Psoriatic skin molecular and histopathologic profiles after treatment with risankizumab versus ustekinumab
Authors: 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
Journal: Journal of Allergy and Clinical Immunology (2018)

BackgroundIL-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.ObjectiveWe 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.MethodsLesional 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.ResultsRisankizumab 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.ConclusionRisankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4. 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. 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. 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. 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. Risankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4.