Psoriatic skin molecular and histopathological profiles following treatment with risankizumab versus ustekinumab

Publication date: Available online 20 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Sudha Visvanathan, Patrick Baum, Richard Vinisko, Ramona Schmid, Mary Flack, Bojan Lalovic, Oliver Kleiner, Judilyn Fuentes-Duculan, Sandra Garcet, Justin W. Davis, Kristie M. Grebe, Jay S. Fine, Steven J. Padula, James G. Krueger

Abstract

Background

Interleukin (IL)-23 contributes to the activation, maintenance, and proliferation of T helper 17 cells and plays a major role in psoriasis pathophysiology. IL-23p19 inhibition with risankizumab had superior clinical responses in psoriasis compared with ustekinumab (dual IL-12/23 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 biopsies from 81 patients with moderate-to-severe plaque psoriasis participating in two different studies (a Phase I risankizumab study and a Phase II study of risankizumab vs ustekinumab) were analyzed by histopathology, immunohistochemistry, and RNA-sequencing.

Results

Risankizumab induced a rapid decrease in protein and transcriptomic biomarkers associated with the IL-23 pathway which were maintained through 8 weeks. At Week 4, risankizumab decreased histopathologic biomarker expression including K16, Ki67, CD3, lipocalin-2, CD11c, DC-LAMP, β-defensin 2, and S100A7; global histopathology scoring revealed that 54% and 69% of patients treated with 90 or 180 mg risankizumab, respectively, were graded as 'excellent improvement' versus 29% for ustekinumab. At Week 4, there was a common decrease in 2645 genes expressed in lesional skin between 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.

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