JAK Inhibitors for Treatment of Alopecia Areata.
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ABSTRACT:
SUBMITTER: Wang EHC
PROVIDER: S-EPMC6475885 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
JAK Inhibitors for Treatment of Alopecia Areata.
Wang Eddy H C EHC Sallee Brigitte N BN Tejeda Christina I CI Christiano Angela M AM
The Journal of investigative dermatology 20180726 9
The advancement of genetic and preclinical studies has uncovered the mechanisms involved in the pathogenesis of alopecia areata (AA). The development of targeted therapies using small molecules blocking specific pathways for the treatment of AA is underway. By repurposing Food and Drug Administration-approved small molecule JAK inhibitors as treatments for AA, it has been demonstrated that JAK inhibitors can effectively reverse hair loss in patients with moderate to severe AA. In this review, we ...[more]
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Project description:Alopecia areata (AA) is a chronic, immune-mediated form of nonscarring alopecia that is multifactorial and results in localized patches. It is often described as a self-limiting condition that results in the spontaneous regrowth of hair in most cases. However, this regrowth may take several months or years to occur in some patients, leading to the development of psychoemotional trauma in those that are affected. Although several therapies for AA have been developed and tested, there is no specific treatment that has been approved, leading to the availability of many off-label conventional treatment options, with very limited responses. More recently, with the advancement of pre-clinical and genetic studies, a greater understanding of the pathomechanisms involved in the development of AA has been uncovered. This has resulted in the introduction of targeted therapies that use small molecules to block specific pathways involved in AA pathophysiology. As such, the use of janus kinase (JAK) inhibitors for treatment of AA has emerged. JAK inhibitors block the T-cell mediated inflammatory response thought to be the driving factor behind AA pathogenesis, by inhibiting the janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway, leading to a reversal of hair loss in AA patients. Thus, in an effort to demonstrate the efficacy of JAK inhibitors in the treatment of AA, several studies have been published within recent years. However, the question remains, "Are JAK inhibitors effective and safe in the management of Alopecia Areata?". This review aims to provide a comprehensive report on the role, efficacy, and outcomes of using JAK inhibitors in the treatment of AA. To competently answer the research question highlighted, the most recent, quality articles published over a 10-15-year period were sourced using PubMed, NCBI, Research gate, Medline, Cochrane Central Register of Controlled Trials, EMBASE and Google scholar. The literature search was primarily focused on randomized controlled trials (RCTs); however, in the absence of such, only the most recently published case reports, case series, clinical trials and open-label studies published to date were included.
| S-EPMC8242127 | biostudies-literature
Project description:Background Alopecia areata (AA) is an immune disease characterized by non-scarring hair loss. With the widespread application of JAK inhibitors in immune-related diseases, attention is being given to their role in the treatment of AA. However, it is unclear which JAK inhibitors have a satisfactory or positive effect on AA. This network meta-analysis aimed to compare the efficacy and safety of different JAK inhibitors in the treatment of AA. Methods The network meta-analysis was performed according to the PRISMA guidelines. We included randomized controlled trials as well as a small number of cohort studies. The differences in efficacy and safety between the treatment and control groups were compared. Results Five randomized controlled trials, two retrospective studies, and two prospective studies involving 1689 patients were included in this network meta-analysis. In terms of efficacy, oral baricitinib and ruxolitinib significantly improved the response rate of patients compared to placebo [MD = 8.44, 95% CI (3.63, 19.63)] and [MD = 6.94, 95% CI, (1.72, 28.05)],respectively. Oral baricitinib treatment significantly improved the response rate compared to non-oral JAK inhibitor treatment [MD=7.56, 95% CI (1.32,43.36)]. Oral baricitinib, tofacitinib, and ruxolitinib treatments significantly improved the complete response rate compared to placebo [MD = 12.21, 95% CI (3.41, 43.79)], [MD = 10.16, 95% CI (1.02, 101.54)], and [MD = 9.79, 95% CI, (1.29, 74.27)], respectively. In terms of safety, oral baricitinib, tofacitinib, and ruxolitinib treatments significantly reduced treatment-emergent adverse event rates compared with conventional steroid treatment [MD = 0.08, 95% CI (0.02, 0.42)], [MD = 0.14, 95% CI (0.04, 0.55)], and [MD = 0.35, 95% CI, (0.14, 0.88)], respectively. Conclusion Oral baricitinib and ruxolitinib are excellent options for the treatment of AA owing to their good efficacy and safety profiles. In contrast, non-oral JAK inhibitors do not appear to have satisfactory efficacy in treating AA. However, further studies are required to verify the optimal dose of JAK inhibitors for AA therapy.
| S-EPMC10150113 | biostudies-literature
Project description:Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γc) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γc cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.
| S-EPMC9470217 | biostudies-literature
Project description:Alopecia areata is an autoimmune disorder characterized by transient, non-scarring hair loss and preservation of the hair follicle. Hair loss can take many forms ranging from loss in well-defined patches to diffuse or total hair loss, which can affect all hair-bearing sites. Patchy alopecia areata affecting the scalp is the most common type. Alopecia areata affects nearly 2% of the general population at some point during their lifetime. Skin biopsies of affected skin show a lymphocytic infiltrate in and around the bulb or the lower part of the hair follicle in the anagen (hair growth) phase. A breakdown of immune privilege of the hair follicle is thought to be an important driver of alopecia areata. Genetic studies in patients and mouse models have shown that alopecia areata is a complex, polygenic disease. Several genetic susceptibility loci were identified to be associated with signalling pathways that are important to hair follicle cycling and development. Alopecia areata is usually diagnosed based on clinical manifestations, but dermoscopy and histopathology can be helpful. Alopecia areata is difficult to manage medically, but recent advances in understanding the molecular mechanisms have revealed new treatments and the possibility of remission in the near future.
| S-EPMC5573125 | biostudies-other
Project description:Alopecia areata (AA) is a relapsing, chronic, immune-mediated disease characterized by nonscarring, inflammatory hair loss that can affect any hair-bearing site. AA clinical presentation is heterogeneous. Its pathogenesis involves immune and genetic factors and several pro-inflammatory cytokines involved in AA pathogenesis, including interleukin-15 and interferon-γ, as well as Th2 cytokines, such as IL-4/IL-13, that signal through Janus kinase (JAK) pathway. AA treatment aims to stop its progression and reverse hair loss, and JAK inhibition has been shown to stop hair loss and reverse alopecia and has exhibited promising results in treating AA in clinical trials. Baricitinib, an oral, reversible, selective JAK1/JAK2 inhibitor, was shown to be superior to placebo on hair growth after 36 weeks of treatment in adults with severe AA in a phase 2 trial and recently in two phase 3 trials (BRAVE-AA1 and BRAVE-AA2). In both studies, the most common adverse events were upper respiratory tract infections, urinary tract infection, acne, headache, and elevated creatine kinase levels. On the basis of these trial results, baricitinib was recently approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) for the treatment of adults with severe AA. Nevertheless, longer trials are needed to determine the long-term efficacy and safety of baricitinib in AA. Current trials are ongoing and are planned to remain randomized and blinded for up to 200 weeks.
| S-EPMC10191081 | biostudies-literature
Project description:BackgroundAlopecia areata (AA) is an autoimmune, nonscarring hair loss disorder with slightly greater prevalence in children than adults. Various treatment modalities exist; however, their evidence in pediatric AA patients is lacking.ObjectiveTo evaluate the evidence of current treatment modalities for pediatric AA.MethodsWe conducted a systematic review on the PubMed database in October 2019 for all published articles involving patients <18 years old. Articles discussing AA treatment in pediatric patients were included, as were articles discussing both pediatric and adult patients, if data on individual pediatric patients were available.ResultsInclusion criteria were met by 122 total reports discussing 1032 patients. Reports consisted of 2 randomized controlled trials, 4 prospective comparative cohorts, 83 case series, 2 case-control studies, and 31 case reports. Included articles assessed the use of aloe, apremilast, anthralin, anti-interferon gamma antibodies, botulinum toxin, corticosteroids, contact immunotherapies, cryotherapy, hydroxychloroquine, hypnotherapy, imiquimod, Janus kinase inhibitors, laser and light therapy, methotrexate, minoxidil, phototherapy, psychotherapy, prostaglandin analogs, sulfasalazine, topical calcineurin inhibitors, topical nitrogen mustard, and ustekinumab.LimitationsEnglish-only articles with full texts were used. Manuscripts with adult and pediatric data were only incorporated if individual-level data for pediatric patients were provided. No meta-analysis was performed.ConclusionTopical corticosteroids are the preferred first-line treatment for pediatric AA, as they hold the highest level of evidence, followed by contact immunotherapy. More clinical trials and comparative studies are needed to further guide management of pediatric AA and to promote the potential use of pre-existing, low-cost, and novel therapies, including Janus kinase inhibitors.
| S-EPMC8556406 | biostudies-literature
Project description:Alopecia areata (AA) is a common autoimmune disease resulting from damage of the hair follicle by T cells. The immune pathways required for autoreactive T cell activation in AA are not defined limiting clinical development of rational targeted therapies. Genome-wide association studies (GWAS) implicated ligands for the NKG2D receptor (product of the KLRK1 gene) in disease pathogenesis. Here, we show that cytotoxic CD8(+)NKG2D(+) T cells are both necessary and sufficient for the induction of AA in mouse models of disease. Global transcriptional profiling of mouse and human AA skin revealed gene expression signatures indicative of cytotoxic T cell infiltration, an interferon-γ (IFN-γ) response and upregulation of several γ-chain (γc) cytokines known to promote the activation and survival of IFN-γ-producing CD8(+)NKG2D(+) effector T cells. Therapeutically, antibody-mediated blockade of IFN-γ, interleukin-2 (IL-2) or interleukin-15 receptor β (IL-15Rβ) prevented disease development, reducing the accumulation of CD8(+)NKG2D(+) T cells in the skin and the dermal IFN response in a mouse model of AA. Systemically administered pharmacological inhibitors of Janus kinase (JAK) family protein tyrosine kinases, downstream effectors of the IFN-γ and γc cytokine receptors, eliminated the IFN signature and prevented the development of AA, while topical administration promoted hair regrowth and reversed established disease. Notably, three patients treated with oral ruxolitinib, an inhibitor of JAK1 and JAK2, achieved near-complete hair regrowth within 5 months of treatment, suggesting the potential clinical utility of JAK inhibition in human AA.
| S-EPMC4362521 | biostudies-literature
Project description:BackgroundAlopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined.MethodsThis was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome.ResultsOf 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment.ConclusionsAt the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease.Trial registrationClinicalTrials.gov NCT02197455 and NCT02312882.FundingThis work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.
| S-EPMC5033755 | biostudies-literature
Project description:Two patients with alopecia areata were treated with systemic ruxolitinib. Skin biopsies were taken before starting treatment and 12 weeks after starting treatment. We used microarrays to assess changes in gene expression of affected skin before and after starting treatment Two patients with alopecia areata were recruited for our study. Skin biopsies of affected scalp were taken prior to starting treatment with oral ruxolinitib. Additional skin biopsies were taken 12 weeks after starting treatment. Scalp skin biopsies were taken from patients without alopecia areata for comparison. RNA was extracted, cDNA libraries were made and profiled on affymetrix microarray chips.
2014-08-17 | E-GEOD-58573 | biostudies-arrayexpress
Project description:IntroductionAlthough there is growing evidence supporting the effectiveness of Janus kinase (JAK) inhibitors in treating alopecia areata, the high rate of recurrence following drug discontinuation has led to prolonged treatment courses and raised concerns about long-term safety. In clinical practice, caution should be exercised while using JAK inhibitors for various indications, and a comprehensive pre-treatment screening.MethodsThis study presents an analysis of screening data collected from real-world settings before the initiation of Janus kinase inhibitors in patients with alopecia areata. Investigators collected retrospective medical data characterizing patients' screening data. Data on demographic and clinical data, including age, sex, disease duration, severity of alopecia tool scale, history of prior treatment, and treatment regimen were recorded.ResultsIn this cohort (N = 218), JAK inhibitors were initiated for 163 of 218 (74.8%) alopecia areata patients. The numbers of patients positive for antinuclear antibodies, hepatitis B surface antigen, hepatitis C virus antibodies, human immunodeficiency virus antibody, treponema pallidum hemagglutination assay, and thyroid-stimulating hormone were 32 (32/176), 10(10/218), 0 (0/218), 0 (0/218), 3 (3/218) and 9 (9/176), respectively. The number of patients with T-cell spot positive or imaging of the chest indicating tuberculosis was 37 (37/218).DisccusionOur data provide additional information on the safety profile of JAK inhibitors in patients with alopecia areata. As such, it is necessary and crucial to screen for JAK inhibitors before it is used, particularly for individuals with a high risk of tuberculosis, hepatitis B, and other infections.
| S-EPMC10619649 | biostudies-literature