{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T13:49:41Z","timestamp":1780580981883,"version":"3.54.1"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Rituximab (RTX), an anti\u2010CD20 monoclonal antibody, has been used to treat autoimmune diseases such as rheumatoid arthritis (RA). However, variability in therapeutic response to RTX remains a challenge. Here, a systems model is developed to mimic B cell differentiation leading to antibody\u2010secreting cells (ASCs), including plasmablasts (PBs) and plasma cells (PCs). The model features the localization of B cell subsets in the bone marrow and secondary lymphoid organs and incorporates the internalization process of the CD20\u2013RTX complex. To reproduce clinical data from patients with RA receiving RTX and glucocorticoids, pharmacokinetic models for the drugs were built and respective pharmacodynamic profiles of CD19\n                    <jats:sup>+<\/jats:sup>\n                    and CD20\n                    <jats:sup>+<\/jats:sup>\n                    cells and PBs were well captured by optimizing model parameters, which were estimated with good precision. As ASCs are the primary source of pathogenic autoantibodies in RA, the extent and duration of ASC depletion were hypothesized as drivers of therapeutic response to RTX. Global sensitivity analyses identified the CD20\u2013RTX binding affinity and elimination rate constant (i.e., Fc\u03b3\u2010mediated degradation, internalization) as major determinants of both CD19\n                    <jats:sup>+<\/jats:sup>\n                    cells and ASCs. The influence of baseline PBs and PCs on ASCs was also suggested, providing potential mechanisms underlying responder and non\u2010responder variability. The model accurately reproduced the temporal changes in CD19\n                    <jats:sup>+<\/jats:sup>\n                    cells after combination treatment with RTX and glucocorticoids suggesting successful model validation. This study provides a mechanistic framework and insights into key drivers of responses to CD20\u2010depletion treatment using B cell dynamics as an indirect biomarker of clinical endpoints, which might ultimately improve therapeutic outcomes.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70151","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T12:51:52Z","timestamp":1764075112000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["B Cell Differentiation Model for Identifying Predictors of Responses to Rituximab\u2010Mediated B Cell Depletion in Rheumatic Diseases"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0519-6543","authenticated-orcid":false,"given":"Tomohisa","family":"Nakada","sequence":"first","affiliation":[{"name":"Discovery Technology Laboratories, Research Division Mitsubishi Tanabe Pharma Corporation  Yokohama Japan"},{"name":"Division of Pharmacokinetics\u2010Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences University at Buffalo, SUNY  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4848-0440","authenticated-orcid":false,"given":"Donald E.","family":"Mager","sequence":"additional","affiliation":[{"name":"Division of Pharmacokinetics\u2010Pharmacodynamics and Systems Pharmacology, Department of Pharmaceutical Sciences University at Buffalo, SUNY  Buffalo New York USA"},{"name":"Enhanced Pharmacodynamics, LLC  Buffalo New York 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