{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:31:54Z","timestamp":1786977114314,"version":"build-2736575974"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","award":["Innovative Research Award"],"award-info":[{"award-number":["Innovative Research Award"]}],"id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","award":["R\u2010Bridge Award"],"award-info":[{"award-number":["R\u2010Bridge Award"]}],"id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disease manifested as polyarteritis nodosa, stroke, and bone marrow failure. Leveraging an international cohort of 200 DADA2 cases, we aimed to characterize the diagnostic utility of a plasma ADA2 enzyme activity assay and understand the implications of residual ADA2 activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Data were collected from individuals who underwent ADA2 testing from 2018 to 2025. Plasma ADA2 activity was determined using an established spectrophotometric assay. ADA2 variants were analyzed in transfected cells by enzyme assay and western blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We determined that plasma ADA2 activity is 99.0% and 96.0% sensitive and 99.7% and 98.8% specific in distinguishing genetically confirmed DADA2 cases from controls and carriers, respectively. Eighteen individuals with DADA2 (9%) possessed detectable ADA2 activity, including several cases with levels seen in carriers. Residual ADA2 activity was associated with the vasculitis\/inflammatory phenotype but not with disease severity. Genotype analysis revealed that 14 of 18 cases with residual plasma activity possessed at least one hypomorphic missense variant with greater than 20% residual ADA2 function when overexpressed in 293T cells, often occurring in trans with a more deleterious variant. In vitro analysis revealed that missense ADA2 variants exert variable dominant\u2010negative effects by forming large intracellular protein aggregates via disulfide bond formation at a cysteine residue (Cys408).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We confirmed the utility of plasma ADA2 activity as a diagnostic assay and showed that the inflammatory phenotype of DADA2 occurred in cases with residual activity. In vitro findings illustrate potential interactions of ADA2 variants to synergistically disrupt protein function.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.43412","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T15:20:44Z","timestamp":1761664844000},"page":"734-742","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Diagnostic Implications and Correlates of Plasma Adenosine Deaminase 2 Activity and\n                    <scp>\n                      <i>ADA2<\/i>\n                    <\/scp>\n                    Variants"],"prefix":"10.1002","volume":"78","author":[{"given":"Jian","family":"Yue","sequence":"first","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"},{"name":"Department of Rheumatology and Immunology Guangdong Second Provincial General Hospital  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney E.","family":"LeSon","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey A.","family":"Rimland","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"},{"name":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kailey","family":"Brodeur","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"},{"name":"Medical Scientist Training Program UMass Chan Medical School  Worcester Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Weng","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan E.","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9832-2395","authenticated-orcid":false,"given":"Michael T.","family":"Lam","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5700-8529","authenticated-orcid":false,"given":"Manpreet","family":"Meyer","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seigo","family":"Okada","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts"},{"name":"Department of Pediatrics Yamaguchi University Graduate School of Medicine  Yamaguchi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L. 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