{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:36:38Z","timestamp":1791246998025,"version":"4.1.0"},"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R03DE031340"],"award-info":[{"award-number":["R03DE031340"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["1KL2TR002374"],"award-info":[{"award-number":["1KL2TR002374"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008648","name":"Pfizer Foundation","doi-asserted-by":"publisher","award":["WI199662 and # WI236322"],"award-info":[{"award-number":["WI199662 and # WI236322"]}],"id":[{"id":"10.13039\/100008648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE033396"],"award-info":[{"award-number":["R01DE033396"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec021\">\n<jats:title>Objective<\/jats:title>\n<jats:p>Our objective was to define the effect of JAK inhibitor (JAKinib) withdrawal on JAK\/STAT biochemical response in the context of systemic rheumatic diseases.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec022\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells (MSCs) and human umbilical vein endothelial cells (HUVECs). We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec023\">\n<jats:title>Results<\/jats:title>\n<jats:p>Type I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFN\u03b3-stimulated MSCs and HUVECs in a time- and dose- dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapid <jats:italic>increase<\/jats:italic> of pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec024\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Type I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might explain adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0311706","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T17:29:32Z","timestamp":1750094972000},"page":"e0311706","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["JAK inhibitor withdrawal causes a transient pro-inflammatory cascade: A potential mechanism for major adverse cardiac 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