{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:30:07Z","timestamp":1791228607628,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Antiphospholipid syndrome (APS) is a thromboinflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody (aPL)\u2013positive patients using whole\u2010blood transcriptomics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole\u2010blood RNA sequencing was performed on 174 aPL\u2010positive patients, including those with primary APS (n\u00a0=\u00a0102), secondary APS (n\u00a0=\u00a029), and aPL positivity without classifiable APS (n\u00a0=\u00a043). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four transcriptionally distinct clusters were identified. At one end of the spectrum, cluster 1 showed up\u2010regulation of ribosomal and metabolic pathways and down\u2010regulation of mechanistic target of rapamycin (mTOR), NETosis, and Hippo\/interleukin\u20106 (IL\u20106) signaling. In contrast, cluster 4 exhibited the opposite pattern, with strong up\u2010regulation of mTOR, NETosis, and Hippo\/IL\u20106 signaling. Cluster 2 demonstrated modest enrichment in messenger RNA processing and amino acid metabolism, and cluster 3 showed biosynthetic suppression with mild Hippo\/IL\u20106 activation. Clinically, cluster 4 stood out with higher IgG anticardiolipin and anti\u2013\u03b2\n                      <jats:sub>2<\/jats:sub>\n                      \u2010glycoprotein I positivity, elevated neutrophil counts, and increased urine protein\u2010to\u2010creatinine ratios. Immune deconvolution revealed distinct cell type profiles: cluster 1 was lymphoid predominant; cluster 2 had a balanced composition; cluster 3 was enriched in Treg cells, natural killer cells, macrophages, mast cells, and memory B cells; and cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features, including white matter lesions, seizures, and cardiac valve disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study reveals four endotypes of aPL\u2010positive patients, a step toward personalized medicine for APS through pathway\u2010informed stratification and therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70021","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T05:58:19Z","timestamp":1765864699000},"page":"1124-1133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular Stratification of Antiphospholipid Syndrome Through Integrative Analysis of the Whole\u2010Blood\n                    <scp>RNA<\/scp>\n                    Transcriptome"],"prefix":"10.1002","volume":"78","author":[{"given":"Amala","family":"Ambati","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"},{"name":"ProMedica Rheumatology ProMedica Toledo Hospital  Sylvania Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiyang","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"},{"name":"Department of Dermatology University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2730-4587","authenticated-orcid":false,"given":"Katarina","family":"Kmetova","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherwin","family":"Navaz","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire K.","family":"Hoy","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrus","family":"Sarosh","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Tambralli","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Navarro\u2010Mendoza","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Mayo Clinic  Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann E.","family":"Gudjonsson","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"},{"name":"Department of Dermatology University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-8945","authenticated-orcid":false,"given":"J. Michelle","family":"Kahlenberg","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"},{"name":"Department of Dermatology University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline A.","family":"Madison","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"},{"name":"Division of Pediatric Rheumatology, Department of Pediatrics University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1749-5719","authenticated-orcid":false,"given":"Al\u00ed","family":"Duarte\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Mayo Clinic  Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0995-9771","authenticated-orcid":false,"given":"Jason S.","family":"Knight","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6721-7755","authenticated-orcid":false,"given":"Yu","family":"Zuo","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000932"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.42624"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000926"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41610"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(25)00094-3"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.01753.x"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34473"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-3288"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-022-03520-6"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44645-6"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00487"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2022.102978"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2019.102311"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1351446"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-024-01123-7"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-020-00936-1"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93897"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keae397"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2024-225664"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adc9656"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000941"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:BIRY.0000046889.60018.8c"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12011"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2015.1071794"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/ehjopen\/oeae046"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000115557.25127.8D"}],"container-title":["Arthritis &amp; 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