{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T17:21:15Z","timestamp":1786296075443,"version":"build-2736575974"},"reference-count":24,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ACR Open Rheumatology"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The study objective was to evaluate the safety, tolerability, pharmacodynamics, and preliminary efficacy of ATI\u2010450 with methotrexate in patients with rheumatoid arthritis (RA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A parallel\u2010assignment, placebo\u2010controlled, investigator\u2010blinded\/patient\u2010blinded multicenter study evaluated patients with moderate\u2010to\u2010severe RA aged 18 to 70\u2009years. Eligible patients were randomized (1:1) to ATI\u2010450 50\u2010mg oral tablets twice daily or placebo with a stable weekly dose of methotrexate for 12\u2009weeks. The primary objective was to assess ATI\u2010450 safety and tolerability. The secondary objectives were to assess the median percentage change from baseline high\u2010sensitivity C\u2010reactive protein (hs\u2010CRP) levels, the mean change from baseline in Disease Activity Score in 28 joints based on CRP level (DAS28\u2010CRP) and Rheumatoid Arthritis Magnetic Resonance Imaging Score hand\u2010wrist assessments of synovitis or bone erosion at week 12, and the proportion of patients with American College of Rheumatology 20\/50\/70 (ACR 20\/50\/70) and with DAS28\u2010CRP scores of less than 2.6. The exploratory outcomes were change from baseline in endogenous and ex vivo\u2013stimulated cytokine levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ATI\u2010450 was well tolerated with no severe adverse events reported. ATI\u2010450 reduced median hs\u2010CRP levels by 42% or more at all posttreatment timepoints. In the ATI\u2010450 group, a mean (median) decrease in DAS28\u2010CRP score of 2.0 (2.1) was observed at week 12; proportions of patients with an ACR 20\/50\/70 response in the per\u2010protocol population were 60%, 33%, and 20%, respectively, at week 12. Endogenous plasma levels of key inflammatory cytokines (tumor necrosis factor \u03b1, macrophage inflammatory protein 1\u03b2, interleukin 6, interleukin 8) were reduced across the 12 treatment weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the first clinical study demonstrating that selective mitogen\u2010activated protein kinase (MAPK)\u2013activated protein kinase 2 (MK2) pathway blockade leads to a sustained antiinflammatory effect. This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acr2.11517","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T00:26:52Z","timestamp":1672964812000},"page":"63-70","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Selective Inhibition of the <scp>MK2<\/scp> Pathway: Data From a Phase\u00a0<scp>IIa<\/scp> Randomized Clinical Trial in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"5","author":[{"given":"David","family":"Gordon","sequence":"first","affiliation":[{"name":"(current address: Johnson &amp; Johnson, Spring House, Pennsylvania), Aclaris Therapeutics, Inc  Wayne Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Kivitz","sequence":"additional","affiliation":[{"name":"Altoona Arthritis &amp; 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