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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.
The Journal of Allergy and Clinical Immunology
|April 10, 2016
Summary
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.
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