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J Allergy Clin Immunol. 2018 Dec 20. pii: S0091-6749(18)32785-4. doi: 10.1016/j.jaci.2018.11.042. [Epub ahead of print]

Psoriatic skin molecular and histopathologic profiles after treatment with risankizumab versus ustekinumab.

Author information

1
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn. Electronic address: sudha.visvanathan@boehringer-ingelheim.com.
2
Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
3
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn.
4
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY.
5
AbbVie, North Chicago, Ill.
6
AbbVie, Worcester, Mass.
7
Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.

Abstract

BACKGROUND:

IL-23 contributes to the activation, maintenance, and proliferation of TH17 cells and plays a major role in psoriasis pathophysiology. IL-23p19 inhibition with risankizumab resulted in superior clinical responses in patients with psoriasis compared with ustekinumab (dual IL-12/IL-23 inhibitor), but comparative molecular effects have not been established.

OBJECTIVE:

We investigated the similarities and differences in molecular and histopathologic profiles in skin lesions from patients with psoriasis receiving risankizumab versus ustekinumab at an early time point.

METHODS:

Lesional skin biopsy samples from 81 patients with moderate-to-severe plaque psoriasis participating in 2 different studies (a phase I risankizumab study and a phase II study of risankizumab vs ustekinumab) were analyzed by using histopathology, immunohistochemistry, and RNA sequencing.

RESULTS:

Risankizumab induced a rapid decrease in levels of proteins and transcriptomic biomarkers associated with the IL-23 pathway, which were maintained through 8 weeks. At week 4, risankizumab decreased histopathologic expression of biomarkers, including K16, Ki67, CD3, lipocalin-2, CD11c, dendritic cell lysosome-associated membrane glycoprotein, β-defensin 2, and S100A7; global histopathologic scoring revealed that 54% and 69% of patients treated with 90 or 180 mg of risankizumab, respectively, were graded as experiencing "excellent improvement" versus 29% of patients treated with ustekinumab. At week 4, there was a common decrease in expression of 2645 genes expressed in lesional skin between patients receiving risankizumab and ustekinumab and a significant decrease in 2682 genes unique to risankizumab treatment. Risankizumab more strongly downregulated expression of genes associated with keratinocytes, epidermal cells, and monocytes, versus ustekinumab.

CONCLUSION:

Risankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4.

KEYWORDS:

IL-12; IL-17; IL-23; Risankizumab; biomarkers; psoriasis; ustekinumab

PMID:
30578873
DOI:
10.1016/j.jaci.2018.11.042
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