Abrocitinib downregulates genes linked to inflammation in patients with atopic dermatitis
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Key takeaways:
- Abrocitinib improved clinical signs and reduced itch.
- Expression of MMP-12, KRT16, S100A8, S100A9 and S100A12 significantly decreased.
- There were no serious treatment-emergent adverse events.
Abrocitinib downregulated genes associated with inflammation, epidermal hyperplasia, and T helper 2 and T helper 22 responses in the skin of patients with moderate to severe atopic dermatitis, according to a study published in Allergy.
Also, there were no new or unexpected safety findings, Emma Guttman-Yassky, MD, PhD, Waldman Professor and System Chair of the Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai Medical Center, and colleagues wrote.
The study included 46 adults with chronic moderate to severe AD in addition to recent inadequate response to medicated topical therapy or a need for systemic therapies to achieve disease control.
Fourteen patients (mean age, 41.4 years; 50% women) received 200 mg of abrocitinib (Cibinqo, Pfizer), 16 (mean age, 46.6 years; 69% women) received 100 mg, and 16 (mean age = 38.9 years; 19% women) received placebo, with daily doses of each for 12 weeks.
The abrocitinib groups experienced significant dose-dependent decreases in MMP-12, KRT16, S100A8, S100A9 and S100A12 at weeks 4 and 12, with the 200 mg group also experiencing decreases at week 2, compared with baseline.
CCL18 expression had a similar trend, including significant decreases for the 200 mg group at weeks 2, 4 and 12 and for the 100 mg group at week 12, although the decreases for the 100 mg group approached significance at week 4. Decreases in CCL17 expression reached significance for the 200 mg group at week 12.
The 200 mg group also had lower biomarker levels for KRT16, S100A8, S100A9 and S100A12 at weeks 2, 4 and 12 compared with placebo, in addition to MMP-12 and CCL18 at week 12, with the difference approaching significance at week 2.
The expression of various T helper (Th) 2 and Th17/22 inflammatory markers significantly decreased by weeks 2, 4 and 12 with treatment, with larger decreases in the 200 mg group, compared with baseline. The expression of these markers remained high through week 12 for the placebo group.
Treatment significantly inhibited the expression of many genes related to Th17 as well, the researchers said, such as IL-36G, PI3, DEFB4B, CXCL1, CXCL2 and IL-19.
The expression of CXCL10 and CXCL11, which are Th1 immune response markers, was significantly decreased from baseline at weeks 4 and 12 in the 200 mg group, and CXCL9 was significantly decreased at week 12. The 100 mg group had more variable responses, the researchers said.
The expression of claudin-8, claudin-23 and loricrin, which are genes associated with the epidermal barrier, and IL-34 and IL-37, which are anti-inflammatory or negative regulator genes, also experienced dose-dependent increases with treatment.
FLG, which is another gene associated with the epidermal barrier, increased in expression at weeks 2, 4 and 12 in the placebo group compared with baseline but remained comparable with baseline levels at all timepoints in the treatment groups.
The 200 mg group experienced significant decreases in Ki-67, which the researchers called a marker of epidermal hyperplasia, at week 12 and in epidermal thickness at weeks 2, 4 and 12. The 100 mg group had a significant decrease in Ki-67 at week 4.
Also, the 200 mg group saw significant decreases in T cells (CD3+) and epidermal dendritic cells (CD11c+, Fc epsilon R1+ and CD206+) at weeks 2 and 4. The 100 mg group had significant decreases in CD3+ at week 2, CD11c+ at weeks 2 and 4 and Fc epsilon R1+ cells at week 2.
Additional significant decreases in the 200 mg group included epidermal thickness at week 12, CD3+ cells at weeks 2 and 4 as well as CD11c+ and Fc epsilon R1+ cells at week 2 compared with placebo. The 100 mg group also had significant decreases in Fc epsilon R1+ levels at week 2 compared with placebo.
Patients with an itch response, defined as an improvement of four points or more in Peak Pruritus Numerical Rating Scale (PP-NRS), had greater mean-fold decreases from baseline in gene expression of MMP-12, KRT16, CCL17, CCL18, CCL26, S100A8, S100A9 and S100A12 than those patients who did not have an itch response in the 200 mg group.
The responders and non-responders in the 100 mg group had comparable decreases. Overall, mean-fold decreases from baseline in Ki-67, epidermal thickness, CD11c+, Fc epsilon R1+ and CD206+ epidermal dendritic cells in addition to CD3+ T cells among patients with an itch response showed similar trends, compared with patients who did not have an itch response.
Post hoc correlation analyses revealed significant correlations between changes in Eczema Area and Severity Index (EASI), Investigator’s Global Assessment (IGA) and Peak Pruritus Numerical Rating Scale (PP-NRS) scores and lesional biomarkers in the expression of KRT-16, CCL18, S100A8, S100A9 and S100A12.
Also, there was a correlation between CCL17 expression and changes in EASI but not between CCL17 expression and changes in IGA or PP-NRS.
Twenty-five (54%) of the patients in the full cohort experienced at least one treatment-emergent adverse event, the most common in the treatment group being nausea, dizziness and headache. None of the patients in the treatment group had any serious treatment-emergent adverse events, nor were there any cardiovascular events, malignancies or opportunistic infections.
Based on these decreases in the expression of genes that are downstream of Th2 and Th22 immune responses, as well as on the upregulation of barrier molecules downregulated by Th2/Th22 cytokines and negative regulators, with correlations with itch improvement and skin clearance, the researchers concluded that blocking Th2 and Th22 pathways in patients with moderate to severe AD has a therapeutic effect.