{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T05:22:56Z","timestamp":1787721776342,"version":"build-2784847793"},"reference-count":50,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RC 03\u201012"],"award-info":[{"award-number":["RC 03\u201012"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp;amp; Rheumatology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Methotrexate (MTX) is the first\u2010line therapy for juvenile idiopathic arthritis (JIA), but up to 40% of patients do not respond to it. Low inosine triphosphate pyrophosphatase (ITPA) activity has been associated with reduced clinical remission. We investigated the role and underlying mechanisms of ITPA in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      ITPA enzymatic activity was measured by high\u2010performance liquid chromatography with ultraviolet detection in erythrocyte lysates from patients with JIA (enrolled in Trieste, Italy; Florence, Italy; and Kansas City, Missouri) receiving weekly MTX (10\u201315 mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      ) for at least 12 months. Remission was evaluated by Wallace et al criteria.\n                      <jats:italic>ITPA<\/jats:italic>\n                      rs1127354, which reduces enzyme activity, was genotyped. Immortalized human hepatocytes were transfected with either an\n                      <jats:italic>ITPA<\/jats:italic>\n                      \u2010containing or empty plasmid to evaluate cytotoxicity (MTT), ADORA\n                      <jats:sub>2A<\/jats:sub>\n                      expression (quantitative polymerase chain reaction), intracellular cyclic AMP (cAMP) (enzyme\u2010linked immunosorbent assay), PKA\u2010C\u03b1 expression (immunoblot), and extracellular adenosine metabolites (liquid chromatography\u2013tandem mass spectrometry).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 195 patients with JIA (mean age: 8 years, range: 0\u201322 years, 74% female participants) were enrolled. Patients reaching remission (48%) had higher ITPA activity than nonresponders during therapy and at treatment onset (meta\u2010analysis:\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0004 and\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.007, respectively). Predictive cutoffs for overall and onset measurements were identified: 181.9 and 177.8 nmol of inosine monophosphate per hour. None of the patients with variant\n                      <jats:italic>ITPA<\/jats:italic>\n                      rs1127354 achieved remission (Fisher's exact test\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0063); however, 48% of wild\u2010type patients failed to respond. ITPA\u2010overexpressing cells showed elevated MTX sensitivity, cAMP levels, PKA\u2010C\u03b1 expression, and hypoxanthine (all\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05, two\u2010way analysis of variance).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ITPA activity is a promising predictive biomarker for MTX response in JIA, outperforming\n                      <jats:italic>ITPA<\/jats:italic>\n                      rs1127354 genotyping. Its predictive value is evident at treatment initiation, supporting its use for personalized treatment. Mechanistically, higher enzyme activity may enhance MTX efficacy through the adenosine\/inosine\u2010ADORA\n                      <jats:sub>2A<\/jats:sub>\n                      pathway.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70097-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70097","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T09:29:02Z","timestamp":1772962142000},"page":"1989-1999","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inosine\u2010Triphosphate\u2010Pyrophosphatase Activity as a Potential Predictor of Methotrexate Remission in Juvenile Idiopathic Arthritis"],"prefix":"10.1002","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9280-6349","authenticated-orcid":false,"given":"Sofia","family":"Sindici Forgiarini","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Health Sciences University of Trieste  Trieste Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Lucaf\u00f2","sequence":"additional","affiliation":[{"name":"Department of Life Sciences University of Trieste  Trieste 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