, concurrent medication such as low doses of oral minoxidil and clarithromycin were advised in order to increase the efficacy and inhibit the hepatic metabolism of tofacitinib [15].
A meta-analysis performed on 275 patients with AA in clinical trials and observational studies revealed good to complete response in 54% and partial response in 26.1% to tofacitinib with 24% recurrence mostly after discontinuation. Oral dosage and duration of treatment are probably influencing the efficacy. According to this meta-analysis, the efficacy of oral tofacitinib dose did not differ significantly in children compared to adults [13]. Moreover, disease severity and duration were not the defining factors of response rate [4, 13].
Although oral tofacitinib is an effective option for severe AA, the positive effects are not durable after discontinuation. It should be continued at least for one year before deciding to taper or discontinue it [16]. In a survey, 25% showed relapse mostly during discontinuation [3]. In our study, AA flares occurred despite treatment or more commonly when tapering, eventually leading to starting a topical adjuvant agent or increasing the dosage. In general, early discontinuation may lead to relapse, treatment failure, or incomplete regrowth.
Regarding the safety profile, mild adverse effects such as upper respiratory tract infection and headache were the most common complaints following oral tofacitinib. Although acne was noted commonly as the aforementioned side effect, it was not specifically investigated as a side effect of tofacitinib. No significant side effects were reported in our study. Malgorzeta reported that the most common side effects of JAK inhibitors in patients with AA are acne and headache [17]. Nevertheless, a higher numerical not statistical risk of nonmelanocytic skin cancers such as squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma are reported following the long-term intake of 10 mg daily of oral tofacitinib in patients with rheumatoid arthritis [18]. Although the only JAK inhibitor that has been approved by the FDA for severe AA is baricitinib (JAK 1 and JAK 2), but selecting a JAK inhibitor depends mainly on its availability, cost, and selectivity to JAK receptors with recent studies showing better side effect profile for pan-JAK inhibitor (tofacitinib) [19].
Several limitations should be addressed in this study including a small number of patients, short-term follow-up, probable bias in SALT score assessment by a nonblind dermatologist, absence of a control group, and finally retrospective data.
5. Conclusion
Tofacitinib emerged in recent years as a potential treatment for severe and even refractory forms of AA. Despite rapid initial response with oral tofacitinib, flare and decrease in efficacy could be observed after several months of continuation of the therapy. Even though oral tofacitinib is generally well tolerated by children and adults, more long-term surveillance is needed to investigate its long-extended safety.
Consent
Written informed consent was obtained from the patients.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors’ Contributions
Robabeh Abedini designed the work, wrote and revised the draft, and agreed on all aspects of the study. Saman Al-Zahawi conceptualized the study, collected and analyzed the data, and agreed on all aspects of the study. Soorosh Dehghan wrote the draft, collected the data, followed-up the patients, and agreed on all aspects of the study. Narges Ghandi supervised the study, analyzed the data, approved the final manuscript, and agreed on all aspects of the study. Maryam Nasimi interpreted the data, discussed and approved the final draft, and agreed on all aspects of the study. Zahra Razavi conceptualized the study, wrote and revised the draft, approved the final draft, and agreed on all aspects of the study.
Acknowledgments
The study was conducted on personal capacity.
Open Research
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
