Evaluating Current and Emergent JAK Inhibitors for Alopecia Areata: A Narrative Review

Abstract

Alopecia areata (AA) is an autoimmune condition characterized by non-scarring hair loss on the scalp, face, and body, affecting approximately 2% of the global population. Current treatments, including topical corticosteroids, topical immunotherapies, and systemic immunosuppressants, often demonstrate inconsistent efficacy and raise concerns about long-term safety, emphasizing the need for safer and more effective therapies. Janus kinase (JAK) inhibitors have emerged as a promising treatment option, offering a targeted approach by addressing the immune-mediated mechanisms driving hair follicle destruction in AA. Recent clinical advances have led to FDA approval of three JAK inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—based on pivotal trials showing significant hair regrowth. Baricitinib has demonstrated durable efficacy, with 35–40% of patients achieving a Severity of Alopecia Tool (SALT) score ≤ 20 at 36 weeks. Ritlecitinib similarly reported 23% of patients achieving a SALT score ≤ 20 at week 24. Deuruxolitinib has also shown efficacy with 31% of patients achieving a SALT score ≤ 20 at 24 weeks. Off-label use of JAK inhibitors like tofacitinib and ruxolitinib have also demonstrated efficacy in limited studies. This review aims to consolidate and summarize the latest clinical evidence and trial data on JAK inhibitors for AA, providing an up-to-date resource for clinicians and researchers to guide evidence-based management and optimize therapeutic outcomes.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01517-9.

Plain Language Summary

Alopecia areata is a condition where a person’s immune system, which normally protects the body, mistakenly attacks their own hair. This causes hair to fall out on the head, face, or even all over the body. Treatments including different creams, steroid shots, or pills that dampen the immune system are used to help with hair regrowth, but these therapies can have serious side effects. Janus kinase inhibitors are being increasingly used in dermatology to help treat people with alopecia areata. These medications work by calming down the part of the immune system that is attacking the hair. Three Janus kinase inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—have been approved by the United States Food and Drug Administration. In clinical trials, many people who took these medications grew back a significant amount of their hair within several months. Some Janus kinase inhibitors that have been approved for other conditions, like tofacitinib and ruxolitinib, have also shown promise in treating alopecia areata. As other medications in this drug class are being tested in clinical trials, new data continue to emerge. This review outlines the unique features of each Janus kinase inhibitor, including how they work, how they are processed in the body, and the results of major clinical trials.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01517-9.

Key Summary Points

• Alopecia areata (AA) is an autoimmune disorder causing hair loss

• The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway drives inflammation, making JAK inhibitors a key therapeutic target

• FDA-approved options including baricitinib, ritlecitinib, and deuruxolitinib, as well as other off-label JAK inhibitors, have demonstrated efficacy in trials and in practice, highlighting the expanding role of oral and topical JAK inhibitors in revolutionizing AA management

Introduction

Alopecia areata (AA) is an autoimmune condition of non-scarring hair loss on the scalp, face, and body [1]. Global disease prevalence is 2%, with 80% of adult AA beginning by age 40, and a 2.3:1 predilection for females [2, 3]. AA pathogenesis is poorly understood, but likely involves environmental, genetic, and autoimmune factors, with the leading theory being hair follicle immune privilege collapse [4]. This leads to inflammatory cells targeting the hair bulb and increased MHC class I and II expression presenting self-antigens to CD8 + and CD4 + T-cells, as well as to natural killer cells [5]. Given the uncertainty of AA’s pathogenesis, many traditional therapies have lacked targeted approaches. Despite the availability of both local and systemic treatments, their efficacy is inconsistent, and safety concerns related to chronic immunosuppression remain [6, 7].

Discovery of the Role of the JAK-STAT Pathway in AA

A type I cytotoxic pathway is postulated to drive AA, with NKG2D-expressing CD8 + T-lymphocytes being essential for AA onset [7]. Increased IL-15 in the outer root sheath activates these cells, leading to IFN-γ release, hair follicle activation, and upregulation of IL-15, NKG2D ligands and MHC molecules [7]. A seminal genome-wide association study in 2010 by Christiano et al. identified multiple genetic loci associated with AA, including HLA-DR/DQ, IL-2/IL-21, ULBP3/ULBP6, and CTLA4, highlighting shared genetic pathways with other autoimmune diseases and revealing the contribution of the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway [8]. In contrast to traditional non-specific AA treatments, JAK inhibitors directly modulate the immune mechanisms underlying hair follicle destruction in AA while evading widespread immunosuppression [4, 6]. JAK inhibitors function by selectively blocking different JAK isoforms (JAK1, JAK2, JAK3, and TYK2), which consequently disrupts downstream signaling molecules contributing to disease pathogenesis (Fig. 1 and Table 1) [9].

Fig. 1.

Mechanism of action of Janus kinase (JAK) inhibitors in alopecia areata (AA). AA is driven by IL-15 signaling from the outer root sheath, leading to activation of the JAK-STAT pathway via the IFN-γ receptor and subsequent upregulation of pathogenic CD8⁺ NKG2D⁺ T cells. This immune response promotes inflammation and hair follicle destruction, as shown in the affected hair follicle on the left. JAK inhibitors, such as baricitinib, deuruxolitinib, and ritlecitinib, disrupt this pathway by blocking JAK-STAT signaling, thereby reducing CD8⁺ NKG2D⁺ T cell activation and halting disease progression, shown on the right

Table 1.

Janus kinase (JAK) inhibition profiles of topical and systemic treatments for alopecia areata (AA)

JAK inhibitor	JAK 1	JAK 2	JAK 3	TYK 2
Baricitinib	+  +	+  +	–	–
Ritlecitinib	–	–	+  +	+
Deuruxolitinib	+  +	+  +	–	–
Tofacitinib	+	–	+  +	–
Ruxolitinib	+  +	+  +	–	–
Delgocitinib	+	+	+	+

 +  +  = strong inhibition, +  = some inhibition, – = no inhibition

A subsequent series of animal and human investigations ultimately cemented the JAK-STAT pathway as a therapeutic target in AA. Reversibility of JAK-STAT was first demonstrated in vivo by grafting lesional skin onto a mouse host and administering ruxolitinib and tofacitinib, which successfully prevented the upregulation of CD8 + NKG2D + T cells and the onset of AA [10]. These findings were further corroborated by the first reported case in which a patient with both psoriasis and AA experienced resolution of both conditions following treatment with tofacitinib [7]. A subsequent small-scale phase 2 study in humans using ruxolitinib showed at least 50% hair regrowth in 75% of patients, further validating the rationale for JAK inhibitor use in AA and paving the way for landmark trials following shortly after [11].

Current Use of JAK Inhibition in AA

Baricitinib, ritlecitinib, and deuruxolitinib are three JAK inhibitors approved for the treatment of severe AA (Table 2, Supplementary Material) [12, 13]. Tofacitinib, ruxolitinib, and delgocitinib are other JAK inhibitors that have demonstrated efficacy as off-label options for the treatment of AA, and other drugs are currently in development (Table 2). By examining the latest evidence on FDA-approved and off-label JAK inhibitors, this review will highlight the growing utility of this medication class for the management of AA and suggest future directions for drug development and clinical practice.

Table 2.

Food and drug administration (FDA) approval status and efficacy data for topical and systemic Janus kinase (JAK) inhibitors used in alopecia areata (AA)

Treatment	FDA approval	Efficacy in key trials
Baricitinib (oral)	Yes (2022)	35–40% achieved ≥ 80% scalp hair coverage (SALT ≤ 20) in BRAVE-AA1/AA2 trials by week 36;21 sustained through week 15224
Ritlecitinib (oral)	Yes (2023, age 12 +)	32% achieved ≥ 80% scalp hair coverage by week 24 in ALLEGRO phase 3 trial;28 increasing to 45% at 1 year and 61% at 2 years30
Deuruxolitinib (oral)	Yes (2024)	41% achieved ≥ 80% scalp hair coverage (SALT ≤ 20) by week 24 in THRIVE-AA1/AA2 trials;36,76 continued improvement through 68 weeks38
Tofacitinib (oral)	No	58% achieved ≥ 50% SALT reduction in cohort studies; combination with prednisone improved regrowth but increased adverse events51
Ruxolitinib (oral)	No	41% SALT reduction at 3 months, 58% at 6 months in small trials;11 faster onset compared to oral tofacitinib (by ~ 4 weeks)52
Tofacitinib (topical)	No	75% of patients had partial hair regrowth after 28 weeks, applied twice daily64
Ruxolitinib (topical)	Yes (for vitiligo, AD)	31% had partial hair regrowth after 28 weeks, applied twice daily;64 phase 2 study showed no significant regrowth vs. placebo66
Delgocitinib (topical)	No	SALT score improvements by 12 weeks in 20 patients but not significant vs. placebo70

AD atopic dermatitis, SALT severity of alopecia tool

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

FDA-Approved JAK Inhibitors

Baricitinib was the first JAK inhibitor approved in June 2022 after pivotal trials demonstrated its efficacy in adults with severe AA [13]. This approval was followed by ritlecitinib in June 2023 for patients aged ≥ 12 years [13]. Deuruxolitinib obtained FDA approval in July 2024, but its commercial debut remained on hold because of a patent-related injunction, although this has been very recently rendered vacant [13]. All three of these medications carry the standard black-box warning required by the FDA for JAK inhibitors warning patients of potential severe adverse events, including serious infections, cardiovascular events, cancer, and death [14].

Baricitinib

Pharmacokinetics and Dosing

Baricitinib is a selective inhibitor of JAK1 and JAK2, which subsequently blocks immune cell activation and cytokine production (Table 1) [15, 16]. Peak plasma concentrations are reached within 1 h of oral administration [17]. It has a half-life of 12–16 h and an oral bioavailability of ~ 80% [17]. The drug is primarily renally filtrated and excreted via urine [17]. Starting dose is 2 mg daily but can be increased to 4 mg daily for severe AA or for poor response at 2 mg. It is recommended to reduce dosage back to 2 mg daily once an acceptable response has been achieved [18].

Pivotal Trials

Baricitinib demonstrated rapid onset of action, with initial hair regrowth observed in patients in as early as 12 weeks [19, 20]. In the pivotal parallel and identical BRAVE-AA1 and BRAVE-AA2 trials, which collectively enrolled > 1200 adults with severe AA, 35–40% of patients treated with 4 mg daily achieved at least 80% scalp hair coverage as measured by Severity of Alopecia Tool (SALT) score by week 36 [20]. Clinical responses to baricitinib were stratified based on the timing of improvement, highlighting its ability to deliver early and sustained benefits, particularly in patients achieving rapid regrowth within the first 12–24 weeks of therapy [21, 22]. Baricitinib has shown sustained efficacy in managing severe AA, with long-term data reinforcing its initial trial outcomes. Results from the BRAVE-AA2 trial up to week 152 highlight its potential for long-term disease management, with results of down-titration and sustained efficacy providing key data for future clinical decision-making and risk-benefit considerations in treatment goals (Table 2) [23].

Assessing Efficacy and Safety

A long-term pooled analysis from the BRAVE-AA1 and BRAVE-AA2 trials supports sustained efficacy in the setting of continuous treatment. Among patients initially treated with 4 mg daily who achieved significant scalp hair regrowth (SALT score ≤ 20) by week 52, only 66% of those down-titrated to 2 mg maintained their response at week 104, and 59% continued this trend at week 152 [23]. In comparison, 91% of patients who remained on the 4 mg dose sustained a SALT score ≤ 20 response at week 104 and 89% at week 152 [23]. Patients who lost treatment benefit after down-titration showed significant response upon resuming the 4 mg dose, with 67% regaining a SALT score ≤ 20 after 48 weeks of re-treatment [23].

Thirty-nine percent of mixed responders at week 52 (patients who achieved a SALT score ≤ 20 in prior visits, but not at week 52, or patients who had significant hair regrowth in eyebrows or eyelashes defined as a ≥ 2-point increase from eyebrow or eyelash baseline using Clinician-Reported Outcome Measures, ClinRO) reached SALT score ≤ 20 by week 104 [24]. These findings highlight a cohort of patients for whom eyebrow and eyelash regrowth may serve as an indicator of gradual and consistent scalp hair growth despite slower onset of action.

A sub-study of the BRAVE-AA1 phase 3 trial assessed the effects of baricitinib withdrawal in 654 adults with severe AA who had been successfully treated for 1 year [25]. At week 52, patients who had achieved significant scalp hair regrowth (SALT score ≤ 20) were re-randomized to either continue baricitinib or switch to placebo [25]. By week 152, 80% of patients who discontinued baricitinib experienced a loss of treatment benefit within 3–6 months compared to only 7% among those who continued treatment [25]. However, upon re-treatment, 63% of patients on the 2-mg dose and 88% on the 4-mg dose recaptured a SALT score of ≤ 20, demonstrating that sustained therapy is necessary for most patients to achieve and maintain benefit [25].

Common adverse effects include upper respiratory infections (URI), nausea, hyperlipidemia, acne, and headaches [15]. However, serious risks such as venous thromboembolism, elevated liver enzymes, and exacerbation or onset of severe infections have been reported in patients with AA [15]. These risks necessitate regular monitoring of liver function, lipid levels, and complete blood counts [15].

Ritlecitinib

Pharmacokinetics and Dosing

Ritlecitinib is a selective inhibitor of JAK3 and the tyrosine kinase expressed in the TEC family (Table 1) [26]. This dual inhibition modulates immune pathways implicated in the pathogenesis of AA [26]. Peak plasma levels occur within 2 h [26]. Its oral bioavailability is ~ 64% with an average half-life of 1.3–2.3 h [26]. The drug undergoes hepatic metabolism primarily via CYP3A4 [26]. Dosage for severe AA is typically 50 mg once daily orally [26].

Pivotal Trials

The ALLEGRO phase 2b/3 trial serves as a landmark study for ritlecitinib, having enrolled 718 participants aged ≥ 12 years with severe AA, defined as > 50% scalp hair loss [27]. Twenty-three percent of those receiving 50 mg ritlecitinib with no loading dose achieved a primary endpoint of SALT < 20 at week 24, which was the dosing that was ultimately approved [27]. This trial also included adolescents, making it one of the first large-scale studies to explore ritlecitinib efficacy in younger populations (Table 2) [27].

Assessing Efficacy and Safety

A post hoc analysis of the ALLEGRO 2b/3 trial demonstrated that > 85% of patients treated with ritlecitinib in the original ALLEGRO trial that reached a SALT score < 20 by week 24 maintained this response when continuing ritlecitinib through week 48. However, only 22–34% of patients that had a SALT score > 20 by week 24 reached a SALT score < 20 by week 48 [28]. After 1 year, 45% of participants achieved significant scalp hair regrowth (≤ 20% scalp hair loss) while using 50 mg ritlecitinib, with this proportion increasing to 61% after 2 years [29]. About 80% of individuals maintained hair regrowth between the first and second years of treatment in all groups, regardless of baseline SALT score, showcasing the benefit of continued treatment [29].

In the latest interim efficacy results, ritlecitinib continues to demonstrate successful scalp hair regrowth, increasing from 40–45% of patients achieving SALT < 20 by month 12 after consistent use of 50 mg daily ritlecitinib to 46–61% of patients achieving the same result by month 24 [29]. While ritlecitinib appears effective across patient groups, higher rates of discontinuation due to lack of efficacy were found in patients with alopecia totalis (AT) or universalis (AU) in groups receiving 50 mg ritlecitinib daily (37–44%) at data cutoff in 24-month long-term phase 3 trials [29]. Rates of discontinuation due to lack of efficacy for non-AT/AU participants were 26–31% [29]. Importantly, 45–47% of participants in the 50 mg dose groups had AT/AU at baseline [29].

Eyelash and eyebrow hair regrowth was observed over time with a ≥ 2 grade clinical score assessment increase from baseline in patients who did not have normal baseline eyebrows and eyelashes [27]. In patients with clinical response by week 24, 52–94% had achieved significant eyelash assessment score increase, and 70–97% had successfully achieved eyebrow assessment score increase through week 48 [28]. In those who did not achieve primary outcome clinical response, 17–30% eventually achieved an eyelash score increase by week 48, while 20–33% achieved the same result for eyebrow assessments [28].

Similar to baricitinib’s withdrawal data, a 24-week trial extension on patients who discontinued ritlecitinib demonstrated that the median time to meet re-treatment criterion (defined as ≥ 30% loss of hair regrowth) was 16 weeks, indicating hair loss symptoms began recurring within 4–6 months after stopping treatment [30]. The rates of sustained efficacy were not directly measured in this study, but 18% of ritlecitinib-treated patients did not meet re-treatment criterion after 24 weeks, indicating a small subset of patients had sustained hair regrowth with treatment discontinuation [30]. This suggests that treatment for a period > 24 weeks may have the added benefit of sustained efficacy and hair growth even after drug discontinuation in some individuals.

Common side effects include gastrointestinal effects, including nausea and diarrhea, headaches, and nasopharyngitis [26]. Rare but serious risks include liver enzyme elevation, pulmonary embolism, and hematologic changes, such as lymphopenia, and infectious risks, including appendicitis and sepsis [26, 31]. Regular monitoring of absolute lymphocyte counts, platelet counts, and liver enzymes are indicated [26].

Deuruxolitinib

Pharmacokinetics and Dosing

Deuruxolitinib is a selective JAK1 and JAK2 inhibitor (Table 1) [32]. Peak plasma concentration occurs within 1–2 h post-dose, and the half-life is approximately 4 h [32]. It has a bioavailability of 90%, and is primarily metabolized by CYP2C9, with steady-state levels reached in 1 to 2 days with twice-daily dosing [32]. Dosing for deuruxolitinib is typically 8 mg twice daily by mouth [32].

Pivotal Trials

Pooled analysis of the fundamental THRIVE-AA1 and THRIVE-AA2 phase 3 trials, which enrolled > 1000 adults with severe AA (defined as ≥ 50% scalp hair loss), showed that 31% of patients on the 8-mg deuruxolitinib twice-daily dose achieved SALT < 20 by week 24 [33]. The 12-mg twice-daily dose showed superior efficacy, with 42% of patients in the THRIVE-AA1 trial reaching SALT30 compared to 30% with the 8 mg dose [34]. In the extension study, the 12-mg twice-daily dosing was associated with an increased risk of serious adverse events, including three cases of pulmonary embolism [34]. Subsequently, this deuruxolitinib trial underwent partial clinical hold by the FDA, and the 12-mg trial arm was discontinued because of thrombotic risk [35]. Only the 8-mg dose was brought forward for FDA approval (Table 2) [34].

Assessing Efficacy and Safety

A proportion of responders achieved visible regrowth as early as 12 weeks, but continued improvement was seen at 36 weeks, suggesting greater benefit with prolonged treatment [34]. Treatment with 8 mg twice daily showed continued incremental improvement in hair growth after 68 weeks [36]. Importantly, these trials included patients with chronic disease (duration > 8 years), demonstrating efficacy in populations considered less responsive to treatment [34].

In a recent article, eyelash and eyebrow regrowth were evaluated using the Brigham Eyebrow Tool for Alopecia (BETA) and the Brigham Eyelash Tool for Alopecia (BETA) in 300 patients receiving deuruxolitinib 8 mg twice daily. Significant improvements were observed by week 24 compared to placebo (p < 0.0001), with BETA changes of 1.2 and BELA changes of 1.4 [37].

While relapse rates after treatment withdrawal are still under investigation, current data suggest that, like other FDA-approved JAK inhibitors, deuruxolitinib is most effective when used as a long-term treatment [38].

Adverse effects of deuruxolitinib include gastrointestinal disturbance, hypercholesterolemia, and risks of thrombosis due to elevated platelet count [32, 34]. Prior to initiating use, it is recommended to perform genetic testing to assess for CYP2C9 variants, concomitant CYP2C9 inhibitor use, active or latent tuberculosis, viral hepatitis infection, complete blood counts including absolute lymphocyte and neutrophil counts as well as hemoglobin, and complete any necessary immunizations [32]. Complete blood counts, including absolute lymphocyte counts, neutrophil counts, and hemoglobin, should be monitored regularly [32].

Off-Label Oral JAK Inhibitors

Tofacitinib and ruxolitinib were among the first JAK inhibitors to be used off-label in treatment of AA [39, 40]. While off-label prescribing may allow access to cheaper generic treatments, it also raises concerns about short- and long-term safety monitoring, dosing consistency, and reliable data, as these medications have fewer trial data in AA, and backing for their use relies on older trials, case reports, and clinical experience rather than regulatory approval. Oral tofacitinib is currently FDA-approved for multiple rheumatologic and gastroenterologic autoimmune diseases [41]. Oral ruxolitinib is FDA-approved for myelofibrosis, polycythemia vera, and graft-versus-host disease [42, 43].

Oral Tofacitinib

Pharmacokinetics and Dosing

Tofacitinib is a selective inhibitor of JAK1 and JAK 3, reducing the cytokines and JAK signal transduction that contribute to AA (Table 1) [44]. Peak plasma concentrations are reached within 0.5–1 h of oral administration [45]. The extended-release version has a half-life of approximately 6–9 h and an oral availability of 74% [45]. Tofacitinib is primarily metabolized in the liver by CYP3A4 and is excreted by both the liver and kidneys [41, 45, 46]. Oral tofacitinib as monotherapy has shown efficacy when dosed at 5 mg twice daily [47]. Additionally, low-dose tofacitinib at 5 mg once daily has demonstrated efficacy and is considered a cost effective alternative [48].

Assessing Efficacy and Safety

In a 2024 randomized double-blind controlled trial of 104 participants with at least 50% hair loss, oral tofacitinib 5 mg twice daily was compared to oral azathioprine 2 mg/kg. The primary outcomes of the trial, which were the mean SALT scores at baseline and after 6 months, showed an 84% reduction in the SALT score in the tofacitinib-treated group after 6 months [46, 49].

The largest study for tofacitinib in AA to date is a retrospective cohort study of 90 patients. Fifty-eight percent of tofacitinib 5 mg twice-daily treated patients achieved > 50% reduction in SALT score over 18 months [50]. Another randomized clinical trial compared tofacitinib 5 mg twice daily to ruxolitinib 20 mg twice daily in 75 patients with severe AA and found similar mean changes in SALT scores for both groups (95% vs 94%, respectively.) [51]. Dual therapy of tofacitinib 5 mg twice daily with pulsed prednisone 300 mg monthly was explored in patients with at least 40% scalp hair loss; results showed increased hair regrowth compared to oral tofacitinib 5 mg twice-daily monotherapy [50]. About 8% of all patients treated with tofacitinib in the study reported worsening or newfound acne vulgaris, but no serious adverse events occurred [50].

Relapse rates after treatment cessation are relatively high, similar to other JAK inhibitors used in AA. In the previous study, disease relapse occurred in almost two-thirds of patients after treatment cessation in the tofacitinib-treated group [51]. In a 2016 open-label, single-arm trial of 66 patients with AA with > 50% hair loss taking tofacitinib 5 mg twice daily, 20 patients experienced hair loss beginning at a median of 8.5 weeks after discontinuation [52]. In one retrospective study, 52% of patients who discontinued tofacitinib after 3 months experienced a relapse in the following 3 months, yet those on combination therapy with low-dose IL-2 had a lower incidence of relapse [53].

The black box warning issued for all JAK inhibitors originated years ago after the release of safety data from a trial in patients > 50 years old with at least one pre-existing cardiovascular risk factor, suggesting heightened cancer and cardiovascular risks in rheumatoid arthritis patients treated with oral tofacitinib [14, 54]. Current data suggest low-dose oral tofacitinib is well tolerated, with few reported adverse events [39, 49, 50, 55]. However, data for safety outcomes in patients with AA are very limited. A recent retrospective chart review consisting of 36 children and adolescents aged ≤ 16 years with baseline SALT score > 20 on oral tofacitinib, either 5 mg or 10 mg daily, showed that two patients had to discontinue treatment due to urinary tract infection (UTI) and leukopenia, while seven others reported acneiform eruptions, dyspepsia, transaminitis, and hypertriglyceridemia [56]. Tofacitinib has also been associated with increased risk of URIs and nasopharyngitis [46, 55]. Other mild gastrointestinal symptoms including diarrhea have also been reported [46, 55]. Routine monitoring of lipids, liver enzymes, lymphocyte counts, neutrophil counts, and hemoglobin is recommended [41].

Oral Ruxolitinib

Pharmacokinetics and Dosing

Ruxolitinib is a JAK1 and JAK2 inhibitor that reaches peak plasma concentration within 1–2 h, with a half-life of approximately 3–6 h (Table 1) [57]. Oral bioavailability is 95%, and steady-state is typically achieved within 4–5 days with twice-daily dosing [57]. Ruxolitinib is mainly metabolized by CYP3A4 [58]. Dosing at 20 mg twice daily has shown efficacy in open-label studies [11]. A case report demonstrated sustained response in a child with severe AA when tapered to 10 mg twice daily for 8 months, then 10 mg once daily for 3 months, and then 10 mg every other day indefinitely after having received initial treatment of 20 mg twice daily for 4 months [59].

Assessing Efficacy and Safety

Studies on ruxolitinib are limited to open-label pilot and parallel studies. An open-label clinical trial treated 12 participants who had moderate-to-severe AA with a baseline SALT score of 66% ± 28% with oral ruxolitinib 20 mg twice daily for 3–6 months [11]. This demonstrated a 41% reduction in SALT score after 3 months and a 58% reduction after 6 months [11]. Another open-label parallel study compared ruxolitinib 20 mg twice daily to tofacitinib 5 mg twice daily in 75 patients with severe AA. Initial time to hair regrowth for patients treated with ruxolitinib was 4 ± 3 weeks, which was significantly shorter than for those treated with tofacitinib, who experienced an initial time to hair regrowth of 7 ± 2 weeks (p = 0.003) [51]. There was no significant difference between the two treatment groups in hair regrowth (95% reduction in SALT score) after 6 months or in disease relapse rates at 3-month follow-up [51].

Oral ruxolitinib is a generally well-tolerated medication with no reported major adverse events [11, 51, 57]. Limited data show associations with an increased risk of infection including URIs, UTIs, and bronchitis [11, 51]. Monitoring during treatment should consist of complete blood counts and lipid panels [58].

Off-Label Topical JAK Inhibitors

Topical ruxolitinib was approved in 2021 for the treatment of atopic dermatitis (AD) and in 2022 for non-segmental vitiligo [60]. Topical tofacitinib and delgocitinib are two other off-label JAK inhibitors available topically that show promise for the treatment of AA. In contrast to oral JAK inhibitors, topical formulations have the benefit of localized efficacy with limited systemic absorption, reducing the risk of side effects [61].

Topical Tofacitinib

Pharmacokinetics and Dosing

As mentioned above, tofacitinib selectively inhibits JAK1 and JAK3, blocking downstream cytokine signaling [62]. Topical tofacitinib penetrates the stratum corneum and reaches the deep layers of epidermal and dermal layers. Measurable systemic levels of tofacitinib were detected using 2% ointment, suggesting systemic absorption does occur, albeit to a negligible degree compared to oral formulations [63]. Currently, data on the pharmacokinetics of topical tofacitinib are significantly limited compared to its oral formulation.

Assessing Efficacy and Safety

Topical tofacitinib efficacy has been analyzed in only one clinical trial to date, in which 16 patients with alopecia universalis were randomized to receive either 2% tofacitinib or 1% ruxolitinib cream applied twice daily [64]. After 28 weeks of treatment on the scalp and face, 75% of patients treated with topical tofacitinib reported partial hair regrowth based on subjective clinical observation [64]. This is in comparison to 31% of patients who experienced regrowth with 1% ruxolitinib, 63% of patients who exhibited partial regrowth with topical clobetasol dipropionate 0.005%, and no regrowth observed in placebo-treated patients [64]. These data are difficult to interpret given the weak outcome measures in this study. Long-term data remain to be collected; however, relapse rates have been demonstrated to be relatively high in the oral formulation, as described above.

The only clinical trial available on topical tofacitinib reported no common or serious side effects [64]. Despite the extensive side effect profile of its oral counterpart, topical tofacitinib has limited systemic absorption, hence its safety profile.

Topical Ruxolitinib

Pharmacokinetics and Dosing

Ruxolitinib is a selective JAK1 and JAK2 inhibitor that reduces cytokine-mediated immune responses [65]. Topical ruxolitinib does not result in detectable plasma levels in once-daily dosing, but plasma concentrations do reach quantifiable levels with regular twice-daily application [65]. Metabolism occurs predominantly in the skin, and the CYP3A4 pathway plays a minimal role compared to oral formulation of the drug [65]. The half-life is 116 h for topical formulations [65].

Assessing Efficacy and Safety

A phase 1 prospective study was conducted to analyze the efficacy and safety of topical tofacitinib 2%, topical ruxolitinib 1%, and topical clobetasol dipropionate 0.005% versus placebo in promoting hair regrowth in 16 alopecia universalis patients [64]. Thirty-one percent of patients reported partial hair regrowth with administration of 1% ruxolitinib twice daily after 28 weeks [64]. However, these results were based on subjective clinical observation, not a validated instrument [64]. A larger phase 2 study of 90 participants with moderate-to-severe AA showed conflicting results, with participants treated with 1.5% ruxolitinib cream showing no significant differences in SALT score changes compared to placebo [66]. A large network meta-analysis of JAK inhibitors in AA challenges these findings because of the limited sample size, delineating the ongoing uncertainty regarding the agent’s efficacy [67].

Side effects for topical ruxolitinib were rare but included dry skin, itching, peeling, or folliculitis at the application site [66].

Topical Delgocitinib

Pharmacokinetics and Dosing

Delgocitinib is a selective JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) inhibitor that blocks multiple cytokine-mediated signaling pathways (Table 1) [68]. Delgocitinib has a half-life of ~ 20 h with topical administration, and peak plasma levels occur within 2–6 h following topical application [69]. Topical bioavailability is roughly 0.6% compared to systemic administration [69].

Assessing Efficacy and Safety

In a phase 2a clinical trial, 31 patients with moderate-to-severe AA received delgocitinib ointment 30 mg/g daily for 12 weeks. Among the 20 treated patients, SALT score improvements ranged from < 1% to 69% [70]. However, the mean SALT score improvement at 12 weeks was not significantly different from the placebo-treated group [70].

Delgocitinib’s safety profile is still under investigation, but has been well tolerated with no serious adverse events in clinical trials to date [70]. Some delgocitinib-treated patients reported minor adverse events, with folliculitis being most common [70].

Emerging JAK Inhibitors

Upadacitinib, a selective JAK1 inhibitor currently approved for atopic dermatitis, is currently in phase 3 trials for severe AA [71, 72]. Ivarmacitinib, a JAK3 selective inhibitor, has recently undergone a phase 2 clinical trial in which it has demonstrated efficacy in AA [73]. Jaktinib, a novel JAK1 and JAK2 inhibitor, has been evaluated in severe AA via an open-label phase 2 study; the results have still not been made publicly available [74]. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, is FDA approved for treatment of plaque psoriasis but has also shown promise in AA. It is currently in phase 2 clinical trials to evaluate safety and efficacy, and a case report has shown improvement in AU by SALT score [75].

Discussion

The FDA approval of JAK inhibitors has revolutionized the treatment landscape for severe AA, offering the first highly effective therapeutic option for this disease. Baricitinib, ritlecitinib, and deuruxolitinib have demonstrated safety and efficacy in large clinical trials. Additionally, oral and topical off-label JAK inhibitors, such as tofacitinib and ruxolitinib, have shown promising results, further expanding therapeutic possibilities. However, high-quality trials are still needed to validate the efficacy, safety, and durability of treatment response.

Long-term Safety Concerns

All JAK inhibitors carry a black box warning for serious adverse events, including major cardiovascular events, malignancy, thrombosis, and serious infections, derived from a trial of patients with rheumatoid arthritis > 50 years old who also had at least one pre-existing cardiovascular risk factor [54]. Although AA was not represented within the cohort for which the black box warning was issued, long-term exposure still raises concerns, especially given that treatment discontinuation may lead to relapse of disease. Longitudinal safety data continue to emerge; so far, the FDA-approved JAK inhibitors appear to have favorable long-term safety profiles when appropriately dosed, although regular laboratory monitoring is still warranted [15, 26, 32]. Larger prospective trials are ultimately needed to clarify long-term risk profiles.

Predictive Factors for Treatment Response

Across trials, response rates vary widely. However, nearly a third of patients fail to respond, even after extended therapy [25]. Duration of disease, age at onset, extent of body hair loss, and early response within the first few months may predict long-term outcomes, but these factors have not been consistently validated. Post hoc analyses from the BRAVE and ALLEGRO trials suggest that early regrowth, eyebrow or eyelash response, and baseline SALT severity may guide prognosis [24, 28].

Comparative Efficacy Across JAK Inhibitors

Head-to-head comparisons are evidently absent. Baricitinib, ritlecitinib, and deuruxolitinib differ in their kinase selectivity, yet it is unclear how these molecular differences translate clinically. Deuruxolitinib demonstrated numerically higher efficacy at 12 mg twice daily compared to baricitinib 4 mg or ritlecitinib 50 mg, but safety concerns prevented its advancement at that dose [35]. Ritlecitinib’s inclusion of adolescents in trials created a viable treatment avenue for younger patients that its counterparts continue to lack. Off-label comparisons between tofacitinib and ruxolitinib suggest similar short-term efficacy, with the possibility of faster onset with ruxolitinib [51]. There is promise for long-term maintenance therapy across JAK inhibitors; however, differences in relapse rates, durability of response, and patient-reported outcomes across agents have yet to be rigorously studied. Comparative trials or network meta-analyses could help guide drug selection; however, current analyses are limited by the fact that these agents have primarily been compared against placebo rather than directly against one another.

Special Populations: Pediatric and Geriatric Patients

Ritlecitinib’s approval for patients ≥ 12 years of age marks a major milestone for pediatric AA treatment. Evidence surrounding JAK inhibitor usage in children under 12 still largely comes from case series and off-label tofacitinib use. In the previously mentioned retrospective chart review consisting of a 36-patient pediatric cohort treated with oral tofacitinib, 72% achieved SALT50 and SALT75, 67% SALT90, and 53% SALT100 at mean times of 2.8, 4.1, 5.7, and 6.7 months, respectively; adverse events included UTIs, transaminitis, and acneiform eruptions [56]. Long-term effects on immune and hormonal development remain unknown. While AA is reportedly less prevalent in the geriatric population, continuous immunosuppression may confer greater risk. The landmark rheumatoid arthritis safety trial of tofacitinib in adults > 50 years of age that led to the FDA boxed warning also led to the European Medicines Agency’s 2023 measures to avoid JAK inhibitor use in patients > 65 years old, in those with elevated cardiovascular or cancer risk, and current or former long-term smokers [14, 54]. More real-world data in this population are needed to guide safe prescribing.

Conclusion

Despite these promising developments, several challenges remain, including variability in patient response, delayed or non-response, relapse after discontinuation, and open questions regarding long-term safety. AA relapse after JAK inhibitor discontinuation is common, requiring continuous therapy to maintain results as the only known solution to date. Remaining gaps in knowledge regarding JAK inhibitor use in AA include use in mild-to-moderate AA, mitigation of adverse effects at higher doses that may result in more robust results, evaluation of agents that have potential for use in children, and studies on long-term risks versus benefit when using these drugs for extended periods of time. To refine treatment protocols and optimize the use of both FDA-approved and off-label JAK inhibitors, future research should aim to include more long-term safety and efficacy data acquisition, exploration of combination therapies, intermittent dosing schedules or chronic low-dose regimens to maintain results and prevent relapse, and potentially head-to-head comparative trials comparing JAK inhibitors.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

All authors contributed significantly to this work. Conceptualization of the review was done by Arash Mostaghimi. Material preparation, literature review, and original draft preparation were performed by Katherine Sanchez, Hanna Englander, and Lana Salloum. Arash Mostaghimi, Katherine Sanchez, Hanna Englander, Lana Salloum, Samantha Gregoire, Ursula Biba, and Sherry Ershadi have extensively reviewed and critically edited the manuscript. Sherry Ershadi drew and produced the illustration shown as a figure in this manuscript. All authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding

No funding or sponsorship was received for this work or publication of this narrative review article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Dr. Arash Mostaghimi has received consulting fees from AbbVie, ACOM Health, Bioniz, Boehringer Ingelheim, Concert, Digital Diagnostics, Eli Lilly, Equillium, Hims & Hers Health, and Pfizer; equity from ACOM Health, Figure-1, and Hims & Hers Health; licensing/royalties from Concert and Pfizer; and research funding from Aclaris, Concert, Eli Lilly, and Incyte. Dr. Arash Mostaghimi is a member of the Editorial Board for Dermatology and Therapy. Dr. Arash Mostaghimi was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Katherine Sanchez, Hanna Englander, Lana Salloum, Samantha Gregoire, Ursula Biba, and Sherry Ershadi have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.