{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:51:25Z","timestamp":1781675485377,"version":"3.54.5"},"reference-count":149,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Autoinflammatory diseases are increasingly defined at the genetic and pathway levels, yet therapeutic predictability has not advanced in parallel. This disconnect is especially evident in monogenic disorders, in which molecular diagnosis can identify the initiating lesion but does not reliably predict the dominant effector process, organ-specific risk, or the treatment most likely to achieve durable control. Similar clinical phenotypes may arise from distinct molecular defects, whereas disruption of the same pathway, or even the same gene, may produce divergent organ involvement, disease evolution, and therapeutic response. In established disease, the initiating lesion, sustaining inflammatory circuitry, and the process currently driving tissue injury may no longer remain aligned. This review examines how that misalignment complicates therapeutic decision-making in autoinflammation, with emphasis on type I interferonopathies, inflammasome-related disorders, and NF-\u03baB-centered diseases. It argues that treatment should be genotype-informed rather than genotype-determined, integrating the current dominant inflammatory module, organ-prioritized disease burden, disease stage, tissue reversibility, and treatment-limiting complications. A framework that is phenotype-weighted, organ-prioritized, and time-sensitive may better align mechanism-based therapy with real-world clinical outcomes.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1868804","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:52:39Z","timestamp":1781671959000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms outpacing medicine in autoinflammatory diseases"],"prefix":"10.3389","volume":"17","author":[{"given":"Ruyue","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Nephrology and Immunology, Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kead439","article-title":"Old paradigms and new 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