Janus Kinase Inhibition in Congenital Ichthyoses: A Systematic Review of Clinical Evidence

Background and Objectives: Congenital ichthyoses (CIs) cause a damaged skin barrier and persistent skin inflammation; in several subtypes, gene expression studies point to the role of Janus kinase–signal transducer and activator of transcription (JAK-STAT) signalling in that inflammation. JAK inhibitors have, therefore, been tried off-label in a few CI patients. Two recent systematic reviews covered Netherton syndrome or genodermatoses broadly, but neither examined CI as a group, so we set out to map the published clinical experience across CI subtypes. Materials and Methods: Following PRISMA 2020, we searched PubMed/MEDLINE, Scopus, Web of Science Core Collection, and Cochrane CENTRAL in September 2026 (CRD420261511090). Two reviewers independently screened reports and appraised bias with Joanna Briggs Institute checklists, seeking any patient with a congenital ichthyosis, including Netherton syndrome, given a JAK inhibitor with a reported outcome. Results: The search yielded 14 reports describing 15 patients: 13 with Netherton syndrome and 2 with autosomal recessive congenital ichthyosis (ARCI). They received upadacitinib (n = 8), abrocitinib (n = 3), tofacitinib (n = 2), baricitinib (n = 2), or topical delgocitinib (n = 1); one patient took two agents. Most reports described improved redness, itching, and quality of life, yet few measured scaling directly. In the one ARCI patient with RNA sequencing, skin water loss improved only until week 10, although itching and quality of life remained improved. Results were not uniformly positive: one patient did not respond, and several responses waned. Based on a single higher-dose report, a possible dose–durability link could be observed with upadacitinib, and three reports lacked confirmed genetic diagnoses. We found no reports for X-linked, harlequin, or epidermolytic ichthyosis or ichthyosis vulgaris. Conclusions: Clinical evidence for JAK inhibition in CI is limited to case reports and one small real-world series, mainly on Netherton syndrome, and describes current off-label use rather than establishing efficacy. Reported improvements were more consistent for inflammation than for scaling, but the data are sparse and likely affected by publication bias. Until prospective, standardised studies exist, JAK inhibition should remain an individualised, closely monitored, off-label option.