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The 3\u2010month change in the log hsCRP level was the mediator of interest. We used linear regression for the hsCRP level mediator and Cox or Weibull regression for gout\u2010flare outcomes, combining them in causal mediation analysis. We examined the cohort overall, as well as stratified by prevalent gout at baseline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We analyzed 9,221 patients without prevalent gout and 747 with prevalent gout. The Cox regression hazard ratio (HR) for a gout flare was 0.50 (95% confidence interval [95% CI] 0.37\u20130.68) comparing canakinumab with placebo, of which 6% was explained by the mediated effect through hsCRP level reduction in the first 3 months. In the prevalent\u2010gout subgroup, the HR was 0.58 (95% CI 0.36\u20130.95), of which 31% was explained by the mediated effect through hsCRP level reduction. The Weibull analysis gave a proportion\u2010mediated estimate of 47%. The indirect effect via hsCRP level reductions was unclear in the subgroup without prevalent gout.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The first 3\u2010month reduction in hsCRP level was not a good biomarker for canakinumab's protective effect on future gout flares in the overall cohort. Among patients with prevalent gout, there may be a potential role for early hsCRP level reduction as a biomarker for interleukin\u20101\u03b2 inhibitors' future gout\u2010flare benefit.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acr.24832","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T08:11:05Z","timestamp":1638864665000},"page":"817-824","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Canakinumab's Effect Against Subsequent Gout Flares and High\u2010Sensitivity C\u2010Reactive Protein Levels: A Causal Mediation Analysis"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2030-3549","authenticated-orcid":false,"given":"Kazuki","family":"Yoshida","sequence":"first","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Glynn","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyon K.","family":"Choi","sequence":"additional","affiliation":[{"name":"Harvard Medical School and Massachusetts General Hospital  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan M.","family":"Everett","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean G.","family":"MacFadyen","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Ridker","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Solomon","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.4161\/mabs.2.1.10328"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27600"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3297"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200908"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.7326\/M18-1167"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306656"},{"key":"e_1_2_7_9_1","volume-title":"Explanation in causal inference: methods for mediation and interaction","author":"VanderWeele T.","year":"2015"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40381"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-215933"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32814-3"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.7326\/M19-2945"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz542"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.3109\/08820139.2016.1153651"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0031034"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0000000000000253"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.31219\/osf.io\/6c79f"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwy281"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwq332"},{"key":"e_1_2_7_21_1","first-page":"1","article-title":"Mice: multivariate imputation by chained equations in R","volume":"45","author":"Van Buuren S","year":"2011","journal-title":"J Stat Softw"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwaa267"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X14542960"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200003233421202"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/ehjqcco\/qcaa045"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr.24357"}],"container-title":["Arthritis Care &amp; Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acr.24832","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acr.24832","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acr.24832","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T16:28:10Z","timestamp":1759422490000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/acr.24832"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,26]]},"references-count":25,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1002\/acr.24832"],"URL":"https:\/\/doi.org\/10.1002\/acr.24832","archive":["Portico"],"relation":{},"ISSN":["2151-464X","2151-4658"],"issn-type":[{"value":"2151-464X","type":"print"},{"value":"2151-4658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,26]]},"assertion":[{"value":"2021-06-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}