{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T13:21:14Z","timestamp":1783776074421,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,4]],"date-time":"2023-07-04T00:00:00Z","timestamp":1688428800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100002429","name":"Amgen","doi-asserted-by":"publisher","award":["20217149"],"award-info":[{"award-number":["20217149"]}],"id":[{"id":"10.13039\/100002429","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":[[2023,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Beh\u00e7et's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small\u2010molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up\u2010regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We highlight key biologic effects of apremilast on neutrophils in BD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42486","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T11:25:21Z","timestamp":1677756321000},"page":"1628-1637","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Reduction of Neutrophil Activation by Phosphodiesterase 4 Blockade in Beh\u00e7et's Disease"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7583-0445","authenticated-orcid":false,"given":"Alexandre","family":"Le Joncour","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re, Paris, and AP\u2010HP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re, Department of Internal Medicine and Clinical Immunology  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"R\u00e9gnier","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Paris, and Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Maciejewski\u2010Duval","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Paris, and Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwan","family":"Charles","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Paris, and Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Barete","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Paris, and Laboratoire d'excellence TRANSIMMUNOM, Paris, and AP\u2010HP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re, Department of Internal Medicine and Clinical Immunology, Paris, and AP\u2010HP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re, Unit of Dermatology  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Fouret","sequence":"additional","affiliation":[{"name":"AP\u2010HP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re, Department of Anatomopathology  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Rosenzwajg","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Paris, and Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0054-3422","authenticated-orcid":false,"given":"David","family":"Klatzmann","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Paris, and Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-4992","authenticated-orcid":false,"given":"Patrice","family":"Cacoub","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re, Paris, and AP\u2010HP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re, Department of Internal Medicine and Clinical Immunology  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Saadoun","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, UMR S 959, Immunology\u2010Immunopathology\u2010Immunotherapy (I3), Laboratoire d'excellence TRANSIMMUNOM, Paris, and Biotherapy (CIC\u2010BTi), H\u00f4pital Piti\u00e9\u2010Salp\u00eatri\u00e8re, Paris, and AP\u2010HP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re, Department of Internal Medicine and Clinical Immunology  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-7-20"},{"key":"e_1_2_6_3_1","first-page":"588","article-title":"Increased peripheral blood \u03b3\u03b4+ T cells and natural killer cells in Beh\u00e7et's disease","volume":"19","author":"Suzuki Y","year":"1992","journal-title":"J Rheumatol"},{"key":"e_1_2_6_4_1","first-page":"S59","article-title":"Preferential activation of circulating CD8+ and \u03b3\u03b4 T cells in patients with active Beh\u00e7et's disease and HLA\u2010B51","volume":"26","author":"Yasuoka H","year":"2008","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.9.6133"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2230.2011.04159.x"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2013.07.017"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01085"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214335"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2018.08.010"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-019-01253-3"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2010.03.011"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1816594"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408684"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.12107"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im0723s111"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(75)80031-6"},{"key":"e_1_2_6_18_1","first-page":"1332","article-title":"Changes of neutrophil migration without modification of in vitro metabolism and adhesion in Beh\u00e7et's disease","volume":"24","author":"Carletto A","year":"1997","journal-title":"J Rheumatol"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.41.4.421"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.30.3.250"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.38.3.219"},{"key":"e_1_2_6_22_1","first-page":"59","article-title":"Recent research into Beh\u00e7et's disease in Japan [review]","volume":"10","author":"Mizushima Y","year":"1988","journal-title":"Int J Tissue React"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.48.3.206"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-002-8288-1"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab052"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2009.224"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(98)70018-6"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.3.1044"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.12.8454"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017738"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1443-5"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13664"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.590622"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2018.02.012"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2012.01.001"},{"key":"e_1_2_6_36_1","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S0022-3565(24)29287-9","article-title":"Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor\u2010\u03ba\u03b2 and nuclear factor of activated T cells activation","volume":"299","author":"Jimenez JL","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2004.12.001"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.12.7531"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707428"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704644"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.702677"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-011-9404-4"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42486","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42486","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:57:03Z","timestamp":1759928223000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.42486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,4]]},"references-count":41,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1002\/art.42486"],"URL":"https:\/\/doi.org\/10.1002\/art.42486","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,4]]},"assertion":[{"value":"2022-11-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}