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In this study, we developed a quantitative systems pharmacology model of type I IFN\u2010mediated inflammation and applied it for an indirect comparison of anifrolumab, sifalimumab, daxdilimab, and litifilimab pharmacodynamic response, represented in the model by the change in IFN1 gene signature (IFNGS). The model consists of 20 ordinary differential equations and 68 parameters, among which four systemic parameters (including one random effect) were estimated using patient\u2010level data from Phase IIb anifrolumab clinical trial. Within\u2010target and within\u2010pathway validation was performed using study\u2010level pharmacokinetics, IFN\u03b1, and\/or IFNGS data from five anifrolumab, four sifalimumab, one daxdilimab, and one litifilimab trials. The model successfully captured overall trends in IFNGS at clinically relevant doses of these compounds and discriminated IFNGS response between patients with low (&lt;\u20092.75) and high (\u2265\u20092.75) baseline IFNGS. Overprediction of treatment benefit was observed for the low range of anifrolumab doses (100\u2013150\u2009mg every 4\u2009weeks). In contrast, IFNGS response under 150\u2009mg of daxdilimab was underpredicted, despite the accurate description of plasmacytoid dendritic cells and IFN\u03b1 biomarkers. Results of the global sensitivity analysis revealed baseline IFNGS, IFN\u03b1, and IFN\u03b1 fraction as key factors affecting treatment benefit the most. In terms of maximum IFNGS reduction, anifrolumab showed superior potential compared to sifalimumab, daxdilimab, and litifilimab (\u0394IFNGS~25%), which was further enhanced in patients with high baseline IFNGS or IFN\u03b1 (\u0394IFNGS~50%\u201360%).<\/jats:p>","DOI":"10.1002\/psp4.70043","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:10:36Z","timestamp":1747185036000},"page":"1225-1235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An Integrative Mechanistic Model of Type 1 <scp>IFN<\/scp>\u2010Mediated Inflammation in Systemic Lupus Erythematosus"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2342-2495","authenticated-orcid":false,"given":"Alina","family":"Volkova","sequence":"first","affiliation":[{"name":"Modeling and Simulation Decisions FZ \u2010 LLC  Dubai UAE"},{"name":"Marchuk Institute of Numerical Mathematics of the 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