{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T03:15:14Z","timestamp":1782184514591,"version":"3.54.5"},"reference-count":25,"publisher":"BMJ","issue":"1","funder":[{"DOI":"10.13039\/100008795","name":"Manitoba Medical Services Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008795","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008794","name":"Research Manitoba","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006538","name":"Canadian Arthritis Network","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008252","name":"Health Sciences Centre Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008252","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2019,3,14]]},"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Antibodies to citrullinated peptides (anti-CCP) develop in individuals predisposed to rheumatoid arthritis (RA). Neutrophil extracellular traps are a major source of citrullinated antigens and the immunomodulatory host defence peptide LL-37. Vitamin D regulates LL-37 expression. This study assessed the associations of LL-37 and anti-CCP, vitamin D metabolites and vitamin D receptor (VDR) polymorphisms in early inflammatory arthritis (EIA).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Serum LL-37, 25-hydroxy-vitamin D (25OHvitD) and anti-CCP were measured by ELISA in treatment na\u00efve EIA (n = 181). VDR single nucleotide polymorphisms (Fok1, Bsm1, Apa1, Taq1, Cdx-2) and HLADRB1 shared epitope (SE) alleles were detected by DNA amplification. Associations were tested in multivariable models. Median (25%, 75%) or percentiles are reported.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Participants (70 % female, age 56 [45, 66] years, disease activity score [DAS28ESR3var] 3.7 [2.8, 4.8], 41 % anti-CCP positive, 68 % RA) had low serum 25OHvitD; 20.5\u2009nmol\/L (13.9, 29.0). In multivariable models, controlling for age, sex, SE, smoking and vitamin D deficiency, LL37 level (top quartile) associated with anti-CCP seropositivity (OR 22; 95%\u2009CI 4 to 104).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Levels of circulating LL-37 are associated with anti-CCP seropositivity. LL37 activity may be one mechanism linking infection and toxin exposure to anti-CCP generation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2018-000874","type":"journal-article","created":{"date-parts":[[2019,4,30]],"date-time":"2019-04-30T06:10:19Z","timestamp":1556604619000},"page":"e000874","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Human host defence peptide LL37 and anti-cyclic citrullinated peptide antibody in early inflammatory arthritis"],"prefix":"10.1136","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5547-3268","authenticated-orcid":false,"given":"Carol A","family":"Hitchon","sequence":"first","affiliation":[{"name":"University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Meng","sequence":"additional","affiliation":[{"name":"University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani S","family":"El Gabalawy","sequence":"additional","affiliation":[{"name":"University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Larcombe","sequence":"additional","affiliation":[{"name":"University of Manitoba College of Medicine, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2019,4,29]]},"reference":[{"key":"2025090312371234000_5.1.e000874.1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000452"},{"key":"2025090312371234000_5.1.e000874.2","doi-asserted-by":"crossref","unstructured":"Corsiero E , Pratesi F , Prediletto E , et al . NETosis as source of autoantigens in rheumatoid arthritis. Front Immunol 2016;7.doi:10.3389\/fimmu.2016.00485","DOI":"10.3389\/fimmu.2016.00485"},{"key":"2025090312371234000_5.1.e000874.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2015.03.002"},{"key":"2025090312371234000_5.1.e000874.4","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jaut.2019.01.003","article-title":"Neutrophil extracellular traps exert both pro- and anti-inflammatory actions in rheumatoid arthritis that are modulated by C1q and LL-37","volume":"98","author":"Ribon","year":"2019","journal-title":"J Autoimmun"},{"key":"2025090312371234000_5.1.e000874.5","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201344277"},{"key":"2025090312371234000_5.1.e000874.6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700778"},{"key":"2025090312371234000_5.1.e000874.7","doi-asserted-by":"crossref","unstructured":"Frasca L , Palazzo R , Chimenti MS , et al . Anti-LL37 antibodies are present in psoriatic arthritis (PSA) patients: new biomarkers in PSA. Frontiers in immunology 1936;2018.","DOI":"10.3389\/fimmu.2018.01936"},{"key":"2025090312371234000_5.1.e000874.8","doi-asserted-by":"publisher","DOI":"10.1038\/nature06116"},{"key":"2025090312371234000_5.1.e000874.9","doi-asserted-by":"crossref","unstructured":"Dankers W , Colin EM , van Hamburg JP , et al . Vitamin D in autoimmunity: molecular mechanisms and therapeutic potential. Front Immunol 2016;7.doi:10.3389\/fimmu.2016.00697","DOI":"10.3389\/fimmu.2016.00697"},{"key":"2025090312371234000_5.1.e000874.10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.4.2060"},{"key":"2025090312371234000_5.1.e000874.11","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1097\/BOR.0000000000000397","article-title":"Vitamin D and rheumatoid arthritis: an ongoing mystery","volume":"29","author":"Bragazzi","year":"2017","journal-title":"Curr Opin Rheumatol"},{"key":"2025090312371234000_5.1.e000874.12","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"2025090312371234000_5.1.e000874.13","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.080855"},{"key":"2025090312371234000_5.1.e000874.14","doi-asserted-by":"crossref","unstructured":"Larcombe L , Mookherjee N , Slater J , et al . Vitamin D, serum 25(OH)D, LL-37 and polymorphisms in a Canadian First Nation population with endemic tuberculosis. 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Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis. J Transl Med 2018;16.doi:10.1186\/s12967-018-1588-2","DOI":"10.1186\/s12967-018-1588-2"},{"key":"2025090312371234000_5.1.e000874.22","doi-asserted-by":"crossref","unstructured":"Grant M , Kilsg\u00e5rd O , \u00c5kerman S , et al . The human salivary antimicrobial peptide profile according to the oral microbiota in health, periodontitis and smoking. J Innate Immun 2018:1\u201312.doi:10.1159\/000494146","DOI":"10.1159\/000494146"},{"key":"2025090312371234000_5.1.e000874.23","doi-asserted-by":"crossref","unstructured":"Konig MF , Abusleme L , Reinholdt J , et al . Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. 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