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Review

Cytokine-Targeting Biologic Therapies for Alopecia Areata: A Comprehensive Review of Mechanism of Action, Clinical Efficacy, and Adverse Events

by
Simonetta I. Gaumond
1,2,*,
Isabella Kamholtz
1 and
Joaquin J. Jimenez
1,2,*
1
Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
2
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
*
Authors to whom correspondence should be addressed.
Biologics 2025, 5(2), 11; https://doi.org/10.3390/biologics5020011
Submission received: 11 January 2025 / Revised: 2 February 2025 / Accepted: 1 April 2025 / Published: 9 April 2025
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Abstract

:
Background: Alopecia areata (AA) is an autoimmune disease affecting 2% of the global population, often causing localized scalp hair loss that can progress to alopecia totalis or universalis. While corticosteroids and JAK inhibitors are effective, their significant side effects highlight the need for safer, more targeted treatments. Recently, biologics have gained attention as potential treatments for AA. Methods: A review of clinical trials, case series, and case reports published on PubMed was conducted to assess the efficacy of cytokine-targeting biologics for the treatment of AA. Data on the mechanism of action, treatment outcomes, and safety were extracted and analyzed. Results: Cytokine-targeting biologics identified included Dupilumab, Secukinumab, Tralokinumab, Etanercept, Ustekinumab, Infliximab, Adalimumab, and Tildrakizumab. Dupilumab and ustekinumab demonstrated strong efficacy, with dupilumab showing significant regrowth in 89% of cases and ustekinumab in all patients. Tralokinumab demonstrated a 33.75% improvement, with no patients achieving SALT50. Limited efficacy was observed with secukinumab, tildrakizumab, and adalimumab, with 71.4%, 77.8%, and 50% of patients, respectively, showing no response. Disease worsening was observed in patients who received etanercept (29%) and infliximab (50%). Conclusions: Further research is necessary to optimize treatment protocols, identify predictive biomarkers, and, crucially, discover novel and more effective cytokine targets to advance biologics as a cornerstone therapy for AA.

1. Introduction

Alopecia areata (AA) is a chronic autoimmune disorder characterized by patchy, non-scarring hair loss that typically affects the scalp but potentially involves other body areas. Although the exact pathophysiology of AA is unknown, it is likely to result from a combination of autoimmune, genetic, and environmental factors. Following the collapse of immune privilege, autoreactive T cells and other inflammatory cells target the hair follicles and prematurely progress from the anagen (growth) phase to the catagen or telogen phase [1]. This ultimately leads to hair shedding and localized patches of hair loss. Initially, AA presents as small round patches of hair loss; however, over time, these patches can merge, causing larger areas of scalp involvement [1]. As the condition progresses, it can develop into alopecia totalis (AT), characterized by the complete loss of scalp hair, or alopecia universalis (AU), which results in the loss of all body hair, including facial and body hair. AA affects approximately 2% of the global population; however, its more advanced forms, AT and AU, are less common, with a prevalence of approximately 0.02–0.08% [2]. The condition is slightly more prevalent in women and can occur at any age, although the first onset is commonly observed before 40 years of age [3].
Several tools and grading systems can be used to characterize AA lesions. The Severity of Alopecia Tool (SALT) assesses the percentage of scalp hair loss and provides patients with scores ranging from 0 (no hair loss) to 100 (complete hair loss) [4]. A decrease in SALT score correlates with hair regrowth. Another scale used in AA research is the Physician Global Assessment (PGA), which is based on the physician’s evaluation of hair loss and functions on a 5-point scale: 0, no regrowth; 1, <25% of regrowth; 2, 25–49% of regrowth; 3, 50–74% of regrowth; 4, 75–99% of regrowth; and 5, 100% of regrowth [5]. A four-point scale also exists and is referred to as the Hull and Norris scale, which assesses hair regrowth as follows: 1, vellus hair or no hair; 2, sparse pigmented or non-pigmented terminal hair; 3, terminal regrowth with patches of AA; and 4, terminal regrowth in all areas [6]. Hair regrowth assessment is not the sole metric employed; supplementary scales may be used to gauge patients’ quality of life, evaluating their ability to cope with and the degree to which they are impacted by their medical condition. The Dermatology Life Quality Index (DLQI), also known as the patient global assessment, is a questionnaire provided to patients with scores ranging from 0 (minimal impact) to 30 (severe impact), based on various aspects affecting quality of life [7]. A similar questionnaire specific to patients with AA also exists: the Alopecia Areata Quality of Life (AA-QoL). This survey has scores ranging from 0 (poor) to 100 (good), with higher scores indicating better outcomes [8].
Accurate lesion characterization using these tools is essential to evaluate treatment responses and tailor management strategies. Current therapeutic approaches for AA include topical and intralesional treatments, such as corticosteroids, immunotherapy, and minoxidil, which are commonly used for localized AA, while systemic therapies, including corticosteroids, azathioprine, methotrexate, and cyclosporine, are prescribed for more extensive forms of the condition [9]. Janus Kinase (JAK) inhibitors, such as tofacitinib and baricitinib, have emerged as promising options for the treatment of AA. However, despite their effectiveness, both conventional therapies and JAK inhibitors are associated with significant adverse events, which can limit their long-term use.
Treatment with the JAK inhibitor also requires caution in certain populations, such as patients > 65 years old, current or past smokers, those with cardiovascular risk factors, and patients who develop a malignancy or have a known malignancy [10]. The FDA has issued boxed warnings for several JAK inhibitors due to the risks of serious cardiovascular events, blood clots, cancer, and death. Given these safety concerns and the restricted eligibility for JAK inhibitor use, biologic therapies represent a potential therapeutic alternative that may overcome some of these limitations.
Biologic therapies have emerged as promising therapeutic options due to their ability to target immune pathways driving disease progression. Unlike broad-spectrum immunosuppressants and corticosteroids, cytokine-targeting biologics precisely modulate specific molecular and cellular mechanisms by neutralizing specific cytokines or binding to and blocking their receptors [11]. This targeted approach is particularly relevant in AA, where dysregulation of specific cytokines plays a central role in its pathogenesis. For example, elevated levels of IL-4, IL-17, IL-23, and TNF-α have been implicated in the development and progression of AA [12,13]. Inhibiting these cytokines with biologics, among others, may help modulate the underlying inflammatory pathways, thereby reducing inflammation and disease severity. The purpose of this review is to evaluate the efficacy and safety of cytokine-targeting biologics for the treatment of AA.

2. Methods

A literature search of the PubMed database was conducted to identify studies investigating the use of biologics targeting cytokines for the treatment of AA. The search strategy used keywords, such as “alopecia areata”, “biologics”, “cytokines”, and specific cytokine targets, such as “IL-4”, “IL-13”, and “TNF-α”. The inclusion criteria were peer-reviewed articles, including clinical trials, case series, and case reports. To maintain a focus on cytokine-targeting biologics, studies investigating immune cell-modulating biologics or other treatments, such as JAK inhibitors or corticosteroids, were excluded. Articles were excluded if they were reviews, letters, commentaries, conference abstracts, or animal studies. The titles and abstracts of the retrieved articles were screened for relevance, followed by full-text review of eligible studies.
The data extraction process focused on the key aspects of each study, including the biological agent used, its mechanism of action, study design, outcomes, and safety profiles. This comprehensive approach allowed for a thorough analysis of the current state of knowledge regarding cytokine-targeting biologics for AA treatment. By synthesizing findings from various studies, this study aimed to provide a clear overview of the efficacy and safety of these biologics in treating AA. Additionally, this comprehensive review helped identify gaps in the existing literature, highlighting areas where further research is needed to advance our understanding of cytokine-targeting biologics in AA treatment.

3. Results

3.1. Cytokine-Targeting Biologics

3.1.1. Dupilumab

Dupilumab is a human IgG4 monoclonal antibody that binds to the IL-4Rα subunit, shared by both IL-4 and IL-13 surface receptors [14]. IL-13 binds to type 2 IL-4 receptor, which is a heterodimer composed of IL-4Rα and IL-13Rα1. IL-4 can bind to both type 1 and 2 IL-4 receptors, with type 1 being a heterodimer composed of IL-4Rα and a gamma chain (γc) (Figure 1) [15]. By binding to the IL-4Rα subunit, dupilumab prevents IL-4 and IL-13 from binding to their receptors, thereby reducing Th2 inflammation and inhibiting the release of molecules such as chemokines and immunoglobulin E [14].
Dupilumab was evaluated in a double-blind phase IIa trial, in which 60 patients were randomized to receive either placebo (n = 20) or 300 mg subcutaneous (SQ) dupilumab (n = 40) weekly for 24 weeks (Table 1) [16]. Disease worsening (SALT change of −6.5) was observed in the placebo arm, while disease stabilization (SALT change of 2.2) was reported in the dupilumab-treated arm at week 24; dupilumab-treated patients had further improvements at week 48 (13.7) and 72 (29.6). By week 48, 32.5%, 22.5%, 15%, and 10% of the dupilumab-treated patients achieved SALT30/SALT50/SALT75/SALT90 improvement, respectively. Secondary outcomes included eyelash and eyebrow regrowth, assessed using the eyelash/eyebrow assessment (range 0–4, where 0 = none and 4 = very prominent), as well as quality of life scores (AA Symptom Impact Scale and AA Quality of Life Index). Of the dupilumab subjects, 31.8% had eyelash regrowth and 24% had eyebrow regrowth, while the placebo subjects had 18.2% and 7.1%, respectively.
Table 1. Summary of studies investigating cytokine-targeting biologics for the treatment of AA. Only studies with five or more subjects are included in the table.
Table 1. Summary of studies investigating cytokine-targeting biologics for the treatment of AA. Only studies with five or more subjects are included in the table.
Biologic AgentMechanism of ActionStudy DesignTreatment RegimenSample SizeEfficacy Outcomes
DupilumabIL-4 receptor antagonist blocks the binding of IL-4 and IL-13, reduces Th2 inflammationPhase II RCT300 mg SQ weekly for 24 weeks40By week 48, 32.5%, 22.5%, 15%, and 10% of dupilumab patients achieved SALT30/SALT50/SALT75/SALT90 improvement, respectively. Subjects also experienced eyelash (31.8%) and eyebrow (24%) regrowth [16].
Case Series600 mg SQ, followed by 300 mg every 2 weeks10A total of seven had at least 50% hair regrowth after 3 months. Three patients achieved full remission. Three patients did not have any hair regrowth; one experienced disease worsening [17].
Dosing N/A9A total of 44% achieved complete hair regrowth and many achieved SALT50: 22% at month 4, 78% at month 16, and 89% at month 24 [8].
6A total of four (67%) achieved total hair regrowth, one had partial improvement, and one had no treatment response within 6–16 months [18].
SecukinumabBinds to p40 subunit of IL-12/23 and blocks interaction of IL-12 and IL23 with the IL-12Rβ1 receptorRCT300 mg SQ weekly for 5 weeks, then monthly7A total of 71.4% had no response at week 24. One patient had partial hair regrowth and one experienced disease worsening [4].
TralokinumabSelectively binds to and neutralizes IL-13 thereby inhibiting interaction with IL-13R and 13Rα1/IL-4Rα receptor complexesPhase II RCT300 mg SQ every 2 weeks for 24 weeks15None achieved SALT50 at week 24. Overall, patients experienced 33.75% improvement [19].
EtanerceptDimeric fusion protein acting as a decoy receptor, prevents binding to TNFR1 and TNFR2Open-label pilot study50 mg SQ twice weekly for 24 weeks10A total of 29% experienced disease worsening at week 24. None improved by more than 10% [20].
TildrakizumabSelectively binds the p19 subunit thus inhibiting the binding of IL-23 to the IL-23ROpen-label pilot study100 mg SQ at weeks 0, 4, 169A total of 22.2% had a partial response with SALT score decreases (by 11–18 points) by week 28. A total of 77.8% had no response to treatment [21].
In case reports of dupilumab treatment, 89% (40/45) of patients experienced significant hair regrowth, including nine patients with AT or AU. Of the patients receiving 600 mg SQ, followed by 300 mg doses every two weeks, 85% (17/20) achieved complete or near-complete hair regrowth [17,22,23,24,25,26,27,28,29,30], as measured by SALT score improvement [22,28,29,30] or visual observation alone [23,24,25,26,27]. Two had no response to treatment [17], and one experienced disease worsening [17]. Two patients achieved complete regrowth after 2–4 months of dupilumab treatment (with one receiving a 400 mg SQ dose, followed by 200 mg every 2 weeks, and the other with 200 mg SQ doses every 2 weeks), without a specified scale [31,32]. All patients (four out of four) receiving 300 mg SQ dupilumab every 2 weeks, including two with AT or AU, experienced significant regrowth after 6–12 months [33,34,35,36], although one patient experienced some eyebrow loss [36]. Response was measured by SALT score improvement in one case [36] and visual observation with no specified scale in the other studies [33,34,35]. Monthly dosing resulted in near-normal hair density after 28 weeks in one patient (600 mg SQ, followed by 300 mg monthly), with SALT score improving from 70 to 10 [37], and 85% SALT improvement after 10 months in a patient with AU (400 mg SQ, followed by 200 mg monthly) [38]. In studies without specified doses, outcomes ranged with 88% (15/17) of the patients achieving complete or partial regrowth, measured by SALT score improvements [8,18] and visual presentation [39]. One patient did not respond to treatment [18], and one experienced disease worsening [40].
In the phase IIa study, adverse events (AEs) occurred in 25–26.5% of patients, including injection site reactions, conjunctivitis, upper respiratory infections (URIs), and urinary tract infections (UTIs) (Table 2) [16]. One patient discontinued treatment because of reversible drug eruption. Among the case reports, dupilumab was well tolerated with mild side effects, including Schamberg disease [23], dry eye [34], and conjunctivitis [18,30].
Table 2. Summary of adverse events reported in the studies. No serious AEs related to biologic treatment were reported in any study.
Table 2. Summary of adverse events reported in the studies. No serious AEs related to biologic treatment were reported in any study.
Biologic AgentCommon AEsDiscontinuation Due to AEs
DupilumabInjection site reactions, URIs, UTIs, conjunctivitis [16,18,30], Schamberg disease [23], dry eye [34]Yes (reverse drug eruption) [16]
TralokinumabInjection site reactions, corneal abrasion, UTIs, URIs [19]No
EtanerceptInjection site reactions, URIs, fatigue [20]No
InfliximabTrachyonychia, multiple halo nevi [41]No
AdalimumabInjection site reactions, pneumonia, bronchitis [42], Staphylococcus infection, viral meningitis [43]No
TildrakizumabURIs, acne [21]No

3.1.2. Secukinumab

Secukinumab is a human IgG1 monoclonal antibody that targets and neutralizes IL-17A [44]. IL-17A signals through the IL-17 receptor complex, composed of IL-17RA and IL-17RC subunits (Figure 1). By binding to IL-17A, secukinumab prevents its interaction with both subunits of the IL-17 receptor, thereby inhibiting downstream signaling pathways and the release of pro-inflammatory molecules.
Secukinumab was evaluated in a double-blind, randomized controlled trial (RCT) involving adults diagnosed with extensive AA, with 46% (five out of eleven) of patients presenting with AU (Table 1) [4]. Eleven participants were randomized to receive weekly doses of 300 mg SQ secukinumab (n = 7) or placebo (n = 4) for five weeks, followed by monthly maintenance for 20 weeks. In the secukinumab-treated group, 14.3% (one out of seven) of patients responded favorably, with a 35.2% increase in SALT. One patient experienced worsening hair loss, while the remaining patients showed no response.
A case report investigated a male patient with a 25-year history of AU who was subsequently treated with the same dosage regimen of secukinumab [45]. The patient achieved a mild response after six weeks of treatment, with significant hair regrowth on the pubis, eyebrows, and scalp.
Secukinumab treatment was well tolerated, with no adverse events directly attributed to secukinumab treatment in both the RCT and case report [4,45].

3.1.3. Tralokinumab

Tralokinumab is a human IgG4 monoclonal antibody that selectively binds to and neutralizes IL-13 [46,47]. IL-13 binds to both a heterodimeric receptor, composed of IL-13Rα1 and IL-4Rα subunits, as well as a decoy receptor, known as IL-13Rα2 (Figure 1). By binding to IL-13, tralokinumab blocks its interaction with these receptors, thus inhibiting IL-13-mediated signaling pathways and reducing inflammatory responses.

Efficacy Data

Tralokinumab was evaluated in a phase II, randomized, double-blind, placebo-controlled, pilot study involving adults with moderate-to-severe AA (Table 1) [19]. Twenty-two participants were randomized to receive 300 mg SQ tralokinumab (n = 15) or placebo (n = 7) every two weeks for 24 weeks; however, only three participants completed the study (two receiving tralokinumab and one receiving placebo), as most subjects dropped out due to lack of efficacy. At week 24, there was a 33.75% improvement across both tralokinumab subjects (SALT score change of 0.49); no participants achieved SALT50. Tralokinumab subjects rated their QoL higher than placebo subjects, with AA-QoL scores of 58 and 35, respectively.
In a case report of a 33-year-old female with multifocal AA, administration of 600 mg tralokinumab followed by 300 mg biweekly doses led to significant hair regrowth [48]. The patient’s SALT score decreased from 22 to 2 after 6 months, and the DLQI score improved from 13 to 4.
In the pilot study, 53.33% reported an AE, including corneal abrasion (one out of fifteen), UTI (one out of fifteen), URIs (three out of fifteen), and injection site reactions (three out of fifteen) (Table 2) [19]. Nonetheless, tralokinumab was well tolerated, and no serious events were reported [19,48].

3.1.4. Etanercept

Etanercept is a dimeric fusion protein composed of a tumor necrosis factor receptor 2 (TNFR2) region and an Fc portion of a human IgG antibody [49]. Acting as a decoy receptor with the extracellular ligand-binding domain TNFR2, etanercept binds to TNF-α and TNF-β. By neutralizing these cytokines, etanercept prevents their interaction with TNFR1 and TNFR2 surface receptors (Figure 1) and inhibits TNF-mediated inflammatory pathways, including NF-κB signaling.
Etanercept was evaluated in an open-label pilot study in which 17 adult participants, including eight with AT or AU, received 50 mg SQ etanercept twice weekly for 24 weeks, with no controls (Table 1) [20]. No patient achieved more than a 10% improvement in baseline SALT score, while 29% experienced disease worsening. A case report of a patient with AU receiving the same dosage regimen also did not respond to treatment, although no response scale was specified [50].
AEs were reported in 70.6% of subjects receiving etanercept, all of which were mild (Table 2) [20]. The most common AEs were injection site reactions (six out of seventeen), URIs (four out of seventeen), and fatigue (four out of seventeen). Less frequent events included chest pain, headache, diarrhea, UTI, urticaria, hypothyroidism, blurry vision, sunburn, conjunctival cyst, cough, myalgia, bone pain, paresthesia, conjunctivitis, bacterial vaginitis, and joint stiffness. No AEs were reported in this case report [50].

3.1.5. Ustekinumab

Ustekinumab is a human IgG1 monoclonal antibody targeting the shared p40 subunit of IL-12 and IL-23 that binds to the shared p40 subunit of IL-12 and IL-23 (Figure 1) [51]. IL-12 is a heterodimeric cytokine consisting of p40 and p35 subunits, where p40 binds to IL-12Rβ1 and p35 associates with IL-12Rβ2 on the heterodimeric cell surface receptor. Similarly, IL-23 is composed of p40 and p19 subunits, with p40 binding to IL-12Rβ1 and p19 associating with IL-23R. By binding to the p40 subunit, ustekinumab prevents IL-12 and IL-23 from binding with IL-12Rβ1, thereby preventing the p35 (IL-12) and p19 (IL-23) subunits from activating and signaling downstream pro-inflammatory pathways.
Case reports of patients receiving ustekinumab (90 mg SQ) documented significant hair regrowth, with all patients showing substantial improvement after approximately 3–4 months of treatment [52,53,54]. Four months after a single ustekinumab dose, one patient achieved complete remission (SALT score change from 15 to 0), and one patient with AT experienced patchy hair regrowth (SALT change from 100 to 75) [52]. Another patient experienced significant improvements (SALT score change from 35 to 10) three months after receiving two doses. One patient showed significant regrowth of pigmented follicles and increased hair density, as visibly observed by the researchers, after 20 weeks from treatment with ustekinumab at weeks 0 and 4, followed by doses administered every 8 weeks [53]. After receiving ustekinumab at weeks 0, 4, and 6, one patient with AU achieved 85% regrowth, and two patients with AA had partial regrowth (10–25% improvement) at week 20, with response measured by the change in percent involvement before and after treatment [54].
Ustekinumab was well tolerated by patients, with no adverse events reported [52,53,54].

3.1.6. Infliximab

Infliximab is a chimeric IgG1 monoclonal antibody, with both human and murine contents, that binds with high affinity and specificity to the soluble form of TNF-α [55]. Specifically, it binds to the C-D and E-F loops of TNF-α, thus neutralizing the molecule [56]. By doing so, infliximab prevents TNF-α from interacting with TNFR-1 and TNFR-2 surface receptors (Figure 1) and reduces the activation of various downstream inflammatory pathways [57].
Infliximab treatment was documented in two case reports. One patient received three intravenous (IV) infusions of infliximab over six weeks [41]. Visual observation revealed that the patients’ AA worsened and extended to cover nearly the entire scalp, eyelashes, and eyebrows. The second patient received two IV infusions of 5 mg/kg infliximab at weeks one and three [58]. After six weeks of treatment, visual observation indicated patchy hair regrowth, which was maintained for approximately four months, after which the patient relapsed.
Infliximab was well tolerated, with no serious AEs [41,58]. One patient developed trachyonychia and multiple halo nevi after a few weeks of infliximab treatment (Table 2) [41].

3.1.7. Adalimumab

Adalimumab is a human IgG1 monoclonal antibody that targets and neutralizes TNF-α [59]. It binds to TNF-α molecules through interactions with complementarity-determining region sequences (CDRs) in both the heavy and light chains of the antibody [60]. These primarily include CDRs L2 and H2. By binding to TNF-α, adalimumab prevents its interaction with TNFR1 and TNFR2 (Figure 1), thereby inhibiting downstream inflammatory signaling pathways.
Adalimumab was evaluated in a prospective, open-label, single-center pilot study involving three patients; each received 80 mg SQ adalimumab for two weeks, followed by weekly 40 mg for six months [42]. One patient had a positive response to treatment, with significant hair regrowth as assessed by the hair index score (4 to 7), while the other two patients remained at baseline at the end of the study (week 20).
Two patients with AU experienced varying results following therapy with 40 mg SQ adalimumab every other week. One patient achieved complete remission after six months of treatment, with occasional hair shedding between doses, as visually observed [43], while the other did not show any response to adalimumab, with no response scale specified [50].
Adalimumab was well tolerated, with no serious AEs occurring [42,43,50]. In the open-label study, all participants experienced at least one mild-to-moderate adverse event, including the development of pneumonia and bronchitis (Table 2) [42]. Injection site reactions were the most common AE. One patient with AU developed Staphylococcus infections and viral meningitis, as well as occasional hair shedding between doses [43].

3.1.8. Tildrakizumab

Tildrakizumab is a human IgG1 monoclonal antibody that selectively binds to the p19 subunit of IL-23 [21]. IL-23 is a heterodimeric cytokine composed of a p19 and p40 subunit, with p40 binding with IL-12Rβ1 and p19 associating with IL-23R structures of the IL-23 receptor complex. By binding to p19, tildrakizumab prevents IL-23 from binding to the IL-23R receptor (Figure 1), thereby reducing inflammation and inhibiting the release of pro-inflammatory cytokines, such as IL-17 [61,62].
Tildrakizumab was evaluated in a prospective, open-label pilot study involving nine adults with AA, including seven with AT or AU (Table 1) [21]. The patients received 100 mg SQ tildrakizumab at weeks 0, 4, and 16, with no controls. By week 28, 22.2% (two out of nine) of the patients had a partial response, with SALT scores decreasing by 11–18 points, while the remaining participants showed no response.
Overall, tildrakizumab was well-tolerated, with no serious events reported [21]. Mild AEs, including URIs and acne, were experienced by 22.2% of the patients (Table 2).

4. Discussion

AA is a complex autoimmune disorder characterized by non-scarring hair loss. While the exact pathogenesis remains unknown, a growing body of evidence indicates the potential role of dysregulation of the Th1, Th2, and Th17 immune pathways. The introduction of biologic therapies targeting specific cytokines offers new opportunities for managing this challenging condition. In a recent head-to-head meta-analysis, JAK inhibitors (baricitinib, ritlectinib, and ivarmacitinib) demonstrated greater efficacy than biologics (dupilumab, secukinumab, and tralokinumab) based on percent change in SALT score [63]. Despite this, biologic therapies remain an important avenue for treatment, particularly for patients who cannot tolerate JAK inhibitors or have contraindications to their use. This review provides new insights into the safety and efficacy of biologic therapies for AA by examining recently approved cytokine-targeting biologics and incorporating evidence not only from clinical trials but also from case reports and case series as well.
AA is driven by immune-mediated disruption of the hair follicle’s immune privilege. Cytokines, such as IL-4, IL-13, IL-12, IL-17, and TNF-α, play pivotal roles in disease pathogenesis [9]. Th2 cytokines, including IL-4 and IL-13, contribute to chronic inflammation and tissue fibrosis, while Th1 cytokines, such as IL-12 and IFN-γ, exacerbate autoimmune responses [64,65]. Th17 cytokines, including IL-17A, promote neutrophilic inflammation and keratinocyte activation, further amplifying the inflammatory milieu [66,67]. Understanding these pathways provides a rationale for targeting specific cytokines with biologics.
Dupilumab, an IL-4 and IL-13 inhibitor, has been studied extensively. Biweekly dosing resulted in many patients achieving complete or near-complete regrowth within 2–24 months [16,22,23,24,25,26,27,28,31,32,33,34,35]. Some studies reported partial improvements [25,29,30], whereas others observed mixed outcomes [17,36]. Monthly dosing resulted in near-normal hair density [37] and 85% SALT improvement [38]. In studies without specified doses, outcomes ranged from complete or partial regrowth [8,18,39] to no response or disease worsening [18,40].
Interestingly, patients simultaneously presenting with AA and atopic dermatitis (atopic AA) responded better to dupilumab than those presenting with AA alone. In a study of scalp biomarkers from 58 patients (38 receiving dupilumab and 18 receiving placebo), biopsy analysis revealed increased hair keratins and suppression of CD3+ and CD8+ T cells, as well as Th1 and Th2 pathways in dupilumab-treated patients compared with placebo [68]. Additionally, patients with atopic AA showed a 97% improvement in lesional transcriptome after 48 weeks compared to 63% in those with AA only. These findings highlight the role of Th2 skewing in patients with AA, with an exclusive correlation observed between early suppression of Th2 markers and increased hair keratins. The rationale behind targeting IL-4 and IL-13 specifically lies in their role in the Th2 pathway, which mediates chronic inflammation and fibrosis—critical factors contributing to AA [69,70].
While dupilumab is generally effective for AA, there are several isolated reports of patients developing dupilumab-induced AA, illustrating a seemingly paradoxical relationship. Typically, this alopecia arises a few months after initiation of dupilumab treatment [71]. It remains unclear whether this hair loss is a form of true AA or a distinct manifestation of drug-induced alopecia. Some research suggests that dupilumab’s mechanism of action, which leads to an imbalance of cytokines skewing towards a Th1 profile, may alter the immune response in a way that triggers hair loss [72,73]. However, the exact cause remains poorly understood.
Tralokinumab, an IL-13 inhibitor, showed moderate efficacy for the treatment of AA, with 37.5% (six out of sixteen) of patients showing improvement following treatment [19,48]. This biologic works by targeting IL-13 to reduce inflammation and fibrosis, which contribute to hair follicle miniaturization and premature entry into the telogen phase [74,75]. By reducing the inflammation surrounding the hair follicle, tralokinumab may be beneficial in treating AA. However, the limited response observed in these trials suggests that a more aggressive intervention, such as simultaneous targeting of various cytokines (such as IL-4 and IL-13, as seen with dupilumab), might be more effective in modulating the inflammatory environment and promoting hair regrowth.
Conversely, secukinumab, an IL-17A inhibitor, has shown limited efficacy in treating AA. In these studies, minimal benefit was observed for the treatment of AA [4,45]. No change in response to treatment was reported in 62.5% (five out of eight) of the subjects, while two patients had partial responses and one worsened. Despite the known role of IL-17A in AA pathogenesis [76], these results suggest that targeting the Th17 pathway may not be clinically effective for treating AA, and its role in AA pathogenesis should be reconsidered. This highlights the need for further research to better understand the precise mechanisms by which the Th17 pathway contributes to AA and whether targeting this pathway alone is sufficient to address the complexity of the disease.
IL-23, a cytokine associated with the AA signature [77], plays a significant role in the inflammatory processes underlying the disease. Ustekinumab, which targets both IL-12 and IL-23, has yielded promising results in AA treatment. In the case reports, 100% (seven out of seven) of patients treated with ustekinumab reported significant hair regrowth, with 14.2% achieving complete regrowth [52,53,54]. Scalp biopsies from patients treated with ustekinumab revealed increased expression of hair keratins and keratin-associated proteins, along with downregulation of immune genes and the Th2 and Th1 pathways, further supporting its efficacy in promoting hair regrowth [54]. By inhibiting both IL-12 and IL-23, ustekinumab addresses both TH1 and Th17 immune responses, offering a more comprehensive approach than biologics targeting only IL-23, such as tildrakizumab. Tildrakizumab showed less efficacy in treating AA, with 77.8% (seven out of nine) of patients reporting no response and 22.2% (two out of nine) reporting partial response [21]. These findings suggest that targeting IL-23 alone may not be sufficient for the treatment of AA; however, simultaneously targeting IL-12 and IL-23 may yield better treatment outcomes. Targeting IL-12 may be particularly beneficial for more severe forms of AA, where elevated serum levels of IFN-γ, stimulated by IL-12, are often associated with disease progression [78]. By modulating both pathways, ustekinumab may lead to more favorable treatment outcomes.
TNF inhibitors, such as etanercept, infliximab, and adalimumab, have demonstrated limited efficacy in treating AA and may even worsen the condition. Studies on etanercept demonstrated no significant improvement in patients, with no patients experiencing partial regrowth and 27% (three out of eleven) of patients experiencing disease worsening [20,50]. Similarly, infliximab yielded negative results, with one patient having recurrence of hair loss at four months and the other patient with disease worsening at six weeks [41,58]. Adalimumab treatment resulted in mixed outcomes, with 40% (two out of five) of patients responding positively and 60% (three out of five) showing either no response or return to baseline [42,43,50]. Although studies have shown elevated serum TNF-α levels in patients with AA, as well as a potential relationship with AA severity [79,80], the clinical findings suggest that TNF inhibitors are not suitable treatments for AA. In fact, a study investigating spontaneous reports of adverse drug reactions reported that 4.9% of alopecia cases occurred during exposure to TNF-α antagonists [81]. This suggests that the role of TNF-α in modulating the immune response in AA may be more complex than initially thought. Its inhibition might disrupt other necessary immune functions and therefore should be avoided in the management of AA.
Challenges in treating severe forms of AA, such as AT and Au, further underscore the need for effective treatment strategies. Although the prevalence of AT and AU is low in the general population (0.08% and 0.03%, respectively) [2] compared to that of AA (2%), many cases reviewed in this study included patients with more severe forms of the disease. Of the 39 studies analyzed in this review, 23 included subjects with AT or AU. Specifically, 52 patients with AT and AU were included in the study, representing 42.6% of the participants (52/122 subjects). One study included patients with AT and AU as part of their inclusion criteria; however, it did not report the absolute number of patients with AT or AU in their enrolled cohort [19]. It is worth mentioning that treatments are more effective in patchy AA than in AT or AU, since advanced disease stage is generally considered a poor prognostic sign [82,83,84]. Moreover, it has been elucidated that although initial regrowth may be seen in cases of AT or AU, the duration of response is usually short, and patients relapse more frequently [84].
Given these challenges, the potential for biologic therapies to promote significant hair regrowth, including in areas beyond the scalp, is encouraging. Significant hair regrowth of the eyebrows and eyelashes was specifically reported in 15 studies [8,17,22,25,26,27,28,30,32,33,37,38,43,45,54], highlighting the potential for biologic therapies to restore these areas of hair loss. For example, Cai et al. documented a case in which a patient presenting with AU achieved 85% improvement, with complete regrowth of both the eyebrows and eyelashes [38], suggesting that biologics may be particularly effective for promoting regrowth in these areas. Case reports have shown variability in regrowth timing between the scalp, eyebrows, and eyelash hairs. Yan et al. described a patient with eyebrow regrowth beginning after four weeks of treatment, whereas scalp hair regrowth was first observed at 12 weeks [37].
A plausible explanation for this observation lies in the differences in the hair follicle cell cycles across body sites. Eyelash hairs complete their life cycle within four to 11 months [85], while eyebrow hairs cycle in under five months [86]. In contrast, scalp terminal hairs have a life cycle of at least three years [87], with an anagen phase that can extend up to six years [88]. Due to the shorter cell cycles of eyelash and eyebrow hairs, regrowth in these areas might be expected to occur sooner with treatment, with a faster turnover of follicles allowing for quicker responses to immunomodulatory interventions. On the other hand, the prolonged duration of the anagen phase in scalp hair may delay observable regrowth, even if the underlying treatment mechanisms are effective. This suggests that early treatment success in eyebrows and eyelash regrowth may serve as an indicator of overall treatment efficacy as an early response marker.
A new area of research is dedicated to identifying biomarkers of disease pathogenesis and severity, as well as treatment responses, to help guide clinicians and optimize treatment strategies. Elevated serum levels of IL-6, IL-12, C-reactive protein, and IFN-γ, along with reduced vitamin D levels, have been associated with AA [89,90]. Oxidative stress markers have been implicated in AA pathogenesis, with potential biomarkers including malondialdehyde, advanced glycation end-products, and increased concentrations of ischemic-modified albumin [91]. Elevated levels of pro-inflammatory cytokines, such as IL-2 and IL-17, are linked to increased disease severity in AA [92], suggesting that patients with more extensive forms of AA, such as AT or AU, may respond better to IL-17 inhibitors such as secukinumab. Serum thymus and activation-regulated chemokine (sTARC) levels correlate with disease severity, particularly in patients with AT and AU [93]. Baseline sTARC levels may also predict responses to biologics, as elevated levels are linked to poor outcomes with IV corticosteroid pulse therapy. The systemic immune-inflammation index (SII) has been used to assess AA severity and treatment outcomes [94]. Herein, higher levels of mean platelet volume and neutrophil-lymphocyte ratio and lower levels of high-density lipoprotein were observed in patients with AA, which could potentially guide treatment options. Specifically for dupilumab treatment, higher serum IgE levels were associated with a better clinical response, suggesting that Th2-dominant patients may benefit most from IL-4/IL-13 inhibitors [16].
While biomarkers can offer insights into disease severity and potential treatment efficacy, the safety profiles of cytokine-targeting biologics also play a critical role in treatment decision-making. Generally, the safety profile of these biologics is favorable, with most AEs being mild. Common AEs included injection site reactions, URIs, and UTIs. Dupilumab-related AEs also include conjunctivitis, Schamberg disease, dry eyes, and reverse drug eruption [16,18,23,30,34]. Studies on adalimumab have reported pneumonia, bronchitis, Staphylococcus infection, and viral meningitis [42,43]. Infliximab side effects were only reported in one patient, which included trachyonychia and multiple halo nevi [41]. Etanercept also causes common side effects of injection site reactions and URIs in addition to fatigue [20]. Tralokinumab-related AEs were noted in only one study, which included corneal abrasion and UTI [19]. The only Tildrakizumab-specific AE was acne in one report [21]. Other biologics had no reported AEs related to treatment.
These findings emphasize that TNF antagonists pose the highest risk of developing adverse reactions, including increased susceptibility to opportunistic infections due to their broad-spectrum immunomodulatory effects. TNF-α plays a critical role in immune modulation, and its inhibition may result in a more generalized immunosuppression than targeting specific cytokines. Therefore, it is crucial to weigh the efficacy of each biologic against its safety profile.

5. Conclusions

Cytokine-targeting biologics have emerged as a novel therapeutic approach for alopecia areata (AA), offering a more targeted alternative to conventional therapies. This comprehensive review highlights that biologics, such as dupilumab and ustekinumab, which simultaneously target key cytokines, such as IL-4/13 and IL-12/23, demonstrate notable efficacy, with many patients achieving significant or near-complete hair regrowth. Conversely, biologics targeting single cytokines such as secukinumab and tralokinumab have shown limited efficacy, suggesting that monotherapy targeting isolated cytokines may not be sufficient to address the complex inflammatory processes involved in AA.
Current evidence indicates that biologic therapies have not demonstrated the same level of efficacy as JAK inhibitors in the treatment of AA, with variable and often limited clinical responses. This highlights the need to refine therapeutic strategies by identifying more relevant cytokine targets and further elucidating the key immunopathogenic pathways driving disease progression and resolution. By advancing our understanding of cytokine-mediated pathways and optimizing biologic therapies, the future of AA management could shift toward more precise, effective, and tolerable treatments.

Author Contributions

S.I.G. (conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, validation, visualization, and writing—original draft, review, and editing); I.K. (data curation, formal analysis, investigation, validation, and writing—original draft and editing); J.J.J. (conceptualization, investigation, methodology, project administration, supervision, validation, and writing—review and editing). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Biologics 05 00011 g001
Figure 1. Mechanism of action of cytokine-targeting biologics. (Adalimumab (ADA), infliximab (IFX), etanercept (ETA), ustekinumab (USTE), tildrakizumab (TIL), secukinumab (SEC), dupilumab (DUP), and tralokinumab (TRA).
Figure 1. Mechanism of action of cytokine-targeting biologics. (Adalimumab (ADA), infliximab (IFX), etanercept (ETA), ustekinumab (USTE), tildrakizumab (TIL), secukinumab (SEC), dupilumab (DUP), and tralokinumab (TRA).
Biologics 05 00011 g001
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MDPI and ACS Style

Gaumond, S.I.; Kamholtz, I.; Jimenez, J.J. Cytokine-Targeting Biologic Therapies for Alopecia Areata: A Comprehensive Review of Mechanism of Action, Clinical Efficacy, and Adverse Events. Biologics 2025, 5, 11. https://doi.org/10.3390/biologics5020011

AMA Style

Gaumond SI, Kamholtz I, Jimenez JJ. Cytokine-Targeting Biologic Therapies for Alopecia Areata: A Comprehensive Review of Mechanism of Action, Clinical Efficacy, and Adverse Events. Biologics. 2025; 5(2):11. https://doi.org/10.3390/biologics5020011

Chicago/Turabian Style

Gaumond, Simonetta I., Isabella Kamholtz, and Joaquin J. Jimenez. 2025. "Cytokine-Targeting Biologic Therapies for Alopecia Areata: A Comprehensive Review of Mechanism of Action, Clinical Efficacy, and Adverse Events" Biologics 5, no. 2: 11. https://doi.org/10.3390/biologics5020011

APA Style

Gaumond, S. I., Kamholtz, I., & Jimenez, J. J. (2025). Cytokine-Targeting Biologic Therapies for Alopecia Areata: A Comprehensive Review of Mechanism of Action, Clinical Efficacy, and Adverse Events. Biologics, 5(2), 11. https://doi.org/10.3390/biologics5020011

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