Summary The glycome undergoes characteristic changes during histogenesis and organogenesis, but our understanding of the importance of select glycan structures for tissue formation and homeostasis is incomplete. Here, we present a human organotypic platform that allows genetic dissection of cellular glycosylation capacities and systematic interrogation of the roles of distinct glycan types in tissue formation. We used CRISPR-Cas9 gene targeting to generate a library of 3D organotypic skin tissues that selectively differ in their capacity to produce glycan structures on the main types of N- and O-linked glycoproteins and glycolipids. This tissue library revealed distinct changes in skin formation associated with a loss of features for all tested glycoconjugates. The organotypic skin model provides phenotypic cues for the distinct functions of glycoconjugates and serves as a unique resource for further genetic dissection and identification of the specific structural features involved. The strategy is also applicable to other organotypic tissue models.

ImportanceTumor necrosis factor-α inhibitor (TNFi)–associated psoriasis is a rare adverse event following TNFi treatment. Data on the risk of developing TNFi-associated psoriasis when treated with TNFi are sparse.ObjectiveTo investigate the associated risk between new-onset psoriasis and TNFi treatment compared with nonbiologic conventional treatment.Design, Setting, and ParticipantsUsing Danish national registries (1995-2018), this cohort study included patients with inflammatory bowel disease (IBD) and/or rheumatoid arthritis (RA) who received either conventional therapy or TNFi treatment. Patients may not have been diagnosed with psoriasis prior to initiation of treatment. Patients were followed up for up to 5 years. Cox regression models with robust variance were used to compare the risk of developing any type of psoriasis, nonpustular psoriasis, and pustular psoriasis. Patients receiving conventional therapy were used as reference. Data analysis was performed from January 1995 to December 2018.ExposuresFor the present study, the term conventional therapy was used for the nonbiological therapy. For biological therapy, a distinction was made between TNFi treatment and non-TNFi biological therapy.Main Outcomes and MeasuresThe outcome of psoriasis was defined as a registered International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code of psoriasis and/or having 2 consecutive prescriptions of topical vitamin D analogues.ResultsThe study included 109 085 patients, of which 62% were female. Median (IQR) age was 50 (34-64) years. Of the included patients, 108 024 received conventional therapy and 20 910 received TNFi treatment. During follow-up, 1471 (1.4%) patients developed any type of psoriasis, of which 1332 developed nonpustular psoriasis, 127 patients developed palmoplantar pustulosis, and 12 patients developed generalized pustulosis. The incidence rates for developing any type of psoriasis per 1000 patient-years were 3.0 (95% CI, 2.9-3.2) for conventional therapy and 7.8 (95% CI, 7.5-8.9) for TNFi. During treatment with TNFi, the hazard ratio was 2.12 (95% CI, 1.87-2.40; P < .001) for developing nonpustular psoriasis and 6.50 (95% CI, 4.60-9.23; P < .001) for pustular psoriasis compared with conventional treatment. Exposure needed for 1 additional patient to be harmed was 241 patient-years for any type of TNFi-associated psoriasis, 342 patient-years for nonpustular psoriasis, and 909 patient-years for pustular psoriasis.Conclusions and RelevanceIn a Danish nationwide cohort of patients with immune-mediated inflammatory diseases treated with TFNi or conventional treatment and no history of psoriasis, in TFNi-treated patients, nonpustular types of psoriasis constituted the most events, whereas pustular types of psoriasis had the highest relative risk. Although the risk of new-onset psoriasis increased for both nonpustular and pustular types of psoriasis in TFNi-treated patients, the absolute risk remained modest at 241 patient-years of exposure need for 1 additional event and an estimated absolute risk difference around 5 per 1000 patient-years, indicating that the approach to treatment of patients in need of TNFi treatment should not change.

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