{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:20:09Z","timestamp":1789708809694,"version":"4.0.1"},"reference-count":50,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006483","name":"AbbVie","doi-asserted-by":"publisher","award":["RGRMEX119413"],"award-info":[{"award-number":["RGRMEX119413"]}],"id":[{"id":"10.13039\/100006483","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>JAK inhibition (JAKi) is effective in seronegative spondyloarthropathy (SpA) spectrum disorders, but Tyk2 inhibition failed in SpA spectrum ulcerative colitis, and tofacitinib showed minimal benefit in Crohn disease, which highlights the complex role for JAK\/STAT signaling in different inflammatory processes. In this study, we investigated whether JAKi might paradoxically activate entheseal innate immunity and aimed to identify the key regulatory cytokines involved in this process.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Spinal entheseal tissue was activated with Toll\u2010like receptor (TLR) agonists, including TLR4 and interleukin\u20101 (IL\u20101) family proteins, and entheseal T cells were activated with anti\u2010CD3\/anti\u2010CD28 with IL\u201023\/IL\u20101\u03b2. JAKi via upadacitinib (JAK1\/JAK2), deucravacitinib (Tyk2), and ritlecitinib (JAK3) inhibition was evaluated using multiplex cytokine assays, intracellular flow, and bulk RNA sequencing (RNAseq) and cytokine blocking or stimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Following interferon \u03b3 stimulation, JAK1 inhibition blocked STAT1 phosphorylation in entheseal cells and strongly blocked activated entheseal T cell tumor necrosis factor \u03b1 (TNF\u03b1), IL\u201017A, and IL\u201017F production. The opposite effect was evident in entheseal myeloid cell with exaggerated TLR4 and other adjuvant\u2010mediated cytokine production including IL\u201023 (~10\u2010fold increase;\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001) or TNF\u03b1 (~10\u2010fold increase;\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.0001). This myeloid effect was induced by upadacitinib and deucravacitinib but not ritlecitinib, suggesting IL\u201010R JAK1\/Tyk2 signaling. Bulk RNAseq showed a multifaceted impact of JAKi on myeloid activation with strong M1 type monocyte polarization under TLR4 stimulation and JAK1 inhibition confirmed by flow cytometry. Direct IL\u201010 inhibition recapitulated inflammatory cytokine elevations and IL\u201010R agonist largely, but not completely, rescued this phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings help explain the emergent efficacy of Tyk2 blockade in SpA spectrum\u2013related arthritis that is not IL\u201010 dependent but indicates why such strategies may not be a panacea for SpA spectrum disorder\u2013related intestinal inflammation.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art43210-toc-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.43210","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T03:25:04Z","timestamp":1746415504000},"page":"1373-1386","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Paradoxical Activation of Entheseal Myeloid Cells by\n                    <scp>JAK1<\/scp>\n                    and Tyk2 Inhibitors via Interleukin\u201010 Antagonism"],"prefix":"10.1002","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4105-3550","authenticated-orcid":false,"given":"Sami","family":"Giryes","sequence":"first","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom, and B. 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