JAK Inhibitors for Alopecia Areata: Approved Therapies, Efficacy, and Unanswered Questions

Abstract

Alopecia areata (AA) is a common autoimmune disorder characterized by non-scarring hair loss. While traditionally viewed as a T-cell-mediated disease, recent advances have elucidated the central role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in its pathogenesis, establishing a self-sustaining inflammatory loop. The identification of this pathway has transformed AA from a condition with limited therapeutic options to one with targeted biological interventions. Over the past five years, multiple JAK inhibitors have received regulatory approval or shown promising results in clinical trials. Baricitinib, a selective JAK1/JAK2 inhibitor, became the first FDA-approved systemic treatment for severe AA, followed by ritlecitinib, which targets JAK3 and TEC family kinases and deuruxolitinib targeting the JAK1/2. Other agents, including ivarmacitinib, and the topical agent delgocitinib, are under active investigation, offering varying selectivity profiles and routes of administration. Compared with conventional therapies, JAK inhibitors such as baricitinib and ritlecitinib demonstrated therapeutic efficacy rates of 40–50% in Phase III clinical trials. Because head-to-head trials among JAK inhibitors in AA remain lacking, the comparative efficacy discussed in this review is derived primarily from indirect, cross-trial comparisons and network meta-analyses. Despite these remarkable advances, the field currently faces several significant challenges, including variable treatment responses, incomplete hair regrowth in patients with severe AA, potential long-term safety risks, and the absence of validated biomarkers to guide patient selection or predict therapeutic outcomes. Comparative efficacy, treatment challenges, and future directions including combination strategies and biomarker-guided therapy are also discussed to support informed clinical decision-making and highlight unmet needs in AA treatment.

Introduction

Alopecia areata (AA) is a chronic, relapsing autoimmune disease characterized by non-scarring alopecia, with a global prevalence of approximately 2%. It presents a broad clinical spectrum, ranging from localized scalp hair loss to total scalp alopecia (alopecia totalis, AT) or universal body hair loss (alopecia universalis, AU).1,2 The Severity of Alopecia Tool (SALT) is commonly used clinically to assess the severity of hair loss.1,2 Beyond physical symptoms, AA imposes profound psychological burden on patients and substantially impairs quality of life. Multiple studies have reported markedly elevated rates of anxiety, depression and social dysfunction among affected individuals.3

Conventional therapies, including topical, intralesional and systemic glucocorticoids as well as contact immunotherapy, often yield inconsistent efficacy and unsatisfactory safety profiles.4 For mild AA, topical and intralesional glucocorticoids remain first-line options with acceptable risk–benefit profiles; however, for patients with moderate-to-severe disease (SALT ≥ 50), conventional systemic therapies have historically been limited by incomplete efficacy, high relapse rates upon discontinuation, and cumulative toxicity with prolonged use. The introduction of Janus kinase (JAK) inhibitors—the first class of targeted systemic agents to receive regulatory approval for severe AA—has substantially altered this treatment landscape, offering mechanism-based therapy directed at the core pathogenic pathway of the disease.5 Herein, we review the current evidence on JAK inhibitors for AA, focusing on their comparative efficacy, safety, and unresolved clinical questions to guide clinical decision-making.

The pathogenesis of AA centers on the collapse of hair follicle immune privilege (IP), driven by the IFN-γ/IL-15-JAK/STAT signaling axis, which acts as the central hub driving disease amplification and prematurely terminating the anagen phase.6–9 Genome-wide association studies have identified polymorphisms in JAK family genes and their downstream signaling components as susceptibility loci for AA, providing a mechanistic rationale for targeting this pathway.10,11 The recognition of the JAK/STAT pathway as the final common cascade integrating upstream immune abnormalities has fundamentally transformed the treatment landscape of AA. The development and clinical translation of multiple JAK inhibitors for moderate-to-severe AA represent one of the most important therapeutic advances in dermatology in recent years.12,13

Building on this mechanistic rationale, a growing number of JAK inhibitors have been developed for moderate-to-severe AA. These agents competitively bind the ATP-binding pocket of JAK enzymes, suppressing STAT phosphorylation and downstream proinflammatory gene transcription,14,15 yet they differ substantially in their selectivity profiles across JAK1, JAK2, JAK3, and TYK2. These pharmacologic distinctions span three main categories: dual JAK1/JAK2 inhibition (baricitinib, deuruxolitinib), JAK3/TEC kinase inhibition (ritlecitinib), and selective JAK1 inhibition (upadacitinib, ivarmacitinib).2,16–20 These agents have demonstrated remarkable therapeutic success in severe and refractory AA, with prominent hair regrowth and significant improvements in patients’ mental health.21,22

Despite these remarkable therapeutic successes, JAK inhibitors still face major challenges in many aspects. First, while some of these agents have received regulatory approval for AA in one or more regions, direct comparative evidence regarding their relative efficacy across different AA subtypes, severity grades, and patient populations remains limited. There is substantial interindividual heterogeneity in treatment responses. Factors affecting therapeutic outcomes, including baseline disease severity, disease duration, atopic status, previous treatment history, and specific AA subtypes, remain poorly elucidated with respect to their roles in treatment response.5 Beyond approved indications, several additional JAK inhibitors—including tofacitinib, abrocitinib, brepocitinib, and deucravacitinib—have demonstrated therapeutic activity in clinical studies, further broadening the clinical landscape but also contributing to widespread off-label use.23 Furthermore, the optimal treatment duration, long-term safety profiles, recommendations for combined medication, and tapering or discontinuation strategies remain active areas of research. There is also a major knowledge gap regarding the identification of predictive biomarkers to guide individualized therapeutic decision-making. Meanwhile, given the relatively young age of AA onset in many patients, the efficacy and safety of JAK inhibitors in children and adolescents still require further investigation.

These considerations raise fundamental questions that remain to be addressed. The selectivity profile of a given JAK inhibitor meaningfully influences clinical outcomes in specific patient subgroups, and treatment selection can be optimized based on disease characteristics, comorbidities, and individual risk profiles. However, existing reviews have largely focused on individual agents or mechanistic aspects, and lack a comprehensive comparative evaluation of efficacy, safety, and long-term management across the full spectrum of JAK inhibitors for AA. Therefore, this review aims to provide a clinically oriented synthesis of the current evidence, integrating three perspectives for the first time: (i) a comparative analysis of clinical efficacy and safety across all JAK inhibitors studied in AA, including approved agents, those in late-stage development, and those used off-label, drawing on both trial-level and real-world evidence; (ii) a critical assessment of combination strategies, special population considerations, and long-term management, areas that have received limited attention in previous reviews; and (iii) a systematic discussion of unanswered questions that define the current research agenda, from predictive biomarkers to optimal treatment duration.

Pathological Mechanism of AA

Physiological State of IP of Hair Follicles

Immune privilege (IP) represents an immunological adaptive phenomenon predominantly occurring in sites such as the cornea, brain, placenta and hair follicles, where even mild inflammation can trigger irreversible tissue damage.24,25 Under physiological conditions, hair follicles maintain an IP state. Anagen hair follicles sustain local immune quiescence by downregulating MHC class I molecules and expressing a variety of immunosuppressive factors, including TGF-β, α-MSH, and IDO.25–29 Within normal hair follicle cells, the JAK-STAT signaling pathway maintains a tightly regulated basal activation state. This prevents excessive activation of pro-inflammatory STAT signals downstream of interferons and helps sustain low expression levels of MHC class I molecules.26,30–32 The crosstalk among hair follicle keratinocytes, melanocytes, and resident antigen-presenting cells collectively maintains immune tolerance homeostasis, which serves as the foundation of normal hair growth.30

Upstream Initiating Pathways of T Cell Activation

Aberrant activation of T cells is a pivotal contributor to the pathogenesis of AA. The initiation of early autoimmune responses required for T cell activation generally relies on the capture and presentation of hair follicle autoantigens by antigen-presenting cells. Plasmacytoid dendritic cells (pDCs) represent one of the most upstream cellular participants in AA pathogenesis, and their early activation is an essential prerequisite for the formation of the AA immune microenvironment. pDCs are major secretory cells of type I interferons, particularly IFN-α.33,34 In the pathological context of AA, nucleic acid triggers—potentially derived from viral pathogens, oxidative stress, or endogenous nucleic acids released by early apoptotic hair follicle cells—activate intracellular Toll-like receptor signaling in pDCs, triggering robust release of IFN-α into the local microenvironment.35,36

IFN-α enhances CD8⁺ T cell and NK cell cytotoxicity, initiates early CXCL10 production, and induces apoptosis in hair follicle cells — together priming the local microenvironment for the subsequent JAK-STAT-driven immune attack.27 This pDC-dependent mechanism of IFN-α release acts at an extremely upstream position in AA pathogenesis and serves as the trigger for the collapse of hair follicle immune privilege.37 Beyond pDC activation, peripheral macrophages exhibit a pronounced polarization toward the M1 phenotype during the early stage of AA onset.38 M1 macrophages secrete high levels of proinflammatory cytokines, among which interleukin-18 (IL-18) and interleukin-1β (IL-1β) are the most critical, further promoting the differentiation and persistence of Th1 and Tc1 cell subsets.39

These microenvironmental changes facilitate autoreactive T cell recognition of exposed follicular autoantigens (eg, melanogenesis-associated proteins or keratinocyte peptides). Concurrently, costimulatory dysregulation sustains pathogenic T cell survival.37 Physiologically, Tregs suppress effector T cell–APC binding via CD80/CD86, but AA patients exhibit Treg deficiency or dysfunction.40 The OX40–OX40L axis promotes T cell survival while inhibiting Treg activity,41–43 and RIPK1 upregulation in DCs and CD8⁺ T cells enhances antigen presentation, T cell recruitment, and cytotoxicity.44,45 Together, RIPK1 and OX40–OX40L drive persistent NF-κB activation, establishing a pro-autoimmune microenvironment that licenses sustained JAK–STAT signaling and subsequent follicular destruction (Figure 1).46–51

Figure 1.

The pathophysiological mechanisms of AA and JAK-STAT pathway in hair follicle.

Abbreviations: CXCL10, C-X-C motif chemokine ligand 10; IFN, interferon; IL, interleukin; JAK, janus kinase; MHC, major histocompatibility complex; NK cell, natural killer cell; STAT, signal transducer and activator of transcription; Th1 cell, Type 1 T helper cell; Treg, regulatory T cell. Downward arrows indicate the reduction.

The Core JAK-STAT Signaling Pathway in T Cells and Hair Follicle Cells

Following the sensitization, expansion, and survival protection of autoreactive T cells mediated by upstream mechanisms, the substantial tissue destruction of AA initiates locally within hair follicles. At this stage, the JAK-STAT signaling axis converts extracellular cytokine signals into immune cell infiltration and transcriptional reprogramming in follicular epithelial cells, thereby driving a self-perpetuating cycle of tissue destruction.34 As mentioned above, the collapse of IP constitutes the direct trigger of AA pathogenesis. When the concentration of local proinflammatory cytokines overwhelms the inhibitory capacity of IP-maintaining factors such as TGF-β and α-MSH, the threshold for immune privilege collapse is crossed,34 among which IFN-γ plays a dominant role. One of the core hallmarks of IP collapse during AA development is the marked upregulation of MHC class I and class II molecules on the surface of hair follicle keratinocytes.30 The increased presentation of endogenous hair follicle autoantigens recruits CD8⁺ T cells to perifollicular sites, where these CD8⁺ T cells bind to MHC class I via the T cell receptor.29 Meanwhile, NK cells are also recruited and engaged to directly attack hair follicle cells.52,53 By contrast, MHC class II expressed by hair follicles interacts with the TCR on CD4⁺ T cells. Upon activation, T helper cells secrete IFN-γ, which is critical for the subsequent activation of multiple immune cell populations.4,25,27,54

Specifically, upon the binding of IFN‑γ to its heterodimeric receptor (IFNGR1/IFNGR2) on the surface of hair follicle epithelial cells, the receptor undergoes conformational changes. This induces reciprocal trans‑phosphorylation and activation of Janus kinases (predominantly JAK1 and JAK2) coupled to its intracellular domain. Activated JAK1/JAK2 phosphorylate specific tyrosine residues within the intracellular receptor segment, facilitating cytoplasmic signal transduction and creating high‑affinity docking sites for signal transducer and activator of transcription 1 (STAT1). Once recruited to the receptor complex, STAT1 is phosphorylated by JAKs. Phosphorylated STAT1 monomers dissociate from the receptor and rapidly form stable homodimers, also termed interferon‑gamma activating factor (IGAF).55 These STAT1 dimers subsequently translocate rapidly into the nucleus and directly bind to interferon‑gamma activated sequence (GAS) elements in the promoter regions of target genes.56

Accordingly, gene regulation in hair follicle cells is profoundly altered. First, STAT1 upregulates the expression of MHC molecules on the hair follicle cell surface. Nuclear STAT1 dimers directly bind to the promoter of interferon regulatory factor 1 (IRF1) and potently induce its transcription and expression.57 Subsequently, newly synthesized IRF1 cooperates with persistently activated STAT1 to jointly target specific promoter regions of the class II major histocompatibility complex transactivator (CIITA). As the master regulator of MHC class II gene expression, CIITA recruits histone acetyltransferases (HATs) and other chromatin remodeling complexes to reshape chromatin architecture, thereby driving robust transcription of MHC class II genes.58 Second, the IFN-γ/STAT1/IRF1 axis directly initiates the transcription of MHC class I heavy chains and β2-microglobulin.29 In addition, this inflammatory cascade induces hair follicle cells to express natural killer group 2 member D (NKG2D) ligands, including UL16-binding protein 3 (ULBP3) and MHC class I polypeptide-related sequence A (MICA). These ligands engage the NKG2D receptor on cytotoxic immune cells such as NK cells and CD8⁺ T cells, serving as guiding markers for the subsequent targeted destruction of hair follicles.34

Furthermore, the IFN-γ-triggered JAK-STAT signaling pathway in hair follicle cells establishes a robust chemokine gradient, recruiting large numbers of T cells from the peripheral circulation into the deep dermis.34 In hair follicle epithelial cells (especially outer root sheath cells and inner root sheath cells) as well as dermal papilla cells, STAT1 activation drives substantial transcription and secretion of Th1-associated chemokines, including CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC).59 These three chemokines bind and activate the G-protein-coupled receptor CXCR3 on the surface of Th1 and Tc1 effector T cells.37 When follicle-derived CXCL9/10/11 diffuse into the surrounding vasculature and engage CXCR3 on T cells, they trigger robust calcium influx and rapid F-actin polymerization within T cells, markedly accelerating their directional migration toward hair follicle lesions.60,61

During the acute onset phase of AA, this chemokine axis recruits a dense mixed lymphocyte population consisting of CXCR3⁺ CD4⁺ and CD8⁺ T cells, which accumulate around the hair bulb and histopathologically form the hallmark swarm of bees infiltration characteristic of AA. As the disease progresses to the chronic stage, CXCR3⁺ CD8⁺ T cells gradually become the predominant infiltrating population, residing persistently around hair follicles and sustaining long‑term hair loss.4 After chemokine-guided lymphocyte recruitment into the lesional microenvironment, T cells physically anchor to the follicular epithelium and local vascular endothelium to execute effective tissue destruction. This process is also mediated by the IFN‑γ/JAK‑STAT pathway, which drives aberrant overexpression of cellular adhesion molecules to complete the final step of leukocyte infiltration. In hair follicle epithelial cells, STAT signaling directly upregulates the expression of intercellular adhesion molecule‑1 (ICAM‑1) and vascular cell adhesion molecule‑1 (VCAM‑1). ICAM‑1 on the follicle surface binds to lymphocyte function‑associated antigen‑1 (LFA‑1) on T cells, providing strong physical adhesion. This stable intercellular anchorage enables lymphocytes to penetrate the epithelial layer and infiltrate deep into the hair bulb, establishing the structural basis for subsequent contact‑dependent cytotoxic killing via T cell‑derived cytotoxic mediators.62

Once this autoimmune microenvironment is established, the chronic self-sustaining nature of AA relies on a positive inflammatory feedback loop dominated by JAK-STAT signaling. First, the recruited perifollicular CXCR3⁺ T cell population is highly enriched for CD8⁺NKG2D⁺ T cells. Since hair follicles already upregulate stress ligands (eg, MICA) during early immune privilege collapse, the T cell receptor recognizes autoantigens presented by follicular MHC class I molecules, while the activating receptor NKG2D engages stress ligands on the follicle surface. This dual stimulation fully activates CD8⁺ T cells and drives robust local overproduction of IFN-γ. Large amounts of T cell-derived IFN-γ rapidly bind to receptors on adjacent hair follicle keratinocytes. As elaborated earlier, this activates STAT1 via the JAK1–JAK2 axis. In addition to upregulating MHC and chemokine expression, STAT1 also induces the production of IL-15 and its specific chaperone receptor IL-15Rα, which form a stable complex.6,63 Keratinocytes directly present the surface-bound IL-15/IL-15Rα complex to infiltrating CD8⁺NKG2D⁺ T cells via IL-2Rβ and the common γ chain (γc). This triggers a distinct intracellular Janus kinase signaling cascade in T cells mediated by JAK1 and JAK3. The JAK1/JAK3 heterodimer subsequently phosphorylates and activates STAT5, as well as partial STAT3, in the T cell nucleus.64–66 Within CD8⁺ T cells, activation of the JAK1/JAK3-STAT5 pathway efficiently promotes T cell survival, protects these pathogenic lymphocytes from microenvironment-induced apoptosis, and lowers the threshold for secondary TCR reactivation. Most importantly, it further reinforces the capacity of T cells to continuously synthesize and secrete IFN-γ. Newly released IFN-γ in turn acts back on hair follicle keratinocytes, sustaining the persistent induction of CXCL10 and IL-15 and thereby perpetuating the self-amplifying inflammatory loop.66–68

In addition to JAK1, JAK2 and JAK3, TYK2, the fourth member of the JAK family, also plays an indispensable role in the JAK‑STAT signaling network of AA and has attracted increasing research attention. TYK2 pairs with JAK2 to transduce IL‑12 signaling and drive Th1 cell differentiation; it also partners with JAK1 to mediate IL‑23 signaling, supporting the maintenance and expansion of Th17 cells.69,70 Both Th1 and Th17 cells have been confirmed to participate in AA pathogenesis, indicating that TYK2‑related immune pathways constitute another critical axis of immune dysregulation. Genome‑wide association studies have identified TYK2 gene polymorphisms as susceptibility loci for AA, further validating the relevance of this signaling axis.65,70 Collectively, the JAK‑STAT pathway establishes a progressively escalating, self‑amplifying inflammatory loop within the local hair follicle microenvironment (Figure 1).

Complete Disruption of Hair Follicle Cycle Induced by JAK-STAT Pathway and Aberrant Immune Microenvironment

The relentless activation of the JAK-STAT inflammatory positive feedback loop ultimately leads to alopecia, the most intuitive clinical manifestation of AA. This results from the interruption of the highly proliferative cycle of anagen hair follicles by molecular signals, accompanied by extensive apoptosis within the hair bulb. A normal hair follicle cycle, particularly the initiation and sustained maintenance of the anagen phase, relies on persistent activation of the canonical Wnt/β-catenin signaling pathway.71 In the AA microenvironment, elevated IFN-γ concentrations activate JAK kinases in surrounding cell populations, triggering robust STAT3 phosphorylation and nuclear translocation. This cascade upregulates the secretion of Dickkopf-related protein 1 (DKK1) in these mesenchymal cells.72 DKK1 is one of the most potent secreted specific antagonists of the canonical Wnt pathway.73 Suppression of Wnt/β-catenin signaling mediated by the IFN-γ/STAT3/DKK1 pathological axis deprives hair follicles of the transcriptional drive required for sustained growth. Consequently, the anagen phase is shortened, and hair follicles morphologically shift toward the catagen phase.74 Recent studies have revealed that microRNAs (miRNAs), as post-transcriptional regulators, broadly modulate cell fate transitions, paracrine signaling, inflammation and fibrosis via the RISC complex, and are capable of activating hair follicle stem cells to enter the anagen phase through the Wnt/β-catenin and Shh pathways. Multiple miRNA-based therapeutic agents and delivery technologies have achieved substantial advances in recent years.75

Highly proliferative keratinocytes and melanocytes within the anagen hair bulb are extraordinarily susceptible to the immune storm. The intense inflammatory microenvironment activates the DNA damage response network and cellular stress sensors in follicular epithelial cells. This induces cellular stress, p53 activation, and an imbalance of the Bcl-2/Bax ratio, thereby initiating the intrinsic apoptotic pathway.27,76–78 Meanwhile, p53 activation combined with the extrinsic cytokine microenvironment markedly upregulates the expression of the death receptor Fas (CD95) on hair follicle keratinocytes. Infiltrating CD8⁺ T cells express Fas ligand (FasL), which binds to Fas and subsequently recruits Fas-associated death domain (FADD) protein.79 In addition, CD8⁺ T cells and NK cells release cytotoxic granules such as granzyme B (GZMB) and perforin.29,34 Emerging evidence further indicates that IFN-γ can mediate the activation of gasdermin D (GSDMD).80 Collectively, these factors induce pore formation in the keratinocyte membrane and trigger downstream cascades including caspase-1/8 signaling, ultimately driving hair follicle apoptosis or pyroptosis.10,27,81,82

Collectively, the above apoptotic and pyroptotic pathways do not operate independently. While driving cell death, IFN‑γ/JAK‑STAT signaling simultaneously impairs the regenerative and reparative potential of hair follicles via the STAT3/DKK1‑mediated inhibition of the Wnt pathway. As a result, hair follicles can neither sustain normal growth nor mount effective repair following immune assault, falling into irreversible catagenic collapse. These combined insults lead to complete structural stromal breakdown within the hair follicle, forcing separation of the hair shaft from the dermal papilla. The follicle subsequently enters a dystrophic state and rapidly transitions into the telogen phase. Clinically, this ultimately manifests as acute hair shedding (exogen) and the pathognomonic feature of exclamation mark hairs in AA patients (Figure 1).

Other Relevant Factors

In addition to immune dysregulation and hair follicle injury, the pathogenesis of AA is also associated with a variety of other contributing factors. The collapse of hair follicle immune privilege occurs on a background of genetic susceptibility.83 Furthermore, abnormalities in oxidation-related genes impair the defense capacity against oxidative stress, constituting an integral component of the genetic predisposition.27,84 Against this genetic backdrop, environmental triggers such as seasonal variation, viral infection, ultraviolet radiation, and dietary factors (eg, soybean oil intake) may initiate disease onset.85,86 Psychological stress stimulates neuropeptide secretion via the neuro-endocrine-immune axis,87 directly inducing perifollicular inflammation and driving premature entry into the catagen phase.25 Moreover, gut microbiota dysbiosis may further promote aberrant activation of autoreactive T cells88 and amplify the overall immune response.89 These factors may aggravate the JAK-STAT pathway and jointly facilitate the onset of AA, and the specific underlying mechanisms remain to be further elucidated (Figure 1).

JAK Inhibitors

The JAK family consists of four subtypes: JAK1, JAK2, JAK3, and TYK2. Based on target selectivity, currently available JAK inhibitors can be classified into several categories, including JAK1 inhibitors, JAK1/2 inhibitors, JAK1/3 inhibitors, JAK3/TEC inhibitors, TYK2 inhibitors, and TYK2/JAK1 inhibitors. Among these agents, baricitinib and ritlecitinib have been approved for the treatment of AA by FDA, EMA and NMPA, while several other candidates remain in clinical trials or are widely used off-label. We herein categorize clinically available JAK inhibitors for the treatment of AA based on their differential JAK subtype selectivity, with detailed discussion presented below (Table 1 and Figure 2).

Table 1.

Overview of JAK Inhibitors for Alopecia Areata Treatment

JAK Inhibitor	Mechanism of Action	Route of Administration	Pivotal Clinical Trials	Approval Status	Suitability for Adolescents
Baricitinib	JAK1/JAK2	Oral (2/4 mg QD)	BRAVE-AA1 and BRAVE-AA2 (NCT03570749, NCT03899259)	FDA: ≥18; severe AA; EMA: ≥18; severe AA; NMPA: ≥18; severe AA	On Phase III clinical trial: NCT05723198
Deuruxolitinib	JAK1/JAK2	Oral (12 mg BID)	THRIVE-AA1 and THRIVE-AA2 (NCT04518995, NCT04797650)	FDA: ≥18; severe AA	On Phase III clinical trial: NCT07133308
Ruxolitinib	JAK1/JAK2	Oral (10–25 mg QD) and Topical	NA	Off-label	Off-label
Ritlecitinib	JAK3/TEC	Oral (30/50 mg QD)	ALLEGRO Phase 2a, ALLEGRO-LT, AALEGRO Phase 2b/3 (NCT02974868, NCT03732807, NCT04006457)	FDA: ≥12; severe AA; EMA: ≥12; severe AA; NMPA: ≥12; severe AA	Approved
Tofacitinib	JAK1/JAK3	Oral & Topical	NA	Off-label	Off-label
Brepocitinib	JAK1/TYK2	Oral	AALEGRO 2a	Off-label (During the trial)	No data available
Deucravacitinib	TYK2	Oral	NA	Off-label (During the trial)	No data available
Ivarmacitinib	JAK1	Oral	NCT05470413	NMPA: ≥18; severe AA	No data available
Upadacitinib	JAK1	Oral	NCT06012240	EMA: ≥18; severe AA	On Phase III clinical trial: NCT06012240, NCT07023302
Abrocitinib	JAK1	Oral	NA	Off-label	Off-label

Abbreviations: AA, alopecia areata; BID, Bis In Die; EMA, European Medicines Agency; FDA, US Food and Drug Administration; NMPA, National Medical Products Administration; QD, Quaque Die.

Figure 2.

JAK-STAT signaling pathway and cytokine drivers in alopecia areata, current status of application, efficacy and development prospects of JAK inhibitors in the treatment of AA.

Abbreviations: CK, Creatine Kinase; MACE, Major Adverse Cardiovascular Event; MN, microneedle; TEC, Tec Protein Tyrosine Kinase; TYK2, Tyrosine Kinase 2; URTI, upper respiratory tract infection. An upward-pointing arrow indicates an increased level of the indicator.

Ivarmacitinib

Ivarmacitinib is a highly selective, JAK1 inhibitor. Its inhibitory potency against JAK1 is more than 10-fold, 77-fold, and 420-fold greater than its activity against JAK2, JAK3, and TYK2, respectively, which helps mitigate the risk of adverse effects typically associated with the inhibition of alternative targets like JAK2.19,90 This agent has been approved in China for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS), and AA.

Key Findings

A multicenter, randomized, double-blind, placebo-controlled Phase II clinical trial evaluated the efficacy and safety of ivarmacitinib in adult patients with moderate-to-severe AA (NCT04346316).91 A total of 94 subjects were enrolled and randomized into four groups to receive oral ivarmacitinib at doses of 2 mg once daily (QD) (n=23), 4 mg QD (n=23), 8 mg QD (n=24), or placebo (n=24) for 24 weeks. The primary endpoint was the percentage change from baseline in the SALT score at week 24.91 Subsequently, a Phase III clinical trial was conducted (NCT05470413), screening 330 patients who were randomized to receive ivarmacitinib 8 mg QD, 4 mg QD, or placebo. The treatment regimen was divided into two distinct phases: a double-blind treatment period (weeks 0–24), where the three groups received their assigned interventions; and an extension treatment period (weeks 24–52). In the extension phase, patients originally in the placebo group were re-randomized to receive either ivarmacitinib 4 mg QD or 8 mg QD through week 52.92,93

These clinical trials demonstrated that ivarmacitinib possesses robust therapeutic efficacy. Phase II results showed that at week 24, the percentage change from baseline in SALT score for the ivarmacitinib 2 mg, 4 mg, and 8 mg groups was −30.51%, −56.11%, and −51.01%, respectively—all significantly superior to the placebo group. In both the 4 mg and 8 mg groups, the proportion of patients achieving SALT ≤ 20 exceeded 40%, while those achieving SALT ≤ 10 exceeded 30%. Furthermore, significant efficacy was observed in both the 4 mg and 8 mg groups for patients with moderate-to-severe (baseline SALT 50–94) as well as those with AT or AU.91,94 Phase III study results further indicated that at week 24, the 4 mg and 8 mg dose groups achieved favorable outcomes across both SALT ≤ 20 and SALT ≤ 10 endpoints. The efficacy of ivarmacitinib was maintained or even further improved throughout the 52-week treatment period; notably, similar therapeutic trends were observed in patients who switched from placebo to ivarmacitinib.92,93 Additionally, a case report of a patient with a poor response to tofacitinib who subsequently achieved a favorable outcome with ivarmacitinib further highlights the complex etiology of AA and the clinical heterogeneity of JAK inhibitor responses among different patients.95

However, compared with other JAK inhibitors, the efficacy of ivarmacitinib is often less pronounced, presenting challenges and raising skepticism regarding its clinical utility in severe AA. In some meta-analyses evaluating various JAK inhibitors at different dosages for AA treatment, ivarmacitinib ranked lower across several outcome measures96,97 (Table 2).

Table 2.

Summary of Key Clinical Studies of JAK Inhibitors

Study	Country	Intervention	Treatment Duration	Sample Size	Age	Sex (F/M)	Study Type	SALT Score
Zhou et al91	China	Ivarmacitinib (2 mg QD; 4 mg QD; 8 mg QD) and PBO	24-week treatment period + 4-week follow-up	Total = 71 (2 mg QD: 23; 4 mg QD: 23; 8 mg QD: 24; PBO: 24)	Ivarmacitinib 2 mg QD: 36.0 ± 10.4; Ivarmacitinib 4 mg QD: 33.3 ± 12.2; Ivarmacitinib 8 mg QD: 37.9 ± 13.7; PBO: 34.7 ± 9.4	52 / 42	Phase II RCT, randomized, double-blind, Placebo-controlled	W24 SALT change: 2 mg: −30.5% (BL 65.2); 4 mg: −56.1% (BL 62.1); 8 mg: −51.0% (BL 63.9); PBO: −19.9% (BL 61.3)
UP-AA M23-716 (ongoing)	United States	Upadacitinib (15 mg QD; 30 mg QD) and PBO	24 weeks	NA	NA	NA	Phase III RCT, randomized, double-blind, Placebo-controlled	W24 SALT≤10: 15 mg: 36.0%; 30 mg: 47.1%; PBO: 1.4%
Brett King et al98	United States	Baricitinib (2 mg QD, 4 mg QD) and PBO	36 weeks	Total N = 1200 (2 mg: 340; 4 mg: 515; PBO: 345)	2 mg: 38.5; 4 mg: 37.1; PBO: 37.3	728 / 472	Phase III RCT, randomized, double-blind, parallel-group, Placebo-controlled	W36 SALT≤20: BRAVE-AA1: 2 mg: 22.8% (BL 86.8); 4 mg: 38.8% (BL 85.3); PBO: 6.2% (BL 84.7) BRAVE-AA2: 2 mg: 19.4% (BL 85.6); 4 mg: 35.9% (BL 84.8); PBO: 3.3% (BL 85.0)
Brett King et al99	United States	Deuruxolitinib (8 mg BID, 12 mg BID) and PBO	24 weeks	Total = 706 (8 mg: 351; 12 mg:215; PBO: 140)	8 mg: 37.0 (18–65); 12 mg: 36.0 (18–65); PBO: 38.5 (18–65)	437 / 269	Phase III RCT, randomized, double-blind, Placebo-controlled	W24 SALT≤20: 8 mg: 29.6% (BL 85.5±18.4); 12 mg: 41.5% (BL 85.2±18.4); PBO: 0.8% (BL 88.1±15.1)
Kennedy Crispin et al100	United States	Tofacitinib 5 mg BID	12 weeks	Total = 66	37 (19–65)	35 / 31	Phase II Single-Arm Trial, 2-center, open-label, single-arm trial	Median SALT improvement: 21% SALT Improvement >50%: 32% Improvement 5%-50%: 32%
Brett King et al 101	United States	Ritlecitinib (200 mg QD for 4weeks + 50 mg QD; 200 mg QD for 4weeks + 30 mg QD; 50 mg QD; 30 mg QD; 10 mg QD) and PBO	24-week PBO-controlled period + 24-week extension period	Total = 718 (200 mg for 4weeks + 50 mg: 132; 200 mg for 4weeks + 30 mg: 130; 50 mg: 130; 30 mg: 132; 10 mg: 63; PBO: 131)	200 mg for 4weeks + 50 mg: 34.5; 200 mg for 4weeks + 30 mg: 33.7; 50 mg: 32.4; 30 mg: 33.7; 10 mg: 34.3; PBO: 34.0	443 / 272	Phase IIb-III RCT, randomized, double-blind, Placebo-controlled	W24 SALT≤20: 200→50: 31% (BL 90.3); 200→30: 22% (BL 90.5); 50: 23% (BL 90.3); 30: 14% (BL 90.0); 10: 2% (BL 88.3); PBO: 2% (BL 93.0)

Abbreviations: BID: Bis In Die; F: female; M: male; PBO: placebo; QD: Quaque Die; SALT: severity of alopecia tool; W: week; m: month.

Safety and Adverse Events

The overall incidence of treatment-emergent adverse events (TEAEs) was comparable across the different dose groups (65.2%–75.0%), most of which were mild-to-moderate in severity, with upper respiratory tract infection (URTI) being the most frequently reported. In the Phase II study, two severe adverse events were recorded: one case of stage III follicular lymphoma (noting pre-existing lymphadenopathy, which was assessed by the investigator as potentially treatment-related) and one case of COVID-19 pneumonia in the placebo group.91 In the Phase III study, a total of seven serious adverse events (SAEs) were reported, including endometriosis, thyroid cancer, complicated appendicitis, teratoma, stage III follicular lymphoma, cervical dysplasia, and acute myocardial infarction.92 Although no signals of the most concerning serious cardiovascular or thromboembolic risks—class-wide concerns for JAK inhibitors—were observed,91,92 the safety profile of ivarmacitinib warrants continued monitoring, particularly as a novel JAK inhibitor carrying a black box warning.

Future research is required to further elucidate the efficacy of ivarmacitinib in severe AA/AT/AU and other refractory forms of AA, as well as its therapeutic potential in pediatric and adolescent populations.

Upadacitinib

Upadacitinib is a selective JAK1 inhibitor with a selectivity for JAK1 approximately 40-fold, 130-fold, and over 190-fold greater than that for JAK2, JAK3, and TYK2, respectively; it is capable of simultaneously modulating both Th1 and Th2 signaling pathways.102,103 The agent functions by competitively binding with ATP at the nucleotide-binding site, thereby inhibiting kinase activity and the phosphorylation of downstream effector molecules, which ultimately blocks the formation of STAT dimers. Upadacitinib has been approved by the FDA and EMA for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and atopic dermatitis (AD). Furthermore, it has received EMA approval for the treatment of moderate-to-severe AA in adults and is currently under review by the FDA.20

Key Findings

UP-AA M23-716 is a randomized, placebo-controlled, double-blind Phase 3 program comprising two parallel pivotal studies. This trial demonstrated the efficacy of upadacitinib and serves as the definitive evidence supporting its regulatory approval for the treatment of AA. The participants had a mean baseline SALT score of 83.8. In Period A, subjects were randomized to receive upadacitinib 15 mg QD, 30 mg QD, or placebo for 24 weeks. At week 24, 36.0% and 47.1% of patients in the upadacitinib 15 mg and 30 mg groups, respectively, achieved a SALT ≤ 10 response for scalp hair regrowth (NCT06012240). Furthermore, a series of clinical reports have demonstrated that upadacitinib exhibits significant efficacy and a favorable safety profile across various AA phenotypes, including refractory cases such as AT and AU.104–108 Flora et al reported that in 25 patients with AA treated with upadacitinib (15 mg or 30 mg QD) for 24 weeks, the mean SALT score decreased from 50 to 2, accompanied by a significant improvement in patient-reported quality of life, as evidenced by Dermatology Life Quality Index (DLQI) scores.109 Notably, a 67-year-old patient with AT achieved near-complete remission of systemic hair loss after four months of treatment with upadacitinib at a dose of 15 mg QD. Additionally, a case report described a 55-year-old woman with seropositive RA who developed progressive AA (SALT =50) during golimumab and leflunomide therapy that was refractory to intralesional corticosteroids; upon switching to upadacitinib (15→30 mg) for RA management, hair regrowth occurred within 6 weeks with SALT improvement to approximately 15 at 3 months, suggesting JAK1 inhibition as a pragmatic therapeutic consideration when AA arises during TNF-α inhibitor therapy.110 Interestingly, although the patient abruptly discontinued the medication at month 4, the regenerated systemic hair was maintained for nearly six months, providing a valuable clinical reference for future dose reduction or discontinuation trials of upadacitinib in specific populations.111 A new long-term real-world study of upadacitinib (≥12 months) reported SALT50, SALT75 and SALT90 response rates of 90.0%, 80.0% and 56.67% at month 12, with superior early therapeutic efficacy observed in patients with an atopic background.112 Furthermore, the first meta-analysis focusing on upadacitinib also revealed its favorable response rates and safety profile.113

Given the extensive approved indications of upadacitinib, numerous immune-related diseases have been reported to be treated with this agent. Furthermore, various immune-mediated conditions frequently coexist in certain populations; consequently, numerous case reports have demonstrated the pleiotropic efficacy of upadacitinib across different immune disorders, including AD, Crohn’s disease, sarcoidosis, and PsA.111,114–117 Specifically, AD and AA often occur as comorbidities due to shared immune-mediated pathogenic mechanisms. Upadacitinib can concurrently alleviate symptoms of both AA and AD—including improvements in SCORAD (SCORing Atopic Dermatitis)—thereby circumventing potential adverse outcomes associated with conventional systemic glucocorticoids or dupilumab in these specific patient populations.118–122 However, a real-world study involving 19 patients with comorbid moderate-to-severe AD and AA highlighted potential challenges: although over half the patients exhibited a rapid and favorable response (with a statistically significant reduction in mean SALT scores as early as week 4), 47.1% of patients failed to achieve at least a 50% improvement (non-responders) by week 16.123 In instances of more complex multi-comorbidities, combination therapies may be required. For example, a patient with AA comorbid with PsA and uveitis achieved significant clinical improvement across all three conditions following dual-target therapy with upadacitinib and risankizumab.124 Similarly, another case involving comorbid AA, AD, Crohn’s disease, vitiligo and eosinophilic gastrointestinal disease demonstrated significant remission of all four conditions under upadacitinib monotherapy, suggesting that upadacitinib may act on common therapeutic targets across diverse immune-mediated diseases.125–128 Given this evidence, upadacitinib may emerge as a preferred therapeutic option for AA patients with concurrent immune-mediated comorbidities, pending broader regulatory approvals (Table 2).

Use of Upadacitinib in Adolescents

Currently, ritlecitinib remains the only JAK inhibitor approved for the treatment of AA in adolescents. Consequently, the use of upadacitinib in this population is considered off-label, yet it is widely implemented in clinical practice. Multiple clinical studies have demonstrated that upadacitinib maintains a favorable overall benefit-risk profile in children and adolescents with AA, including various refractory subtypes.125–128 Given that the FDA has approved upadacitinib for both adolescent AD and adult AA, pediatric and adolescent patients with comorbid AD and AA receive upadacitinib as an off-label intervention for their hair loss. In one instance, a child with AU and comorbid AD achieved complete hair regrowth and total resolution of AD symptoms after three months of upadacitinib therapy, highlighting its high therapeutic potency.127 Retrospective research investigating pediatric patients with concurrent AD and AA revealed that significant hair regrowth occurred within the first month of upadacitinib treatment, with substantial improvements in SALT scores at 12 months and no reported SAEs. Notably, one patient with the ophiasis phenotype achieved complete hair regrowth.129 Additional case reports further substantiate the robust dual efficacy of upadacitinib,130 providing valuable clinical evidence for the management of pediatric patients suffering from comorbid AA and AD.

A limited number of clinical studies have reported favorable outcomes for upadacitinib in pediatric AA patients with other comorbid autoimmune diseases. One case involved a child with AU and a family history of autoimmune disorders, presenting with comorbidities including AD, seasonal allergies, and asthma. Laboratory investigations revealed multiple abnormalities, such as elevated levels of IgE and eosinophils, while genetic analysis identified several mutations. The patient had previously failed minoxidil therapy and was subsequently transitioned to upadacitinib 15 mg QD. After three months of treatment, the child exhibited significant scalp hair regrowth along with marked improvement in eyebrows and eyelashes. Accounting for the physiological differences between pediatric and adult populations, the dosage was tapered to 15 mg four times per week for maintenance; the patient’s hair recovery has remained stable for over one year.131 Another rare instance involved a pediatric patient with AA comorbid with refractory segmental vitiligo. Following treatment with upadacitinib combined with narrowband ultraviolet B (NB-UVB) therapy, the lesion areas for both vitiligo and AA were significantly reduced, offering a novel therapeutic approach for children with this specific comorbidity.132 In light of its robust dual efficacy, upadacitinib may be considered an ideal alternative therapy for adolescent AA, particularly in AA patients with concurrent AD.133

Across multiple clinical trials and case reports, upadacitinib has demonstrated consistent efficacy and safety in pediatric and adolescent patients with AA, positioning it as a promising candidate to become the next JAK inhibitor approved for adolescent AA treatment. A Phase III clinical trial conducted in Japan enrolled 123 adolescents (aged ≤ 12 years) and adults with AA to receive upadacitinib, with a projected maximum treatment duration of up to 104 weeks. This study, which aims to evaluate long-term efficacy and safety, is expected to serve as one of the pivotal clinical trials supporting the regulatory approval of upadacitinib for the treatment of adolescent AA (NCT07023302).

Safety and Adverse Outcomes

Baricitinib, ritlecitinib and upadacitinib remain the most widely utilized JAK inhibitors in current clinical practice. However, a real-world study comparing these three agents demonstrated that upadacitinib outperformed the others in SALT score improvement and induced faster follicular activation, albeit with a slightly higher incidence of creatine phosphokinase (CPK) elevation. These findings indicate that upadacitinib is a highly promising novel JAK inhibitor for the treatment of severe AA, laying the groundwork for its broader clinical adoption, although its safety profile warrants further investigation.134 A retrospective study of 23 patients employing a flexible dosing regimen (ranging from 7.5 mg to 30 mg QD for 36 weeks) reported that primary adverse effects were mild, including acne (26.1%), folliculitis (21.7%), and upper respiratory tract infections (8.7%).135 Conversely, one case report described a 55-year-old female patient who unexpectedly developed AA one year into upadacitinib therapy for AD, raising questions regarding the potential for upadacitinib to paradoxically trigger drug-induced alopecia136 (Table 3).

Table 3.

Ongoing Clinical Trials

JAK Inhibitor	Registration Number	Sponsor & Place	Population	Intervention	Study Type	Progress
Upadacitinib	NCT07023302	AbbVie; Japan	123 people 12 years and older with severe AA	High dose, low dose or PBO for 104 m	Phase 3 randomized, placebo-controlled, double-blind	Recruiting
Abrocitinib	NCT07242638	Icahn School of Medicine at Mount Sinai; United States	56 people with SD and at least one inflammatory skin condition AD or AA	Abrocitinib 100 mg QD for 60W	Phase 2b, single-center, open-label, basket	Recruiting
Baricitinib	NCT06797310	National Taiwan University Hospital; Taiwan	30 people with active AA and progressive hair loss	Baricitinib 4 mg QD for 16W or 4 mg QD for 16W + 2 mg QD for 16WAD	Phase 3, single-center, open-label, prospective trial	Not yet recruiting
	NCT05723198	Eli Lilly and Company; United States	595 children aged from 6–18 with severe AA	Baricitinib high dose or low dose and PBO	Phase 3, double-blind, randomized, placebo-controlled trial	Recruiting
Ruxolitinib	NCT05398809	NIAID; United States	People aged 12 to 65 years with APECED and severe AA.	Ruxolitinib for 8 months and dose increases at weeks 8 and 16	Phase 2; Open-Label	Recruiting
Deuruxolitinib	NCT07133308	Sun Pharmaceutical Industries, Inc; United States	355 adolescents aged 12 to less than 18 years with severe AA	Randomized to receive deuruxolitinib or PBO for 24W and deuruxolitinib for 52W	Phase 3, double-blind, randomized, placebo-controlled	Recruiting
Tofacitinib	NCT07406204	Hayat Abad Medical Complex, Peshawar; NA	78 adults aged 18 to 60 with severe AA	Tofacitinib 10 mg BID or methotrexate 0.2–0.4 mg/kg once weekly for 12 weeks	Phase 4, single-center, parallel-group, randomized controlled trial	Recruiting
Ritlecitinib	NCT06531109	Pfizer; United States, China, France, Japan, United Kingdom	NA	NA	Phase 3, observational	Recruiting
	NCT07029828	Pfizer; United States	140 people participated in the previous study or with severe AA	Ritlecitinib high dose or low dose for 36m	Phase 3, long-term, double-blind extension	Recruiting
	NCT07029711	Pfizer; United States, Japan	225 children aged from 6–12 with severe AA	Ritlecitinib high dose QD, low dose QD or PBO for 24 m	Phase 3 randomized, double-blind, placebo-controlled	Recruiting
	NCT06873945	Pfizer; United States, Canada, China, Czechia, Japan, Poland, South Korea, Spain, Taiwan,	550 people 12 years and older with severe AA	Ritlecitinib 5 mg QD, 10 mg QD for 13m	Phase 3, external and synthetic placebo-controlled randomized	Recruiting
Deucravacitinib	NCT07508488	Icahn School of Medicine at Mount Sinai; United States	20 adults with severe AA	Deucravacitinib 6mg BID for 48 weeks	Phase 2, interventional	Recruiting

Abbreviations: AA, Alopecia Areata; AD, Atopic Dermatitis; APECED, Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; DS, Down Syndrome; NIAID, National Institute of Allergy and Infectious Diseases.

Abrocitinib

Abrocitinib is an oral small-molecule selective JAK1 inhibitor that mainly regulates biological effects mediated by cytokines including IL-4, IL-23, IL-22, and IL-31. It exhibits 28-fold, over 340-fold, and 43-fold greater selectivity for JAK1 relative to JAK2, JAK3, and TYK2, respectively, and preferentially suppresses STAT phosphorylation mediated by JAK1 and its associated kinases.137,138 It has currently been approved in multiple regions for the treatment of moderate-to-severe AD in adults and adolescents aged 12 years and older.139

Since abrocitinib is predominantly applied in the treatment of AD, relevant research on its use for AA remains limited to small-scale clinical trials, retrospective analyses, and case reports. One retrospective study enrolled 13 patients with severe AA who were unresponsive to prior therapies including systemic glucocorticoids, baricitinib, and tofacitinib. All patients received oral abrocitinib at a daily dose of 50–200 mg. After an average treatment duration of 8.85 months, the mean SALT score decreased significantly from a baseline of 74.62 to 42.54, and six patients achieved a therapeutic endpoint of SALT ≤ 20.140,141 Other retrospective studies have also confirmed the favorable efficacy and safety profile of abrocitinib in AA.142,143

In terms of specific AA subtypes, multiple reports have demonstrated the favorable efficacy of abrocitinib across various forms of AA. A case series included 6 patients with severe diffuse AA treated with oral abrocitinib 100 mg QD for at least 12 weeks. The SALT scores of all patients dropped below 20 after 8 weeks of treatment, and 4 patients achieved complete remission by Week 12.142 The study also noted that all patients had allergic rhinitis and most presented elevated IgE levels. It was speculated that concomitant atopic or allergic conditions may predict a better response to abrocitinib, which aligns with the hypothesis linking diffuse AA to allergy and increased IgE levels.142,144 An 11-year-old child with diffuse AA also attained stable therapeutic effects under abrocitinib 100 mg QD.145 In addition, abrocitinib has shown therapeutic benefits for AT/AU. One case study reported a patient who developed AT following drug reaction with eosinophilia and systemic symptoms (DRESS), and achieved a good response to abrocitinib at doses of 100 mg and 200 mg QD.146

Given that abrocitinib has been approved for AD in adults and adolescents, and AD is a common comorbidity of AA, numerous clinical reports have focused on patients with AA complicated by AD. One 12-year-old patient had suffered from AD since early childhood and subsequently developed AA during the disease course. The patient was administered abrocitinib 200 mg QD. After 12 weeks, cutaneous lesions improved markedly, accompanied by significant reductions in AD-related indicators including the Pruritus Numeric Rating Scale (P-NRS) and Eczema Area and Severity Index (EASI). The dose was then tapered to 100 mg QD, and the patient achieved complete resolution of AA lesions within one year.147 Another case study described a 14-year-old adolescent with AD complicated by AU. Following 12 weeks of treatment with abrocitinib 200 mg QD, systemic hair regrowth was observed, involving eyebrows, eyelashes and axillary hair. By Week 52, dense terminal hair regrowth had been achieved.148 Some patients who developed AA during clinical trials for AD treatment also exhibited a favorable response to abrocitinib, highlighting its dual therapeutic potential for both conditions.149

Although the above evidence preliminarily demonstrates the efficacy of abrocitinib in AA, a systematic review indicated that, compared with other immune-mediated diseases, abrocitinib has the longest median time to noticeable improvement when used for AA, reaching up to 10 months, which poses a clinical challenge for its application in AA.150 Abrocitinib exhibits a favorable safety profile. In the aforementioned retrospective study, all adverse events were mild. The most common adverse reactions were folliculitis (15.38%), nausea (15.38%), and abnormal laboratory findings (15.38%), while the majority of patients remained free of adverse reactions140 (Table 3).

Baricitinib

Baricitinib is an oral, reversible, and selective JAK1/JAK2 inhibitor, exhibiting approximately 100-fold greater selectivity for JAK1 and JAK2 over JAK3.151 It exerts its therapeutic effect by inhibiting the JAK1 and JAK2 signaling pathways and suppressing cytokines that drive the survival and activation of CD8+ T cells, thereby facilitating hair regrowth.66,152 By 2022, baricitinib had secured approval from both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA); it subsequently received approval from the National Medical Products Administration (NMPA) in 2023 for the treatment of severe AA in adults.18,153 Furthermore, a recent study utilizing scalp tape-strip RNA sequencing characterized the molecular response profiles of AA patients receiving baricitinib, demonstrating a partial normalization of inflammatory signatures. These findings provide further validation of the underlying mechanism and clinical efficacy of baricitinib in the management of AA.154

Key Findings

Eli Lilly conducted several large-scale clinical trials. BRAVE-AA1 and BRAVE-AA2 are two independent, ongoing, randomized, double-blind, placebo-controlled, parallel-group Phase 3 trials. Their findings, along with results from follow-up studies, supported the global regulatory approval of baricitinib for the treatment of severe AA (NCT03570749, NCT03899259). In these studies, adults with a confirmed diagnosis of AA were enrolled; severe AA was defined as a SALT score ≥ 50. Patients with diffuse AA or other forms of hair loss, such as androgenetic alopecia that might interfere with clinical assessments, were excluded. Eligible participants were randomized in a 3:2:2 ratio to one of three oral treatment arms: baricitinib 4 mg QD, baricitinib 2 mg QD, or placebo. Treatment was administered continuously for 36 weeks. Concurrent use of other 5α-reductase inhibitors (eg, finasteride) or minoxidil (oral or topical) was permitted, provided that patients had been on a stable dose for at least 12 months prior to randomization and the dosage was expected to remain unchanged throughout the trial period.98

The BRAVE-AA1 and BRAVE-AA2 trials primarily evaluated the proportion of patients achieving a SALT score ≤ 20 at Week 36. In BRAVE-AA1, the proportion was 38.8% in the baricitinib 4 mg group, 22.8% in the 2 mg group, and 6.2% in the placebo group. In BRAVE-AA2, the corresponding rates were 35.9%, 19.4%, and 3.3%, showing a consistent trend.98 Baricitinib also demonstrates favorable long-term efficacy. In a follow-up study, the maintenance rate of SALT ≤ 20 at Week 152 was 89.1% in the 4 mg group and 83.6% in the 2 mg group. Furthermore, 79.1% of patients in the 4 mg group and 70.1% in the 2 mg group achieved a SALT score ≤ 10. Accordingly, most patients who attained a satisfactory response at Week 52 maintained their therapeutic benefit with continuous treatment for up to 3 years, and a considerable proportion of patients with severe AA achieved near-complete scalp hair regrowth.155 A cohort study enrolling 330 patients applied trichoscopy to dynamically monitor hair regrowth. Vellus hair regeneration could be detected on trichoscopy as early as 4 to 5 weeks after treatment initiation, and most patients achieved remarkable hair recovery within 2 to 6 months. This trial included multiple severe subtypes of alopecia areata, verifying that baricitinib delivers consistent therapeutic efficacy across all AA phenotypes.156

However, patient responses to baricitinib are highly heterogeneous. King et al categorized responders from the BRAVE-AA1 and BRAVE-AA2 trials into three subgroups: early responders, gradual responders, and late responders. In their analysis, early responders were defined as patients who first achieved a SALT score ≤ 30 within 12 weeks of treatment initiation. Gradual responders first reached SALT ≤ 30 between Week 12 and Week 36. Late responders were those who attained SALT ≤ 30 for the first time between Week 36 and Week 52. In addition, non-responders were defined as patients who never achieved SALT ≤ 30 within 52 weeks. The speed of treatment response was strongly correlated with baseline disease severity; patients with very severe AA were more likely to be late responders.157 Favorable responders typically had a shorter duration of the current disease flare and a shorter overall disease course at baseline, and were more likely to have non-universal AA, no atopic background, and milder eyebrow/eyelash loss. A Japanese study of 27 patients with severe AA treated with baricitinib (most of whom had refractory subtypes such as AT/AU or ophiasis) also indicated that the duration of the current AA flare significantly influenced treatment outcomes, highlighting the necessity of early intervention.158,159 Beyond these clinical factors, Muñoz‑Barba et al found that early responders (who tended to achieve better overall efficacy) had significantly higher baseline erythrocyte sedimentation rate (ESR) levels compared with non-responders. This suggests that the therapeutic effect of baricitinib is closely associated with systemic inflammatory status and may provide further insight into the pathogenesis of AA.160

Nevertheless, even in patients with severe baseline disease, baricitinib treatment strengthened their confidence of “never giving up”.161 Senna et al discussed a unique and key subgroup of “partial responders” at Week 52. These patients did not meet the criteria for a full response at Week 52, but had previously achieved partial response or showed obvious improvement in eyebrow and eyelash regrowth. This group represents patients with delayed treatment response or those whose hair quality improves earlier than hair density. Despite their initial incomplete response, 39.1% of them eventually achieved substantial hair regrowth (SALT ≤ 20) by Week 104 with continuous treatment.162 Therefore, prolonged continuous treatment with baricitinib yields better therapeutic outcomes, supporting the necessity of clinical patience in the management of AA.

To address key clinical questions including whether long-term responders can safely discontinue baricitinib, the risk of relapse after withdrawal, and the efficacy of retreatment following relapse, researchers conducted a follow-up study after the BRAVE-AA1/2 trials. This trial enrolled patients who achieved a therapeutic response (SALT score ≤ 20) during the initial 52-week treatment period with baricitinib, while excluding those with insufficient clinical response after at least 12 weeks of standard treatment. At Week 52, patients were re-stratified according to treatment response: responders in the 2 mg group continued on 2 mg; responders in the 4 mg group were re-randomized to remain on 4 mg, taper down to 2 mg, or discontinue baricitinib (withdrawal). The study aimed to evaluate the efficacy and safety of continuous treatment from Week 52 to Week 152, as well as disease changes after drug withdrawal or dose reduction.155,163

Relapse severity varied across different stages, and overall disease severity gradually worsened with prolonged drug discontinuation or dose reduction. The early period (Weeks 4–8) served as a high-risk window, during which approximately 10–20% of patients began to lose their therapeutic response. The risk became more pronounced in the medium-to-long term: 50–60% of patients lost treatment benefits by Week 24, and the proportion reached as high as 80% by Week 152.163 After relapse, retreatment with baricitinib achieved a therapeutic success rate of 87.5% in the 4 mg group and 63% in the 2 mg group. Most patients were able to regain a favorable response, while a subset of patients with a short disease course and mild baseline severity maintained long-term efficacy without relapse.155,163,164 Accordingly, King et al explored the question of “How Long to Treat to Achieve Desired Treatment Outcome” among patients in the 4 mg cohort of the BRAVE-AA1/2 trials.165 Therefore, most patients with moderate-to-severe AA require long-term maintenance therapy to sustain hair regrowth, indicating that AA is a chronic and relapsing autoimmune disease.

Baricitinib also demonstrates favorable efficacy in other clinical trials. A 52-week real-world study enrolled 23 patients with severe AA, more than half of whom presented with AT/AU, ophiasis, or accompanying eyebrow and eyelash loss. Most patients had a long disease course (mean 22 years) and had previously received treatments including corticosteroids and cyclosporine. The Skindex-16 scale was used for evaluation, with the mean score decreasing from 56.23 at baseline to 36.53 at Week 52. The HADS scale indicated improvements in psychological status, and the mean SALT score in these patients with refractory AA decreased from 83.66 at baseline to 42.41 at the final follow-up.166 To investigate the effects of baricitinib on AA at the trichoscopic and microscopic levels, Piraccini et al conducted a 48-week retrospective, observational, multicenter study involving 253 patients. At Week 48, the mean SALT score decreased significantly from 93.7 to 26.5 (p < 0.001), confirming the efficacy of baricitinib in inducing extensive scalp hair regrowth. Concurrent trichoscopic examination revealed reductions in disease activity markers: follicular keratotic plugs, broken hairs, and dystrophic hairs decreased markedly, while regrown hair increased sharply from 7.1% to 80.2%. These findings provide direct and robust microscopic evidence that baricitinib effectively activates hair follicles and promotes entry into the anagen phase167 (Table 2).

Use of Baricitinib in Special Populations

To date, only ritlecitinib has been approved as a JAK inhibitor for the treatment of severe AA in children and adolescents. Consequently, baricitinib is frequently used off-label in this population. Further research into the efficacy of baricitinib among children and adolescents will facilitate its official approval for this age group, allowing broader access to treatment for minors with severe AA. In a randomized controlled trial, Zhang et al compared the efficacy of tofacitinib and baricitinib in children and adolescents with moderate-to-severe AA. Nearly half of the 100 pediatric patients achieved stratified therapeutic responses according to baseline disease severity. Although the efficacy rate of baricitinib in pediatric patients in this study was lower than that reported in adult trials, non-standard dosing regimens were adopted in this investigation. Even so, given the limited clinical data on JAK inhibitors for pediatric AA, the trial confirmed that both agents are effective and well tolerated in the pediatric population.168 Other studies have focused on pediatric patients with severe AA receiving standard doses of baricitinib (4 mg or 2 mg). After an average treatment duration of 6.5 months, 45.5% of patients achieved a 50% reduction in SALT score, demonstrating clinically meaningful efficacy and favorable tolerability. Additional studies have also verified its therapeutic effects in children.169,170 A recent retrospective study that compared several JAK inhibitors among children likewise confirmed the satisfactory therapeutic efficacy of baricitinib.171

Special subtypes of AA are generally associated with a poor prognosis, including AT/AU and various refractory AA cases complicated by eyebrow, eyelash, or nail involvement. Therefore, in-depth investigation focused on this specific patient population is of great importance. The BRAVE-AA1 and BRAVE-AA2 trials indicated that patients with refractory or severe AA exhibit inferior treatment responses compared with those with patchy AA (ordinary AA) or mild AA. Even so, baricitinib still yields highly satisfactory therapeutic outcomes relative to non-JAK inhibitor regimens, particularly in patients with very severe AA (SALT score ≥ 95).172 First, its efficacy shows a clear dose-dependent pattern: the 4 mg dose consistently outperforms the 2 mg dose and is more likely to induce a systemic therapeutic response, with overall hair regrowth significantly superior to both the 2 mg and placebo groups.98,164,173 Second, therapeutic efficacy on the scalp is correlated with hair regrowth in other body regions. Among patients with eyebrow and eyelash loss, over 70% of those who achieved a satisfactory scalp response (SALT score ≤ 20 at Week 52) also attained concurrent eyebrow and eyelash regrowth. Interestingly, even in patients with an inadequate scalp response, approximately 35% to 49% still presented isolated improvements in eyebrow or eyelash regrowth.174,175

In a real-world study, Ibba et al reported that baricitinib treatment significantly promoted eyebrow and eyelash regrowth. Nearly 70% of patients achieved a ClinRO EB score of 0 or 1, defined as complete eyebrow coverage or only minimal gaps, with a score improvement of ≥2 points from baseline; this proportion was slightly higher than the scalp hair response rate of 61.5%.176

Another retrospective analysis of 36 patients with severe AA showed that after 24 weeks of oral baricitinib 4 mg QD, the eyelash regrowth rate was 83.3% and the eyebrow regrowth rate was 82.7%.177 In an additional retrospective study, Moussa et al enrolled 29 adolescent patients with severe AA treated with oral baricitinib combined with minoxidil. Among treatment responders, 78% achieved complete or near-complete eyebrow regrowth, and the eyelash regrowth rate reached 80%.178 These findings highlight the outstanding efficacy of baricitinib in promoting facial hair regrowth in both adult and adolescent patients, which plays a vital role in improving facial appearance and overall quality of life.

To better evaluate eyebrow regrowth in patients with AA, Ji et al established the modified Brigham AA Eyebrow Assessment tool (mBETA). The results showed that 72.6% of patients achieved mBETA80 (≥80% improvement) at Week 36. Consistent with previous studies, the response rate of eyebrows was also higher than that of the scalp (≥80% improvement in SALT score).179 In addition, patients with more severe AA frequently present with nail involvement, which substantially impairs their quality of life. In a study by Starace et al, 37 patients with AU (mean baseline SALT score = 100) received baricitinib 4 mg QD for 48 weeks. Encouragingly, the mean SALT score decreased to 16.3 at the final evaluation, the average number of affected nails dropped from 6.4 to 2.1, and ClinRO scores also improved significantly. Notably, there was no statistically significant correlation between improvements in SALT score and nail changes, indicating differential therapeutic responses between hair and nail lesions.180

Baricitinib also yields a satisfactory facial hair regrowth rate in male patients. In a real-world study involving 36 participants, Vílchez et al reported a beard regrowth rate of 83.3%.177 Multiple retrospective studies have demonstrated improvements in patient-reported outcomes, including reductions in Dermatology Life Quality Index (DLQI), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7) scores, indicating alleviated psychological burden.181 Another study enrolling 60 male AA patients with beard involvement who received combined treatment with baricitinib and minoxidil reported complete beard regrowth in 40.0% (24/60) of patients, partial regrowth in 45.0% (27/60), and no regrowth in only 15.0% (9/60). Among patients who achieved complete beard regrowth, 54.2% also attained complete scalp regrowth, suggesting consistency in therapeutic response between the beard and scalp regions.182 In contrast, Trecarichi et al observed beard regrowth in 5 out of 10 male patients with AU treated with baricitinib.183

With the increasing use of JAK inhibitors, research focusing on special populations continues to expand. In patients with Down syndrome (DS), enhanced interferon (IFN) signaling and altered cytokine profiles lead to increased susceptibility to various autoimmune and autoinflammatory diseases, including AA.184 These pathological features provide a rationale for targeting the JAK pathway with JAK inhibitors in DS patients.185,186 Two DS patients with severe AA, one of whom also had vitiligo, were treated with baricitinib 4 mg QD. After 9 to 12 months of treatment, both patients showed marked improvements, with SALT scores declining from baseline levels of 70–80 to near zero. Given the pathological complexity observed in DS, JAK inhibitors currently represent a promising therapeutic option.187

In summary, considering the complexity of clinical management and evidence from various case reports, we conclude that favorable therapeutic outcomes are associated with a shorter disease course and milder baseline condition,158,159 an early treatment response (within 36 weeks),157 higher dosage regimen,98,164,173 and results of immunological examinations including ESR level.160

Safety and Adverse Outcomes

Although baricitinib is considered safe and well tolerated, its immunosuppressive properties may increase the risk of serious infections. Since the use of JAK inhibitors for AA treatment remains relatively novel,188 and studies have found that baricitinib is more likely to induce SAEs than traditional JAK inhibitors such as tofacitinib,189 further safety investigations are warranted. In the BRAVE-AA1, BRAVE-AA2 and their extension studies, the incidence of adverse events was higher in the baricitinib group than in the placebo group, though most events were mild to moderate. Common adverse events (incidence ≥ 5%) included acne, upper respiratory tract infection, headache, elevated CPK (some exceeding 5 times the upper limit of normal, usually asymptomatic), and urinary tract infection.18,98,164,190

Apart from common infections, most other notable adverse events were also mild. Dyslipidemia characterized by elevated LDL and HDL levels was observed in the studies. The incidence of infections such as herpes zoster was low, and serious infections were rare (one case of COVID-19 and two cases of pyelonephritis). The discontinuation rate due to adverse events was low and similar across groups.98 Other small retrospective studies have also reported comparable mild adverse events, including dyslipidemia and liver enzyme abnormalities that resolved after drug withdrawal.191 A study comparing patients with AA and rheumatoid arthritis (RA) found that SAEs occurred occasionally in AA patients, yet the incidence was much lower than that in RA patients, demonstrating the favorable safety profile of baricitinib for AA treatment.192 Furthermore, a retrospective study confirmed that multiple JAK inhibitors exhibit a more desirable adverse event spectrum compared with conventional immunomodulators.193 Overall, baricitinib does not directly induce severe adverse events and presents a satisfactory safety profile. Jeong et al also developed an S-MAP patch loaded with baricitinib for local delivery. In an AA mouse model, its hair growth efficacy was significantly superior to that of the control group (82% vs 31%, P < 0.05), offering a novel strategy for topical administration.194

Baricitinib in Combination with Glucocorticoids

For severe AA patients with an inadequate response to baricitinib monotherapy, glucocorticoids represent the most commonly employed and mechanistically rational adjunctive therapy. Through broad suppression of multiple inflammatory pathways — including inhibition of NF-κB signaling and reduction of pro-inflammatory cytokine production — glucocorticoids complement the JAK-STAT-targeted action of baricitinib at a distinct immunological level. Clinically, glucocorticoid co-administration spans a spectrum of routes and intensities, ranging from topical applications to systemic oral regimens and intravenous pulse therapy, each with distinct indications and risk–benefit profiles.

In a study, 19 patients with severe AA received a stepwise sequential regimen: initial treatment with baricitinib plus topical glucocorticoids; non-responders further received dexamethasone pulse salvage therapy. After 52 weeks, 89.5% of patients achieved a SALT score ≤ 20. Moreover, this strategy complies with relevant regulatory restrictions, expanding the clinical applicability and clinical value of baricitinib.195,196 However, not all studies have confirmed a benefit of upfront systemic glucocorticoid co-administration. Zhang et al conducted a retrospective study comparing a combination group (systemic glucocorticoids administered before or concurrently with baricitinib: compound betamethasone injection 7 mg/mL) and a baricitinib monotherapy group. The results showed no statistically significant difference in the Week 12 early response rate between the two groups. Larger clinical trials are therefore necessary to clarify the actual efficacy of glucocorticoid combination therapy in JAK inhibitor-based treatment for AA197 (Table 3).

Baricitinib in Combination with Oral Minoxidil

Oral minoxidil, a potassium channel opener structurally and pharmacologically unrelated to glucocorticoids, has emerged as another clinically important adjunct to baricitinib in AA management. Unlike baricitinib, which targets the autoimmune destruction of hair follicles via JAK-STAT inhibition, minoxidil promotes hair regrowth by inducing vasodilation and facilitating the transition of telogen follicles into the anagen phase through Wnt/β-catenin-dependent pathways. The complementary and non-overlapping mechanisms of these two agents provide a compelling rationale for their combined use.198

A retrospective study enrolled 28 AA patients treated with baricitinib 4 mg QD combined with oral minoxidil for no less than six months. Among 22 patients with a baseline SALT score of 95–100, 50% (11/22) achieved a SALT score ≤ 20. In comparison with the BRAVE-AA1/AA2 trials, only 28% of matched patients with very severe AA attained the same endpoint with baricitinib monotherapy.199 In a cohort of 77 AA patients treated with baricitinib combined with oral minoxidil, the median time to response was six months, and 63.2% obtained a favorable response (SALT ≤ 20). These findings support the hypothesis that minoxidil can enhance and accelerate the efficacy of JAK inhibitors, particularly in long-standing and refractory AA.200

Ruxolitinib and Deuruxolitinib

Ruxolitinib is a JAK1/JAK2 inhibitor and an early pioneering drug in the JAK inhibitor class. It was first approved in 2011 for the treatment of myelofibrosis (oral formulation), and its topical cream has shown favorable efficacy in autoimmune diseases such as rheumatoid arthritis and psoriasis.201,202 In addition, an in vivo administration experiment conducted in the C3H/HeJ alopecia areata mouse model revealed that ruxolitinib reverses pathological changes of alopecia areata via three synergistic mechanisms simultaneously: blocking the upstream JAK-STAT inflammatory pathway, alleviating cutaneous oxidative stress, and interrupting the inflammatory amplification cycle.203 These findings not only confirm the favorable efficacy of ruxolitinib but also provide insights for investigating the mechanisms of other JAK inhibitors. Deuruxolitinib is a deuterated derivative of ruxolitinib. Deuteration can slow specific metabolic pathways, improving potency and safety. Deuruxolitinib was approved by the FDA in July 2024 for the treatment of severe AA in adults. At a dose of 8 mg twice daily (BID), deuruxolitinib became the third oral JAK inhibitor approved by the FDA for this indication, following baricitinib and ritlecitinib.20,204,205 Because its metabolism primarily depends on the CYP2C9 enzyme, genotyping of this enzyme is mandatory before initiation to prevent drug accumulation and associated adverse reactions in poor metabolizers206 (Table 3).

Ruxolitinib

Ruxolitinib is available in both topical cream and oral formulations. Its immunosuppressive and anti-inflammatory properties make it a therapeutic option for various dermatological conditions.207 Topical ruxolitinib is approved by the EMA/MHRA for non-segmental vitiligo and by the FDA for vitiligo and AD; it is also used off-label for dermatoses such as psoriasis and AA,208 although evidence supporting its efficacy in these disorders remains controversial.209 Successful cases of AA treated with topical ruxolitinib are very rare. For example, a 5-year-old patient with comorbid AA and AD achieved complete resolution of resistant frontal hairline lesions after 12 months of continuous ruxolitinib cream application, but new patches of alopecia developed on the occipital scalp several weeks after discontinuation.210 In most studies, ruxolitinib cream has demonstrated suboptimal efficacy in AA. In a Phase II study by Olsen et al, AA patients were treated with 1.0% or 1.5% ruxolitinib cream BID; none of the patients achieved the primary endpoint (SALT50) after 24 weeks of treatment.211 A series of case reports also indicate that ruxolitinib cream does not produce meaningful efficacy in AA.211–213

However, many studies continue to explore the efficacy of topical JAK inhibitors, as the localized delivery of topical formulations avoids systemic exposure and reduces the risk of adverse outcomes. Pharmacokinetic comparisons between topical and oral administration in minipig models showed that the plasma AUC after oral dosing was 31‑fold higher than after topical application, whereas the steady‑state dermal concentration following topical administration was 507‑fold higher than with oral dosing, indicating favorable local delivery.214 Nonetheless, substantial clinical evidence demonstrating poor efficacy of topical ruxolitinib suggests limitations in drug delivery to deep hair follicles with topical administration. Overall, compared with oral JAK inhibitors, topical ruxolitinib exhibits low bioavailability and inconsistent efficacy.66,215,216

Several early studies investigated the efficacy and safety of oral ruxolitinib. In a Phase II clinical trial by Wiggan et al, patients received oral ruxolitinib 20 mg BID. After 3–6 months of treatment, the mean reduction in hair loss reached 92% (NCT01950780). However, all responders experienced varying degrees of hair loss within 3 months of discontinuation, suggesting that long-term maintenance therapy may be required to sustain efficacy.217 Multiple studies have demonstrated significant scalp hair regrowth with ruxolitinib at various doses, including low-dose regimens.207,218,219 A case study of a patient with comorbid AA and vitiligo reported that hair regrowth began in the frontal and parietal regions at Week 4 of treatment with ruxolitinib 20 mg BID. By Week 12, scalp hair coverage had increased from 63% at baseline to 85%, with marked improvement in vitiligo lesions.220 Ruxolitinib also showed favorable efficacy in pediatric patients. An 8-year-old obese boy with prior inadequate response to intralesional triamcinolone acetonide achieved complete hair regrowth after four months of ruxolitinib 20 mg BID,221 supporting its promising efficacy across diverse populations, including those with comorbidities and pediatric patients.

Of note, several studies have documented excellent hair regrowth in unexpected scalp and extra-scalp sites with ruxolitinib. A patient with 11-year-long AU achieved full beard regrowth after four months of ruxolitinib 20 mg BID.222 In another case, an elderly patient with hypereosinophilia showed marked eyelash regrowth following ruxolitinib treatment.223 One study demonstrated the potent reversing effect of ruxolitinib in chromosomally mediated AA. A 24-year-old female with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), an autosomal recessive autoimmune disorder, accompanied by severe AA showed dramatic improvement in AA after oral ruxolitinib therapy, indicating its ability to overcome genetically driven forms of AA.224

With regard to safety, topical ruxolitinib has a favorable safety profile due to its local administration. Although oral ruxolitinib has been associated with a range of adverse events of varying severity in clinical studies for other conditions, including elevated liver enzymes, increased creatinine related to acute kidney injury, anemia, and some cytopenias,225 adverse events in multiple AA-focused studies have generally been mild. However, because oral ruxolitinib has not undergone large-scale Phase III trials for AA, it is not widely used in clinical practice.213

Deuruxolitinib

THRIVE-AA1 and THRIVE-AA2 are the pivotal randomized, double-blind, placebo-controlled, multicenter Phase III clinical trials supporting the approval of deuruxolitinib for moderate to severe AA in adults (NCT04518995, NCT04797650). Both trials enrolled patients aged 18–65 years with a confirmed diagnosis of AA and a baseline SALT score ≥ 50.99,226 Eligible participants were randomly assigned to receive deuruxolitinib 12 mg BID, 8 mg BID, or placebo for 24 weeks, with multiple follow-up assessments at Weeks 8, 12, 16, and 20.99,226 In THRIVE-AA1, the mean baseline SALT score was 85.9. At Week 24, the SALT ≤ 20 response rate was 29.6% in the 8 mg BID group and 41.5% in the 12 mg BID group, compared with less than 1% in the placebo group. Nearly half or more of patients in the active treatment groups reported being “satisfied” on the SPRO patient satisfaction measure. In addition, SALT ≤ 10 response rates ranged from 20% to 40% in the treatment arms.99 Consistent findings were observed in THRIVE-AA2,226 demonstrating the consistent and favorable efficacy of deuruxolitinib.

In addition, a series of real-world studies and meta-analyses have confirmed the favorable efficacy of deuruxolitinib. As one of the few JAK inhibitors approved for moderate to severe AA, a comparative study of deuruxolitinib with other approved agents such as baricitinib and ritlecitinib found that deuruxolitinib 8 mg BID produced the greatest improvement in SALT scores and represented the optimal short-term option for patients with severe AA.227 Another meta-analysis of multiple JAK inhibitors also supported the strong efficacy of deuruxolitinib 12 mg BID.228 Notably, patients’ expectations regarding their appearance and preferences for hair regrowth sites may vary. For instance, male patients often place greater emphasis on eyebrow regrowth, suggesting that AA treatment should be personalized according to individual patient preferences.229

In terms of safety, both the THRIVE-AA1/2 trials and a series of real-world studies have demonstrated an overall favorable tolerability profile. In the THRIVE-AA1/2 trials, common adverse events included nasopharyngitis, headache, acne, and elevated blood creatine phosphokinase, all typical reactions associated with JAK inhibitors.99,226,230 The incidence of SAEs was low, at approximately 1%. Laboratory abnormalities included increased platelet count, mild elevations in creatine phosphokinase and lipids, and neutropenia in a small number of patients.99,226 Notably, a meta-analysis involving more than 3000 patients comparing deuruxolitinib, brepocitinib, and ritlecitinib found that although deuruxolitinib at 12 mg and 8 mg BID yielded significant efficacy in moderate to severe AA, it was associated with a higher risk of adverse events than other JAK inhibitors97 (Table 2).

Tofacitinib

Tofacitinib is an oral JAK inhibitor that suppresses key inflammatory signaling pathways through the inhibition of JAK1/3 activity. Currently, tofacitinib is primarily indicated for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), ulcerative colitis (UC), and polyarticular course juvenile idiopathic arthritis (pcJIA).231–233 Although substantial experimental evidence has demonstrated the favorable efficacy of tofacitinib in severe AA, the current research focus has shifted toward next-generation agents with enhanced target selectivity and improved safety profiles (eg, ritlecitinib), owing to the black box warning issued by the FDA for tofacitinib as an early-generation JAK inhibitor. This shift has been further reinforced by the commercial decision of the original developer, Pfizer, to voluntarily discontinue pursuit of this indication. Consequently, the use of tofacitinib for AA remains off-label.12 To date, at least five JAK inhibitors have received regulatory approval for the treatment of severe AA across different regions. Nevertheless, as one of the earliest JAK inhibitors to enter the market (first approved in 2012), tofacitinib benefits from an extensive body of accumulated clinical evidence. Moreover, given its comparatively lower treatment cost relative to other JAK inhibitors,234 a high rate of clinical utilization of tofacitinib in the management of AA continues to be observed in numerous retrospective analyses and reviews pertaining to JAK inhibitors.235,236

Key Findings

A series of early-phase clinical trials have provided evidence supporting the use of oral tofacitinib for the treatment of AA.191,237 A Phase II clinical trial conducted by Crispin et al enrolled 66 adult patients with AA (SALT score ≥50%), including those with AT/AU. All subjects received tofacitinib at a dose of 5 mg BID. After three months of treatment, 32% of patients achieved a ≥50% improvement in SALT score, accompanied by systemic therapeutic effects. However, hair loss recurred in all patients within 8.5 weeks following treatment discontinuation, indicating uncertainty regarding the long-term durability of tofacitinib efficacy.100,238 In another early study involving 12 patients with AA, eight individuals achieved a SALT50 response, with significant clinical improvement observed in patients with moderate-to-severe AA. This study was among the first to establish the commonly utilized oral dosing regimens of tofacitinib at 5 mg, 10 mg, and 15 mg (NCT02299297).239 Given the widespread clinical application of tofacitinib, a substantial body of subsequent real-world studies and clinical reports has consistently demonstrated its marked efficacy in AA.235,240–244 Furthermore, a meta-analysis encompassing 275 patients reported that 54.0% achieved a favorable or complete hair regrowth rate, indicating a favorable efficacy and safety profile.245 A comparative study by Paracha et al evaluating the efficacy of tofacitinib versus azathioprine found that at the 6-month follow-up, the mean SALT score in the tofacitinib group (baseline SALT score of approximately 91) improved to 14.1, which was significantly superior to the score of 63.9 observed in the azathioprine group, thereby underscoring the advantage of tofacitinib over certain conventional therapeutic alternatives.246

Beyond its primary effect on scalp hair, tofacitinib exhibits favorable systemic efficacy, manifested as improvements in facial hair and nail involvement. In a study by Asilian et al, patients were administered tofacitinib 5 mg BID for a minimum duration of six months. In addition to a 6.45-fold reduction in scalp alopecia severity relative to baseline, the severity of hair loss in non-scalp regions was reduced 4-fold, and patients with fingernail or toenail involvement exhibited a 1.2-fold reduction in severity scores.247 King et al conducted a systematic investigation into the regeneration of eyebrows and eyelashes. Among a cohort of 98 patients with complete scalp hair loss, 86 exhibited concurrent involvement of eyebrows and eyelashes. Following a minimum of six months of tofacitinib therapy, the overall rate of complete eyebrow/eyelash regrowth ranged from 30% to 40%.248 Regarding beard hair in male patients, a study involving 45 subjects with beard alopecia (including 19 with complete beard loss) reported that 10 patients achieved complete beard regrowth after a mean treatment duration of 16 months. Notably, the extent of beard regrowth demonstrated a significant correlation with scalp therapeutic response.249

Furthermore, accumulating evidence suggests that hair loss affecting distinct anatomical regions may arise from divergent underlying pathogenic mechanisms. A case report described a 5-year-old female patient with ophiasis-pattern AA and concurrent AD who achieved complete hair regrowth following tofacitinib treatment, with the notable exception of the ophiasis-affected area. This selective non-response implicates region-specific pathogenic processes.250 King et al further observed that while severe scalp involvement frequently predicts concomitant eyebrow and eyelash involvement, therapeutic responses across affected sites are not uniformly concordant; scalp hair may regenerate in the absence of eyebrow/eyelash recovery, and vice versa. Consequently, for patients presenting with extensive, multi-site alopecia, the strategic combination of multiple therapeutic modalities may be essential for achieving comprehensive resolution of systemic hair loss.248 Nail involvement in patients with AA confers substantial additional functional impairment and psychological burden. Numerous case reports have documented marked efficacy of tofacitinib in promoting nail regeneration. It is noteworthy, however, that patients with nail involvement typically present with higher baseline SALT scores, and nail improvement often lags temporally behind hair regrowth. This temporal dissociation further underscores the critical importance of sustained, long-term therapy in the management of severe AA.251

With respect to distinct clinical subtypes of AA, numerous retrospective studies and case reports have demonstrated the favorable efficacy of tofacitinib in the management of refractory AT/AU.236,252,253 Nevertheless, the therapeutic response of tofacitinib in this recalcitrant AA population exhibits a degree of inconsistency. In a small-sample retrospective analysis encompassing patients with AT/AU, 58.6% of subjects exhibited an inadequate response to tofacitinib, the majority of whom were diagnosed with refractory AT/AU. This finding underscores the persistent variability and instability associated with the off-label use of tofacitinib as a JAK inhibitor for the treatment of AT/AU.254 Conversely, a parallel body of retrospective evidence continues to affirm the significant efficacy of tofacitinib in AT/AU and other difficult-to-treat AA variants.255–257 In a series of trials inclusive of AT/AU cohorts, the therapeutic efficacy of tofacitinib in patients with AT/AU remained comparatively inferior to that observed in patchy alopecia areata (AAP).258 Given that AT/AU frequently arises from delayed clinical attention and inadequate early intervention, this differential response further reinforces the critical importance of prompt treatment initiation in AA.100,244 Beyond the extensively characterized AT/AU subtypes, uncommon manifestations of AA responsive to tofacitinib have also been documented. A case report involving alopecia areata incognita (AAI)—a condition variably proposed as a distinct AA subtype, though this classification remains a subject of ongoing debate259—described sustained and substantial improvement following treatment with tofacitinib 5 mg BID. Trichoscopic evaluation revealed marked and persistent resolution of yellow dots and short, vellus hairs.260 Furthermore, in a pediatric case, trachyonychia secondary to AA exhibited notable improvement with tofacitinib treatment, thereby extending the demonstrated therapeutic utility of tofacitinib to encompass rarer clinical variants of AA within the pediatric population.261 Collectively, these observations illustrate the broad therapeutic potential of tofacitinib in mitigating diverse manifestations across the AA disease spectrum (Table 2).

Efficacy of Tofacitinib in Specialized or Complex Clinical Scenarios

With the expanding clinical application of tofacitinib, a growing body of evidence has revealed that its therapeutic course is not without obstacles, and it currently faces the dual challenges of heterogeneous efficacy and variable durability of response. The efficacy of tofacitinib in AA is influenced by a multitude of intrinsic and extrinsic factors. A consensus has emerged regarding the impact of patient-intrinsic host characteristics on treatment outcomes: patients who exhibit a favorable response typically present with a shorter disease duration and milder baseline severity, which are associated with more rapid and sustained hair regrowth.262 However, a retrospective study found that tofacitinib yielded greater improvements in SALT scores in patients with severe AA compared with those with non-severe AA.263 Notably, in the study by Crispin et al, patients with pre-treatment perifollicular inflammation (23/28) demonstrated a more pronounced improvement (median improvement of 32.9%) compared to those without inflammation (1.2%).100 Beyond patient-specific host factors, extrinsic influences may also modulate therapeutic responsiveness. Individuals with a history of prior JAK inhibitor exposure often exhibit an attenuated response.262 Furthermore, viral infection exerts a significant impact on the pharmacodynamics of JAK inhibitors. A patient with AT who had been adherent to a stable tofacitinib regimen experienced no further improvement in hair loss upon resumption of tofacitinib for three months following a treatment interruption due to COVID-19 infection. The secretion of cytotoxic mediators, including granzyme and perforin, can trigger programmed cell death, a pathway implicated in both viral pathogenesis and AA. Viral insult may disrupt the immune privilege of the hair follicle, leading to elevated secretion of interferon-gamma (IFN-γ) and precipitating a more robust immune response and cellular injury.264 Conversely, a patient receiving routine antiretroviral therapy for HIV infection developed uncommon hypertrichosis during tofacitinib treatment,265 providing valuable clinical guidance for the application of tofacitinib in this broader patient population. Additionally, a case was reported in which AA developed during treatment with secukinumab for palmoplantar pustulosis (PPP). Following the discontinuation of secukinumab and the subsequent initiation of tofacitinib therapy, both PPP and AA exhibited marked clinical improvement, suggesting that tofacitinib may be effective in ameliorating AA arising secondary to certain biologic agents.266

Furthermore, owing to the complexities inherent in clinical management, dose reduction or discontinuation of tofacitinib has been documented in a considerable number of cases. A retrospective observational cohort study investigated the feasibility of individualized dose-tapering strategies for maintaining disease control following complete remission. This study enrolled 46 patients with AA who had achieved complete hair regrowth following tofacitinib treatment and were subsequently followed for 48 weeks under a structured dose-reduction protocol. The cumulative standard maintenance dose was successfully reduced from 3360 mg to 2162 mg, with only one patient experiencing disease relapse (SALT score ≥20) at Week 48. These findings support the viability of an individualized dose-tapering maintenance regimen for tofacitinib in AA.267 Additional case reports have similarly demonstrated that patients exhibiting a robust initial response to tofacitinib may maintain satisfactory outcomes following appropriate dose reduction.268 Nevertheless, numerous reports continue to indicate a substantial risk of relapse following dose reduction or treatment cessation. One pathological case series described four patients with refractory AA who achieved complete hair regrowth after ≥6 months of tofacitinib therapy. Upon discontinuation of tofacitinib, these patients received adjunctive low-dose interleukin-2 (IL-2) therapy. Notably, three of the four patients maintained complete remission for 11 to 20 months following cessation of all treatment. The remaining patient experienced a localized relapse at five months, which was subsequently controlled with low-dose tofacitinib maintenance therapy, thereby offering a novel perspective on achieving drug-free remission in the context of JAK inhibition.269 Another study identified a significant correlation between baseline immunoglobulin E (IgE) levels and both the durability of remission and therapeutic response; patients with elevated baseline IgE levels generally exhibited superior efficacy, requiring lower doses of tofacitinib and shorter treatment durations. These observations suggest that sequential therapy involving tofacitinib followed by low-dose IL-2 may represent a more cost-effective strategy for managing recalcitrant AA.270 For pediatric and adolescent populations undergoing active growth and development, dose reduction of tofacitinib assumes even greater clinical significance. A case report involving a 14-year-old patient documented complete hair regrowth within just two months of initiating tofacitinib therapy. Subsequently, the tofacitinib dose was reduced to 5 mg QD and combined with topical 0.1% tacrolimus lotion and 5% minoxidil. After five months, marked clinical improvement was maintained, and tofacitinib was ultimately discontinued. Stable hair growth was subsequently sustained with topical therapy alone. This case underscores the potential feasibility of dose reduction or even complete cessation of tofacitinib in patients demonstrating an exceptionally robust therapeutic response, thereby mitigating the risk of systemic adverse effects associated with long-term JAK inhibitor administration.271

More critically, even in the absence of dose reduction, the therapeutic efficacy of tofacitinib may occasionally wane or be lost entirely over time. Several studies have indicated that patients receiving tofacitinib therapy face a considerable probability of disease recurrence during ongoing treatment.272 This observation suggests that although the JAK-STAT signaling pathway plays a pivotal role in the pathogenesis of AA, the initiation and perpetuation of the disease likely involve additional, parallel mechanistic pathways. In instances where monotherapy yields suboptimal outcomes, alternative strategies—including combination therapy, dose optimization, or switching to alternative therapeutic agents (including JAK inhibitors targeting distinct molecular pathways)—should be considered.273 For example, in a study by Wambier et al, tofacitinib demonstrated overall favorable efficacy; however, eight patients experienced subsequent episodes of AA exacerbation during a mean treatment duration of 31 months despite uninterrupted therapy. Encouragingly, all affected patients ultimately achieved hair regrowth restoration to pre-flare levels within one to five months following interventions such as temporary dose escalation of tofacitinib, short-course oral prednisone, or intralesional triamcinolone acetonide injections.274 Similarly, Schwartzberg et al reported in their investigation that eight pediatric patients (38.1%) experienced AA recurrence while maintaining a consistent daily dosing regimen, suggesting that the efficacy of tofacitinib in the pediatric population may exhibit a degree of instability or fluctuation over the course of treatment.275

Tofacitinib benefits from an extensive duration and broad scope of clinical application. Consequently, relative to newer therapeutic agents, it is supported by a comparatively richer repository of invaluable case reports involving comorbid conditions, including a substantial number of genetic and rare disorders. Such reports not only facilitate a deeper mechanistic understanding of disease pathogenesis but also provide critical guidance for the diversification of clinical management strategies. Many immune-mediated disorders are intricately linked to underlying genetic factors. DS as a relatively common chromosomal disorder, is frequently associated with dysregulated immune homeostasis, rendering AA a not infrequent comorbidity within the DS population. In an analysis conducted by Rachubinski et al involving 10 pediatric patients who completed a 16-week course of tofacitinib therapy, the drug demonstrated a favorable safety profile with no evidence of overt immunosuppression. Treatment was associated with amelioration of a spectrum of cutaneous manifestations, including AA and psoriasis, alongside reductions in interferon scores, cytokine composite scores, and titers of pathogenic autoantibodies. These findings collectively attest to the robust efficacy and safety of tofacitinib in this distinct pediatric DS cohort.276 AA also frequently manifests in association with a diverse spectrum of common autoimmune disorders. Beyond concurrent autoimmune skin diseases such as AD, vitiligo, and psoriasis,277–280 various non-cutaneous autoimmune conditions have been documented. A patient diagnosed with steroid-resistant nephrotic syndrome, an autoimmune glomerulopathy, subsequently developed AA that progressed to AU following inadequate response to minoxidil therapy. After one year of tofacitinib treatment, complete regrowth of eyebrows and substantial scalp hair regeneration were achieved. Notably, no recurrence of nephrotic syndrome was observed throughout the treatment course, thereby illustrating the favorable efficacy and safety profile of tofacitinib in patients burdened by multiple concurrent autoimmune disorders.281 Of particular relevance, as previously discussed in the section on pathogenesis, the gut microbiota exerts a discernible influence on immune-mediated diseases, and certain autoimmune conditions are intimately linked to intestinal function. In one illustrative case, a patient with AA and concomitant celiac disease (CD)—a gluten-triggered immune-mediated enteropathy—received tofacitinib at a dosage of 10 mg BID. In addition to improved hair regrowth, the patient achieved immunological tolerance to dietary gluten.282,283 In another case, a male patient with AA and concurrent Crohn’s disease exhibited marked improvement in AA symptoms following treatment with tofacitinib after undergoing colectomy with ostomy placement, ultimately attaining complete hair regrowth within one year. Remarkably, sustained remission was maintained for two years following the cessation of all immunosuppressive therapy. These observations suggest that in patients harboring multiple autoimmune conditions, shared inflammatory pathways and mechanistic interconnections among diverse immune-mediated symptoms may permit broader immunomodulatory benefits through targeted intervention against the primary inflammatory focus.282,284

Use of Tofacitinib in Pediatric and Adolescent Populations

The application and clinical investigation of tofacitinib in pediatric and adolescent populations considerably exceed that of newer-generation JAK inhibitors. This disparity is attributable not solely to the comparatively robust body of real-world evidence supporting tofacitinib use,285,286 but also, and perhaps more critically, to pragmatic considerations. Notably, in certain under-resourced regions, the economic viability and widespread accessibility of tofacitinib render it the sole feasible option for JAK inhibitor-based management of AA.285

Early-phase investigations involving the treatment of 13 adolescents aged 12 to 17 years with tofacitinib demonstrated clinically meaningful hair regrowth in 9 patients after a mean treatment duration of 6.5 months, with a median improvement in SALT score of 93%.287 This seminal observation established proof-of-concept for tofacitinib efficacy in adolescent AA and provided the foundation for subsequent investigations in pediatric and adolescent cohorts. Thereafter, a series of studies employing more robust experimental designs, including randomized controlled trials (RCTs), have furnished increasingly reliable evidence substantiating its therapeutic utility. A 24-week prospective observational study enrolled 50 pediatric patients aged 6 to 16 years with moderate-to-severe AA, presenting with a mean baseline SALT score of 66.2 ± 8.1. Participants received tofacitinib at a dosage of either 2 mg BID or 5 mg BID, stratified by a body weight threshold of 30 kg. Among the 45 patients who completed the treatment course, the mean SALT score declined to 25.7 ± 9.2, with nearly half of the cohort achieving complete or near-complete hair regrowth. Concurrently, significant improvements were documented in both patient/parent satisfaction indices and Paediatric Quality of Life Inventory (PedsQL) scores.288 In an RCT conducted by Wan et al, 100 pediatric patients with moderate-to-severe AA were randomized in a 1:1 allocation to receive either tofacitinib (n=51) or baricitinib (n=49). At Week 24, the proportion of patients achieving the primary endpoint—defined as a SALT score ≤20 for those with severe/very severe baseline disease or a SALT score ≤10 for those with moderate baseline disease—ranged from 30% to 50% across treatment arms, with no statistically significant difference observed between the tofacitinib and baricitinib cohorts. These findings indicate that tofacitinib confers therapeutic efficacy comparable to that of the approved agent baricitinib in the management of pediatric AA.168 Throughout this period, a body of retrospective evidence has further corroborated the effectiveness of tofacitinib in pediatric and adolescent AA populations. These studies consistently report substantial clinical improvement in the majority of treated children, marked reductions in SALT scores, and an absence of SAEs, thereby demonstrating a safety and efficacy profile commensurate with that observed in adult populations.100,289 Moreover, tofacitinib has exhibited notable treatment efficiency in pediatric cohorts: in a study by Mahajan et al, 36 pediatric patients were followed over a six-month course of tofacitinib therapy, during which 72.2% of children attained a SALT75 response within less than four months of treatment initiation, underscoring a comparatively rapid onset of therapeutic benefit.290

Younger age, particularly when accompanied by AT/AU, is associated with greater therapeutic challenges. The heterogeneity in treatment response may be attributable to more robust or recalcitrant underlying pathogenic mechanisms,262,291 which in turn predispose younger patients to a higher incidence of refractory AA subtypes such as AT/AU. Nevertheless, across the majority of studies, tofacitinib has demonstrated systemic therapeutic efficacy in this distinctive pediatric population,285,292 encompassing generalized hair regrowth. In one investigation involving five pediatric patients with treatment-refractory AU, three children achieved complete regrowth of eyebrows and eyelashes following approximately 14 months of tofacitinib therapy.293 Another study evaluating four prepubertal children (aged 8–10 years) with AT/AU treated with tofacitinib 5 mg BID reported substantial hair regrowth in three cases. Notably, one child had previously failed topical tofacitinib applied to the eyebrow region but exhibited a 62% improvement in scalp hair regrowth accompanied by eyebrow improvement following the initiation of oral tofacitinib therapy.294 Given that the rate of SALT score improvement in pediatric patients with AT/AU tends to lag behind that observed in other AA phenotypes, Geng et al emphasized the critical importance of individualized therapeutic strategies—including consideration of combination regimens and dose optimization—and comprehensive response assessment, incorporating both phenotypic severity and the exercise of clinical patience, for this challenging subset of patients.293 The use of JAK inhibitors for the management of AA in very young children remains relatively limited. However, tofacitinib has been extensively investigated in clinical trials for juvenile idiopathic arthritis involving children aged 2 to 18 years (NCT02592434, NCT01500551), thereby facilitating its broader application in the treatment of AA and other immune-mediated dermatoses. A study focusing on three patients aged 5 years or younger with AT/AU, all of whom had proven unresponsive to multiple prior therapeutic modalities, reported favorable outcomes following administration of weight-adjusted, alternating low-dose tofacitinib regimens comprising 2.5 mg QD and 5 mg QD. All three children exhibited substantial systemic hair regrowth, with one patient achieving >90% regrowth after 12 months of treatment. Consistent with prior reports, these findings suggest that low-dose tofacitinib may represent a viable therapeutic option for young children with severe AA who have failed conventional therapies.295

Topical Tofacitinib and Therapeutic Innovations

The robust therapeutic efficacy of oral tofacitinib has been extensively substantiated across numerous studies. Nevertheless, concerns pertaining to systemic adverse effects, suboptimal local targeted bioavailability, and the potential risks inherent to systemic administration have collectively galvanized widespread research interest and innovative development in topical formulations. A number of investigations have accordingly sought to evaluate the utility of topical tofacitinib preparations, with conventional formulations encompassing tofacitinib ointments or gels. Chikhalkar et al prepared a 2% tofacitinib ointment by triturating 5 mg tofacitinib tablets and incorporating the powder into white petrolatum, and subsequently conducted a prospective, vehicle-controlled study. Following six months of treatment with the tofacitinib ointment in 30 patients with AA, 40% of subjects achieved a significant response, defined as a ≥50% improvement in SALT score. The treated areas exhibited a significantly greater proportion of newly emergent upright hairs and terminal hairs relative to control sites, thereby demonstrating that topical tofacitinib is both efficacious and well-tolerated in the management of AA.296 While clinical trials investigating topical tofacitinib formulations for adult AA are currently underway, data pertaining to pediatric populations remain confined to isolated case reports.297 In children and adolescents, the systemic effects of oral tofacitinib administration may confer disproportionate risks owing to the heightened physiological demands of active growth and development. Consequently, the development of topical JAK inhibitors suitable for pediatric and adolescent use assumes particular clinical significance. In one case, a 7-year-old patient with AT exhibited notable hair regrowth within four months following treatment with topical tofacitinib ointment in combination with mometasone.298 A separate investigation evaluated 11 pediatric patients aged 4 to 16 years with severe AA, the majority of whom presented with AT/AU, who were treated with a compounded 2% topical tofacitinib preparation. After a mean treatment duration of 34.5 weeks, the mean SALT score declined by 32.3%. These findings suggest that topical tofacitinib may represent a rational adjunctive or second-line therapeutic option for pediatric AA patients in whom systemic therapy is not desired or is otherwise contraindicated.299

Given the established consensus that topical JAK inhibitors generally exhibit inferior efficacy compared to their oral counterparts, accordingly, investigations combining topical tofacitinib with adjunctive therapeutic modalities have emerged as a key research priority. In one study, 26 patients with AA affecting the eyebrows, eyelashes, or beard region received topical tofacitinib—specifically, 2% tofacitinib gel applied to the eyebrows/beard and 0.005% tofacitinib ophthalmic solution applied to the eyelashes—in conjunction with intralesional corticosteroid injections. Across each category of facial hair involvement, the majority of patients achieved either complete or partial hair regrowth. This favorable outcome may be attributable to the more superficial location of the facial dermal papilla, which likely facilitates enhanced penetration and bioavailability of topically applied agents. These observations suggest that topical tofacitinib may represent a preferential first-line therapeutic strategy for AA affecting facial hair-bearing sites.300 Notably, beyond combination with conventional adjunctive agents such as minoxidil, innovative multimodal approaches have been explored. A case involving a pediatric patient with refractory AA documented complete scalp hair regrowth following six months of treatment with 308-nm excimer light therapy combined with 2% topical tofacitinib gel. Mechanistically, 308-nm excimer light is known to induce apoptosis of T lymphocytes and modulate cutaneous T-cell trafficking,301 thereby potentially exerting synergistic immunomodulatory effects when used in conjunction with localized JAK inhibition.302

Comparative investigations of oral versus topical tofacitinib formulations have revealed that the therapeutic efficacy of 2% ointment preparations remains suboptimal, a limitation that may be partially attributed to the inherent inadequacy of ointment vehicles as optimal carriers for JAK inhibitor delivery.297 Consequently, substantial research efforts are currently directed toward the development of novel topical tofacitinib formulations, with the overarching objective of engineering a localized, targeted drug delivery system capable of augmenting intrafollicular drug concentration, enhancing the payload capacity and cutaneous permeation of topical tofacitinib, while simultaneously minimizing systemic exposure.21 In this context, Martínez et al investigated the utility of microneedle (MN) arrays to enhance the efficiency of intradermal tofacitinib delivery. Hollow MN arrays were fabricated using cross-linked hydrogels incorporating formulation modifiers and subsequently loaded with tofacitinib. In ex vivo studies utilizing neonatal porcine skin, the deposition of tofacitinib delivered via hollow MN arrays containing sodium chloride was marginally superior to that achieved with a control cream formulation. These findings substantiate the capacity of MN arrays to significantly augment intradermal drug delivery and underscore the potential applicability of this technology in the therapeutic management of autoimmune dermatoses.303

Although MN-based systems enable localized drug administration, they are not without the inherent drawback of compromising cutaneous barrier integrity. To circumvent this limitation, Gabr et al developed gelatin-coated transferosomes (GLTS) for topical application, designed to achieve targeted follicular delivery of tofacitinib. In a cohort of seven patients with refractory AA, all subjects exhibited evidence of hair regrowth following 12 weeks of treatment, with improvement rates reaching up to 80%, thereby optimizing therapeutic outcomes while mitigating the potential hazards associated with systemic exposure.304 In a parallel approach, Li et al engineered nanoparticles specifically tailored to enhance transdermal penetration and augment follicular targeting. The therapeutic efficacy of tofacitinib-loaded cationic nanolipid particles (TFB-cNLPs) was rigorously validated through both in vitro and in vivo experimental paradigms. Mechanistically, treatment with TFB-cNLPs was shown to suppress the JAK/STAT signaling pathway, attenuate interferon-gamma (IFN-γ)-induced AA-like manifestations, and reduce the population of CD8⁺NKG2D⁺ T cells in a murine model of AA, thereby providing a mechanistic foundation for the observed therapeutic benefit.305 Additional innovative carrier systems have been designed to further enhance the permeation capacity of tofacitinib, with efficacy substantiated in murine models. Kuchukuntla et al employed poly(lactic-co-glycolic acid) (PLGA) to fabricate optimized tofacitinib-loaded nanoparticle gels (TFN-NPs), which were subsequently formulated into a topical gel preparation (TFN-NPG).306 Similarly, Christmann et al developed 240 nm tofacitinib-loaded squalenyl derivative nanoparticles (TFB SqD NPs), a formulation characterized by a simplified fabrication process and a notably high drug loading capacity of up to 20%. This system markedly enhanced the efficiency of tofacitinib delivery to hair follicles and holds considerable promise for development as a long-term topical therapeutic option for AA.307

Building upon the foundation of novel carrier systems, select emerging tofacitinib formulations incorporate materials that possess intrinsic adjunctive therapeutic properties or exhibit environmental responsiveness, thereby achieving a synergistic effect that transcends the sum of their individual components. Guan et al constructed phospholipid-calcium carbonate hybrid nanoparticles (PL/ACC NPs) designed not only for targeted drug delivery but also for potential neutralization of the acidic microenvironment characteristic of perifollicular inflammation and the provision of calcium signaling cues, thereby cooperatively inhibiting cellular apoptosis. In a murine model of AA, PL/ACC-TFC nanoparticles demonstrated significantly greater suppression of hair follicle cell apoptosis compared to a topical tofacitinib solution control.308 In a distinct approach, Zabihi et al utilized sulfated dendritic polyglycerol with integrated caprolactone backbone segments (dPGS-PCL) as a carrier to load and solubilize tofacitinib. The carrier material dPGS itself functions as an anti-inflammatory polymer with heparin-mimetic properties, capable of attenuating inflammatory cell infiltration. Evaluation in an ex vivo human skin model of inflammation revealed reduced cutaneous inflammation and suppressed activation of STAT3 and STAT5, as assessed through quantification of interleukin-6 (IL-6), interleukin-8 (IL-8), and STAT3/5 phosphorylation status.309 Furthermore, Wang et al developed a composite gel co-loaded with minoxidil and tofacitinib, leveraging the distinct yet complementary mechanisms of action of these two agents to concurrently suppress immune-mediated follicular assault and promote the restoration of the hair follicle growth cycle. In vivo animal studies demonstrated that this dual-agent formulation not only stimulated hair growth but also downregulated the expression of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) in a C3H/HeN murine model of AA, thereby significantly attenuating local inflammatory responses and effectuating a synergistic therapeutic benefit in AA.310

Safety and Adverse Outcomes

As a JAK inhibitor with an extensive history of clinical utilization, tofacitinib benefits from a substantial and well-accumulated body of safety data. In the study conducted by Crispin et al, the most frequently observed adverse events were infectious in nature, with approximately 25.8% of patients experiencing upper respiratory tract infections of varying severity (16.7%), urinary tract infections (3.0%), herpes zoster (1.5%), and cases of conjunctivitis, bronchitis, and paronychia (each occurring at a frequency of 1.5%). Non-infectious adverse events included headache, abdominal pain, and acne (each reported in 7.6% of patients), as well as diarrhea and fatigue (each occurring in 6.1% of patients). Notably, no SAEs were documented, attesting to a favorable overall safety profile.100 In a retrospective analysis conducted by Huang et al involving 11 pediatric patients with AA, mild adverse events comprised transient elevations in hepatic transaminases (one case), a modest reduction in hemoglobin concentration (one case), and folliculitis accompanied by hyperuricemia (one case).100 Additional adverse events encompassed laboratory abnormalities, including elevations in serum lipid levels.248 Collectively, these findings represent the commonly encountered mild adverse reactions associated with JAK inhibitor therapy and demonstrate a consistent and acceptable safety profile across diverse age strata.

However, adverse events associated with tofacitinib therapy for AA have been documented with appreciable frequency. The agent carries a black box warning, and a comparative analysis of six JAK inhibitors—including abrocitinib, baricitinib, and tofacitinib—derived from the FDA Adverse Event Reporting System (FAERS) database identified tofacitinib as the agent associated with the highest number of reported infection-related adverse events.311 Furthermore, isolated case reports have documented the emergence of exacerbated facial acne, anorexia, jaundice, and hepatic injury following tofacitinib treatment.312,313 These findings collectively raise salient safety concerns regarding the clinical application of tofacitinib and underscore the critical importance of real-time health surveillance tailored to individual patient constitutional factors313 (Table 3).

Ritlecitinib

Ritlecitinib is a novel oral inhibitor that highly selectively and irreversibly inhibits JAK3 and the TEC kinase family. It thereby suppresses signal transducer and activator of transcription (STAT) phosphorylation mediated by JAK3-dependent cytokines, including interleukin IL-2, IL-4, IL-7, IL-15 and IL-21. This blocks signaling by multiple cytokines and the cytotoxic activity of T cells, exerting therapeutic effects in autoimmune diseases.314–316 In contrast, it exhibits low affinity for JAK1, JAK2, and tyrosine kinase 2 (TYK2).314,317 Ritlecitinib is used in the treatment of AA, vitiligo, ulcerative colitis, and Crohn’s disease. It was approved by the FDA, EMA, and NMPA in 2023 for the treatment of severe AA in adolescents aged 12 years and older and adults, becoming the second JAK inhibitor approved for AA following baricitinib in 2022.318,319

Key Findings

Several large-scale clinical trials have been performed by Pfizer, including the randomized, double-blind, multicenter phase 2b/3 ALLEGRO trial, phase 2a AALEGRO study, and ALLEGRO-LT long-term extension trial, carried out at 118 centers across 18 countries to support marketing authorization. On this basis, ritlecitinib has been shown in large populations to have favorable efficacy and long-term safety in adolescents (aged 12 years and older) and adults with AA (NCT02974868, NCT03732807, NCT04006457).

In AALEGRO Phase 2b/3 trial, eligible participants had ≥50% scalp hair loss, including AT/AU. 718 patients were ultimately enrolled, including 105 adolescents.101,320,321 The study employed randomized grouping stratified by disease severity and age. Participants were assigned to receive one of the following regimens: ritlecitinib 200 mg loading dose plus 50 mg QD, 200 mg loading dose plus 30 mg QD, 50 mg QD, 30 mg QD, 10 mg QD, or placebo. All subjects received treatment for 24 weeks. After 24 weeks of placebo treatment, participants switched to ritlecitinib 50 mg QD, with or without a 4-week 200 mg loading dose, until week 48 completion of the trial.101,321

The primary endpoint of these trials was scalp efficacy, and ritlecitinib significantly improved patients’ SALT scores. In the AALEGRO Phase 2b/3 trial, the proportion of patients with a SALT score ≤ 20 at Week 24 was as follows: placebo 2%, 10 mg group 2%, 30 mg group 14%, 50 mg group 23%, 200 mg plus 30 mg group 22%, and 200 mg plus 50 mg group 31%. The proportion of patients achieving a Scalp Hair Assessment Score ≤ 10 was also significant, although slightly lower than that for SALT ≤ 20.101 In ALLEGRO-LT, data showed that the proportion of patients achieving SALT ≤ 20 continued to increase from Month 12 (approximately Week 48) to Month 24, indicating that efficacy was maintained or enhanced with longer treatment.322 Response rates rose rapidly during the first 9–12 months of treatment, then stabilized or continued to improve modestly between 12 and 24 months.323 At Month 24, the response rate for SALT ≤ 20 was approximately 73.5% (247/336), and the rate for SALT ≤ 10 was approximately 66.4%.323 To account for bias from early discontinuation, last observation carried forward (LOCF) was used for conservative estimation of observed data, yielding response rates of 60.9% for SALT ≤ 20 and 53.5% for SALT ≤ 10. In addition, 82.4% of patients rated their improvement as “moderate” or “considerable” on the Patient Global Impression of Change (PGI-C), indicating meaningful patient-perceived improvement. Using the Alopecia Areata Patient Priority Outcomes (AAPPO) scale, ritlecitinib treatment was shown to significantly improve quality of life,321,322,324,325 with no evidence of racial differences in efficacy.326

Given the remarkable efficacy of ritlecitinib observed across the AALEGRO trial program, Xi et al conducted a post hoc analysis of a biopsy subgroup from the Phase 2a clinical trial. Using microarray to profile the transcriptome of scalp samples from patients with AA or AT/AU, the study revealed that ritlecitinib downregulated key type I/II immune-related genes (including CCL5, GZMB, CCL13, etc) and genes linked to its mechanism of action (such as JAK3), while upregulating hair keratin genes. Expression changes correlated significantly with clinical response. Notably, the upregulation of hair keratin genes was less pronounced in patients with AT/AU than in those with AA, mechanistically supporting the refractory nature of AT/AU.327

A novel aspect of the ALLEGRO trials was the investigation of various loading-dose strategies. Researchers hypothesized that high-dose ritlecitinib during the initial treatment phase could maximally suppress key immunoregulatory pathways (JAK3/TEC), accelerating clinical response, which could then be sustained with lower maintenance doses (50 or 30 mg). Accordingly, loading-dose regimens were evaluated across all three ALLEGRO trials.322 Of the 718 patients, 262 received a 200 mg daily loading dose for the first four weeks, followed by 50 mg or 30 mg QD for the remainder of the study. Through week 40, the loading-dose groups achieved higher proportions of patients with SALT scores ≤ 20 and ≤ 10 at week 24 compared with the corresponding maintenance-dose-only groups. However, after week 40, the group receiving the 200 mg loading dose plus 50 mg maintenance showed lower rates of SALT ≤ 20 and lower PGI-C scores than the group receiving 50 mg without a loading dose. Furthermore, differences in efficacy measures between the loading-dose and maintenance-only groups narrowed progressively over the course of the trial. Among patients who received placebo for the first 24 weeks and started ritlecitinib at week 24, those administered a 200 mg loading dose showed significantly faster improvements in SALT and PGI-C scores than those receiving only maintenance doses. Together, these findings suggest that ritlecitinib loading-dose therapy is superior to maintenance-only therapy in the short term, but its long-term benefit remains uncertain.101

To further evaluate the long-term safety, tolerability, and durability of hair regrowth with ritlecitinib for up to several years in adults and adolescents (aged 12 years and older), ALLEGRO-LT was performed after the AALEGRO Phase 2b/3 trial (NCT04006457). Its study population includes The Rollover group: patients who previously participated in the Phase 2a or 2b/3 trials and the De novo group: new patients with no prior participation in the aforementioned trials. The treatment regimen consisted of a loading dose of 200 mg QD for 4 weeks, followed by maintenance therapy at 50 mg QD.324

Patients with milder baseline hair loss tended to reach treatment goals faster and at higher rates, but those with severe disease still achieved sustained improvement with continued treatment.322 During the 24-month treatment period, patients showed continuous scalp hair regrowth with no evidence of diminishing efficacy over time,322 and 10.5% of patients only achieved a response after one year of treatment.328 Among patients with poor responses at Week 24 (SALT > 20 or > 10), an additional 22–34% achieved SALT ≤ 20 when treatment was continued to Week 48. In a post hoc analysis of ALLEGRO-LT, ritlecitinib 50 mg induced sustained and profound hair regrowth in nearly half of patients with severe AA.328 Similar findings were reported in other retrospective studies.329–331 Prolonged treatment is critical for some patients, suggesting that early discontinuation should be avoided in those with suboptimal initial responses. Week 24 represents an important efficacy assessment time point but should not serve as the sole decision-making milestone.332 Especially in patients with severe disease (including AT/AU), continued ritlecitinib treatment for more than 12 months remains highly effective.329 A 3-year study following the ALLEGRO trial enrolled 191 patients with baseline SALT ≥ 50. After three years of treatment with ritlecitinib 50 mg QD, 65.1% of patients achieved SALT ≤ 20, and nearly 90% of those who had attained SALT ≤ 20 by Year 1 maintained their efficacy.333

Beyond cosmetic effects on the scalp, AA often causes significant psychological distress due to its profound impact on appearance. Including psychological outcomes in the evaluation of ritlecitinib is therefore essential.334,335 In patients with severe AA treated with ritlecitinib in the ALLEGRO-2b trial, Law et al found that ritlecitinib improved psychological status in a dose-dependent manner. The 50 mg group showed significantly better outcomes in domains such as “self-consciousness and embarrassment” and “interaction with others” compared with the 10 mg group, further supporting a strong dose–response relationship.336 There was also high concordance between patient-reported satisfaction and clinician-assessed improvements in scalp hair regrowth.337 Notably, AA may exert an even greater impact on mental health in children.338 A case report of a 10-year-old girl documented severe pretreatment psychological distress, including anxiety and social avoidance. After 6 months of ritlecitinib 50 mg daily, her SALT score dropped dramatically from 95 to 2. Encouragingly, marked improvements were seen in the “Leisure” and “Personal Relationships” domains of the Children’s Dermatology Life Quality Index (CDLQI). She overcame her avoidance of social activities and became more engaged in daily life and peer interactions339 (Table 2).

Use of Ritlecitinib in Pediatric and Adolescent Populations

ALLEGRO trial is currently the only large‑scale clinical study evaluating a JAK inhibitor for AA in adolescents aged 12 years and older. As the only JAK inhibitor approved for patients aged ≥12 years, ritlecitinib holds significant value for the treatment of severe AA in this population.340 Due to the vulnerability of children and adolescents, those with AA often experience bullying and physical aggression.2 In the ALLEGRO trial, among adolescents receiving ritlecitinib at doses of 30 mg or higher, 17–28% achieved SALT ≤ 20 and 6–28% achieved SALT ≤ 10 by Week 24. Efficacy improved with longer treatment: by Week 48, 20–50% of patients in the 30 mg and higher dose groups reached SALT ≤ 20 or ≤ 10. In the placebo‑switch group, in which patients crossed over to ritlecitinib after 24 weeks of placebo, 33–40% achieved SALT ≤ 20 by Week 48, confirming efficacy in adolescents, with a trend toward better responses than adults at the same dose.320 A real world study also found the greater response in adolescents (48.6%) than in adults (21.9%) to the improvement of SALT score.341 Given its favorable safety profile in ALLEGRO, ritlecitinib represents a viable long‑term treatment option for adolescent AA patients.322 In a real‑world study from an Italian hospital, 12 adolescent patients (median age 16 years) received 50 mg QD for 24 weeks. Mean SALT score decreased from 91 ± 16.6 at baseline to 46 ± 35.7, and emotional and functional scores on the Skindex‑16 improved significantly, providing valuable real‑world evidence of efficacy in adolescents.342 Another 36‑month real‑world study in 30 adolescents also confirmed favorable efficacy but reported 7 cases of folliculitis, a relatively high rate that raises new safety considerations in this age group.343 Other adolescent‑focused real‑world studies yielded results consistent with those of the ALLEGRO 2b/3 trial.344

For children under 12 years of age, ritlecitinib may only be used off-label. Since AA is strongly influenced by genetic factors, many patients develop severe AA during early childhood. Several retrospective real-world studies have therefore filled this knowledge gap, demonstrating favorable efficacy and safety of ritlecitinib in children younger than 12 years. Huang et al conducted a retrospective case series of 10 children with severe AA (most with AU, ophiasis, or refractory disease involving eyebrow/eyelash loss). After a mean treatment duration of 26 weeks with ritlecitinib (some patients also received topical corticosteroids or minoxidil), 100% achieved a SALT score ≤ 20 at Week 24, and 5 patients achieved complete hair regrowth. Of the 4 children with baseline eyebrow/eyelash loss, 3 showed a ClinRO improvement of ≥ 2 points at Week 24. All laboratory results were normal, with no SAEs (2 cases of acute urticaria and 1 case of folliculitis),345 indicating excellent efficacy and safety. Wang et al performed a retrospective study of 18 children aged 5–12 years with severe AA. All received ritlecitinib 50 mg QD (7 also received topical halometasone BID) for a mean of 20 ± 6.6 weeks. The response rate was 85.7% (6/7) in patients with severe AA (SALT 50–94) and 36.4% (4/11) in those with very severe AA (SALT 95–100). Of 14 patients with baseline eyebrow loss, 9 (64.3%) achieved a ClinRO improvement of ≥ 2 points,346 further supporting the real-world efficacy and safety of ritlecitinib in children under 12 with severe AA.

Given the unique physiological characteristics of children, some studies have explored dose adjustments of ritlecitinib in pediatric patients. A Phase 1 trial using an off-label dose of 20 mg QD in children aged 6–12 years demonstrated favorable outcomes.338 In a notable case report, parents of a 4-year-old patient independently reduced ritlecitinib from 50 mg QD to every-other-day administration. After 24 weeks of intermittent low-dose treatment, the patient’s SALT score decreased from 95 to 5, with complete regrowth of eyebrows and eyelashes. This suggests that in pediatric patients who typically have lower body weight and immature metabolic pathways, low-dose or intermittent ritlecitinib may optimize the therapeutic window by balancing efficacy and safety.338,347

Use of Ritlecitinib in Special Populations

AT/AU are severe, refractory subtypes of AA. In the ALLEGRO 2b/3 trial, patients with AT/AU receiving the same dose of ritlecitinib showed weaker responses at Weeks 24 and 48 than those with AAP, yet a substantial proportion still achieved SALT ≤ 20 or SALT ≤ 10. Specifically, 34.8% of AT/AU patients reached SALT ≤ 20 at Month 12, and 59.6% at Month 24.329,348 Notably, 43% of adolescent participants had AT/AU, and they also achieved significant improvement at Month 24.320 A post hoc analysis of ALLEGRO-LT similarly confirmed lower response rates and higher discontinuation rates among patients with AT/AU.328 To explore the mechanistic basis, a post hoc analysis of the AALEGRO Phase 2a trial investigated molecular signatures in scalp biopsies and serum samples from AA patients, revealing distinct immunomolecular profiles between AAP and AT/AU. Microarray transcriptomic profiling assessed changes in gene expression and serum protein levels relative to baseline at Weeks 12 and 24 of treatment. Ritlecitinib upregulated hair follicle keratin genes supporting regrowth and downregulated type I/II immune-related genes and its own target genes. However, the magnitude of these gene expression changes was smaller in AT/AU than in AAP patients, providing a potential molecular explanation for the relative refractoriness of AT/AU.327 Across patients with different baseline characteristics, the efficacy of ritlecitinib was consistent with that observed for baricitinib in BRAVE-AA1/2: patients with more severe disease (higher SALT scores or AT/AU) tended to have poorer responses, highlighting the importance of early intervention during the progression of AA.348

Involvement of the eyebrows, eyelashes, or nails is often regarded as a hallmark of refractory AA. ALLEGRO-LT assessed eyebrow and eyelash improvement using the Eyebrow Alopecia Score (EBA) and Eyelash Alopecia Score (ELA), defined as a ≥ 2-grade improvement from baseline or achievement of normal scores. By Month 24, more than 50–60% of the overall population achieved meaningful eyebrow regrowth, and approximately 50–60% achieved eyelash regrowth, demonstrating favorable regrowth rates. These findings confirm the systemic efficacy of ritlecitinib, which promotes hair growth not only on the scalp but also simultaneously improves eyebrows, eyelashes, and nail involvement.322,324

Real-World Study Findings and Clinical Impact

To better investigate the efficacy and safety of ritlecitinib in complex real world clinical settings, and to account for the multiple AA treatments patients may receive over their lifetime, several real world studies were conducted. These aimed to clarify the clinical use and benefits of ritlecitinib beyond controlled trials, as well as whether prior therapies influence subsequent response to ritlecitinib.349 Such real world studies typically focus on severe AA, special AA subtypes, and the immunological characteristics of patients with refractory disease. Xu et al performed a real world study of 25 patients treated with ritlecitinib 50 mg QD for at least 16 weeks. At Week 16, 19 patients (76.0%) achieved SALT ≤20, accompanied by meaningful eyebrow and eyelash regrowth. Non responders who failed to reach a 50% SALT reduction at Week 16 exhibited significantly higher serum total IgE levels. Given that ritlecitinib selectively inhibits JAK3 and targets type I IL 4R signaling, this suggests patients with more active Th2 immunity, allergic predispositions, or atopic constitution may be less responsive to ritlecitinib.330 Zhang et al conducted a multicenter retrospective study of 100 patients with severe AA, most of whom had refractory and complex presentations including acute AT/AU, ophiasis, sisaipho. Many had comorbid immune related conditions, including thyroid disorders, allergic rhinitis or asthma, AD, and urticaria; 36 patients had previously received other JAK inhibitors. Results were consistent with prior studies: patients with milder baseline disease showed earlier onset and superior efficacy. Furthermore, patients with severe AA but no eyebrow or eyelash involvement were significantly more likely to achieve SALT ≤ 20.331 A separate comparative study of baricitinib and ritlecitinib identified disease duration < 2 years and baseline eyebrow loss (ClinRO ≥ 3) as independent predictors of Week 36 efficacy, further supporting the prognostic significance of eyebrow and eyelash involvement in AA.350

Regarding prior treatment history for AA, multiple studies have shown that patients with previous AA therapies—especially prior JAK inhibitor use—are more likely to exhibit suboptimal responses. Fu et al analyzed 522 patients from the ALLEGRO phase 2b/3 trial, of whom 360 had received prior AA treatments, and detected no significant differences in efficacy or safety at Week 24 or Week 48.351 However, several other real-world studies identified prior JAK inhibitor use as an independent predictor of reduced early efficacy.349,352 Collectively, these findings suggest that patients with a history of JAK inhibitor therapy—potentially due to drug tolerance or inherently refractory disease—require adjusted treatment expectations or strategies when continuing JAK inhibition.349 Other real-world investigations also confirmed that patients previously exposed to JAK inhibitors (including tofacitinib, upadacitinib, and baricitinib) had significantly longer disease duration and poorer responses compared with treatment-naïve patients. Notably, ritlecitinib still achieved near-comparable efficacy in patients unresponsive to other JAK inhibitors, which may be attributed to its distinct JAK subtype selectivity and dual mechanism of also inhibiting TEC family kinases.353 Interestingly, an 11-year-old girl with alopecia totalis (AT) initially received baricitinib treatment for seven months and attained a 65% reduction in SALT score; however, the regrown hair was predominantly white and gray. After switching to ritlecitinib 50 mg once daily, black hair grew back at week 6, and complete hair regrowth with full pigment restoration was achieved at month 6 (SALT 0). This case suggests that prolonged JAK inhibitor therapy may facilitate both hair regrowth and pigment recovery in children with severe alopecia areata.354 These real-world data complement the limitations of large clinical trials such as ALLEGRO, highlighting that patient characteristics—including serum total IgE levels, prior treatment history, and specific AA subtypes—are critically important for personalized treatment regimens in complex clinical practice.

Therefore, given the substantial impact of baseline characteristics on the efficacy of JAK inhibitors, systematic assessment of patients’ baseline features is essential for subsequent clinical treatment. Thaçi et al comprehensively integrated scalp hair loss, eyebrow/eyelash involvement, and total body hair status, and classified AA patients into five classes using the SALT score, EBA/ELA scores, and AAPPO. The classification ranged from non‑AT patients with mostly normal eyebrows, eyelashes, and body hair, to AU patients with nearly complete loss of eyebrows, eyelashes, body hair, and scalp hair. Among patients treated with ritlecitinib at doses of 30 mg or higher, improvements in Patient Global Impression of Change (PGI‑C) and Patient Satisfaction with Hair Growth (P‑Sat) scores were observed in 15.8% to 68.2% of patients across the five classes at Week 24, which were significantly superior to those in the placebo group. This supports the strong statistical explanatory power of this stratification model.355 However, other relevant factors such as atopic status and comorbidities still need to be incorporated into this evaluation framework.

Safety and Adverse Outcomes

Since the use of ritlecitinib for AA is still in the early stages of clinical application, a discussion of its safety profile is highly relevant. Overall, in the ALLEGRO 2b/3 trial, the proportion of patients in the ritlecitinib groups who temporarily discontinued treatment due to adverse events ranged from 6.9% to 10.0%.356 Adverse events (AEs) were also one of the leading causes of permanent treatment discontinuation. Over the 48-week study period, the overall incidence of adverse events across ritlecitinib dose groups was 80%–85%, compared with 83–6% in the placebo crossover group. Notably, different doses did not significantly affect the incidence of adverse reactions.356

In the ALLEGRO 2b/3 trial, most common adverse events with relatively high incidence were mild or moderate in severity, and no deaths were reported during the entire study period. The most frequent specific adverse events included headache (17.7%), SARS-CoV-2 positivity (15.5%), nasopharyngitis (12.4%), and upper respiratory tract infection. In the loading-dose groups, the incidences of urticaria, urinary tract infection, folliculitis, and dizziness were also relatively higher.101 In the ALLEGRO-LT trial, TEAEs occurred in approximately 86.1% of patients, most of which were mild or moderate.324 Other retrospective cohort studies also demonstrated an overall favorable safety profile consistent with previous reports.331

Furthermore, ritlecitinib’s prescribing information carries a boxed warning indicating potential risks of severe infections (including tuberculosis), death, malignant neoplasms, major adverse cardiovascular events (MACE), and thrombosis.314 Thus, even though the incidence of SAEs is only 4.4%, it remains crucial to investigate the potential contribution of ritlecitinib to such events. In the ALLEGRO 2b/3 trial, 14 patients reported 16 SAEs, including 5 cases of severe infections (empyema, sepsis, appendicitis, and diverticulitis), among which empyema and sepsis were considered treatment-related, 2 cases of malignant neoplasms, both breast cancer, with one diagnosed on day 198 and deemed treatment-related and 1 case of pulmonary embolism, considered unrelated to treatment.101 A latest pooled 5-year long-term safety analysis based on the ALLEGRO trial demonstrated no emerging new safety risks during follow-up, with the overall safety profile consistent with previously published data. The incidence rates were 0.1 per 100 patient-years for opportunistic infections, 1.0 per 100 patient-years for herpes zoster, and 0.2 per 100 patient-years for MACE.357 Other clinical trials have reached conclusions consistent with the ALLEGRO trial, confirming that ritlecitinib has an overall favorable safety profile in the studied population, though rare special or SAEs may occur. For example, Okazaki et al reported a case of an AA patient who developed a disseminated maculopapular drug eruption following ritlecitinib treatment,358 and a man developed episodic neuropathic-like musculoskeletal pain.359

Besides the SAEs, the ALLEGRO 2b/3 trial specifically monitored three key adverse events based on preclinical animal studies and the class effect of JAK inhibitors: 8 cases of Herpes zoster, all non‑serious; 30 cases of Neurologic events, including 6 cases of sensorineural hearing loss, all non‑serious with no consistent central hearing impairment identified. None reported with opportunistic infections and major adverse cardiovascular events (MACE) during the study.101 ALLEGRO-LT also focused on these diseases, all of which occurred at low rates (around 1%).324 As a result, the long-term safety profile of ritlecitinib was consistent with the known short-term (48-week) profile, with no new safety signals identified, indicating that long-term use of the drug is safe and manageable.322

Real-world data further support the favorable safety profile of ritlecitinib.349,360 Notably, one study investigated primary and secondary immune responses to meningococcal and tetanus vaccines during ritlecitinib administration, demonstrating good vaccine tolerability and a favorable safety profile in the context of vaccination.361 A meta-analysis including 13 studies showed that the ritlecitinib group had higher incidences of headache, acne, and nasopharyngitis compared with the placebo group, whereas the placebo group had a higher rate of SAEs.362 A retrospective study investigated the effect of ritlecitinib therapy on the lipid profile of patients with AA and found stability in routine lipid parameters. Notably, the atherogenic index of plasma (AIP) was significantly and clinically meaningfully reduced in patients with baseline dyslipidemia, suggesting that ritlecitinib may have therapeutic potential for regulating lipid metabolism.363 However, a prospective cohort study found that the incidence of laboratory abnormalities during ritlecitinib treatment was 61.1%. All abnormal findings were mild (Grade 1–2), though the study was limited by its single-center design. This finding highlights the importance of reassessing the intensity of routine laboratory monitoring in future research.364

Interestingly, beyond objective safety assessments of ritlecitinib (such as observation of adverse outcomes), many studies also incorporated patient satisfaction to provide a “subjective” evaluation of safety, balancing efficacy and safety for a comprehensive assessment of its overall performance. Seneschal et al enrolled 201 patients treated with ritlecitinib or placebo, including those from trials such as ALLEGRO. Six treatment attributes were incorporated, encompassing positive therapeutic value and SAEs to assess the Patient Preference-Weighted Quantitative Benefit-Risk score. The weighted net benefit score for ritlecitinib was found to be higher than that for placebo, indicating that most patients would likely perceive the benefits as outweighing the risks. This confirms the favorable efficacy and safety profile of ritlecitinib from the patients’ subjective perspective.348 Furthermore, Hauber et al compared different doses of ritlecitinib in the ALLEGRO 2b/3 trial and found that, on average, patients were willing to accept the increased potential treatment-related risks associated with the 50 mg dose in exchange for greater efficacy than the 30 mg dose.365 These findings further demonstrate that despite the boxed warning, ritlecitinib achieves convincing efficacy and safety outcomes, laying a foundation for its wider clinical use (Table 3).

Deucravacitinib

Deucravacitinib is an oral selective TYK2 inhibitor currently approved primarily for adult patients with moderate-to-severe plaque psoriasis, with favorable efficacy and a well-established safety profile demonstrated in multiple clinical trials for psoriasis.20,366,367 Beyond psoriasis, it has also been investigated for the clinical management of various immune-mediated inflammatory disorders, including scalp psoriasis, AD, AA, and lichen planus.20,367 As a non-receptor tyrosine kinase within the JAK family, TYK2 serves as a core signaling molecule that modulates the production and secretion of hematopoietic growth factors and proinflammatory cytokines. By specifically inhibiting TYK2 activity, deucravacitinib downregulates the expression of IL-23, type I interferons, and β-defensins, thereby effectively balancing systemic cytokine secretion and suppressing excessive inflammatory responses.368

To explore the efficacy and safety of deucravacitinib, King et al conducted a phase II clinical trial. A total of 94 patients were randomly assigned to receive deucravacitinib 6 mg QD, 6 mg BID, or placebo for a 24-week treatment course. However, the between-group comparison of changes in SALT scores from baseline at week 24 revealed no significant therapeutic benefits of either deucravacitinib dosage relative to placebo. These findings suggest that TYK2 pathway inhibition mediated by deucravacitinib may not serve as a core therapeutic target for hair regrowth in the overall AA population.369 Nevertheless, accumulating case reports have demonstrated the potential efficacy of deucravacitinib in specific patient subgroups, particularly individuals with concomitant psoriasis and AA. One case study described a 68-year-old male patient with severe AA and a 24-year history of plaque psoriasis. Following oral treatment with deucravacitinib 6 mg QD, complete regrowth of scalp and eyebrow hair was achieved within four months, accompanied by full resolution of psoriatic lesions and a PASI score of 0.370 Another report presented a patient who developed sudden AT during psoriasis therapy, with a baseline SALT score of 97 and nearly complete loss of eyebrows, eyelashes, and body hair. After six months of continuous deucravacitinib 6 mg QD treatment, the SALT score decreased significantly to 45.2, with remarkable alleviation of progressive hair loss.371 At present, clinical studies investigating deucravacitinib for AA remain limited in sample size, while available evidence consistently confirms its favorable safety profile.193 Collectively, these clinical observations indicate that the TYK2 signaling pathway may be jointly implicated in the immunopathogenesis of both AA and psoriasis. Previous studies have generally proposed that the core immune cascades driving AA are not directly dependent on TYK2 signaling. As an upstream TYK2-selective inhibitor, deucravacitinib may be capable of exerting broad, systemic immunomodulatory effects beyond single downstream cytokine regulation372 (Table 3).

Brepocitinib

Brepocitinib modulates immune responses via dual inhibition of tyrosine kinase 2 (TYK2) and JAK1. It entered clinical trials for AA as early as 2021, with its efficacy and safety well validated in relevant studies (NCT02974868). However, due to a series of economic strategic adjustments and the competitive impact of ritlecitinib — another agent from the same drug class approved for adolescent patients — brepocitinib has not yet been approved for the treatment of AA. Subsequently, brepocitinib has advanced into clinical trials at various stages for a spectrum of other autoimmune and inflammatory diseases, including cicatricial alopecia, chronic obstructive pulmonary disease (COPD), and Crohn’s disease.373–376 Its research focus has gradually shifted toward the treatment of dermatomyositis,376 greatly expanding its potential clinical application scope.

ALLEGRO 2a was a randomized, double-blind, placebo-controlled phase 2 clinical trial that simultaneously evaluated the efficacy of brepocitinib and ritlecitinib in patients with AA. The study enrolled a total of 142 patients, 47 of whom received brepocitinib with a dosing regimen of 60 mg QD for the first 4 weeks followed by 30 mg QD for the subsequent 20 weeks, totaling a 24-week treatment course.377,378 The results demonstrated the multifaceted therapeutic advantages of brepocitinib. During the drug withdrawal period, 39% of patients in the brepocitinib group completed the phase without meeting the criteria for relapse, a proportion significantly higher than the 18% observed in the ritlecitinib group. Furthermore, the median time to relapse after discontinuation in the brepocitinib group was 24.1 weeks, also significantly superior to that of ritlecitinib.379 Following re-treatment at week 24, 64% of the brepocitinib group regained a SALT30 response, which was significantly higher than the 50% attained by the ritlecitinib group.377 In addition, brepocitinib exhibited systemic therapeutic effects, significantly promoting the regrowth of eyebrows and eyelashes. Concurrently, post-treatment biomarker profiles in lesional skin shifted toward a normal skin phenotype. Specifically, IP-10 levels were significantly reduced, while the expression of keratins (KRTs) and keratin-associated proteins (KRTAPs) progressively increased. Furthermore, inflammatory cytokines were downregulated, and T-cell infiltration showed marked resolution. In tandem with the improvements in SALT scores, AASIS scores also demonstrated significant improvement.377,378,380 Of particular note was the study’s crossover open-label extension (OLE) phase: patients who failed to achieve a ≥30% improvement in SALT score from baseline at week 24 entered a 24-week crossover treatment; 16 patients switched from ritlecitinib to brepocitinib, and 5 patients switched from brepocitinib to ritlecitinib. Following the crossover, none of the 5 patients who switched to ritlecitinib achieved a ≥30% improvement in SALT score or improvement in eyebrow/eyelash scores. In stark contrast, 4 out of the 16 patients (25%) who switched to brepocitinib achieved a SALT score improvement of ≥30% from baseline.381 These findings suggest that brepocitinib may offer superior efficacy compared to ritlecitinib in a subset of patients with refractory AA who exhibit a suboptimal response to initial therapy. This observation further reflects that while the two agents share overlapping mechanisms of action, they possess distinct intrinsic molecular dynamic profiles.380,381 This clinical performance was further supported by a subsequent meta-analysis: after comparing various therapeutic regimens, brepocitinib 30 mg demonstrated the highest efficacy across two primary endpoints—reduction in SALT score and achievement of SALT50 response.97 These data provide robust evidence for the potential of brepocitinib in the management of AA.

However, the safety profile of brepocitinib warrants cautious evaluation. While the drug was generally well-tolerated in clinical trials—with common AEs primarily including upper respiratory tract infections, nasopharyngitis, and headache—two SAEs of rhabdomyolysis were reported in the brepocitinib group during the ALLEGRO 2a trial.377 Furthermore, a meta-analysis indicated that brepocitinib is associated with a higher risk of adverse outcomes compared to other JAK inhibitors,382 with a particularly pronounced incidence of upper respiratory tract infections.383 In light of these safety challenges, in-depth pharmacokinetic (PK) studies have provided critical insights for optimizing clinical application. Research has shown that a high-fat meal reduces both the rate and extent of brepocitinib absorption by 69.9% and 28.3%, respectively; concurrently, drug clearance in Asian populations is 24.3% lower than in other ethnic groups.384,385 These findings suggest that through refined dosing management—such as dietary control and population-specific dose adjustments—it may be possible to maximize therapeutic efficacy while minimizing systemic risks. Against this backdrop, altering the route of administration has emerged as a key strategy to expand the clinical utility of brepocitinib. Beyond the oral formulation, a topical cream formulation offers a new alternative for the treatment of autoimmune skin diseases. Although no statistically significant difference in efficacy was observed compared to vehicle in plaque psoriasis trials,386 topical brepocitinib demonstrated rapid and effective symptom relief in patients with AD, suggesting its potential as a novel therapy for mild-to-moderate AD.387 This differential efficacy not only highlights the potential of topical brepocitinib in specific dermatological conditions but also provides a viable pathway for bypassing the systemic risks associated with oral administration.

Outlook

Nowadays, although the advent of JAK inhibitors marks a major breakthrough in the field of AA treatment, their widespread application in real-world clinical practice has gradually exposed numerous inherent limitations and challenges in long-term management. For instance, long-term safety concerns associated with systemic administration, the almost inevitable high relapse rate after drug discontinuation, and heterogeneous therapeutic responses among patients with varying disease severity and clinical phenotypes all pose severe challenges to current clinical pathways.

Against this backdrop, academic and clinical experts are committed to standardizing the application strategies of JAK inhibitors and actively exploring next-generation targeted drug delivery technologies. Based on the key consensus among specialists in the field of AA, this section systematically discusses the efficacy prediction of JAK inhibitors, standardized strategies for drug tapering and discontinuation (including monotherapy and combined glucocorticoid regimens), the selection of different JAK inhibitor agents, and the future development of novel drug delivery approaches such as nanovesicles and MNs.

Latest Consensus on AA Treatment

Multidimensional Severity Evaluation System

In previous clinical trials and routine practice, the SALT score has long served as the nearly sole criterion for assessing the extent of scalp hair involvement. Nevertheless, reliance solely on the SALT score often fails to fully reflect the real disease burden imposed on AA patients. For example, in patients with severe loss of eyebrow and eyelash hair, changes in facial appearance can lead to profound psychosocial dysfunction, even when the scalp alopecia area does not meet the conventional threshold for severe disease (eg, SALT ≥ 50).388,389 Therefore, the 2024 European expert consensus strongly recommends the combined use of the AA Investigator Global Assessment (AA-IGA) and the AA Severity (AAS) scale for dual grading in clinical practice.390 Under this novel grading framework, even patients with a SALT score below 20 should be actively considered for systemic therapy by clinicians if they meet the moderate-to-severe criteria defined by the AAS scale.2

Recommended Timing for AA Treatment

The pathological progression of AA exhibits prominent time-dependent characteristics. Persistent autoimmune inflammation irreversibly disrupts the microenvironment of hair follicle stem cells (HFSCs), eventually leading to the replacement of follicular structures by fibrotic tissue. Once fibrosis is established, hair follicles lose their regenerative capacity and cannot be restored even if inflammation is thoroughly eliminated by high-dose JAK inhibitor therapy.391 Given this mechanism of irreversible histological damage, early intervention is critically essential for AA management.2,392,393 Systemic therapy (such as JAK inhibitors) should be initiated as early as possible for patients in the acute phase (disease duration ≤ 6 months) or those in a highly active/progressive state.22 Different from the traditional conservative stepwise strategy of topical therapy first, followed by local injection and finally systemic medication, early systemic treatment aims to rapidly block pathological progression before inflammation induces permanent stem cell exhaustion and prevents the disease from entering an irreversible stage.

Screening of Efficacy Predictors for Precision Stratification and Management of AA

Although JAK inhibitors have demonstrated remarkable overall therapeutic efficacy, clinical practice has confirmed substantial heterogeneity in treatment responses among individual patients. Accordingly, systematic identification and validation of efficacy predictors are of critical guiding significance for optimizing patient stratification, rationalizing therapeutic expectations, and formulating individualized follow-up strategies.

The duration of the current disease episode has been widely validated as the core predictor of both short- and long-term responses to JAK inhibitor therapy. Clinical data demonstrate that patients with a shorter disease duration (generally defined as less than 4 years) exhibit significantly greater improvements in SALT scores at 6, 9, and 12 months of treatment, compared with those with a disease course longer than 4 years or even over a decade.167 This finding is pathologically consistent with the principle of early intervention in AA.391 Notably, in patients with an extremely long disease duration, JAK inhibitor treatment can still reverse molecular inflammatory alterations in scalp biopsy specimens, such as the downregulation of inflammation-related gene expression. However, satisfactory macroscopic hair regrowth is often not achieved.100 This implies that such patients may require a higher induction dose during the initial treatment phase, carry an elevated risk of relapse following discontinuation in long-term management, and necessitate an extremely cautious tapering process.

Clinical phenotype represents another critical set of efficacy predictors for AA treatment. Meta-analyses and real-world studies consistently indicate that patients with AT/AU, and ophiasis exhibit a markedly lower response rate and delayed onset of therapeutic effect to JAK inhibitors compared with those with AAP.394 Despite the great difficulty in treatment, accumulating evidence has confirmed that a considerable proportion of these patients can still achieve clinically meaningful scalp hair regrowth after sustained high-dose JAK inhibitor therapy, with longer therapeutic cycles.157,162,166,167,327,328 Beyond clinical phenotypes, microscopic histopathology and trichoscopy also provide abundant predictive information. Studies have shown that scalp biopsy specimens obtained prior to treatment displaying dense peribulbar lymphocyte infiltration (the classic “swarm of bees” inflammatory pattern) reflect an active inflammatory status, in which ongoing hair loss is predominantly driven by the JAK-STAT-mediated cytokine storm.395 In trichoscopic evaluation, the presence of active-phase markers including yellow dots, short vellus hairs, black dots, and exclamation mark hairs supports the timely initiation of JAK inhibitor treatment to block acute disease progression. Such pathological features usually predict prominent improvements in SALT scores following JAK inhibitor therapy.100,396

Rational Selection of Different JAK Inhibitors

There remains no unified consensus on the prioritization and precise selection among these agents. Given that only a small number of head-to-head randomized controlled trials have been conducted to compare different JAK inhibitors, as well as inherent differences among these drugs in terms of applicable age range, receptor selectivity, and safety profile. D’Oria et al conducted a retrospective head-to-head study comparing baricitinib and ritlecitinib, enrolling a total of 160 patients with severe AA: 110 patients received baricitinib 4 mg, while the remaining 50 were treated with ritlecitinib 50 mg. The results demonstrated comparable SALT ≤20 response rates between the two arms at Week 16 and Week 52 (65.5% vs 61.5%). While this research further corroborates the favorable efficacy of both agents, there remains a lack of RCTs that systematically compare the respective strengths and weaknesses of different JAK inhibitors.397

At present, most evidence derives from indirect, cross-trial comparisons and network meta-analyses—approaches that carry interpretive caveats.234 Although the pivotal trials for baricitinib (BRAVE-AA1/2), ritlecitinib (ALLEGRO 2b/3), and deuruxolitinib (THRIVE-AA1/2) all enrolled patients with baseline SALT scores ≥ 50, they differ in primary endpoint timing (Week 36 vs Week 24), concomitant medication policies, and placebo response rates, precluding definitive ranking of agents by efficacy. With these caveats acknowledged, a comparative study found that deuruxolitinib 8 mg BID was associated with the greatest improvement in SALT scores among approved agents, and a separate network meta-analysis corroborated the strong efficacy of deuruxolitinib 12 mg BID.234 Whether the higher response rates observed with deuruxolitinib relative to ritlecitinib reflect genuine pharmacodynamic differences—for instance, dual JAK1/JAK2 inhibition versus JAK3/TEC selectivity—or between-trial heterogeneity remains an open question.

Several conflicting or inconclusive findings further complicate the comparative landscape. First, the role of glucocorticoid co-therapy with baricitinib remains unsettled: while one study reported that stepwise addition of topical and pulse glucocorticoids yielded a SALT≤20 rate of 89.5% at Week 52, an independent retrospective study found no significant difference in early (Week 12) response between combination and monotherapy arms. The discrepancy likely reflects differences in glucocorticoid formulation, timing, disease severity, and the duration of follow-up; prospective studies with standardized protocols are needed to resolve this question.234 Second, the negative Phase II trial of deucravacitinib—a selective TYK2 inhibitor that has demonstrated robust efficacy in psoriasis—underscores a critical mechanistic lesson: TYK2 inhibition alone may be insufficient to disrupt the IFN-γ/IL-15 positive feedback loop in AA, highlighting the functional primacy of JAK1/JAK2 signaling in this disease.234 Finally, a consistent gap exists between clinical trial efficacy and real-world outcomes; real-world cohorts tend to report lower response rates and slower time to response, likely attributable to more heterogeneous patient populations, variable adherence, and less stringent follow-up.

These comparative considerations do not yet permit an evidence-based hierarchy of JAK inhibitors. Rather, they highlight the importance of individualized agent selection guided by patient-specific factors—including disease severity, comorbidity profile, prior treatment history, and regulatory access—pending the availability of head-to-head trials. Currently, clinical medication selection is largely based on the theoretical target specificity of individual JAK inhibitors and personalized assessment of the risk–benefit ratio for each patient.

The cumulative systemic risks associated with long-term use of broad-spectrum pan-JAK inhibitors cannot be ignored,234 and future clinical development is trending toward greater emphasis on long-term safety. Accordingly, next-generation JAK inhibitors with higher target selectivity—such as those specifically targeting JAK3 or the TEC family while completely avoiding JAK2-related disturbances in hematopoiesis and lipid metabolism.234 In the future, further exploration and implementation of large clinical trials are still required to expand the indications and conduct comparative evaluation of various JAK inhibitors.

Therefore, if a satisfactory therapeutic response is not achieved after 6 to 9 months of treatment with a specific JAK inhibitor (it is conventionally considered ineffective if SALT ≤ 20 is not attained within 9 months), clinicians should not directly abandon this therapeutic modality.162,332 Real-world evidence has demonstrated that switching to JAK inhibitors with alternative selectivity profiles can re-induce hair regrowth in a large proportion of previously refractory patients, indicating complementary and partially non-overlapping therapeutic mechanisms among different JAK inhibitors.95,353,381,398 Accordingly, optimizing the strategies for combination use and sequential switching of JAK inhibitors represents a pivotal approach for the management of refractory AA.

As clinical research on JAK inhibitors for AA remains in its early stage, the optimal treatment duration has not yet been clearly defined.164 Studies have identified the 3-month and 6-month time points after systemic treatment initiation as critical early efficacy assessment milestones. The cessation of acute hair loss accompanied by the emergence of vellus hairs or terminal hair regrowth serves as a positive regenerative signal and provides robust evidence for continuing maintenance therapy.143 At 9 to 12 months of treatment, a reduction in SALT score of more than 80% from baseline or the achievement of a SALT score ≤ 20 indicates that scalp hair coverage is likely to recover beyond 80%, which is sufficient to meet the cosmetic demands of most AA patients.

Exploration of Dose Tapering and Discontinuation Strategies

Dose Adjustment and Tapering of JAK Inhibitors

Although JAK inhibitors have demonstrated favorable efficacy in numerous clinical trials and real-world practice, they act as systemic immunosuppressants with non-negligible impacts on the overall immune system. Moreover, most patients with AA develop the disease at a young age.399 Current evidence regarding dose-tapering regimens and relevant case reports remains inconsistent, which substantially compromises the stability of therapeutic outcomes of JAK inhibitor therapy. At present, a high disease relapse rate is commonly observed following treatment discontinuation.163 Future studies are warranted to systematically compare the advantages and disadvantages of rapid versus gradual tapering protocols, and to explore patients’ psychological outcomes, including fear of relapse and concerns over adverse reactions.400

Regarding the discontinuation decision of JAK inhibitors, current clinical consensus recommends entering a maintenance phase once predefined therapeutic targets are achieved, and abrupt self-discontinuation is strongly discouraged. From an immunological perspective, while blocking effector T cells, JAK inhibitors also suppress regulatory T cells (Tregs) that mediate immune regulation and immune tolerance by inhibiting STAT6 phosphorylation,401 leaving the local cutaneous immune microenvironment in a persistent hyperactivated state. Once JAK inhibitor administration is abruptly halted, effector T cells rapidly rebound without sufficient buffering from functional Tregs in the microenvironment. This inevitably triggers an inflammatory storm. Follow-up data have shown that approximately 80% of patients suffer rapid and extensive recurrent loss of newly regrown hair after sudden drug withdrawal.163,379 Faced with this clinical dilemma, exploring optimized tapering protocols that balance therapeutic efficacy and drug toxicity has become a top priority in current clinical research. For patients receiving JAK inhibitor monotherapy, dose reduction should be implemented cautiously to avoid disrupting the restored immune privilege of hair follicles, so as to gradually identify the individual’s lowest effective maintenance dose. Although a universal standardized tapering regimen has not yet been established, several prospective medical centers and real-world retrospective studies have outlined several clinically valuable stepwise dose-reduction pathways.

For instance, Huang et al proposed a skipping-day strategy. For patients with stable complete remission (SALT score ranging from 0 to 4), dose tapering begins by maintaining the single per-dose quantity unchanged while omitting medication on one designated day per week, gradually reducing the total weekly dosage to approximately 86% of the standard regimen.267 If no substantial hair shedding or trichoscopic signs of inflammatory relapse occur during the observation period, the number of drug-free days per week can be further increased. For agents requiring twice-daily administration, the dose and frequency reduction regimen formulated by Sanchez et al recommends tapering to once daily after stable and satisfactory hair regrowth is achieved, followed by continuous observation for 3 to 5 months. If disease activity remains fully controlled without any relapse signals, the dosing frequency can be further reduced to a low-dose twice-weekly schedule, or even long-term alternate-day low-dose maintenance. This approach substantially alleviates the metabolic burden and economic pressure on patients.340

Some clinical trials have incorporated multi-gradient dose groups (eg, 2 mg, 4 mg, and 8 mg per day) in their study design, laying a foundation for the dose-dependent de-escalation strategy of such agents. For severe AA patients, the highest dose (eg, 8 mg or 4 mg daily) is adopted during the induction phase. After complete hair regrowth is achieved, the dosage can be reduced to a lower maintenance dose (eg, 2 mg daily), allowing long-term or even lifelong chronic pathological maintenance at this low-dose level.402

In addition to explorations regarding dose tapering and discontinuation, further research is still needed on higher-dose and off-label dosing regimens. The currently approved dose of ritlecitinib (50 mg QD) may yield insufficient therapeutic effects in a subset of patients. A phase III trial adopted an innovative external placebo-controlled design established based on individual participant data from previous ritlecitinib clinical studies. This design aims to evaluate the efficacy of a higher dose (100 mg QD) without requiring a randomized placebo-controlled arm, thereby meeting higher ethical standards for clinical trials (NCT06873945).403 Nevertheless, cautious clinical judgment is required for off-label use of unapproved doses. The unapproved 200 mg loading dose of ritlecitinib may distort the genuine evaluation of the efficacy and safety profiles of JAK inhibitors, and may also encourage inappropriate clinical adoption of non-standard medication regimens.404,405

Glucocorticoid Tapering in Combined Therapy with Jak Inhibitors

When JAK inhibitors are combined with glucocorticoids, tapering the glucocorticoid dosage is equally critical. Combination regimens of JAK inhibitors plus glucocorticoids are increasingly widely applied in AA treatment and yield more satisfactory efficacy than JAK inhibitor monotherapy. However, whether administered systemically or via frequent local injections, glucocorticoids as broad-spectrum immunosuppressants exert well-documented dose-dependent and time-dependent adverse effects. Studies have indicated that systemic glucocorticoids are not suitable for long-term maintenance therapy and should only be employed for short-term disease control.406,407 Even intralesional triamcinolone injection, which is commonly used in AA management, may lead to cutaneous atrophy, telangiectasia, local hyperpigmentation and other adverse reactions.408 Therefore, in the clinical combined use of JAK inhibitors and glucocorticoids, there is an urgent need to formulate standardized strategies for gradual glucocorticoid tapering while preserving therapeutic efficacy. In such combination regimens, the core principle of dose tapering is to safely and completely withdraw glucocorticoids, with JAK inhibitors serving as a sustained therapeutic barrier. Aouar et al found that although AA patients treated with baricitinib combined with prednisone experienced adverse events such as weight gain, these symptoms gradually alleviated as methylprednisolone was tapered progressively. More importantly, after prednisone discontinuation, baricitinib monotherapy was sufficient to sustain long-term hair regrowth.409

Novel Drug Delivery Routes of JAK Inhibitors

One of the greatest dilemmas currently faced in the treatment of AA is that a disease confined locally to the superficial skin and subcutaneous hair follicles still relies on oral administration, which induces systemic immune suppression throughout the whole body. This not only results in diluted drug efficacy when reaching the target lesion, but also inevitably brings about extensive long-term safety concerns, including myelosuppression, liver function abnormalities, lipid metabolism disorders, and severe infections.410 Therefore, researchers have focused on developing innovative delivery strategies that can precisely deliver immunomodulators directly to local hair follicle lesions, thereby completely decoupling therapeutic efficacy from systemic toxic and side effects.401

In the early stage of local treatment for AA, clinicians often compound oral JAK inhibitors directly into topical creams. Although topical JAK inhibitors have achieved remarkable efficacy in epidermal inflammatory diseases such as AD and vitiligo, they rarely yield satisfactory outcomes in clinical trials for AA.66,208,215,216,296 The fundamental reason lies in the fact that the core pathological lesions of AA are deeply located around the hair bulb and dermal papilla in the deep dermis.410 Conventional macromolecular JAK inhibitors can hardly penetrate the dense and tough stratum corneum for deep percutaneous permeation. Accordingly, simple topical application has been proven insufficient to reverse the underlying pathological changes of moderate-to-severe AA, driving researchers to explore more advanced transdermal targeted delivery technologies.

Nanocarrier Technology

Nanoparticle-based delivery systems exhibit great potential for stratum corneum penetration.305,306,411 Transferosomes and liposomes encapsulate JAK inhibitors within nanoscale lipid carriers composed of phospholipid bilayers, thereby markedly enhancing skin permeability of the drugs. Furthermore, recent studies have demonstrated that gelatin-coated transferosomes, owing to their flexibility and deformability, can directly target and penetrate follicular ostia, releasing payloads deep within hair follicles. This strategy greatly elevates local drug concentration while avoiding systemic absorption via capillary blood vessels.304 Drug-loaded nanovesicles have shown superior therapeutic efficacy compared with aqueous formulations in animal and preclinical models.412

Dual Therapeutic Mechanism of Exosomes

Apart from artificially synthesized nanovesicles, biologically derived exosomes secreted by mesenchymal stem cells (MSCs) have emerged as a promising and transformative delivery carrier.411 Rich in microRNAs and regenerative factors, exosomes have been proven to activate the Wnt/β-catenin signaling pathway in hair follicle stem cells, thereby directly promoting the transition of hair follicles from the telogen phase to the anagen phase. When exosomes are loaded with JAK inhibitors, the encapsulated JAK inhibitors function to eliminate autoimmune T cells in local inflammatory lesions, while the intrinsic bioactive signals carried by exosomes contribute to re-establishing stem cell homeostasis and tissue regeneration. This dual mechanism achieves rapid clearance of local inflammation and prominent hair regrowth in mouse AA models.413 Although this innovative experimental therapy is currently mostly applied to the delivery of minoxidil, it provides a novel theoretical and technical reference for the delivery strategy of JAK inhibitors.

MN Array Therapy

MN technology is currently recognized as one of the most clinically translatable physical permeation strategies.411 MN patches consist of hundreds of micron-scale needles that painlessly penetrate the stratum corneum down to the dermis, creating physical microchannels. Dissolvable or hydrogel MNs fabricated from biocompatible degradable polymers such as hyaluronic acid (HA) and poly(lactic-co-glycolic acid) (PLGA) cause no pain upon insertion into the scalp. After skin penetration, these MNs swell gradually or undergo slow degradation in the dermis, enabling sustained controlled release of loaded drugs.194,303,414

As aforementioned, monotherapy with either systemic or topical JAK inhibitors eliminates pathogenic CD8⁺ T cells yet also inadvertently impairs Tregs that maintain immune tolerance. Researchers have successfully developed a MN patch for the combined delivery of immunomodulators. The patch is loaded not only with trace doses of JAK inhibitors, but also with CCL22, a chemokine that potently recruits Tregs, and IL-2, a growth factor that sustains Treg survival. In mouse models of AA, this composite MN patch blocks locally infiltrating lymphocytes while expanding the Treg population around hair follicles, enabling precise and multifaceted regulation of the local immune microenvironment.401

Collectively, the key to resolving the contradiction between localized skin disease and systemic drug exposure lies in disruptive innovation in drug delivery routes. The therapeutic modalities for AA are continuously evolving, ranging from conventional topical ointments to targeted nanocarrier and exosome vesicles, as well as multi-functional MN array technology.

Non-JAK Emerging Therapies

For patients with inadequate response, intolerance, or contraindications to JAK-inhibitor therapy, multiple non-JAK investigational therapies may serve as potential alternatives or adjuncts. Targeting the OX40-OX40L costimulatory axis with agents such as rocatinlimab and amlitelimab could suppress pathogenic T-cell-mediated follicular damage, though clinical data in AA remain preliminary, whereas complete clinical trials specifically for AA are yet to be performed.415,416 Dupilumab, an IL-4Rα antagonist for type 2 inflammation, shows conflicting real-world outcomes: it may improve AA in patients with comorbid atopic dermatitis, yet paradoxical AA worsening under treatment has also been reported.417–419 The PDE4 inhibitor apremilast yields mixed results in small AA case series, and adequately powered prospective studies are still absent.29,420 Distinct from these immunomodulators, miRNA-based therapeutics using nano-delivery systems aim to activate hair-follicle stem-cells and drive anagen re-entry by upregulating regenerative Wnt/β-catenin and Sonic hedgehog (Shh) pathways instead of suppressing autoimmunity, which awaits further clinical validation.75

Conclusion

The introduction of JAK inhibitors represents a fundamental advance in the management of moderate-to-severe alopecia areata, transforming a condition that previously lacked effective systemic therapy into one with multiple approved, mechanism-based treatment options. Baricitinib, ritlecitinib, and deuruxolitinib have each demonstrated clinically meaningful hair regrowth in pivotal trials, with real-world data corroborating their efficacy across diverse patient populations.

However, several clinically important questions remain unresolved. First, treatment responses are heterogeneous: a subset of patients achieve rapid, complete regrowth, while others experience delayed or partial responses. Current evidence does not permit reliable pre-treatment identification of responders. Second, the long-term safety of JAK inhibitors in the predominantly young AA population, particularly with respect to cardiovascular, thromboembolic, and malignancy risks requires continued surveillance beyond the available 2–3 year data. Third, the optimal duration of therapy, tapering protocols, and strategies to minimize post-discontinuation relapse have yet to be defined through prospective studies. Fourth, as few head-to-head trials are available, selection among approved agents remains guided by patient-specific factors, including age, comorbidity profile, disease severity, and regulatory access—rather than evidence-based hierarchy.

From a practical standpoint, clinicians should approach JAK inhibitor therapy as a long-term, individualized commitment. Baseline screening, regular laboratory monitoring, and age-appropriate vaccination should be integrated into routine care. For patients with inadequate response to monotherapy, combination with oral minoxidil or topical/intralesional glucocorticoids may be considered, although evidence for the latter remains mixed. The future treatment paradigm will likely incorporate JAK inhibitors as backbone therapy, with emerging non-JAK agents, optimized delivery systems, and biomarker-guided strategies progressively addressing the gaps that currently limit precision in AA management.

Funding Statement

This work was supported by the 2026 Medical scientific research project of Chongqing Health Commission (2026WSJK101) and the 2025 District-level Social and Livelihood Project of Jiulongpo District, Chongqing (2025-03-010-Y).

Data Sharing Statement

The data underlying this article will be provided by the corresponding author Yong-Heng Wang (wangyongheng90@163.com) upon reasonable request.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declared that they have no conflict of interest.