Related Experiment Video
Updated: Mar 22, 2026
Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study
James Krueger1, James D Clark2, Mayte Suárez-Fariñas1
1Rockefeller University, New York, NY.
Background:
Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.
Objective:
We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis.
Methods:
Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67(+) keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT](+) nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray.
Results:
In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1(+) cells/μm(2); day 1, median of 332 pSTAT1(+) cells/μm(2); and nonlesional, median of 155 pSTAT1(+) cells/μm(2)). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/TH17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression.
Conclusions:
Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/TH17 pathway.
Insights
Tofacitinib rapidly reduces psoriasis symptoms by targeting Janus kinase/STAT signaling in skin cells. This leads to decreased inflammation, fewer immune cells, and inhibition of key inflammatory pathways for improved skin health.
Area of Science:
- Dermatology
- Immunology
- Pharmacology
Background:
- Psoriasis is a chronic inflammatory skin condition.
- Tofacitinib is an oral Janus kinase (JAK) inhibitor.
- Understanding tofacitinib's mechanism in psoriasis is crucial for treatment.
Purpose of the Study:
- Elucidate the molecular mechanisms of tofacitinib's efficacy in psoriasis.
- Investigate the drug's impact on skin cell signaling and immune cell infiltration.
- Correlate molecular changes with clinical and histological improvements.
Main Methods:
- Randomized trial of 10 mg tofacitinib twice daily versus placebo for 12 weeks in 12 plaque psoriasis patients.
- Skin biopsies analyzed for epidermal features, immune cells, and gene expression.
- Measurements included keratinocyte markers (pSTAT, KRT16), T-cells, dendritic cells (DCs), and cytokine pathways (IL-23/TH17).
Main Results:
- Tofacitinib rapidly reduced pSTAT1/3 signaling in keratinocytes within 1 day.
- Epidermal thickness and KRT16 expression decreased significantly by days 1 and 3.
- Reduced numbers of DCs and T-cells were observed by weeks 1 and 2.
- IL-23/TH17 pathway inhibition occurred by week 4 and persisted.
- Clinical and histological improvements correlated with gene expression changes, particularly IL-17 reduction.
Conclusions:
- Tofacitinib acts through multiple mechanisms in psoriasis.
- Rapidly attenuates JAK/STAT signaling in keratinocytes.
- Reduces cytokine signaling, leading to decreased pathogenic T-cells and DCs.
- Inhibits the IL-23/TH17 inflammatory pathway.
Related Concept Videos
01:24T Cell Types and Functions
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:20The JAK-STAT Signaling Pathway
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
01:24Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
01:16TGF - β Signaling Pathway
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...