{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:20:16Z","timestamp":1760059216385,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GSK"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent concerns regarding the safety of Janus kinase inhibitors (JAKis) have prompted investigation into their impact on immune cell subsets in rheumatoid arthritis (RA) patients. This study aims to analyse alterations in immune cell populations induced by JAKis that may contribute to adverse events, such as infections or malignancies. This study included 78 RA patients meeting ACR\/EULAR criteria with an established treatment with JAKis (tofacitinib, baricitinib, upadacitinib, or filgotinib), 20 healthy donors, and 20 RA patients treated with biological disease-modifying antirheumatic drugs (bDMARDs). Peripheral blood mononuclear cells (PBMCs) were immunophenotyped directly after isolation using multiparametric flow cytometry to characterise innate and adaptive immune-cell subsets. JAKi-treated patients showed a significant reduction in cytotoxic NK Dim (CD3\u2212CD56+CD16+) cells and in the percentage of NK Dim cells expressing the activation marker Nkp30. In CD4+ T cells, the percentage of Th17 (CD3+CD4+CD45RA+CCR6+CXCR3\u2212), Th1-17 (CD3+CD4+CD45RA+CCR6+CXCR3+), and central memory (CM, CD3+CD4+CD45RA+CD62L+) cells was lower in the JAKi group, while effector memory (EM, CD3+CD4+CD45RA\u2212CD62L\u2212) and terminally differentiated CD45RA (TEMRA, CD3+CD4+CD45RA+CD62L\u2212) T helper cells were increased compared to healthy and bDMARD-treated controls. The reduction in NK Dim and Th1-17 cells and the increase in exhausted Th subsets suggest a potential compromise in antiviral immunity and balanced immune responses in JAKi-treated RA patients. These alterations may contribute to an increased risk of infections or malignancies.<\/jats:p>","DOI":"10.3390\/ijms26115160","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T03:52:08Z","timestamp":1748404328000},"page":"5160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Changes in NK Cells and Exhausted Th Cell Phenotype in RA Patients Treated with Janus Kinase Inhibitors: Implications for Adverse Effects"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4928-4000","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Fern\u00e1ndez-Cabero","sequence":"first","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7701-563X","authenticated-orcid":false,"given":"Carmen","family":"Lasa-Teja","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Rheumatology, Hospital Universitario Marqu\u00e9s de Valdecilla, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5745-9072","authenticated-orcid":false,"given":"David","family":"San Segundo","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Immunology, Hospital Universitario Marqu\u00e9s de Valdecilla, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8353-6211","authenticated-orcid":false,"given":"Alejandra","family":"Comins-Boo","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Immunology, Hospital Universitario Marqu\u00e9s de Valdecilla, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2315-8671","authenticated-orcid":false,"given":"Juan","family":"Irure-Ventura","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Immunology, Hospital Universitario Marqu\u00e9s de Valdecilla, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Walias Rivera","sequence":"additional","affiliation":[{"name":"Cantabria Tissue and Blood Bank, Fundaci\u00f3n Marqu\u00e9s de Valdecilla, 39008 Santander, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Luis","family":"Mart\u00edn-Varillas","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Rheumatology, Hospital de Laredo, 39770 Laredo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Mata","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Rheumatology, Hospital de Laredo, 39770 Laredo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Montserrat","family":"Santos","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Rheumatology, Hospital Sierrallana, 39300 Torrelavega, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6789-7236","authenticated-orcid":false,"given":"Elena","family":"Aurrecoechea","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Rheumatology, Hospital Sierrallana, 39300 Torrelavega, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-2285","authenticated-orcid":false,"given":"Ricardo","family":"Blanco","sequence":"additional","affiliation":[{"name":"Immunopathology Group, Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Department of Rheumatology, Hospital 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