FormalPara Key Points

Several pro-inflammatory cytokines involved in alopeica areata (AA) pathogenesis, including interleukin-15, interferon-γ, and type 2 cytokines, signal through the Janus kinase (JAK) pathway.

Baricitinib was shown to be superior to placebo for hair growth after 36 weeks of treatment in adults with severe AA in a phase 2 trial and recently in two phase 3 trials (BRAVE-AA1 and BRAVE-AA2).

On the basis of BRAVE-AA1 and BRAVE-AA2 results, baricitinib was recently approved by the EMA and US FDA for the treatment of adults with severe AA.

1 Introduction

Alopecia areata (AA) is a relapsing, chronic, immune-mediated disease characterized by nonscarring, inflammatory hair loss that can affect any hair-bearing site [1]. AA clinical presentation is significantly heterogeneous. Classically, AA presents as a single or multiple asymptomatic, well-demarcated, circular, and smooth patches of hair loss [1]. Patchy scalp alopecia can progress to alopecia totalis (total scalp hair loss) or alopecia universalis (total body hair loss) [1]. AA affects patients of all genders, ethnicities, and age groups, with an incidence and prevalence in the general population of 0.7–4% and approximately 0.2%, respectively [2, 3]. AA is unusual in children younger than 3 years of age, but common in young people, as up to 66% of patients with AA are younger than 30 years, and only 20% are older than 40 years [4]. AA is associated with an increased overall risk of other concomitant autoimmune diseases (16%), including atopic conditions such as atopic dermatitis (the highest association), vitiligo, autoimmune thyroid disease, and systemic lupus erythematosus [5,6,7,8,9]. In addition, AA has an enormous psychological impact on patients, being associated with high rates of anxiety and depression [3, 10]. Suicides have also been reported in adolescents recently diagnosed with AA who had no previous psychological disorders [3, 10].

AA treatment aims to stop its progression and reverse hair loss. Although spontaneous resolution may occur in mild episodes lasting less than 12 months, extensive AA is unlikely to regress without treatment [11]. Current treatment options are limited. Glucocorticoids (topical, intralesional, and systemic), contact immunotherapy, and other immunosuppressive agents (methotrexate, azathioprine, cyclosporine) have variable efficacy in severe AA cases and are not approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) [12].

AA pathogenesis involves immune and genetic factors [13, 14]. AA has a polygenic inheritance [15]. Several pro-inflammatory cytokines involved in AA pathogenesis, including type 1 [such as interleukin (IL)-15 and interferon-γ (IFN-γ)] and type 2 cytokines (e.g., IL-13) signal through Janus kinase (JAK) pathway [16]. JAK inhibition has shown to stop hair loss and to reverse alopecia once installed, exhibiting promise in treating AA in clinical trials [14, 17]. In patients with significant scalp and/or body hair loss, AA has been associated with systemic inflammation, suggesting the need for systemic treatment [18].

Baricitinib, an oral, reversible, selective JAK1/JAK2 inhibitor, was shown to be superior to placebo on hair growth after 36 weeks of treatment in adults with severe AA, in a phase 2 trial and recently in two phase 3 trials (BRAVE-AA1 and BRAVE-AA2) [17]. On the basis of these trial results, baricitinib was recently approved by the EMA and FDA for the treatment of adults with severe AA [19, 20].

This article intends to review the current literature on baricitinib in AA management.

A review of the published literature was conducted (up until March 2023) using the PubMed database, published abstracts and virtual presentations from scientific meetings, data from industry press releases, and results published on ClinicalTrials.gov. Manuscripts with trial results, case series, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on the topic of the article were selected.

2 The Role of the JAK-STAT Pathway in AA Pathogenesis

The hair follicle has a relative immunological privilege, and AA is associated with abnormalities in this hair follicle immune privilege, with anagen hair follicles, especially the pigment-producing hair follicle, being targeted by inflammatory cells [21, 22]. Cytotoxic CD8+ NKG2D+ T cells have been shown to play a critical role in AA development [14]. The IL-15 upregulation in hair follicles contributes to the loss of its immunological privilege, by triggering the recruitment and activation of CD8+ NKG2D+ T cells, provoking IFN-γ production [14]. The infiltration of this subset of T cells into the hair follicle epithelial layers triggers an upregulation of several γ-chain cytokines and IFN-γ response promoting the CD8+ NKG2D+ T-cell activation and survival [14]. Antibodies against IL-2, IFN-γ, or IL-15Rβ prevented the AA development, reducing the cutaneous accumulation of CD8+ NKG2D+ T cells [14]. A genome-wide association study recognized connections between several genes that control regulatory T-cell activation and proliferation, IL-2/IL-21, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), the antigen region human leukocyte (HLA), and IL-2 receptor A (IL-2RA) and AA [13]. The importance of environmental factors in provoking the disease remains unknown [23]. No correlation between AA and stress hormone levels has been found in controlled clinical studies with humans [24].

The JAK family is composed of four intracellular enzymes (cytoplasmic tyrosine kinases): JAK1, JAK2, JAK3, and TYK2. They interact with type 1 and 2 cytokine receptors and mediate intracellular signal transduction, affecting the cells’ proliferation, migration, differentiation, and apoptosis [25]. JAKs play an essential role in hematopoiesis, immune responses, and host defense [26]. Cell signaling via IL-15, IFN-γ, and several other cytokines involved in AA (IL-2, IL-7, IL-13, and IL-21) occurs through the JAK signal transducer and activator of the transcriptional (STAT) signaling pathway [7,8,9, 14, 18]. In AA, IFN-γ has been shown to promote IL-15 production in hair follicles through JAK1/2 signaling. IL-15 also stimulated IFN-γ production by T cells via JAK1/3 signaling, amplifying the inflammatory response around hair follicles. Thus, JAK inhibitors appear to be a potential therapeutic option for AA treatment [27, 28].

3 Baricitinib

Baricitinib selectively inhibits JAK1 and 2 [29]. Baricitinib exhibited 100-fold selectivity for JAK1 and JAK2 over JAK3. The lower affinity for JAK3 could potentially decrease the immunosuppressive effects expected as a consequence JAK3 inhibition [30]. Baricitinib has an oral bioavailability of approximately 80%. Metabolism is mainly carried out via CYP3A4 [31].The half-life is approximately 12 h. Approximately 75% of the drug is eliminated via urine and 20% via feces. Of the drug eliminated, 69% is unchanged in urine and 15% in feces [29].

Baricitinib is currently approved for the treatment of moderate to severe rheumatoid arthritis (2017/2018, EMA [32] and FDA [33], respectively), moderate to severe atopic dermatitis (2020, EMA [34]), and more recently coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (2022, FDA [35]). In May and June 2022, baricitinib was approved for severe alopecia areata by the EMA [20] and FDA [19], respectively.

3.1 Phase 2 Trials

3.1.1 Clinical Efficacy

BRAVE-AA1 (NCT03570749), a phase 2/3 adaptive, placebo (PBO)-controlled, double-blind trial, evaluated the efficacy and safety of oral baricitinib in patients with AA who had ≥ 50% scalp hair loss. A total of 110 patients were randomized 1:1:1:1 to receive baricitinib 1 mg (28 patients), 2 mg (27 patients), or 4 mg (27 patients) once daily (OD) or placebo (28 patients). The trial had two interim analysis after all patients completed 12/16 weeks and 36 weeks of treatment or early discontinuation. The first interim analysis (12/16 weeks) aimed to identify two doses of baricitinib to advance to a second phase 3 trial (BRAVE-AA2) and study’s phase 3 part, and the second analysis to assess the drug's efficacy and safety [36]. More detailed information can be found in Table 1.

Table 1 Baricitinib results in the treatment of AA
Full size table

The trial included patients with severe AA [Severity of Alopecia Tool (SALT) score of 50–94% of scalp hair loss] or very severe AA (SALT score 95–100%), aged ≥ 18 to ≤ 70 years and ≥ 18 to ≤ 60 years for women and men, respectively, and with a current episode of AA lasting > 6 months to < 8 years, with no spontaneous improvement (≤ 10 point reduction in SALT score) in the past 6 months or lasting > 8 years, but with regrowth episodes in the previous 8 years. Different age limits were set due to differences in the severity and prevalence of androgenetic alopecia (AGA) between the sexes [36].

Patients with “diffuse” AA or other types of alopecia, patients who received topical corticosteroids or topical JAK inhibitors 1 and 4 weeks, respectively, before the start of the study, or intralesional, systemic corticosteroids, or oral JAK inhibitors 8 weeks before randomization, were excluded. During the trial, no other treatments for AA were allowed [36].

In the first interim analysis, the proportion of patients who achieved a ≥ 30% baseline improvement in SALT score (SALT30) at week 12 or ≥ 50% baseline improvement in SALT score (SALT50) at week 16 was used in the decision on the two doses. The primary endpoint in the second interim analysis was the proportion of patients who achieved a SALT score ≤ 20 at week 36 [36].

At week 12, 33.3%, 29.6%, 17.9%, and 10.7% of patients achieved a SALT30 when treated with baricitinib 4 mg, 2 mg, 1 mg, and placebo, respectively. Of patients who completed 16 weeks or discontinued earlier (87 patients), SALT50 response was achieved by 31.8%, 38.1%, 18.2%, and 4.5% patients treated with baricitinib 2 mg (P = 0.057 versus PBO), 4 mg (P = 0.036 versus PBO), 1 mg, and placebo, respectively. On the basis of the results presented, the 2 mg and 4 mg doses were selected for phase 3 studies. Patients on baricitinib 1 mg were transferred to the baricitinib 4 mg group but were not included in subsequent analyses [36].

At week 36, a significantly higher proportion of patients achieved a SALT ≤ 20 in the baricitinib 4 mg and 2 mg group compared with PBO (51.9%, 33.3% versus 3.6%, P = 0.016 and P = 0.001, respectively). Patients treated with baricitinib 4 mg and 2 mg had a significantly greater percent change from baseline in SALT score (least square mean ± standard error) than PBO (− 58.1 ± 7.8, P < 0.001; − 48.2 ± 7.9, P < 0.001; and − 11.7 ± 7.8; respectively). The SALT 10 score was achieved significantly higher in patients in the baricitinib 4 mg (40.7%, P = 0.008) and baricitinib 2 mg (25.9%, P = 0.046) group compared with the PBO (0%). SALT50, SALT75, SALT90, and SALT100 responses were significantly higher in patients treated with baricitinib 4 mg compared with PBO. The more detailed results can be found in Table 1 [36].

3.1.2 Safety

The most frequently observed adverse events (AEs) in patients taking baricitinib were nausea, acne, and upper respiratory tract infection. Treatment-emergent adverse events occurred in 77.8%, 70.4%, and 60.7% of patients on baricitinib 4 mg, 2 mg, and PBO, respectively. In none of the treated groups was there a serious adverse event or death. No thromboembolic events, malignancies, serious infections, or major adverse cardiovascular events were observed [36].

3.2 Phase 3 Trials

3.2.1 Clinical Efficacy

BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) are parallel-group, randomized, double-blind, 36-week, placebo-controlled trials that included 654 and 546 patients, respectively [17]. BRAVE-AA1 was an adaptive phase 2–3 trial as indicated earlier, but the results of the phase 3 part are included here (Table 1). The trials have the same eligibility criteria (already mentioned above) and primary and secondary endpoints. The primary outcome was a SALT score of 20 or less at week 36. Patients were randomized in a 3:2:2 ratio to receive oral baricitinib 4 mg, 2 mg, or placebo OD for 36 weeks [17].

At week 36, the percentage of patients achieving a SALT20 score was 38.8%, 35.9% in the baricitinib 4 mg group, 22.8%, 19.4% in the baricitinib 2 mg group, and 6.2%, 3.3% in the PBO group, in BRAVE-AA1 and BRAVE-AA2, respectively [17]. In BRAVE-AA1 and BRAVE-AA2, the difference between the baricitinib 4 mg group and the PBO group was 32.6 percentage points in both studies [95% confidence interval (CI) 25.6–39.5 and 25.6–39.6, respectively], and the difference between baricitinib 2 mg and placebo was 16.6 and 16.1 percentage points, respectively (95% CI 9.5–23.8 and 9.1–23.2, respectively) (P < 0.001 for each dose versus placebo in both studies) [17]. The results of the baricitinib 4 mg treated group were significantly superior compared with placebo in all the outcomes within the graphical test scheme, in BRAVE-AA1 [37]. In BRAVE-AA2, the baricitinib 4 mg group also differed significantly compared with the placebo, except for SALT10 at week 24 and the two subsequent secondary endpoints. In BRAVE-AA1, the graphical test procedure failed at SALT20 at week 16 in patients on baricitinib 2 mg and a ClinRO Measure for Eyelash Hair Loss score of 0 or 1 with a decrease of at least 2 points from baseline at week 36 did not pass the graphical test scheme. Meanwhile, in BRAVE-AA2, the baricitinib 2 mg group failed the graphical test procedure on the ClinRO measure for eyebrow hair loss at week 36. Additionally, the results of the eight subsequent outcomes did not differ significantly compared with the PBO [17].

Data from the long-term extension periods of BRAVE-AA1 and BRAVE-AA2, after 52 weeks, have recently been published. At 52 weeks, an increase in the proportion of patients achieving a SALT score ≤ 20 and a SALT score ≤ 10 was shown, most pronounced in patients on baricitinib 4 mg. SALT score ≤ 20 was achieved in 21.2% and 24.4% of patients under baricitinib 2 mg and 40.9% and 36.8% under baricitinib 4 mg in BRAVE-AA1 and BRAVE-AA2, respectively. SALT ≤ 10 was achieved in 14.1% and 16.7% of patients under baricitinib 2 mg and 29.9% and 27.8% under baricitinib 4 mg in BRAVE-AA1 and BRAVE-AA2, respectively [38]. Over the 52-week period, the trials also showed that eyebrow and eyelash response rates increased. At week 52, 27.9% and 16.3% of patients with baseline ClinRO Measure for Eyebrow Hair Loss scores of 2 or 3 had an improvement ≥ 2 points and a ClinRO Measure for Eyebrow Hair Loss score of 0 or 1 on baricitinib 2 mg and 39.4 % and 49.7% of patients on baricitinib 4 mg, in BRAVE-AA1 and BRAVE-AA2, respectively. At week 52, 21.6% and 30.3% of patients with baseline ClinRO Measure for Eyelash Hair Loss scores of 2 or 3 had an improvement ≥ 2 points and a ClinRO Measure for Eyebrow Hair Loss score of 0 or 1 on baricitinib 2 mg and 40.7% and 50.7% of patients on baricitinib 4 mg, in BRAVE-AA1 and BRAVE-AA2, respectively [38].

3.2.2 Safety

In BRAVE-AA1, AEs occurred in 59.6%, 50.8%, and 51.3% of patients treated with baricitinib 4 mg, 2 mg, and placebo, respectively. In BRAVE-AA2, AEs occurred in 68.4%, 66.1%, and 63.0% of patients treated with baricitinib 4 mg, 2 mg, and PBO, respectively. The proportions of patients who discontinued the study regimen due to AEs were low and were similar between study groups [17]. Serious AEs occurred in 2.1%, 2.2%, and 1.6% of patients on baricitinib 4 mg, 2 mg, and PBO, respectively, in BRAVE-AA1, and 3.4%, 2.6%, and 1.9%, respectively, in BRAVE-AA2. In both studies, acne and the incidence of urinary tract infections were more common in the baricitinib-treated groups. At least one infection was seen in 31.4% of patients on baricitinib 4 mg, 25.1% on baricitinib 2 mg, and 28.0% on PBO in BRAVE-AA1, and 29.6%, 37.4%, and 29.2% under baricitinib 4 mg, 2 mg, and PBO, respectively, in BRAVE-AA2 (Table 1). Herpes zoster infections occurred in 0.7%, 0.5%, and 0.5% of patients on baricitinib 4 mg, 2 mg, and PBO, respectively, in BRAVE-AA1, and 1.3%, 1.9%, and 0.6%, respectively. respectively, in BRAVE-AA2. All herpes zoster infections were localized [17]. There were no opportunistic infections, venous thromboembolic events, or gastrointestinal perforations in any of the studies. In BRAVE-AA1, a patient with cardiovascular risk factors suffered a myocardial infarction on baricitinib 2 mg. In BRAVE-AA2, one case of prostate cancer was reported in a patient on a PBO and one case of B-cell lymphoma in a patient on baricitinib 4 mg [17]. In BRAVE-AA1, one patient with a history of gastrointestinal bleeding experienced grade 4 anemia (defined as a hemoglobin level < 6.5 g/dl) when treated with baricitinib 4 mg and had to discontinue the study. In both studies, elevated levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were observed in approximately 25% and 40% of baricitinib-treated patients, respectively [17]. The recently published 52-week data showed that the most frequent treatment-emergent AEs included headache, upper respiratory tract infection, nasopharyngitis, urinary tract infection, COVID-19 infection, acne, and creatine phosphokinase elevation. The frequency of discontinuations due to AEs was low and similar between groups. During the BRAVE-AA1 extension phase, there was one case of herpes zoster, COVID-19, and appendicitis on baricitinib 4 mg, all patients recovered, and none discontinued. During the BRAVE-AA2 extension period, a COVID-19 infection in one patient on baricitinib 4 mg led to study discontinuation. In BRAVE-AA1, squamous cell carcinoma and ductal carcinoma in situ were reported after 16 months and 10 months in a patient on baricitinib 2 mg and 4 mg, respectively. No opportunistic infections, tuberculosis, venous thromboembolism (VTE), gastrointestinal perforations, or deaths were reported in any of the studies during the extension period. Most laboratory changes were similar between the baricitinib groups in both studies and similar to those reported in the 36-week data [38].

4 Discussion

AA is a chronic autoimmune disease with a huge impact on patients’ quality of life, especially in a severe form [1]. Recent advances in the AA pathogenesis have shown that JAK-STAT pathway plays a role in intracellular signaling of cytokines involved in the development of AA [14]. Therefore, JAK inhibitors are being investigated as therapies for this disorder [39,40,41,42]. Tofacitinib, a pan-JAK inhibitor, has been widely used off-label in the management of AA. Case series and open-label studies have demonstrated that tofacitinib is effective in the treatment of adults and adolescents with AA [43,44,45]. However, as tofacitinib is a pan-JAK inhibitor, it may be associated with adverse events [46]. Furthermore, a recent study comparing tofacitinib with tumor necrosis factor inhibitor showed that tofacitinib was associated with a higher risk of adverse cardiovascular events and cancers [47]. Baricitinib, a JAK1–JAK2 inhibitor, was recently approved for AA, after being studied for the treatment of adults with severe AA through two studies that included 1200 patients (BRAVE-AA1 and BRAVE-AA2) [17]. Several other JAK inhibitors are under investigation in ongoing clinical trials, namely CTP-543, deuruxolitinib, an oral inhibitor of JAK1 and JAK2, in phase 3 trial (NCT04518995) [48]; ritlecitinib, an inhibitor of JAK3 and tyrosine kinase expressed in hepatocellular carcinoma, in phase 2b/3 and 3 trials (NCT03732807 and NCT04006457) [49, 50]; and brepocitinib, an inhibitor of JAK1 and TYK2, in a phase 2 trial (NCT05076006) [51].

Baricitinib was superior to placebo at 36 weeks in potentiating hair growth, with a greater proportion of patients achieving significant hair regrowth resulting in 80% or more scalp coverage with baricitinib 2 mg and 4 mg compared with PBO. Similar results were reported with the Scalp Hair Assessment PRO instrument. At week 36, most patients that achieved the primary endpoint reached SALT90. In contrast to patients treated with baricitinib 4 mg, where the secondary endpoints supported the primary endpoint, the results for most key secondary outcomes with 2 mg baricitinib did not support the results for the primary outcome. Among patients with substantial eyebrow and eyelash hair loss at baseline, improvements in the area’s coverage were seen for patients taking baricitinib 4 mg OD at 36 weeks. The BRAVE-AA1 hierarchical analysis was changed on the basis of the BRAVE-AA2 results, which may have limited conclusions regarding secondary outcomes in BRAVE-AA1. In both studies, the most common AEs were upper respiratory tract infections, urinary tract infection, acne, headache, and elevated creatine kinase levels. Herpes zoster occurred in a low percentage of patients, but in BRAVE-AA2 it was slightly more common in patients treated with baricitinib compared with PBO [17]. Approximately 40% of patients on baricitinib had an increase in HDL levels, and about a quarter of patients treated with baricitinib had an increase in LDL cholesterol. The most recent data showed that the proportion of patients achieving hair, brow, and eyelash growth increased over 52 weeks of treatment, and the safety findings were consistent with the known safety profile of baricitinib. Although hair growth with baricitinib is superior to placebo, it is important to note that the proportion of patients achieving SALT 75, SALT 90, and SALT 100 responses is relatively low (< 50%).With the objective of verifying the adverse effects for longer periods, the extension phases of the trials are ongoing [52].

In both studies, several groups of patients were excluded, mainly patients with an episode lasting 8 years or longer without any hair growth and patients with a previous inadequate response to oral JAK inhibitors. It is not known whether the excluded patients would have benefited from baricitinib treatment. Several studies performed with tofacitinib in AA have shown that patients with a current episode of AT or AU of longer than 10 years in duration were less likely to respond to treatment. It may be possible that a long duration of current episode of AA decreases the probability of therapeutic response, highlighting the importance of early treatment of severe AA with JAK inhibitors [44, 53, 54].

Furthermore, despite efforts to limit the influence of AGA on trial results, it is possible that this influence may have partially affected the assessment of disease severity and response to treatment. Given the AA impact on patients’ quality of life, another limitation of the two studies is the omission of quality-of-life measures results. It could be argued that such measures, rather than hair regrowth, should be the primary endpoints [52]. In fact, a small trial with weekly dupilumab in AD showed significant changes in quality-of-life assessments with drug that correlated with clinical hair regrowth evaluations [7]. Further, the durability of hair growth after treatment cessation or reduction (from 4 to 2 mg) with baricitinib was not documented. The effects of withdrawing tofacitinib and ruxolitinib (JAK1/2 inhibitor) have been evaluated in uncontrolled studies, occurring within 8 weeks after stopping treatment [44, 45, 55]. Recently, a single-blind extension of a phase 2a randomized clinical trial with brepocitinib and ritlecitinib evaluated the maintenance, withdrawal, and retreatment of these drugs in the AA treatment. It was shown that only 18% and 39% of patients treated with ritlecitinib and brepocitinib, respectively, did not require retreatment after withdrawal. The median time after the discontinuation to re-treatment was 16.1 and 24.1 weeks with ritlecitinib and brepocitinib, respectively. The study showed that treatment effectiveness appears to have decreased after retreatment compared with the initial response. Therefore, additional studies are needed to demonstrate the withdrawal effect of baricitinib treatment in these patients [56].

On the basis of the results from the phase 3 trials, baricitinib was recently approved by the FDA and EMA as a first-in-disease systemic treatment for adults with severe AA. The recommended starting dose is baricitinib 2 mg/day, with an increase to 4 mg/day if treatment response is inadequate. For patients with nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider treating with 4 mg/day. As there are no studies combining therapies with baricitinib, the concomitant use of baricitinib with other biological immunomodulators, JAK inhibitors, cyclosporine, or other potent immunosuppressants is not recommended [19, 20].

During its November 2022 meeting, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended measures to minimize risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders [57]. These side effects include cardiovascular conditions, blood clots, cancer, and serious infections. These recommendations follow a review of available data, including the final results from a clinical trial of the tofacitinib and preliminary findings from an observational study involving baricitinib. The PRAC recommends that these medicines be used in the following patients only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past, and those at increased risk of cancer. The PRAC also recommends using JAK inhibitors with caution in patients with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism, VTE) other than those listed above. Further, the doses should be reduced in some patient groups who may be at risk of VTE, cancer, or major cardiovascular problems. These recommendations will provide important guidance to physicians in evaluating appropriate treatment choices for patients with AA. Nevertheless, it is important to highlight that these recommendations emerged from the data mainly in patients with rheumatoid arthritis, and until now baricitinib has been shown to have a favorable safety profile in patients with AA. Moreover, compared with the current available therapeutic options to treat AA (in particular systemic immunosuppressants), baricitinib appears to have a more favorable benefit/risk ratio [58, 59].

This approval marks a milestone in the treatment of patients with extensive AA, who face significant daily challenges, including social stigma, limited public knowledge about the disease, and a lack of treatment options.

Recently, hair regrowth with JAK inhibitors raised interest in the treatment of AA and shed additional light on its evolving pathogenesis and effect on patients [60]. As seen in other chronic inflammatory skin diseases, this approval is expected to be the launch pad for the emergence of new targeted therapies for this long-neglected condition.

5 Conclusion

In the phase 3 studies with severe AA, oral baricitinib OD was superior to placebo in terms of hair growth. Longer trials are needed to determine the efficacy and safety of baricitinib in AA. Current trials are ongoing and are planned to remain randomized and blinded for up to 200 weeks.