{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:59:24Z","timestamp":1791557964786,"version":"4.3.4"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T00:00:00Z","timestamp":1612915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Curr Rheumatol Rep"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose of Review<\/jats:title>\n                <jats:p>Complement activation is a key event in the pathogenesis of tissue inflammation and injury in systemic lupus erythematosus (SLE). This review is aimed at comparing the usefulness of measurement of complement proteins in serum\/plasma (C3, C4) to complement activation (split) products in plasma and on circulating blood cells for SLE diagnosis, disease monitoring, and prognosis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Recent Findings<\/jats:title>\n                <jats:p>Complement split products, C3dg, iC3b, and C4d, are elevated in SLE, and C3dg\/C3 and iC3b\/C3 ratios correlate with active SLE. C4d also is higher in patients with lupus nephritis. An elevated level of the alternative pathway split product, Bb, in early lupus pregnancy is a predictor of adverse outcomes in SLE patients with antiphospholipid antibodies. Elevated levels of cell-bound complement activation products (CB-CAPs), namely, B cell-bound C4d (BC4d) and erythrocyte-bound C4d (EC4d), within a multiparameter assay panel, may predict transition to SLE more than other lupus biomarkers. EC4d better correlates with lupus disease activity than low plasma complement levels. Elevated platelet-bound C4d (PC4d) correlates with thrombosis in SLE. Both EC4d and PC4d are increased in primary and secondary anti-phospholipid syndrome, and anti-beta2glycoproteinI antibodies may directly activate the complement system.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Summary<\/jats:title>\n                <jats:p>Abnormal levels of plasma complement split products and CB-CAPs support complement activation as an important pathogenetic mechanism in SLE and the antiphospholipid syndromes. These tests show promise for the diagnosis of SLE and monitoring of disease activity.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11926-021-00984-1","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T10:58:16Z","timestamp":1613041096000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":177,"title":["A Review of Complement Activation in SLE"],"prefix":"10.1007","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7248-6623","authenticated-orcid":false,"given":"Arthur","family":"Weinstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta V.","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra J.","family":"Zack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,10]]},"reference":[{"key":"984_CR1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1556\/EuJMI.2.2012.2.2","volume":"2","author":"PN Nesarkigar","year":"2012","unstructured":"Nesarkigar PN, Spiller B, Chavez R. The complement system: history, pathways, cascade and inhibitors. Eur J Microbiol Immunol. 2012;2:103\u201311. https:\/\/doi.org\/10.1556\/EuJMI.2.2012.2.2.","journal-title":"Eur J Microbiol Immunol"},{"key":"984_CR2","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1056\/NEJM200104053441406","volume":"344","author":"MJ Walport","year":"2001","unstructured":"Walport MJ. Complement. First of two parts New Engl J Med. 2001;344:1058\u201366.","journal-title":"First of two parts New Engl J Med"},{"key":"984_CR3","first-page":"698","volume":"37","author":"JH Vaughan","year":"1951","unstructured":"Vaughan JH, Bayles TB, Favour CB. The response of serum gamma globulin level and complement titer to adrenocorticotropic hormone (ACTH) therapy in lupus erythematosus. J Lab Clin Med. 1951;37:698\u2013702.","journal-title":"J Lab Clin Med"},{"key":"984_CR4","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1056\/NEJM196803072781004","volume":"278","author":"PH Schur","year":"1968","unstructured":"Schur PH, Sandson J. Immunologic factors and clinical activity in systemic lupus erythematosus. New Engl J Med. 1968;278:533\u20138. https:\/\/doi.org\/10.1056\/NEJM196803072781004.","journal-title":"New Engl J Med"},{"key":"984_CR5","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/0002-9343(83)90613-7","volume":"74","author":"A Weinstein","year":"1983","unstructured":"Weinstein A, Bordwell B, Stone B, Tibbetts C, Rothfield NF. Antibodies to native DNA and serum complement (C3) levels. Application to the diagnosis and classification of systemic lupus erythematosus. Am J Med. 1983;74:206\u201316.","journal-title":"Am J Med"},{"key":"984_CR6","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1002\/art.1780390304","volume":"39","author":"JM Esdaile","year":"1996","unstructured":"Esdaile JM, Abrahamowicz M, Joseph L, MacKenzie T, Li Y, Danoff D. Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus. Why some tests fail. Arthritis Rheum. 1996;39:370\u20138.","journal-title":"Arthritis Rheum"},{"key":"984_CR7","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1007\/s11926-004-0012-5","volume":"6","author":"C-C Liu","year":"2004","unstructured":"Liu C-C, Manzi S, Danchenko N, Ahearn JM. New advances in the measurement of complement activation: lessons of systemic lupus erythematosus. Curr Rheumatol Rep. 2004;6:375\u201381.","journal-title":"Curr Rheumatol Rep"},{"key":"984_CR8","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1002\/art.1780251101","volume":"25","author":"EM Tan","year":"1982","unstructured":"Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271\u20137.","journal-title":"Arthritis Rheum"},{"key":"984_CR9","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1002\/art.40930","volume":"71","author":"M Aringer","year":"2019","unstructured":"Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism\/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71:1400\u201312.","journal-title":"Arthritis Rheumatol"},{"key":"984_CR10","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1177\/0961203310366572","volume":"19","author":"J Nossent","year":"2010","unstructured":"Nossent J, Kiss E, Rozman B, Pokorny G, Vlachoyiannopoulos P, Olesinka M, et al. Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus. Lupus. 2010;19:949\u201356. https:\/\/doi.org\/10.1177\/0961203310366572.","journal-title":"Lupus"},{"key":"984_CR11","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1002\/art.41093","volume":"72","author":"R Ramsey-Goldman","year":"2020","unstructured":"\u2022\u2022 Ramsey-Goldman R, Alexander RV, Massarotti EM, Wallace DJ, Narain S, Arriens C, et al. Complement activation in patients with probable systemic lupus erythematosus and ability to predict progression to American College of Rheumatology-classified systemic lupus erythematosus. Arthritis Rheumatol. 2020;72:78\u201388. https:\/\/doi.org\/10.1002\/art.41093This cross-sectional and longitudinal study showed that cell-bound complement activation products (CB-CAPs) are more prevalent than low complement levels in probable lupus and better predicted transition to SLE than other biomarkers.","journal-title":"Arthritis Rheumatol"},{"key":"984_CR12","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1002\/1529-0131(199912)42:12<2682::AID-ANR26>3.0.CO;2-6","volume":"42","author":"SG Barr","year":"1999","unstructured":"Barr SG, Zonana-Nacach A, Madger LS, Petri M. Patterns of disease activity in systemic lupus erythematosus. Arthritis Rheum. 1999;42:2682\u20138.","journal-title":"Arthritis Rheum"},{"key":"984_CR13","doi-asserted-by":"publisher","first-page":"1822","DOI":"10.3899\/jrheum.100007","volume":"37","author":"AJ Steinman","year":"2010","unstructured":"Steinman AJ, Gladman DD, Ibanez D, Urowitz MB. Prolonged serologically active clinically quiescent systemic lupus erythematosus: frequency and outcome. J Rheumatol. 2010;37:1822\u20137. https:\/\/doi.org\/10.3899\/jrheum.100007.","journal-title":"J Rheumatol"},{"key":"984_CR14","doi-asserted-by":"publisher","unstructured":"\u2022 Merrill JT, Petri MA, Buyon J, Ramsey-Goldman R, Kalunian K, Putterman C, et al. Erythrocyte bound C4d in combination with complement and autoantibody status for the monitoring of SLE. Lupus Science & Medicine. 2018:5e000263. https:\/\/doi.org\/10.1136\/lupus-2018-000263This compilation of three prospective studies demonstrated that EC4d is superior to low complement levels in monitoring disease activity in SLE.","DOI":"10.1136\/lupus-2018-000263"},{"key":"984_CR15","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1177\/0961203310371154","volume":"19","author":"DJ Birmingham","year":"2010","unstructured":"Birmingham DJ, Irshaid F, Zou X, Tsao BP, Wu H, Yu CY, et al. The complex nature of serum C3 and C4 as biomarkers of renal flare. Lupus. 2010;19:1272\u201380.","journal-title":"Lupus"},{"key":"984_CR16","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1136\/ard.2008.094508","volume":"68","author":"G Moroni","year":"2009","unstructured":"Moroni G, Radice A, Giammarresi G, Quaglini S, Leoni A, Li Vecchi M, et al. Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis. Ann Rheum Dis. 2009;68:234\u20137. https:\/\/doi.org\/10.1136\/ard.2008.094508.","journal-title":"Ann Rheum Dis"},{"key":"984_CR17","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1177\/0961203310379871","volume":"20","author":"A Matrat","year":"2011","unstructured":"Matrat A, Veysseyre-Balter C, Trolliet P, Villar E, Dijoud F, Bienvenue J, et al. Simultaneous detection of anti-C1q and anti-double stranded DNA autoantibodies in lupus nephritis: predictive value for renal flares. Lupus. 2011;20:28\u201334.","journal-title":"Lupus"},{"key":"984_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2018.00581","volume":"9","author":"A Troldborg","year":"2018","unstructured":"\u2022 Troldborg A, Jensen L, Deleuran B, Stengaard-Pedersen K, Thiel S, Jensenius JC. The C3dg fragment of complement is superior to conventional C3 as a diagnostic biomarker in systemic lupus erythematosus. Front Immunol. 2018;9:1\u201310 This study optimized the method for measuring C3dg, a split product of C3, and demonstrated that it was better than C3 in distinguishing SLE from normal control patients.","journal-title":"Front Immunol"},{"key":"984_CR19","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/art.40747","volume":"71","author":"AH Kim","year":"2019","unstructured":"\u2022 Kim AH, Strand V, Sen DP, Fu Q, Mathis NL, Schmidt MJ, et al. Association of blood concentrations of complement split product iC3b and serum C3 with systemic lupus erythematosus disease activity. Arthritis Rheumatol. 2019;71:420\u201330. https:\/\/doi.org\/10.1002\/art.40747This study demonstrated that iC3b, a C3 split product, and the iC3b\/C3 ratio better distinguish active from inactive SLE than C3 and C4 levels.","journal-title":"Arthritis Rheumatol"},{"key":"984_CR20","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.ab.2015.01.024","volume":"15","author":"E Schramm","year":"2015","unstructured":"Schramm E, Staten N, Zhang Z, Bruce S, Kellner C, Atkinson JP, et al. A quantitative lateral flow assay to detect complement activation in blood. Anal Biochem. 2015;15:78\u201385.","journal-title":"Anal Biochem"},{"key":"984_CR21","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1186\/s13075-017-1470-2","volume":"19","author":"M Martin","year":"2017","unstructured":"\u2022 Martin M, Smolag KI, Bj\u00f6rk A, Gullstrand B, Okr\u00f3j M, Leffler J, et al. Plasma C4d as marker for lupus nephritis in systemic lupus erythematosus. Arthritis Res Ther. 2017;19:266\u201375. https:\/\/doi.org\/10.1186\/s13075-017-1470-2This study showed that C4d, an important split product in the classical complement pathway, as well as the C4d\/C4 ratio is associated with active lupus nephritis.","journal-title":"Arthritis Res Ther"},{"key":"984_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2020.582737","volume":"11","author":"M Martin","year":"2020","unstructured":"\u2022\u2022 Martin M, Trattner R, Nilsson SC, Bj\u00f6rk A, Zickert A, Blom AM, et al. Plasma C4d correlates with C4d deposition in kidneys and with treatment response in lupus nephritis patients. Front Immunol. 2020;11:1\u201312. https:\/\/doi.org\/10.3389\/fimmu.2020.582737This more recent study showed that C4d is deposited in glomeruli in lupus nephritis, and a drop in the C4d\/C4 ratio correlated with the response of lupus nephritis to therapy.","journal-title":"Front Immunol"},{"key":"984_CR23","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.3899\/jrheum.171033","volume":"45","author":"A Troldborg","year":"2018","unstructured":"Troldborg A, Thiel S, Trendelenburg M, Friebus-Kardash J, Nehring J, Steffensen R, et al. The lectin pathway of complement activation in patients with systemic lupus erythematosus. J Rheumatol. 2018;45:1136\u201344. https:\/\/doi.org\/10.3899\/jrheum.171033.","journal-title":"J Rheumatol"},{"key":"984_CR24","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1007\/s10067-008-0838-8","volume":"27","author":"OA Monticielo","year":"2008","unstructured":"Monticielo OA, Mucenic T, Xavier RM, Brenol JCT, Chies JAB. The role of mannose binding lectin in systemic lupus erythematosus. Clin Rheumatol. 2008;27:413\u20139. https:\/\/doi.org\/10.1007\/s10067-008-0838-8.","journal-title":"Clin Rheumatol"},{"issue":"1","key":"984_CR25","doi-asserted-by":"publisher","first-page":"e000236","DOI":"10.1136\/lupus-2017-000236","volume":"4","author":"R Ramsey-Goldman","year":"2017","unstructured":"\u2022 Ramsey-Goldman R, Li J, Dervieux T, Alexander RV. Cell-bound complement activation products in SLE. Lupus Sci Med. 2017;4(1):e000236 This review highlighted literature on the use of CB-CAPs in SLE diagnosis.","journal-title":"Lupus Sci Med"},{"issue":"1","key":"984_CR26","doi-asserted-by":"publisher","first-page":"e000318","DOI":"10.1136\/lupus-2019-000318","volume":"6","author":"MA Petri","year":"2019","unstructured":"\u2022\u2022 Petri MA, Conklin J, O\u2019Malley T, Dervieux T. Platelet-bound C4d, low C3 and lupus anticoagulant associate with thrombosis in SLE. Lupus Sci Med. 2019;6(1):e000318 This study showed that PC4d may be an important marker for thrombosis in SLE.","journal-title":"Lupus Sci Med."},{"key":"984_CR27","first-page":"1","volume":"0","author":"E Svenungsson","year":"2020","unstructured":"\u2022 Svenungsson E, Gustafsson JT, Grosso G, Rossides M, Gunnarsson I, Jensen-Urstad K, et al. Complement deposition, C4d, on platelets is associated with vascular events in systemic lupus erythematosus. Rheumatology. 2020;0:1\u201311 This more recent study supported the prior study that high PC4d levels correlate with vascular events in SLE.","journal-title":"Rheumatology"},{"key":"984_CR28","doi-asserted-by":"publisher","first-page":"2152","DOI":"10.1172\/JCI\/136094","volume":"130","author":"E Gavrilaki","year":"2020","unstructured":"Gavrilaki E, Brodsky RA. Complementopathies and precision medicine. J Clin Invest. 2020;130:2152\u201363. https:\/\/doi.org\/10.1172\/JCI\/136094.","journal-title":"J Clin Invest"},{"key":"984_CR29","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1136\/ard.2008.090670","volume":"68","author":"K Oku","year":"2009","unstructured":"Oku K, Atsumi T, Bohgaki M, Amengual O, Kataoka H, Horita T, et al. Complement activation in patients with primary antiphospholipid syndrome. Ann Rheum Dis. 2009;68:1030\u20135. https:\/\/doi.org\/10.1136\/ard.2008.090670.","journal-title":"Ann Rheum Dis"},{"key":"984_CR30","doi-asserted-by":"publisher","first-page":"773","DOI":"10.3389\/fimmu.2019.00773","volume":"10","author":"PA Lonati","year":"2019","unstructured":"\u2022 Lonati PA, Scavone M, Gerosa M, Borghi MO, Pregnolato F, Curreli D, et al. Blood cell-bound C4d as a marker of complement activation in patients with the antiphospholipid syndrome. Front Immunol. 2019;10:773 This study demonstrated that EC4d and PC4d were increased in APS and that a monoclonal antibody to beta2glycoprotein1 induced deposition of C4d on the surface of activated platelets.","journal-title":"Front Immunol."},{"key":"984_CR31","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1182\/blood.2019003863","volume":"135","author":"S Chaturvedi","year":"2020","unstructured":"\u2022\u2022 Chaturvedi S, Braunstein EM, Yuan X, Yu J, Alexander A, Chen H, et al. Complement activity and complement regulatory gene mutations are associated with thrombosis in APS and CAPS. Blood. 2020;135:239\u201351 This interesting study provided evidence that beta2glycoprotein antibodies activate complement directly providing a link between complement activation and thrombosis.","journal-title":"Blood"},{"key":"984_CR32","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1136\/annrheumdis-2017-212224","volume":"77","author":"MY Kim","year":"2018","unstructured":"\u2022\u2022 Kim MY, et al. Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and\/or anti-phospholipid antibodies. Ann Rheum Dis. 2018;77:549\u20135. https:\/\/doi.org\/10.1136\/annrheumdis-2017-212224This study of a large number of pregnant SLE patients showed that elevated levels of the alternative pathway split product, Bb, in the first trimester predict adverse pregnancy outcomes.","journal-title":"Ann Rheum Dis"},{"key":"984_CR33","doi-asserted-by":"publisher","first-page":"2090","DOI":"10.1182\/bloodadvances.2018019596","volume":"2","author":"MH Park","year":"2018","unstructured":"Park MH, Caselman N, Ulmer S, Weitz IC. Complement-mediated thrombotic microangiopathy associated with lupus nephritis. Blood Advances. 2018;2:2090\u20134. https:\/\/doi.org\/10.1182\/bloodadvances.2018019596.","journal-title":"Blood Advances"},{"key":"984_CR34","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1186\/s12882-020-01888-5","volume":"21","author":"RD Wright","year":"2020","unstructured":"\u2022 Wright RD, Bannerman F, Beresford MW, Oni L. A systematic review of the role of eculizumab in systemic lupus erythematosus-associated thrombotic microangiopathy. BMC Nephrology. 2020;21:245. https:\/\/doi.org\/10.1186\/s12882-020-01888-5This review of uncontrolled but interesting studies showed that TMA-associated lupus nephritis might respond to the complement inhibitor, eculizumab.","journal-title":"BMC Nephrology"},{"key":"984_CR35","doi-asserted-by":"publisher","first-page":"e364","DOI":"10.1097\/CCM.0000000000000231","volume":"42","author":"T Muroya","year":"2014","unstructured":"Muroya T, Kannan L, Ghiran IC, Shevkoplyas SS, Paz Z, Tsokos M, et al. C4d deposits on the surface of RBCs in trauma patients and interferes with their function. Crit Care Med. 2014;42:e364\u201372.","journal-title":"Crit Care Med"},{"key":"984_CR36","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1177\/0961203312454342","volume":"21","author":"O Borschukova","year":"2012","unstructured":"Borschukova O, Paz Z, Ghiran IC, Liu C-C, Kao AH, Manzi S, et al. Complement fragment C3d is colocalized within the lipid rafts of T cells and promotes cytokine production. Lupus. 2012;21:1294\u2013304.","journal-title":"Lupus"},{"key":"984_CR37","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1111\/imr.12852","volume":"295","author":"EE West","year":"2020","unstructured":"West EE, Kunz N, Kemper C. Complement and human T cell metabolism: location, location, location. Immunol Rev. 2020;295:68\u201381.","journal-title":"Immunol Rev"}],"container-title":["Current Rheumatology Reports"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11926-021-00984-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s11926-021-00984-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11926-021-00984-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T19:06:44Z","timestamp":1613761604000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s11926-021-00984-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,10]]},"references-count":37,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["984"],"URL":"https:\/\/doi.org\/10.1007\/s11926-021-00984-1","relation":{},"ISSN":["1523-3774","1534-6307"],"issn-type":[{"value":"1523-3774","type":"print"},{"value":"1534-6307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,10]]},"assertion":[{"value":"5 January 2021","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2021","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"AW is a research consultant to Exagen Inc. He has received >\u2009$10,000 stock options. RVA and DJA are employees of Exagen Inc.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"This article does not contain any studies with human or animal subjects performed by any of the authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}],"article-number":"16"}}