{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T15:15:58Z","timestamp":1789917358175,"version":"4.0.1"},"reference-count":28,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,10,28]],"date-time":"2015-10-28T00:00:00Z","timestamp":1445990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["UL1-TR000157"],"award-info":[{"award-number":["UL1-TR000157"]}]},{"name":"Boston University Medical Center Clinical and Translational Science Institute"},{"name":"Boston University Medical Center Microarray Resource Core Facility"},{"name":"NIH (National Institute of Arthritis Musculoskeletal and Skin Disease","award":["5P30-AR-061271 [Boston University National Scleroderma Core Centers]"],"award-info":[{"award-number":["5P30-AR-061271 [Boston University National Scleroderma Core Centers]"]}]},{"name":"NIH (National Institute of Arthritis Musculoskeletal and Skin Disease","award":["1P50-AR-060780 [Boston University Scleroderma Center of Research Translation]"],"award-info":[{"award-number":["1P50-AR-060780 [Boston University Scleroderma Center of Research Translation]"]}]},{"name":"NIH (National Institute of Arthritis Musculoskeletal and Skin Disease","award":["2R01-AR-051089"],"award-info":[{"award-number":["2R01-AR-051089"]}]},{"DOI":"10.13039\/100001845","name":"Scleroderma Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001845","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008590","name":"Dr. Ralph and Marian Falk Medical Research Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008590","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Clinician Scientist Development Award"},{"name":"Kellen Foundation at the Hospital for Special Surgery"},{"name":"Novartis and by the Rudolph Rupert Scleroderma Program at the Hospital for Special Surgery"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To define a pharmacodynamic biomarker based on gene expression in skin that would provide a biologic measure of the extent of disease in patients with diffuse cutaneous systemic sclerosis (dcSSc) and could be used to monitor skin disease longitudinally.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Skin biopsy specimens obtained from a cohort of patients with dcSSc (including longitudinal specimens) were analyzed by microarray. Expression of genes correlating with the modified Rodnan skin thickness score (MRSS) were examined for change over time using a NanoString platform, and a generalized estimating equation (GEE) was used to define and validate longitudinally measured pharmacodynamic biomarkers composed of multiple genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Microarray analysis of genes parsed to include only those correlating with the MRSS revealed prominent clusters of profibrotic\/transforming growth factor \u03b2\u2013regulated, interferon\u2010regulated\/proteasome, macrophage, and vascular marker genes. Using genes changing longitudinally with the MRSS, we defined 2 multigene pharmacodynamic biomarkers. The first was defined mathematically by applying a GEE to longitudinal samples. This modeling method selected cross\u2010sectional <jats:italic>THBS1<\/jats:italic> and longitudinal <jats:italic>THBS1<\/jats:italic> and <jats:italic>MS4A4A<\/jats:italic>. The second model was based on a weighted selection of genes, including additional genes that changed statistically significantly over time: <jats:italic>CTGF<\/jats:italic>, <jats:italic>CD163<\/jats:italic>, <jats:italic>CCL2<\/jats:italic>, and <jats:italic>WIF1<\/jats:italic>. In an independent validation data set, biomarker levels calculated using both models correlated highly with the MRSS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Skin gene expression can be used effectively to monitor changes in SSc skin disease over time. We implemented 2 relatively simple models on a NanoString platform permitting highly reproducible assays that can be applied directly to samples from patients or collected as part of clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39287","type":"journal-article","created":{"date-parts":[[2015,8,3]],"date-time":"2015-08-03T12:37:20Z","timestamp":1438605440000},"page":"3004-3015","source":"Crossref","is-referenced-by-count":104,"title":["A Longitudinal Biomarker for the Extent of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis"],"prefix":"10.1002","volume":"67","author":[{"given":"Lisa M.","family":"Rice","sequence":"first","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Ziemek","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Stratton","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah R.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina M.","family":"Padilla","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison L.","family":"Mathes","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy B.","family":"Christmann","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Stifano","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Browning","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Whitfield","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine at Dartmouth University Medical School  Hanover  New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F.","family":"Spiera","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Hospital for Special Surgery  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Simms","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Lafyatis","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston  Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,10,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27220"},{"key":"e_1_2_7_3_1","first-page":"S30","article-title":"Nilotinib (Tasigna\u2122) in the treatment of early diffuse systemic sclerosis: a single group, open label pilot clinical trial: one year results [abstract]","volume":"65","author":"Gordon JK","year":"2013","journal-title":"Arthritis Rheum"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth078"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth349"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22186"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202814"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1198\/000313002533"},{"key":"e_1_2_7_9_1","unstructured":"WrightK.Corrgram: plot a correlogram. 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