Alopecia areata (AA) is an autoimmune hair loss disorder, with Janus kinase inhibitors (JAKis) emerging as an effective treatment. However, concerns about malignancy risk remain due to boxed warnings primarily based on studies in rheumatoid arthritis. This retrospective cohort study evaluated the association between JAKis and malignancy risk in AA using the TriNetX Global Collaborative Network. Patients with severe AA were categorized by treatment history, including JAKis, traditional immunosuppressants, and no systemic treatment. Propensity score-matched Cox proportional hazards models assessed the risks of squamous cell carcinoma (SCC)/basal cell carcinoma (BCC), internal malignancies, and hematologic malignancies. Among matched cohorts of 920 patients treated with traditional immunosuppressants and 920 treated with JAKis (mean follow-up: 1,302 and 1,229 days, respectively), SCC/BCC risk was not significantly different (HR = 0.324 [0.065, 1.609]). However, internal malignancy (HR = 4.906 [2.168, 11.101]) and hematologic malignancy (HR = 8.713 [1.104, 68.796]) risks were significantly higher with traditional immunosuppressants. No significant difference in malignancy risk was observed between 446 JAKi-treated and 446 untreated patients. These findings align with previous meta-analyses in autoimmune diseases, which have not linked JAKis to an increased malignancy risk. While this study found no evidence that JAKis elevate malignancy risk, the role of JAK-STAT signaling in cancer remains complex. Given AA's unclear baseline malignancy risk and this study's retrospective nature and limited follow-up, longer-term studies are needed to better understand the long-term safety of JAKis in AA and refine risk assessment and screening strategies.

Cutaneous leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania, and although parasites influence disease severity, cytotoxic CD8 T cell responses mediate damage to the infected skin. We found that the cytotoxic protein perforin was expressed in CD8 T cells only upon recruitment to Leishmania-infected skin, suggesting that lesional inflammatory cues induced perforin. Here, using a mouse model of Leishmania major infection, we demonstrated that the expression of perforin was driven by a combination of hypoxia and IL-15, both of which are microenvironmental signals present within Leishmania-infected skin. We also demonstrated that the major sources of Il15 mRNA in cutaneous leishmaniasis lesions are neutrophils and macrophages and that macrophages exposed to hypoxia in vitro produce more Il15. Since perforin is only present in lesions, we reformulated a small molecule perforin inhibitor for topical application and found that local inhibition of perforin is sufficient to ameliorate disease in established cutaneous leishmaniasis. Thus, topical perforin inhibition may be considered a therapeutic strategy for patients with cutaneous leishmaniasis and other inflammatory skin diseases where cytotoxic CD8 T cells contribute to disease pathogenesis.

Background Alopecia areata (AA), a disorder of non-scarring hair loss with a variable relapsing and remitting course, is a common autoimmune disease in children. Although it often presents as several focal small patchy bald lesions, early onset AA can lead to a total loss of scalp hair, even body hairs, a severe subtype. Atopic diseases are common concurrent disorders in AA, especially among those with early onset severe type of hair loss. Whether atopic diseases increase the risk of AA in the paediatric population of Taiwan, remains unclear. Objective To identify if atopic diseases increase the risk of AA among pre-teens and teenagers in Taiwan. Methods From Taiwan National Health Insurance Database 2010, we used the claims data to clarify the risk of AA in pre-teens and teenagers with atopic diseases (atopic dermatitis, allergic conjunctivitis, asthma, allergic rhinitis and food allergy) as compared to the general population. Cox proportional hazards model yielded hazard ratios (HRs) to address the impact of atopic diseases, sex and age on AA risk after adjusting for covariates and subsequent stratified analyses. Results Overall, 21,070 children (10,535 patients with atopic diseases and 10,535 normal cohort) aged over nine years were recruited. During a follow-up of 15 years, 39 (0.37%) cases were identified to have AA in the atopic diseases group, while 11 (0.10%) had developed AA in the normal cohort. As compared with the normal population, the paediatric population with atopic diseases had a 9.66-fold higher risk of developing AA. The risk was greater for boys and increased with advanced age. In the atopic diseases group, pre-teens and teenagers with food allergies and Sjogren's syndrome were more likely to have AA. Limitations Only one ethnic group. Conclusion All atopic diseases enhanced the risk of developing AA in Taiwan pre-teens and teenagers. Children with atopic diseases should be monitored to look for the development of AA.

Alopecia areata (AA) is a complex, chronic inflammatory skin disorder characterized by unpredictable, nonscarring hair loss, affecting millions worldwide. Its pathogenesis remains poorly understood, driven by intricate interactions among immune dysregulation, genetic predisposition, and environmental triggers. Despite significant advances in identifying these contributing factors, substantial gaps persist in our understanding of the full spectrum of AA's molecular mechanisms and in the development of effective therapeutic approaches. This review aims to comprehensively explore the immunological, genetic, epigenetic, and environmental factors underlying AA, with a focus on immune-mediated mechanisms. We also evaluate diagnostic approaches and recent advancements in assessing disease severity. Furthermore, the review discusses evolving therapeutic options, including traditional therapies, biologics, small-molecule agents, and emerging treatments. The academic value of this work lies in its synthesis of current knowledge on the multifaceted nature of AA, providing insights for future research and clinical practice. By elucidating the interconnected factors underlying AA, this review seeks to advance both understanding and management of this prevalent, clinically challenging disorder.

The JAK pathway is central to mammalian cell communication, characterized by rapid responses, receptor versatility, and fine-tuned regulation. It involves Janus kinases (JAK1, JAK2, JAK3, TYK2), which are activated when natural ligands bind to receptors, leading to autophosphorylation and activation of STAT transcription factors [1, 2]. JAK-dependent signaling plays a pivotal role in coordinating cell communication networks across a broad spectrum of biological systems including development, immune responses, cell growth, and differentiation. JAKs are frequently mutated in the aging hematopoietic system [3, 4] and in hematopoietic cancers [5]. Thus, dysregulation of the pathway results in various diseases, including cancers and immune disorders. The binding of extracellular ligands to class I and II cytokine receptors initiates a critical signaling cascade through the activation of Janus kinases (JAKs). Upon ligand engagement, JAKs become activated and phosphorylate specific tyrosine residues on the receptor, creating docking sites for signal transducer and activator of transcription (STAT) proteins. Subsequent JAK-mediated phosphorylation of STATs enables their dimerization and nuclear translocation, where they function as transcription factors to modulate gene expression. Under physiological conditions, JAK-signaling is a tightly regulated mechanism that governs cellular responses to external cues, such as cytokines and growth factors, ensuring homeostasis and maintaining the functional integrity of tissues and organs. Highly defined regulation of JAK-signaling is essential for balancing cellular responses to inflammatory stimuli and growth signals, thus safeguarding tissue health. In contrast, dysregulated JAK-signaling results in chronic inflammation and unrestrained cellular proliferation associated with various diseases. Understanding the qualitative and quantitative differences at the interface of physiologic JAK-signaling and its aberrant activation in disease is crucial for the development of targeted therapies that precisely tune this pathway to target pathologic activation patterns while leaving homeostatic processes largely unaffected. Consequently, pharmaceutical research has targeted this pathway for drug development leading to the approval of several substances with different selectivity profiles towards individual JAKs. Yet, the precise impact of inhibitor selectivity and the complex interplay of different functional modules within normal and malignant cells remains incompletely understood. In this review, we summarize the current knowledge on JAK-signaling in health and disease and highlight recent advances and future directions in the field.

To explore the mechanism of action of baicalin (BA) in the treatment of triple-negative breast cancer (TNBC) based on network pharmacology, molecular docking and molecular dynamics simulations and in vitro validation.

The inhibitory effects of different concentrations of baicalin on the proliferation of MDA-MB-231, 4T1, MCF-7, and MCF-10A cell lines were evaluated by CCK8 assay with clone formation assay. Three compound target prediction platforms, Swiss Target Prediction, SEA and Pharmmapper, were used to predict baicalin-related targets, and mapped with the triple-negative breast cancer-related targets retrieved from GeneCards and OMMI databases to obtain the potential targets of baicalin for the treatment of triple-negative breast cancer; the STRING database and the STRING database and Cytoscape software were used to construct the protein interaction network and screen the core targets; GO and KEGG enrichment analyses were performed on the core targets; the binding of baicalin to the key targets of triple-negative breast cancer was verified by molecular docking and molecular dynamics simulation; and the expression of the relevant proteins was verified.

Baicalin showed more obvious antiproliferative effects on triple-negative breast cancer cell lines at certain concentrations, and had less effect on the proliferation of normal breast cells. A total of nine core targets of baicalin in the treatment of triple-negative breast cancer, including AKT1, ESR1, TNF-α, SRC, EGFR, MMP9, JAK2, PPARG, and GSK3B, were identified through the construction of the PPI protein interactions network and the 'Traditional Chinese Medicine-Component-Target-Disease' network, and a total of 252 targets related to the intersected targets were identified in the GO analysis. GO analysis enriched a total of 2,526 Biological process, 105 Cellular component and 250 Molecular function related to the intersecting targets; KEGG analysis enriched a total of 128 signaling pathways related to the intersecting targets; molecular docking results and molecular dynamics studies found that baicalin was able to interact with MMP9, TNF-α, JAK2, PPARG, GSK3B, and other core targets of baicalin for the treatment of triple-negative breast, MMP9, TNF-α, and JAK2 target proteins, and had significant changes in the expression levels of the target proteins.

Baicalin inhibits the protein expression of MMP9, TNF-α and JAK2 and their related signaling pathways in the treatment of triple-negative breast cancer.

Inflammatory nail disorders can have a significant impact on patients' quality of life owing to aesthetic and functional concerns. They are also challenging to treat because the therapeutic armamentarium is quite limited. This systematic review aims to report the efficacy and safety of Janus kinase and Tyrosine kinase 2 inhibitors in treating these conditions.

We conducted a comprehensive search on PubMed, Cochrane, and Embase Library to find eligible case reports, case series, single-arm clinical trials, and randomized controlled trials. We used the following search terms from inception until 15 December, 2024: "nail" AND "jak inhibitors" OR "tofacitinib" OR "baricitinib" OR "abrocitinib" OR "ruxolitinib" OR "deuruxolitinib" OR "upadacitinib" OR "ritlecitinib" OR "deucravacitinib" (nine searches in total).

Of 441 articles found, 31 were included in this study. The most extensively studied drug was tofacitinib, followed by baricitinib, deucravacitinib, upadacitinib, and abrocitinib. Janus kinase/Tyrosine kinase 2 inhibitors demonstrated improvements in inflammatory nail conditions, with generally mild adverse events (nasopharyngitis and transient laboratory abnormalities being most common). The topical formulation of tofacitinib, the only one studied in these nail diseases, also demonstrated promising results with minimal systemic absorption and no side effects.

This review highlights Janus kinase/Tyrosine kinase 2 inhibitors as a valuable addition to the therapeutic arsenal for inflammatory nail disorders while emphasizing the importance of safety assessments and tailored treatment approaches. The long-term safety of Janus kinase/Tyrosine kinase 2 inhibitors still needs further investigation and the potential for adverse events emphasizes the need for tailored therapeutic strategies, including more studies on topical formulations.

Emerging evidence reveals significant epidemiologic, genetic, and immunologic connections between atopic dermatitis, vitiligo, and alopecia areata, challenging previously established notions of their distinct pathogenic and molecular signatures. Exploring these commonalities not only enhances our understanding of each disease's pathogenesis, but also supports the development of unified treatment strategies for these frequently co-occurring disorders. This review examines key immune players shared across the 3 conditions, including cytokines, immune cells, and signaling pathways. Building on these insights, we also evaluate a range of therapeutic options-ranging from treatments approved by the Food and Drug Administration to those currently in clinical trials-alongside proposed future therapeutic targets. This comprehensive approach aims to advance our management of these interconnected autoimmune and inflammatory disorders with greater precision.

Alopecia Areata (AA) is a common form of scarless alopecia. Its pathogenesis may be related to T cell-mediated autoimmune attack on hair follicles. Its clinical manifestations are mostly round or oval patches of AA, which can progress to Alopecia Totalis (AT) and Alopecia Universalis (AU). In severe cases, it affects the psychological health and quality of life of patients. In the past, the treatment of AA mainly relied on intra-lesional or systemic application of glucocorticoids, minoxidil or immunomodulators, which had problems such as limited efficacy and high recurrence rate. Some studies have also found that JAK inhibitors have improved effects on many autoimmune diseases, including AA. This case report presents a patient with AA who achieved significant therapeutic effects from treatment with Tofacitinib Citrate Sustained-Release Tablets, manufactured by Qilu Pharmaceutical Company in China. Due to the recurrence rate of AA, patients are likely to need long-term medication. The resulting economic burden cannot be ignored. We therefore investigated the mechanisms and economic benefits of various JAK inhibitors in the treatment of AA, in order to provide better guidance to patients with recurring disease who need long-term medication, and to their doctors in choosing a more rational therapeutic agent according to the patient's condition and economic status.

Hair loss disorders pose a substantial global health burden, affecting millions of individuals and significantly impacting quality of life. Despite the widespread use of approved therapeutics like minoxidil and finasteride, their clinical efficacy remains limited. These challenges underscore the pressing need for more targeted and effective therapeutic solutions. This review examines the latest innovations in hair loss drug discovery, with a focus on small-molecule inhibitors, biologics, and stem cell-based therapies. By integrating insights from molecular mechanisms and leveraging advancements in research methods, the development of next-generation therapeutics holds the potential to transform the clinical management of hair loss disorders. Future drug development for hair loss disorders should prioritize antibody therapy and cell-based treatments, as these approaches offer unprecedented opportunities to address the limitations of existing options. Antibody therapies enable precise targeting of key molecular pathways involved in hair follicle regulation, providing highly specific and effective interventions. Similarly, cell-based therapies, including stem cell transplantation and dermal papilla cell regeneration, directly address the regenerative capacity of hair follicles, offering transformative potential for hair restoration.

Background: Alopecia areata is an autoimmune disorder that causes hair loss in clumps about the size and shape of a quarter. The estimated prevalence of the disorder is approximately 1 in 1000 people, with a lifetime risk of approximately 2 percent. One of the systemic therapies for alopecia areata consists of the use of glucocorticoids or immunosuppressants. Methods: Baricitinib (BCT) is a Janus kinase (JAK) 1 and 2 selective inhibitor used as an immunosuppressant drug. In this study, three olive oil BCT formulations (Oil A, Oil B, and Oil C, which differ in their content in squalene, tocopherol, tyrosol, and hydroxytyrosol) have been developed for topical delivery. The formulations were physicochemically characterized and the in vitro drug release and ex vivo permeation through human skin tissues were assessed. Results: The results showed nearly identical viscosity across all three formulations, exhibiting Newtonian behavior. The mathematical modeling used to describe the drug release profiles was the one-site binding hyperbola for all formulations. Oil-based formulations showed a slow BCT penetration into human skin. Skin integrity remained intact during the experiments, with no signs of irritation or alterations observed. In addition, all the formulations proved their efficacy in vivo. Conclusions: Among the formulations, Oil A demonstrated the highest ability retention capacity (Qr = 1875 ± 124.32 ng/cm2) in the skin, making it an excellent candidate for further investigation in the treatment of alopecia areata.

Alopecia areata (AA) are hair loss disorders with distinct pathogenetic mechanisms involving immune dysregulation and microRNA modulation. AA, a T cell-mediated autoimmune disease, is characterized by sudden hair loss, with interferon-gamma (IFN-γ) playing a pivotal role in pathogenesis. The upregulation of IFN response genes, including IFN-inducible chemokines CXCL9, CXCL10, and CXCL11, in lesional skin reflects the activation of the IFN response pathway and contributes to immune cell recruitment and inflammation.

Recent research highlights the role of SIRT1, a class III histone deacetylase, in modulating immune responses in AA. SIRT1 inhibition promotes the production of Th1 cytokines and chemokines, impairing inflammation, while SIRT1 activation suppresses autoreactive responses through NF-κB deacetylation and STAT3 phosphorylation. Additionally, antisense oligonucleotides (ASOs) targeting miR-485-3p show therapeutic potential in promoting hair regrowth and mitigating inflammation in murine models of androgenic alopecia (AGA) and AA.

Understanding chemokine dysregulation provides key insights into AA pathogenesis and highlights TAMI-M as a potential therapy for reducing inflammation and promoting hair regeneration. These findings advance the exploration of immune, microRNA, and SIRT1 pathways as targets for novel hair loss treatments.

This subgroup analysis of the ALLEGRO phase 2b/3 study (NCT3732807) assessed the efficacy and safety of multiple doses of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, in Asian patients with alopecia areata (AA). Patients aged ≥12 years with AA and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (with or without 4-week 200-mg loading dose ["200/50" or "200/30"]) or 10 mg or placebo for 24 weeks, followed by a 24-week extension, in which patients initially assigned to placebo switched to 200/50 or 50 mg. In this subgroup analysis, Asian patients with response based on achieving a Severity of Alopecia Tool (SALT) score ≤20, SALT ≤10, ≥2-grade improvement or normal score on the eyebrow assessment (EBA) scale, and ≥2-grade improvement or normal score on the eyelash assessment (ELA) scale were evaluated through week 48. Safety was monitored throughout. In total, 186 Asian patients were randomized to ritlecitinib 200/50 mg (n = 33), 200/30 mg (n = 28), 50 mg (n = 43), 30 mg (n = 34), 10 mg (n = 17), placebo to 200/50 mg (n = 14), or placebo to 50 mg (n = 17). The proportions of patients treated with ritlecitinib ≥30 mg achieving a SALT score ≤20 response were 9.1%-36.4% at week 24 vs 0% for the 10-mg group and 3.2% for placebo. At week 48, 26.5%-55.6% of patients treated with ritlecitinib ≥30 mg achieved a SALT ≤20 response. At week 48, the proportions of patients treated with ritlecitinib ≥30 mg with EBA response were 41.9%-71.1% and with ELA response were 40.7%-57.9%. The most common adverse events were nasopharyngitis, folliculitis, upper respiratory tract infection, and urticaria. No serious or opportunistic infections, major adverse cardiovascular events, thromboembolic events, malignancies, or deaths were reported. Ritlecitinib demonstrated clinical efficacy and acceptable safety over 48 weeks in Asian patients ≥12 years with AA and ≥50% hair loss. Results for the Asian subpopulation were consistent with the overall population in the ALLEGRO-2b/3 study.

Alopecia areata (AA) is a chronic, autoimmune skin disease characterized by non-scarring hair loss. Baricitinib, a Janus kinase inhibitor (JAKi), prevents hair loss and promotes hair regrowth by inhibiting the inflammatory Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway involved in cytotoxic T cell responses targeting hair follicles. The introduction of JAKi has transformed treatment against severe AA. However, treatment responses to JAKi are highly variable among patients, and the predictors of responsiveness remain insufficiently elucidated. This study aimed to identify independent predictive factors for the efficacy of baricitinib in patients with severe AA using multivariate analyses. A retrospective study was conducted on 70 severe AA patients who started baricitinib treatment at Tohoku University Hospital between July 2022 and August 2023. The primary outcome was the percentage of patients achieving a Severity of Alopecia Tool (SALT) score of ≤20 after 9 months of baricitinib treatment. Multivariate analysis assessed potential predictors of baricitinib treatment responses, including AA type, sex, age, disease duration, history of atopic dermatitis, intravenous methylprednisolone pulse (IVMP) therapy, and Clinician-Reported Outcome (ClinRO) measures for eyebrows and eyelashes. Achievement of a SALT score of ≤20 and SALT score improvement rates were used as objective variables in the multivariate analyses. Among the 70 patients completing 9 months of baricitinib treatment, 41% achieved a SALT score of ≤20. Multivariate analyses identified several independent predictors for positive outcomes, including shorter disease duration (≤4 years), history of IVMP, therapy SALT score of ≤95 at baricitinib initiation, and female sex. Further, we found differential response patterns based on AA type and sex. Specifically, AA type significantly influenced treatment responses, with ophiasis alopecia (OA) associated with the poorest improvement rate. In summary, the response to baricitinib in AA is significantly influenced by sex, AA type, disease duration, history of IVMP, and pre-treatment SALT score.

Androgenetic alopecia (AGA) is the most common cause of hair loss worldwide. The significant psychological and social impact of AGA continues to drive demand for more effective treatments beyond the limited options currently available.

The authors review the key components of AGA pathogenesis, as well as current treatments, and therapeutic techniques under development. Innovative strategies for AGA drug discovery are still needed, given the significant unmet medical needs and the limited efficacy of both current and emerging treatments. The authors outline relevant preclinical models, such as hair follicle (HF) cell cultures, 3D spheroids, organoids, follicle explants, and animal models, highlighting their advantages and limitations in AGA research. Finally, they summarize the primary objectives in AGA treatment development, including direct hair growth promotion, interference with androgen signaling, and HF rejuvenation, identifying key pathogenesis intervention points for treatment development.

Developing better in vitro models, possibly using induced pluripotent stem cell (iPSC) systems, could greatly accelerate drug discovery. Similarly, a superior in vivo model could significantly expedite drug discovery. Near future development research should focus on drug delivery improvements. Longer term, treatments targeting AGA's underlying pathophysiology and promoting HF rejuvenation or true regeneration would provide the most benefit to prospective patients.

Liver tissue-resident memory T (TRM) cells play a pivotal role in hepatic immune responses. Their unique residence within liver sinusoids allow continuous antigen surveillance. In this review, we highlight the role of liver TRM cells in protective immunity and disease pathology. Comparisons between human and murine liver TRM cells reveal species-specific characteristics, suggesting the need for human-focused studies. One key finding is the involvement of liver TRM cells in viral hepatitis, where they can both control infection and contribute to liver damage. Liver TRM cells also exhibit dual roles in metabolic-associated steatotic liver disease, promoting inflammation and fibrosis while also contributing to fibrosis resolution. In autoimmune liver diseases, such as autoimmune hepatitis and primary sclerosing cholangitis, the presence of liver TRM cells correlates with disease severity. In this review, we underscore the importance of liver TRM cells in vaccine development, particularly vaccines against malaria. Future research should focus on the mechanisms governing TRM-cell formation, maintenance, and function, with the aim of supporting their protective roles while mitigating detrimental effects. Advancing our understanding of liver TRM cells will enhance our knowledge of liver immunology and inform novel therapeutic strategies for liver disease management.

Alopecia areata is a highly frequent disease with great variability in clinical presentation, severity, and prognosis. It has a significant negative impact on quality of life, especially in the moderate and severe forms.

To disseminate guidelines, prepared by a group of Brazilian experts, for the treatment and follow-up of patients with alopecia areata.

Eight specialists from different university centers with experience in alopecia areata were appointed by the Brazilian Society of Dermatology to reach a consensus on its treatment. Using the adapted DELPHI methodology, relevant elements were considered and then an analysis of the recent literature was carried out and the text produced. Consensus on the guidelines was defined with the approval of at least 70% of the panel of experts.

Treatments vary according to patient age and disease severity. Intralesional injectable corticosteroid therapy was considered the first option for localized disease in adults. In severe cases, Janus Kinase inhibitors are the treatment with the highest level of evidence. Systemic corticosteroid therapy and immunosuppressants (corticosteroid-sparing agents) are also options in these cases. Contact immunotherapy (diphencyprone) is an alternative for stable extensive cases. The assessment of side effects is as important as the hair regrowth rate.

Both alopecia areata (AA) and vitiligo share common pathogenesis involving, interferon-γ (IFN-γ) and interleukin-15 (IL-15) signalling pathways that activate cytotoxic CD8+ T lymphocytes. These shared mechanisms may explain why both diseases respond to currently available treatments (e.g. topical/systemic corticosteroid) and emerging treatment modalities. As compared with the speed of re-pigmentation in vitiligo lesions, the regeneration of pigmented terminal hair follicles in AA lesions appears fast in response to treatments targeting the inhibition of the Janus kinases (JAKs) and other kinases. We summarize the commonalities and differences between AA and vitiligo focusing on the treatment modalities, followed by recent findings associated with hair follicle stem cells (HFSC) in hair bulge (HBg) and melanocyte stem cells (McSC) in HBg and hair germ (HGm). We then discuss how HFSC and HGm-McSC are involved in the initiation of anagen phase, followed by pigmented terminal hair regrowth in the recovering AA lesions in association with immunology. We also discuss how HBg-McSC contribute to the migration of fully dendritic mature melanocytes into interfollicular epidermis and the equal distribution of melanin in recovering vitiligo lesions. Finally, we present four hypotheses to elucidate the delayed distribution of melanin by mature melanocytes in depigmented vitiligo lesions from the aspects of stem cell biology, as compared with quick hair recovery in AA: (1) McSC are less abundant than HFSC. (2) McSC require a long travel, whereas HFSC reside close to hair regeneration trigger point. (3) Keratinocyte scaffold to accept melanin is not well preserved, whereas scaffold for hair regrowth is well preserved. (4) Inhibitors targeting JAKs and other kinases have less direct effects on melanocyte proliferation and differentiation in vitiligo than hair regrowth in AA. Our review provides an overview of treatment modalities and bridges the gap between scientific advancement and clinical practice in AA and vitiligo management.

Alopecia areata (AA) is an autoimmune hair loss disorder that commonly affects children. While mild disease may improve spontaneously or with topical therapies, patients with more extensive involvement typically require systemic treatment. This narrative review examines the literature describing systemic therapies for pediatric AA. High-quality evidence is extremely limited, with the majority of evidence coming from case reports and series. Janus kinase inhibitors are the only class of medications with systematic data supporting their use. There are an increasing number of reports suggesting that oral minoxidil may be beneficial, especially as an adjunctive treatment. Some patients with AA and comorbid atopy may benefit from treatment with dupilumab. Systemic corticosteroids may provide initial improvement, but the risk for adverse effects precludes long-term use, and efficacy is often lost once discontinued. There is very little literature to support the use of traditional immunomodulatory medicines such as methotrexate, cyclosporine, and azathioprine.

Ikaros, which is encoded by the Ikaros family zinc finger 1 (IKZF1) gene, is a zinc finger transcription factor. We have previously generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the IKZF1 isoform into epithelial cells expressing keratin 5, which develop patchy alopecia. However, there has been no detailed in vivo investigation of the function of IKZF1 in alopecia or of Ikaros expression in hair follicles of alopecia patients. Our aim was to investigate whether IKZF1 overexpression is involved in the pathogenesis of alopecia areata (AA) using Ikzf1 Tg and to examine Ikaros expression in human scalp skin. We grossly and histologically examined the alopecic lesions of Ikzf1 Tg and the skin of wild-type (WT) mice and the associated mRNA expression of inflammatory mediators. We also examined Ikaros' expression in human scalp skin. Grossly and histologically, we found that the Ikzf1 Tg developed AA-like lesions. Immunohistochemically, the hair follicles of the Ikzf1 Tg expressed high levels of the NKG2D ligand H60 and contained infiltrating CD8+NKG2D+ T cells. Interleukin 15, tumour necrosis factor-α, CXC chemokine ligand (Cxcl)1, Cxcl10, Cxcl11, signal transducer and activator of transcription (STAT)1, STAT3, Janus kinase (JAK)1 and JAK3 mRNA expression were significantly higher in the alopecic lesions of the Ikzf1 Tg than in the WT mice. Ikzf1 Tg given corticosteroid injections exhibited hair regrowth. Immunohistochemical analysis of scalp hair follicles showed that Ikaros was more highly expressed in AA patients than in non-AA controls. Our study suggests that IKZF1 and Ikaros are involved in the pathogenesis of AA.

Chronic erythroderma is a potentially life-threatening condition that can be caused by various diseases, but approximately 30% of cases remain idiopathic, often with insufficient treatment options.

We sought to establish a molecular disease map of chronic idiopathic erythroderma (CIE).

We performed single-cell RNA sequencing combined with T-cell receptor sequencing of blood and skin from 5 patients with CIE and compared results with 8 cases of erythrodermic cutaneous T-cell lymphoma (eCTCL), 15 cases of moderate to severe atopic dermatitis, 10 cases of psoriasis, and 20 healthy control individuals.

In eCTCL, we found strong expansion of CD4+ malignant clones with a CCR7+SELL+ central memory phenotype. In contrast, CIE exhibited a pattern of low-level, but consistent, expansion of CD8A+KLRK1+ T-cell clones, both in blood and in skin. KLRK1 was also expressed by CCR10+FUT7+ skin-homing CIE blood T cells that had increased proliferation rates and were absent in all other conditions. While patients with CIE and eCTCL lacked the strong type 2 or type 17 immune skewing typically found in atopic dermatitis or psoriasis, respectively, they were characterized by upregulation of MHC II genes (HLA-DRB1, HLA-DRA, and CD74) in keratinocytes and fibroblasts, most likely in an IFN-γ-dependent fashion. Overall, we found the strongest upregulation of type 1 immune mediators in CIE samples, both in the expanded CD8A+ clones and in the tissue microenvironment.

Despite the notion that CIE might be a mere bundle of various yet uncharacterized disease processes, we found specific pathogenic signatures in these patients, which were different from other forms of erythroderma. These data might help to improve our pathogenic understanding of the blood and skin compartments of CIE, aiding in discovery of future treatment targets.

Dermal papilla cells (DPCs) are a crucial subset of mesenchymal cells in the skin responsible for regulating hair follicle development and growth, making them invaluable for cell-based therapies targeting hair loss. However, obtaining sufficient DPCs with potent hair-inducing abilities remains a persistent challenge. In this study, the Food and Drug Administration (FDA)-approved drug library was utilized to screen small molecules capable of reprogramming readily accessible human skin fibroblasts into functional DPCs. In the initial screening, five candidate small molecules were identified from a pool of 1,817 compounds, and the small molecule peficitinib was further identified by the further hair follicle regeneration experiments. Following peficitinib treatment, fibroblasts derived from primary human foreskin and scalp exhibited the capability to induce hair growth and possessed a molecular profile highly similar to that of primary DPCs. We refer to these cells as dermal papilla cell-like cells (DPC-LCs). Furthermore, transcriptome analysis showed that the wingless/integrated (Wnt) signaling pathway and the transforming growth factor β (TGF-β) signaling pathway, both of which play crucial roles in hair follicle morphogenesis, are upregulated and enriched in these DPC-LCs. These functional DPC-LCs offer a promising avenue for obtaining a plentiful supply of hair-inducing cells, thereby advancing the development of therapeutic strategies for hair loss treatment.

Alopecia areata (AA) is an autoimmune non-scarring hair loss that arises in genetically susceptible individuals, potentially in combination with environmental triggers or inciting events, of which the exact mechanism is not yet fully understood. Genome wide association studies have demonstrated an association between AA and variants in HLA haplotypes on chromosome 6 which correlate with other autoimmune conditions as well as other gene variants. Familial and twin studies also confer additional evidence to a genetic component. AA pathogenesis relies on immune privilege collapse at the hair follicle (HF) bulb in the anagen hair cycle phase. Immune privilege collapse is associated with upregulation of IFN-γ, ultimately activating JAK-STAT pathway resulting in upregulation of MHC class I and II in the HF and subjecting it to attack by NKG2D+ CD8 T cells. The complex interplay between pro-inflammatory cytokines such as IFN-γ, IL-2, IL-15 and their use of JAK-STAT signaling are important in perpetuation of AA.

To investigate the involvement and mechanisms of PPARα agonists in alopecia areata (AA).

AA models were established using skin grafting, adoptive T-cell transfer, and TCR retrograde T-cell transfer methods. Relative PPARα expression levels in C3H/HeJ AA mice and AA patients were evaluated using qPCR and immunohistochemistry (IHC). Hair changes in mice following treatment were documented photographically, while immunofluorescence staining was employed to assess inflammatory factor dynamics in the skin. Additionally, ELISA and flow cytometry were used to analyze AA-related immune factors and cell populations in treated mice.

PPARα agonists demonstrated protective effects in C3H/HeJ skin graft AA models and TCR transgenic AA mice, promoting early reversal of AA. They effectively inhibited T effector cell function and exerted immunomodulatory effects.

The PPARα signaling pathway plays a key role in AA pathogenesis. PPARα agonists show therapeutic potential for AA as an inflammatory condition.

Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (P2, P9, P13) showed favorable stability, permeability, and pharmacokinetics. Notably, P2 and P13 significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from P2 and P13, respectively. These findings highlight the potential of prodrug strategies to enhance itaconate's cellular permeability and oral bioavailability, paving the way for clinical translation.

We have previously demonstrated that receptor-interacting serine threonine kinase 1 (RIPK1) is expressed in hair follicles and regulates the hair cycle. In a mouse model, RIPK1 inhibitors also accelerated the telogen-to-anagen transition and elongated the anagen period. Here, we first investigated the involvement of RIPK1 in alopecia areata (AA). The mRNA and protein expression of RIPK1 was increased in the skin of an AA mouse model. Single-cell RNA sequencing and immunohistochemistry showed that RIPK1 was highly increased in dendritic cells (DCs) and CD8+ T cells. RIPK1 inhibitors (i.e., Necrostatin-1s and GSK2982772) delayed the onset of AA in the mouse model and reduced the numbers of DCs and CD8+ T cells in AA skin. The RIPK1 inhibitors also increased the hair length in a mouse hair organ culture mimicking AA. Collectively, these results suggest that RIPK1 is involved in AA onset via modulating immune cells, and RIPK1 inhibitors could prevent AA onset.

The oral Janus kinase (JAK) inhibitor baricitinib is approved by the U.S. Food and Drug Administration for the treatment of alopecia areata (AA). We report a case of dual improvement of AA and immune thrombocytopenia (ITP) with oral baricitinib monotherapy, which may suggest linked autoimmune pathophysiology. In phase III clinical trials of baricitinib for AA, reports of rare adverse haematological events include neutropenia and anaemia. While a history of haematological comorbidities may raise concern for many clinicians when considering treatment with a JAK inhibitor, this clinical vignette suggests that baricitinib may be considered and safely administered in those with concomitant AA and ITP. A 56-year-old man with a history of AA, ITP and vitiligo presented to the clinic for relapse of his steroid-resistant hair loss which had previously been treated with tofacitinib. In consultation with the patient's haematologist, baricitinib 2 mg daily was started with close platelet monitoring then doubled to 4 mg after platelets showed improvement at the 6-month follow-up. Fourteen months after initiating baricitinib, improvement in white and dark hair regrowth was observed, and platelets remained normal. Thus, baricitinib may be considered for the dual treatment of AA and ITP with regular platelet monitoring and co-management with haematology colleagues.

Alopecia, a common dermatological condition, poses significant psychological and social challenges. Despite the availability of various treatments, their efficacy is often limited by poor bioavailability and delivery challenges. Nanostructured lipid carriers have emerged as promising advanced drug delivery systems for alopecia treatment due to their ability to encapsulate both hydrophilic and lipophilic compounds, enhancing their stability, solubility, and controlled release. This manuscript explores the potential of Nanostructured lipid carriers as innovative delivery platforms for alopecia therapeutics, focusing on their formulation, characterization, and application in topical treatments. The unique properties of Nanostructured lipid carriers, including their small size, biocompatibility, and ability to target specific skin layers, are discussed in relation to improving the penetration and therapeutic efficacy of active ingredients such as minoxidil, finasteride, and plant-derived compounds. Additionally, we highlight the role of Nanostructured lipid carriers in improving scalp penetration, reducing side effects, and offering a more efficient alternative to conventional treatments. The manuscript concludes with insights into future trends, challenges, and the clinical potential of Nanostructured lipid carriers-based formulations in revolutionizing alopecia treatment.

Alopecia areata (AA) is a common non-scarring hair loss disorder associated with autoimmune conditions. However, the pathobiology of AA is not well understood, and there is no targeted therapy available for AA.  METHODS: In this study, differential gene expression analysis, immune status assessment, weighted correlation network analysis (WGCNA), and functional enrichment analysis were performed to identify shared genes associated with both immunological response and AA. Machine learning methods were then used to identify three hub genes as potential diagnostic markers for AA. External validation was performed, and the correlation of hub genes with immune infiltration, immune checkpoint genes, and key marker genes and pathways were evaluated.

Three hub genes were identified, which accurately predicted the progression of AA and the immune status. The hub genes were found to be diagnostic markers for AA with high predictive accuracy. External validation confirmed the efficacy of these markers in identifying AA patients.

Overall, the study provides a novel approach for the diagnosis, prevention, and treatment of AA. The findings could potentially lead to the development of targeted therapies for AA based on the identified hub genes. The study also highlights the potential of machine learning and bioinformatics analysis in identifying new biomarkers for autoimmune diseases.

Alopecia areata (AA) is a common autoimmune disease, causes sudden hair loss on the scalp, face, and sometimes other areas of the body. Previous studies have suggested more severe manifestations and higher recurrence rates in children than in adults. Moreover, pediatric AA patients with atopic predisposition often exhibit elevated IgE levels, early onset, and a poor prognosis.

This study aimed to investigate the impact of age and IgE levels on AA by conducting RNA sequencing on scalp samples from AA patients with atopic predisposition, age-matched healthy controls, and AA samples with varying IgE levels.

We employed the single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm in conjunction with gene expression analysis to assess immune infiltration. Differential gene expression analysis was performed using the DESeq package in R. Immunohistochemical staining and qPCR was performed to validate these findings.

Our results revealed a more pronounced inflammatory immune infiltration in AA patients across all age groups compared to healthy controls. Pediatric AA was characterized by an upregulation of genes controlling inflammatory responses, such as the IFN-γ pathway and JAK-STAT cascade, contrasting to adult AA. Compared to age-matched healthy controls, pediatric AA patients exhibited a significant increase in the infiltration of B cell subtypes, mast cells, and regulatory T cells. Additionally, high IgE levels in AA patients led to the upregulation of IFN-γ pathway genes, compared to AA patients with normal IgE levels.

In summary, the heightened immune and inflammatory responses, along with the more significant infiltration of immune cells in pediatric AA with atopic predisposition, may explain the increased clinical severity and recurrence rates. Dissecting these molecular mechanisms sheds some light on the contributions of age and IgE to the pathogenesis and progression of AA, revealing potential age-specific and allergy-related therapeutic targets.

The hair follicle is a complex of mesenchymal and epithelial cells acquiring different properties and characteristics responsible for fulfilling its inductive and regenerative role. The epidermal and dermal crosstalk induces morphogenesis and maintains hair follicle cycling properties. The hair follicle is enriched with pluripotent stem cells, where dermal papilla (DP) cells and dermal sheath (DS) cells constitute the dermal compartment and the epithelial stem cells existing in the bulge region exert their regenerative role by mediating the epithelial-mesenchymal interaction (EMI). Many studies have developed and focused on various methods to optimize the EMI through in vivo and in vitro approaches for hair regeneration. The culturing of human hair mesenchymal cells resulted in the loss of trichogenicity and inductive properties of DP cells, limiting their potential application in de novo hair follicle generation in vivo. Epithelial stem cells derived from human hair follicles are challenging to isolate and culture, making it difficult to obtain enough cells for hair regeneration purposes. Mesenchymal stem cells and epithelial stem cells derived from human hair follicles lose their ability to form hair follicles during culture, limiting the study of hair follicle formation in vivo. Therefore, many attempts and methods have been developed to overcome these limitations. Here, we review the possible and necessary cell methods and techniques used for human hair follicle regeneration and the restoration of hair follicle cell inductivity in culture.

Alopecia areata (AA) is an autoimmune skin disease. Observational studies have reported an association between AA and cancer. However, the causal relationship between AA and cancer has not been reported. We employed a two-sample Mendelian randomization (MR) study to assess the causality between AA and 17 subtypes of cancers.

We employed a two-sample Mendelian randomization (MR) study to assess the causality between AA and 17 subtypes of cancers. AA and cancers' association genome-wide association study (GWAS) data were collected. The inverse variance weighted (IVW) method was utilized as the principal method in our Mendelian randomization (MR) study, with additional use of the MR-Egger, weighted median, simple mode, and weighted mode methods. After that, we explored the underlying biological mechanisms by Bioinformatic Analysis.

According to our MR analysis, AA has a causal relationship with hepatic bile duct cancer (HBDC, (odds ratio [OR] = 0.944, 95% confidence interval [CI] = 0.896-0.994, P-value = 0.030) and colorectal cancer (CRC, OR = 0.981, 95% CI = 0.963-0.999, P-value = 0.046). AA could decrease the risk of HBDC and CRC. No causal link between AA and other subtypes of cancers was observed. No heterogeneity or pleiotropy was observed. Furthermore, disease-related genes were obtained, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results showed that the set of genes associated with immunity-inflammatory signaling pathway.

This study provided new evidence of the relationship between AA with HBDC and CRC. AA may play a protective role in both HBDC and CRC progression. This could provide newer avenues for research in search of treatment for HBDC and CRC.

The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.

Alopecia universalis (AU) is a severe form of alopecia areata characterized by the complete loss of scalp and body hair. While Janus kinase (JAK) inhibitors like baricitinib have shown promise in promoting hair regrowth in severe cases of AU, unexpected side effects, such as hair depigmentation, have not been widely reported. We present the case of a young male with AU who experienced progressive and extensive whitening of his scalp and body hair following treatment with baricitinib. After one month of therapy, the patient observed both black and white hairs emerging, which gradually turned entirely white by the second month. Over the course of seven months, the whitening of the hair persisted, with no repigmentation observed. Laboratory tests and clinical evaluations indicated no significant adverse effects, suggesting that baricitinib was well tolerated. Dermoscopic examination revealed predominantly white terminal hairs. While the mechanisms underlying this phenomenon remain unclear, we discuss potential interactions between JAK inhibition and melanocyte function, suggesting that baricitinib's modulation of the JAK-STAT pathway may impact melanogenesis and hair pigmentation. This case highlights the need for further investigation into the effects of JAK inhibitors on hair pigmentation and the potential for hair whitening as an uncommon side effect. Understanding these mechanisms is essential for improving treatment strategies for AU and addressing patient concerns regarding pigmentation changes during therapy.

Alopecia areata (AA) is a chronic, nonscarring hair-loss disorder associated with significant quality-of-life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1- and Th2-driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking.

Lesional and nonlesional scalp biopsies obtained from AA patients with (n = 16) or without (n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA-seq, RT-PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold-change| > 1.5 and false-discovery rate <0.05.

AA scalp exhibited robust upregulation of Th1- (IFNG, CXCL9, CXCL10, CXCL11) and Th2-related products (CCL26, CCR4, IL10, IL13, TSLP, TNFRSF4/OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2-skewing (IL10, IL13, IL33, CCR4, CCL26). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40+ and OX40L+ leukocytes, regardless of atopic background.

Our results suggest some atopy-associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients.

While IL-23 inhibitors, which include guselkumab, tildrakizumab, and risankizumab, are currently FDA-approved solely for the treatment of psoriasis, several other inflammatory skin conditions have been associated with elevated IL-23 levels. The purpose of this review is to summarize and interpret the literature surrounding the off-label uses of IL-23 inhibitors in dermatologic practice.

We conducted searches on PubMed and ClinicalTrials.gov for clinical trials, observational studies, case series, and case reports assessing use of the three IL-23 inhibitors for non-psoriatic dermatologic conditions.

Conditions exhibiting promising response to treatment with IL-23 inhibitors include hidradenitis suppurativa, lichen planus, pityriasis rubra pilaris, pyoderma gangrenosum, dissecting cellulitis of the scalp, congenital ichthyosiform erythroderma, lichen planus pemphigoides, acrofacial vitiligo, lichen planopilaris, frontal fibrosing alopecia, lupus erythematosus tumidus, and Stewart-Treves angiosarcoma.

Current literature suggests that IL-23 inhibitors may be effective in treating these conditions due to shared pathophysiologic pathways with psoriasis. Although these results are promising, further research through large-scale, randomized clinical trials is needed to further evaluate the efficacy and safety of IL-23 inhibitors in treating these off-label conditions.

The autoimmune hair loss condition alopecia areata (AA) exacts a substantial psychological and socioeconomic toll on patients. Biotechnology companies, dermatology clinics, and research institutions are dedicated to understanding AA pathogenesis and developing new therapeutic approaches. Despite recent efforts, many knowledge gaps persist, and multiple treatment development avenues remain unexplored.

This review summarizes key AA disease mechanisms, current therapeutic methods, and emerging treatments, including Janus Kinase (JAK) inhibitors. The authors determine that innovative drug discovery strategies for AA are still needed due to continued unmet medical needs and the limited efficacy of current and emerging therapeutics. For prospective AA treatment developers, the authors identify the pre-clinical disease models available, their advantages, and limitations. Further, they outline treatment development opportunities that remain largely unmapped.

While recent advancements in AA therapeutics are promising, challenges remain, including the lack of consistent treatment efficacy, long-term use and safety issues, drug costs, and patient compliance. Future drug development research should focus on patient stratification utilizing robust biomarkers of AA disease activity and improved quantification of treatment response. Investigating superior modes of drug application and developing combination therapies may further improve outcomes. Spirited innovation will be needed to advance more effective treatments for AA.