{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:18:04Z","timestamp":1788239884139,"version":"build-2803163510"},"reference-count":15,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Dermatology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pustular psoriasis (IL\u201036\/Th17) and atopic dermatitis (Th2) are associated with different but partially overlapping inflammatory pathways. Sequential expression of these phenotypes in the same patient is uncommon. We describe a 64\u2010year\u2010old woman with longstanding psoriasis vulgaris, asthma, allergic rhinitis, and a family history of atopy who developed generalized pustular psoriasis after biologic treatments. Genetic testing identified a novel, previously unreported heterozygous\n                    <jats:italic>IL36RN<\/jats:italic>\n                    frameshift variant, c.319del (p.Leu107Serfs\n                    <jats:italic>65).<\/jats:italic>\n                    Over subsequent months, the pustular phenotype was replaced by chronic, intensely pruritic, xerotic, eczematous dermatitis fulfilling the Hanifin\u2013Rajka criteria. Serial biopsies demonstrated mild spongiosis and an eosinophil\u2010rich superficial perivascular infiltrate. Risankizumab and adalimumab were temporally associated with pustular exacerbations, whereas dupilumab was followed by worsening of the eczematous phenotype without recurrent pustulation. Methotrexate 15\u2009mg weekly, which restrains both axes, together with topical treatment was associated with sustained near\u2010complete clearance through Month 12. To our knowledge, this is the first report of a three\u2010class biologic paradox in a single patient. Sequential single\u2010pathway blockade in a genetically destabilized immune network may disinhibit alternative effector arms with cytokine shunting. Inborn errors of immunity should be considered in refractory inflammatory dermatoses\u2014even in geriatric patients\u2014and pathway\u2010specific biologics used cautiously when the underlying immune architecture is monogenically perturbed.\n                  <\/jats:p>","DOI":"10.1111\/1346-8138.70478","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:45:14Z","timestamp":1788237914000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Pustules to Pruritus: A Novel\n                    <scp>\n                      <i>IL36RN<\/i>\n                    <\/scp>\n                    Frameshift Variant Reveals a Triple Biologic Paradox and a Th17\u2010To\u2010Th2 Phenotypic Transition"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3757-277X","authenticated-orcid":false,"given":"Furkan","family":"\u00c7al\u0131c\u0131o\u011flu","sequence":"first","affiliation":[{"name":"Kayseri Faculty of Medicine, Kayseri City Hospital, Department of Dermatology, Urticaria&amp;Angioedema&amp;Atopic Dermatitis Center of Reference and Excellence Clinic Health Sciences University  Kayseri T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8012-9986","authenticated-orcid":false,"given":"Ne\u015fecan","family":"\u00c7al\u0131c\u0131o\u011flu","sequence":"additional","affiliation":[{"name":"Kayseri Faculty of Medicine, Kayseri City Hospital, Department of Dermatology, Urticaria&amp;Angioedema&amp;Atopic Dermatitis Center of Reference and Excellence Clinic Health Sciences University  Kayseri T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5034-7083","authenticated-orcid":false,"given":"Muhammet Ensar","family":"Do\u011fan","sequence":"additional","affiliation":[{"name":"Kayseri Faculty of Medicine, Kayseri City Hospital, Department of Medical Genetics Health Sciences University  Kayseri T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4475-6032","authenticated-orcid":false,"given":"Y\u00fccel","family":"Tekin","sequence":"additional","affiliation":[{"name":"Kayseri Faculty of Medicine, Kayseri City Hospital, Department of Pathology Health Sciences University  Kayseri T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9269-2619","authenticated-orcid":false,"given":"Rag\u0131p","family":"Erta\u015f","sequence":"additional","affiliation":[{"name":"Kayseri Faculty of Medicine, Kayseri City Hospital, Department of Dermatology, Urticaria&amp;Angioedema&amp;Atopic Dermatitis Center of Reference and Excellence Clinic Health Sciences University  Kayseri T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"753","DOI":"10.3390\/genes16070753","article-title":"Decoding Non\u2010Coding RNA Regulators in DITRA: From Genomic Insights to Potential Biomarkers and Therapeutic Targets","volume":"16","author":"Spanou S.","year":"2025","journal-title":"Genes"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1056\/NEJMra2023911","article-title":"Atopic Dermatitis","volume":"384","author":"St\u00e4nder S.","year":"2021","journal-title":"New England Journal of Medicine"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1001\/jamadermatol.2023.4846","article-title":"Risk of Paradoxical Eczema in Patients Receiving Biologics for Psoriasis","volume":"160","author":"Al\u2010Janabi A.","year":"2024","journal-title":"JAMA Dermatology"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"2460582","DOI":"10.1080\/09546634.2025.2460582","article-title":"Expanding the Therapeutic Horizons of Spesolimab: A Review of Off\u2010Label Applications for Inflammatory Skin Diseases","volume":"36","author":"Zhang H.","year":"2025","journal-title":"Journal of Dermatological Treatment"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/jdv.18727","article-title":"Spesolimab, an Anti\u2013Interleukin\u201036 Receptor Antibody, in Patients With Moderate\u2010To\u2010Severe Atopic Dermatitis: Results From a Multicentre, Randomized, Double\u2010Blind, Placebo\u2010Controlled, Phase IIa Study","volume":"37","author":"Bissonnette R.","year":"2023","journal-title":"Journal of the European Academy of Dermatology and Venereology"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"9143","DOI":"10.1038\/s41598-021-88491-2","article-title":"Methotrexate Reduces Circulating Th17 Cells and Impairs Plasmablast and Memory B\u2010Cell Expansions Following Pneumococcal Conjugate Immunization in RA Patients","volume":"11","author":"Nived P.","year":"2021","journal-title":"Scientific Reports"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"250","DOI":"10.4103\/idoj.idoj_58_25","article-title":"An Unusual Case of Refractory Pemphigoid Gestationis With Neonatal Involvement: An Intricate Therapeutic Challenge","volume":"17","author":"\u00c7al\u0131c\u0131o\u011flu F.","year":"2026","journal-title":"Indian Dermatology Online Journal"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.waojou.2026.101380","article-title":"The Definition of Response and Inadequate Response to Topical Corticosteroid Treatment in Atopic Dermatitis and Related Skin Inflammatory Diseases: A GA2LEN ADCARE Statement Paper","volume":"19","author":"Zuberbier T.","year":"2026","journal-title":"World Allergy Organization Journal"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.jaci.2014.09.043","article-title":"IL36RN Mutations Define a Severe Autoinflammatory Phenotype of Generalized Pustular Psoriasis","volume":"135","author":"Hussain S.","year":"2015","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/jid.2012.490","article-title":"Rare Pathogenic Variants in IL36RN Underlie a Spectrum of Psoriasis\u2010Associated Pustular Phenotypes","volume":"133","author":"Setta\u2010Kaffetzi N.","year":"2013","journal-title":"Journal of Investigative Dermatology"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.cyto.2022.155897","article-title":"Role of IL\u201036 Cytokines in Psoriasis and Other Inflammatory Skin Conditions","volume":"156","author":"Sachen K. L.","year":"2022","journal-title":"Cytokine"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/1346-8138.15788","article-title":"Significance of IL36RN Mutation Analyses in the Management of Impetigo Herpetiformis: A Case Report and Review of Published Cases","volume":"48","author":"Yoshikawa M.","year":"2021","journal-title":"Journal of Dermatology"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"1434127","DOI":"10.3389\/fimmu.2024.1434127","article-title":"Dual Blockade of IL\u201017A and IL\u201036 Pathways via a Bispecific Antibody Exhibits Enhanced Anti\u2010Inflammatory Potency","volume":"15","author":"Ma X.","year":"2024","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1159\/000380876","article-title":"A Case of Old\u2010Age\u2010Onset Generalized Pustular Psoriasis With a Deficiency of IL\u201036RN (DITRA) Treated by Granulocyte and Monocyte Apheresis","volume":"7","author":"Tominaga C.","year":"2015","journal-title":"Case Reports in Dermatology"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.5336\/dermato.2025-109123","article-title":"Remarkable Response to Upadacitinib in a 77\u2010Year\u2010Old Patient With Recurrent Erythroderma","volume":"1","author":"\u00c7al\u0131c\u0131o\u011flu F.","year":"2026","journal-title":"Turkiye Klinikleri Journal of Dermatology"}],"container-title":["The Journal of Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1346-8138.70478","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/1346-8138.70478","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/1346-8138.70478","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:45:25Z","timestamp":1788237925000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/1346-8138.70478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":15,"alternative-id":["10.1111\/1346-8138.70478"],"URL":"https:\/\/doi.org\/10.1111\/1346-8138.70478","archive":["Portico"],"relation":{},"ISSN":["0385-2407","1346-8138"],"issn-type":[{"value":"0385-2407","type":"print"},{"value":"1346-8138","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"assertion":[{"value":"2026-05-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"1346-8138.70478"}}