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Long-term remissions and marked decreases in resident memory T cells following high induction dosing with risankizumab in randomized patients with moderate-to-severe plaque psoriasis

ABSTRACT: The phase 2 KNOCKOUT (NCT05283135) study evaluated higher-than-approved doses of risankizumab, an interleukin-23 inhibitor, for treatment of moderate-to-severe plaque psoriasis. Patients received either 300 or 600 mg of risankizumab at Weeks 0, 4, and 16 and were monitored through Week 100 without further dosing. Efficacy and safety were tracked throughout the study and RNASeq was performed on lesional/non-lesional tissue. Nine patients per treatment group completed dosing. At Weeks 28 and 52, Psoriasis Areas and Severity Index 75/90/100 responses were achieved by 94.4%/94.4%/83.3% and 77.8%/61.1%/44.4% of all patients, respectively, with no new safety signals. At Week 52, TRM cell numbers in lesional skin were markedly reduced, with numbers similar to non-lesional resident memory T cell numbers at Week 0. High skin clearance rates with higher-than-approved initial dosing of risankizumab with prolonged maintenance of skin clearance, despite the lack of continuous dosing, represent a potential novel treatment strategy for patients with psoriasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305818 | GEO | 2025/10/17

REPOSITORIES: GEO

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Project description:Background: Plaque psoriasis is a chronic autoimmune disorder characterized by the development of red scaly plaques. To date psoriasis lesional skin transcriptome has been extensively studied, whereas only few proteomic studies of psoriatic skin are available. Aim: The aim of this study was to compare protein expression patterns of lesional and normally looking skin of psoriasis patients with skin of the healthy volunteers, reveal differentially expressed proteins and identify changes in cell metabolism caused by the disease. Methods: Skin samples of normally looking and lesional skin donated by psoriasis patients (n = 5) and samples of healthy skin donated by volunteers (n = 5) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After protein identification and data processing, the set of differentially expressed proteins was subjected to protein ontology analysis to characterize changes in biological processes, cell components and molecular functions in the patients' skin compared to skin of the healthy volunteers. Results: The performed analysis identified 405 and 59 differentially expressed proteins in lesional and normally looking psoriatic skin compared to healthy control. We discovered decreased expression of KNG1, APOE, HRG, THBS1 and PLG in normally looking skin of the patients. Presumably, these changes were needed to protect the epidermis from spontaneous activation of kallikrein-kinin system and delay the following development of inflammatory response. In lesional skin, we identified several large groups of proteins with coordinated expression. Mainly, these proteins were involved in different aspects of protein and RNA metabolism, namely ATP synthesis and consumption; intracellular trafficking of membrane-bound vesicles, pre-RNA processing, translation, chaperoning and degradation in proteasomes/immunoproteasomes. Conclusion: Our findings explain the molecular basis of metabolic changes caused by disease in skin lesions, such as faster cell turnover and higher metabolic rate. They also indicate on downregulation of kallikrein-kinin system in normally looking skin of the patients that would be needed to delay exacerbation of the disease.

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Long-term remissions and marked decreases in resident memory T cells following high induction dosing with risankizumab in randomized patients with moderate-to-severe plaque psoriasis

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