{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:10:18Z","timestamp":1790277018384,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T00:00:00Z","timestamp":1555891200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009032","name":"Pfizer UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ACR Open Rheumatology"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>A subset of patients with seropositive rheumatoid arthritis (<jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>) do not mount a C\u2010reactive protein (<jats:styled-content style=\"fixed-case\">CRP<\/jats:styled-content>) response during flares. We hypothesize that these patients are more likely to experience poor clinical care and less likely to respond to traditional therapy. This study questioned whether this presentation was associated with worse disease outcome and distinct immunological features.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using Power Doppler ultrasound, 48 <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> patients with active synovitis were recruited; 30 had normal (n)<jats:styled-content style=\"fixed-case\">CRP<\/jats:styled-content> (5 mg\/L or less) and 18 had high (h)<jats:styled-content style=\"fixed-case\">CRP<\/jats:styled-content> (more than 5 mg\/L) levels. All had equivalent disease burden assessed by other clinical and laboratory parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Time to diagnosis and time to first disease\u2010modifying antirheumatic drug were significantly longer in <jats:styled-content style=\"fixed-case\">nCRP<\/jats:styled-content> compared with <jats:styled-content style=\"fixed-case\">hCRP<\/jats:styled-content> patients (<jats:italic>P<\/jats:italic> &lt; 0.05). Significantly more <jats:styled-content style=\"fixed-case\">nCRP<\/jats:styled-content> patients needed escalation to biologics after 2\u2010year follow\u2010up (<jats:italic>P<\/jats:italic> = 0.01). The inflammatory milieu was also different between the two subgroups. Synergy between inflammatory cytokines observed in <jats:styled-content style=\"fixed-case\">hCRP<\/jats:styled-content> patients was lost in <jats:styled-content style=\"fixed-case\">nCRP<\/jats:styled-content> patients, and <jats:styled-content style=\"fixed-case\">nCRP<\/jats:styled-content> patients had significantly increased regulatory T\u2010cell (Treg) frequencies that correlated positively with predictors of poor disease outcome. Conversely, <jats:styled-content style=\"fixed-case\">hCRP<\/jats:styled-content> but not <jats:styled-content style=\"fixed-case\">nCRP<\/jats:styled-content> patients demonstrated a significant upregulation of alternative complement pathway factors that correlated negatively with Treg frequency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Patients with <jats:styled-content style=\"fixed-case\">nCRP<\/jats:styled-content> during flares of <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content> had an altered immunological profile compared with <jats:styled-content style=\"fixed-case\">hCRP<\/jats:styled-content> patients and experienced diagnostic delays and responded less favorably to conventional treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acr2.1021","type":"journal-article","created":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T06:43:12Z","timestamp":1555915392000},"page":"145-155","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Characterization of a Subset of Patients With Rheumatoid Arthritis for Whom Current Management Strategies are Inadequate"],"prefix":"10.1002","volume":"1","author":[{"given":"Claire M.","family":"Bradford","sequence":"first","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"McDonnell","sequence":"additional","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Raj","sequence":"additional","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Robinson","sequence":"additional","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Cole","sequence":"additional","affiliation":[{"name":"University College London Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashank","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"University College London Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Gonz\u00e1lez\u2010Serrano","sequence":"additional","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Mak","sequence":"additional","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuf Cem","family":"Eskiocak","sequence":"additional","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Isenberg","sequence":"additional","affiliation":[{"name":"University College London and University College London Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8911-4113","authenticated-orcid":false,"given":"Coziana","family":"Ciurtin","sequence":"additional","affiliation":[{"name":"University College London and University College London Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-3396","authenticated-orcid":false,"given":"Elizabeth C.","family":"Jury","sequence":"additional","affiliation":[{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica J.","family":"Manson","sequence":"additional","affiliation":[{"name":"University College London Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210715"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.21649"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2016-000382"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780340819"},{"key":"e_1_2_7_6_1","first-page":"9","article-title":"The acute phase and function in early rheumatoid arthritis. 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