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JAK3/TEC and TYK2/JAK1 inhibitors demonstrate significant improvement in scalp alopecia areata biomarkers

ABSTRACT: We present the biopsy sub-study results from the first randomized, placebo-controlled clinical trial in patients with alopecia areata (AA) with ≥50% scalp hair loss and ≤7 years since the last AA episode. In this sub-study, we evaluated the molecular responses to PF-06651600, an oral inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and PF-06700841, an oral TYK2/JAK1 inhibitor, versus placebo in nonlesional and lesional scalp biopsies of biopsy samples from patients with AA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148346 | GEO | 2022/01/25

REPOSITORIES: GEO

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JAK3/TEC and TYK2/JAK1 inhibitors demonstrate significant improvement in scalp alopecia areata biomarkers

Project description:JAK3/TEC and TYK2/JAK1 inhibitors demonstrate significant improvement in scalp alopecia areata biomarkers

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Project description:In this study, we aimed to elucidate the profile of lesional and non-lesional keloid skin compared to normal skin. We performed gene (RNAseq, qRT-PCR) and protein (immunohistochemistry) expression analyses on biopsy specimens obtained from lesional and non-lesional skin of African American (AA) keloid patients compared to healthy skin from AA controls. We found that lesional versus normal skin showed significant up-regulation of markers of T-cell activation/migration (ICOS, CCR7), Th2- (IL-4R, CCL11, TNFSF4/OX40L), Th1- (CXCL9/CXCL10/CXCL11), Th17/Th22- (CCL20, S100As) pathways, and JAK/STAT-signaling (JAK3) (false-discovery rate [FDR]<0.05).

2020-10-19 | GSE158395 | GEO

Molecular and Cellular Responses to the TYK2/JAK1 Inhibitor, PF 06700841, Reveal Reduction of Skin Inflammation in Plaque Psoriasis

Project description:The interleukin (IL)-23/T-helper type 17 cell axis is a target for psoriasis. The tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) inhibitor, PF 06700841, will directly suppress TYK2-dependent IL-12 and IL-23 signaling and JAK1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF 06700841 improves the clinical manifestations of psoriasis. Patients (n=30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n=14) or 100 mg (n=7) PF 06700841, or placebo (n=9) for 28 days. Biopsies were taken from non-lesional and lesional skin at baseline, weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and RT-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and ~70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF 06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of pro-inflammatory cytokines that require TYK2 and JAK1 for signal transduction.

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Human Alopecia Areata Skin Profiling

Project description:Our goal was to develop a transcriptomic description of affected alopecic scalp skin from patients with alopecia areata. 5 biological replicates of skin samples from 5 separate AA patients compared with 5 similar scalp samples from healthy control patients

2014-08-17 | E-GEOD-45512 | biostudies-arrayexpress

First characterization of the transcriptome of lung fibroblasts of SSc patients and healthy donors of African ancestry.

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Plucked hair follicles from patients with chronic discoid lupus erythematosus show a disease-specific molecular signature

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Extensive alopecia areata is reversed by IL-23 cytokine antagonism

Project description:Alopecia areata (AA) is a prevalent disease associated with major emotional distress, and lacks effective, safe therapeutics for patients with extensive hair loss. This is the first report of hair regrowth with specific cytokine antagonism, in three patients with extensive hair loss ranging from 40% scalp involvement to alopecia universalis. Ustekinumab, an IL-12/23p40 antagonist that is highly effective in psoriasis, showed impressive ability to induce hair regrowth, coupled with suppression of inflammatory pathways and upregulation of hair keratins. Our report suggests that extensive AA is reversible using targeted treatments, opening the door for specific cytokine antagonism for this debilitating disease. We evaluated hair regrowth in three AA patients at 20 weeks after treatment with 3 subcutaneous doses of 90mg ustekinumab given at weeks 0, 4, and 16. Skin biopsies of lesional and non-lesional scalp (when available) were taken at baseline (week 0) and at week 20. We also obtained biopsies from three healthy individuals.

2015-12-08 | E-GEOD-74761 | biostudies-arrayexpress

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2023-08-30 | GSE212757 | GEO

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Project description:The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.

| S-EPMC11258076 | biostudies-literature

Expression data from colonic biopsy samples of infliximab treated ulcerative colitis patients

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