{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T06:31:18Z","timestamp":1791613878144,"version":"4.3.4"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"BMBF Grant MelAutim \u2018Systems medicine of melanoma and autoimmunity in the context of immunotherapy\u2019","doi-asserted-by":"publisher","award":["01ZX1905E"],"award-info":[{"award-number":["01ZX1905E"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"BMBF Grant MelAutim \u2018Systems medicine of melanoma and autoimmunity in the context of immunotherapy\u2019","doi-asserted-by":"publisher","award":["01ZX2205E"],"award-info":[{"award-number":["01ZX2205E"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Cutaneous side effects are the most common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) and affect 70\u201390% of patients. Besides diverse types of exanthema, rare skin toxicity includes bullous dermatoses in 0.3% of cases. Systemic steroids are the first-line treatment for immune-related bullous pemphigoid (irBP); however, some cases are corticosteroid-resistant. IrBP is one of the irAEs most frequently chronic and associated with long-term steroid use. However, steroids may interfere with tumor response. Therefore, alternative treatment strategies for irBP are desperately needed. Dupilumab, a monoclonal antibody blocking the receptor binding of interleukin-4 (IL-4) and interleukin-13 (IL-13), has been successfully used to treat spontaneous forms of bullous pemphigoid (BP). In this study, we analyzed the gene expression profiles of BP and irBP. Patients and Methods: A retrospective multicenter study evaluated the gene expression profiles of irBP and BP in comparison to healthy controls. Gene expression analyses of skin biopsies were performed using NanoString technology from patients with BP (n = 17), irBP (n = 19), and healthy skin (n = 24) after the patients had consented to participate in this study, and differentially expressed genes (DEGs) were determined using Rosalind software. Results: Compared to healthy skin, BP showed 167 DEGs, and irBP revealed 99 DEGs. Some of the DEGs from irBP and BP vs. healthy skin overlapped. Specifically, IL-4- and IL-13-associated genes were upregulated in both irBP and BP compared to healthy skin. Interestingly, expression profiles of BP vs. irBP also showed 13 DEGs. Conclusions: These findings suggest a possibility for therapeutic efficacy of IL-4 and IL-13 inhibitors in the treatment of irBP.<\/jats:p>","DOI":"10.3390\/cancers17111845","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T05:09:12Z","timestamp":1748840952000},"page":"1845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Interleukin-4 and -13 Gene Expression Profiles in Immune-Related Bullous Pemphigoid Indicate Efficacy of IL-4\/IL-13 Inhibitors"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9649-3423","authenticated-orcid":false,"given":"Lisa","family":"Arnold","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital LMU, LMU Munich, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0809-8404","authenticated-orcid":false,"given":"Monika","family":"Morak","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital LMU, LMU Munich, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1496-8207","authenticated-orcid":false,"given":"Nora","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital LMU, LMU Munich, 80336 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0229-8931","authenticated-orcid":false,"given":"Carola","family":"Berking","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Uniklinikum Erlangen, Deutsches Zentrum Immuntherapie, Comprehensive Cancer Center Erlangen\u2014EMN, Friedrich-Alexander University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1389-9292","authenticated-orcid":false,"given":"Matthias","family":"Schefzyk","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7575-6230","authenticated-orcid":false,"given":"Jessica C.","family":"Hassel","sequence":"additional","affiliation":[{"name":"Department of Dermatology and National Center for Tumor Diseases (NCT), Medical Faculty Heidelberg, Heidelberg University, NCT Heidelberg, a Partnership Between DKFZ and University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6488-1917","authenticated-orcid":false,"given":"Mirjana","family":"Ziemer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Allergology and Venerology, University Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars E.","family":"French","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital LMU, LMU Munich, 80336 Munich, Germany"},{"name":"Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7921-2820","authenticated-orcid":false,"given":"Ralf","family":"Gutzmer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum Campus Minden, 32429 Minden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothee","family":"Nashan","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Hospital Dortmund, 44137 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Heinzerling","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital LMU, LMU Munich, 80336 Munich, Germany"},{"name":"Department of Dermatology, Uniklinikum Erlangen, Deutsches Zentrum Immuntherapie, Comprehensive Cancer Center Erlangen\u2014EMN, Friedrich-Alexander University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ejca.2022.08.029","article-title":"Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients\u2019 health-related quality of life","volume":"176","author":"Schulz","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e007324","DOI":"10.1136\/jitc-2023-007324","article-title":"Management of immune-related cutaneous adverse events with dupilumab","volume":"11","author":"Kuo","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1111\/bjd.21836","article-title":"Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: A multicentre observational study","volume":"187","author":"Kawsar","year":"2022","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e722","DOI":"10.1111\/jdv.19860","article-title":"Checkpoint inhibitor-induced bullous pemphigoid differs from spontaneous bullous pemphigoid","volume":"38","author":"Kramer","year":"2024","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1016\/j.jaad.2022.08.001","article-title":"A retrospective case series of 20 patients with immunotherapy-induced bullous pemphigoid with emphasis on management outcomes","volume":"87","author":"Bur","year":"2022","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1824645","DOI":"10.1080\/2162402X.2020.1824645","article-title":"Association of baseline systemic corticosteroid use with overall survival and time to next treatment in patients receiving immune checkpoint inhibitor therapy in real-world US oncology practice for advanced non-small cell lung cancer, melanoma, or urothelial carcinoma","volume":"9","author":"Drakaki","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.annonc.2021.02.016","article-title":"IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies","volume":"32","author":"Barrios","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.2217\/imt.15.69","article-title":"Drug evaluation review: Dupilumab in atopic dermatitis","volume":"7","author":"Hamilton","year":"2015","journal-title":"Immunotherapy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/cea.13491","article-title":"Mechanisms of Dupilumab","volume":"50","author":"Harb","year":"2020","journal-title":"Clin. Exp. Allergy"},{"key":"ref_10","first-page":"1584","article-title":"Integrative epidemiology and immunotranscriptomics uncover a risk and potential mechanism for cutaneous lymphoma unmasking or progression with dupilumab therapy","volume":"155","author":"Carey","year":"2024","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.jdin.2024.01.002","article-title":"A real-world study of dupilumab in patients with atopic dermatitis including patients with malignancy and other medical comorbidities","volume":"15","author":"Metko","year":"2024","journal-title":"JAAD Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5021\/ad.2021.33.1.1","article-title":"Therapeutic New Era for Atopic Dermatitis: Part 1. Biologics","volume":"33","author":"Ahn","year":"2021","journal-title":"Ann. Dermatol."},{"key":"ref_13","unstructured":"(2018). nCounter Advanced Analysis 2.0 Plugin for nSolver Software User Manual, NanoString Technologies, Inc.. Available online: https:\/\/nanostring.com\/wp-content\/uploads\/MAN-10030-03_nCounter_Advanced_Analysis_2.0_User_Manual.pdf."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s40257-023-00832-1","article-title":"Advancements in Bullous Pemphigoid Treatment: A Comprehensive Pipeline Update","volume":"25","author":"Karakioulaki","year":"2024","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.molimm.2011.12.008","article-title":"IL-4 regulates chemokine CCL26 in keratinocytes through the Jak1, 2\/Stat6 signal transduction pathway: Implication for atopic dermatitis","volume":"50","author":"Bao","year":"2012","journal-title":"Mol. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1365-2249.2011.04464.x","article-title":"Up-regulation of CCL11 and CCL26 is associated with activated eosinophils in bullous pemphigoid","volume":"166","author":"Wozel","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1210\/er.2007-0001","article-title":"The complex role of estrogens in inflammation","volume":"28","author":"Straub","year":"2007","journal-title":"Endocr. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1111\/bjd.13717","article-title":"Management of bullous pemphigoid: The European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology","volume":"172","author":"Feliciani","year":"2015","journal-title":"Br. J. Dermatol."},{"key":"ref_19","unstructured":"Worm, M.S.B. (2019). S2k-Leitlinie Diagnostik und Therapie des Pemphigus vulgaris\/foliaceus und des Bull\u00f6sen Pemphigoids, Deutsche Gesellschaft f\u00fcr Kinder- und Jugendmedizin e.V. (DGKJ). Deutsche Dermatologische Gesellschaft e.V. (DDG)."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1001\/archderm.1994.01690060083010","article-title":"Nicotinamide and tetracycline therapy of bullous pemphigoid","volume":"130","author":"Fivenson","year":"1994","journal-title":"Arch. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1001\/archderm.144.7.946-a","article-title":"Comparative effectiveness of azathioprine or mycophenolate mofetil as an adjuvant for the treatment of bullous pemphigoid","volume":"144","author":"Bystryn","year":"2008","journal-title":"Arch. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wojtczak, M., Nolbrzak, A., Wo\u017aniacka, A., and \u017bebrowska, A. (2023). Can Methotrexate Be Employed as Monotherapy for Bullous Pemphigoid? Analysis of Efficiency and Tolerance of Methotrexate Treatment in Patients with Bullous Pemphigoid. J. Clin. Med., 12.","DOI":"10.3390\/jcm12041638"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0190-9622(96)80085-5","article-title":"Treatment of bullous pemphigoid with dapsone: Retrospective study of thirty-six cases","volume":"34","author":"Bouscarat","year":"1996","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Berkani, N., Joly, P., Golinski, M.L., Colliou, N., Lim, A., Larbi, A., Riou, G., Caillot, F., Bernard, P., and Bedane, C. (2019). B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine pattern in patients with bullous pemphigoid. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-40203-7"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jdcr.2022.12.006","article-title":"Bullous pemphigoid treated with Janus kinase inhibitor upadacitinib","volume":"32","author":"Nash","year":"2023","journal-title":"JAAD Case Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.jdcr.2017.03.008","article-title":"Adalimumab-associated bullous pemphigoid in a patient with ulcerative colitis","volume":"3","author":"Wessman","year":"2017","journal-title":"JAAD Case Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e010638","DOI":"10.1136\/jitc-2024-010638","article-title":"Long-term mortality outcomes among immunotherapy recipients treated with dupilumab for the management of cutaneous immune-related adverse events","volume":"13","author":"Khattab","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Scott, T.E., Lewis, C.V., Zhu, M., Wang, C., Samuel, C.S., Drummond, G.R., and Kemp-Harper, B.K. (2023). IL-4 and IL-13 induce equivalent expression of traditional M2 markers and modulation of reactive oxygen species in human macrophages. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-46237-2"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/s41573-022-00520-5","article-title":"Macrophages as tools and targets in cancer therapy","volume":"21","author":"Mantovani","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/s41586-024-07962-4","article-title":"The type 2 cytokine Fc-IL-4 revitalizes exhausted CD8(+) T cells against cancer","volume":"634","author":"Feng","year":"2024","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s40257-022-00685-0","article-title":"Dupilumab Provides Acceptable Safety and Sustained Efficacy for up to 4 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis","volume":"23","author":"Beck","year":"2022","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.4049\/jimmunol.2200922","article-title":"Requirements of IL-4 during the Generation of B Cell Memory","volume":"210","author":"Chakma","year":"2023","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/S1470-2045(24)00278-X","article-title":"Multi-organ immune-related adverse events from immune checkpoint inhibitors and their downstream implications: A retrospective multicohort study","volume":"25","author":"Wan","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Carbone, M.L., Capone, A., Guercio, M., Reddel, S., Silvestris, D.A., Lulli, D., Ramondino, C., Peluso, D., Quintarelli, C., and Volpe, E. (2023). Insight into immune profile associated with vitiligo onset and anti-tumoral response in melanoma patients receiving anti-PD-1 immunotherapy. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1197630"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Eshaq, A.M., Flanagan, T.W., Ba Abbad, A.A., Makarem, Z.A.A., Bokir, M.S., Alasheq, A.K., Al Asheikh, S.A., Almashhor, A.M., Binyamani, F., and Al-Amoudi, W.A. (2025). Immune Checkpoint Inhibitor-Associated Cutaneous Adverse Events: Mechanisms of Occurrence. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26010088"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.anai.2021.02.009","article-title":"Immune-related cutaneous adverse events due to checkpoint inhibitors","volume":"126","author":"Wang","year":"2021","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_37","first-page":"pe55","article-title":"Untangling the complex web of IL-4- and IL-13-mediated signaling pathways","volume":"1","author":"Finkelman","year":"2008","journal-title":"Sci. Signal"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/S1567-5769(02)00209-6","article-title":"The immunogenic peptide for Th1 development","volume":"3","author":"Takatsu","year":"2003","journal-title":"Int. Immunopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1684\/ejd.2018.3366","article-title":"Immunoglobulin E and bullous pemphigoid","volume":"28","author":"Cozzani","year":"2018","journal-title":"Eur. J. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.clim.2006.03.014","article-title":"Increased expression of Th2-associated chemokines in bullous pemphigoid disease. Role of eosinophils in the production and release of these chemokines","volume":"120","author":"Wellemans","year":"2006","journal-title":"Clin. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1111\/1346-8138.16428","article-title":"Treatment of bullous pemphigoid with dupilumab: Dupilumab exerts its effect by primarily suppressing T-helper 2 cytokines","volume":"49","author":"Takamura","year":"2022","journal-title":"J. Dermatol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/11\/1845\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:44:42Z","timestamp":1760031882000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/11\/1845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,31]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cancers17111845"],"URL":"https:\/\/doi.org\/10.3390\/cancers17111845","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,31]]}}}