{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:09:04Z","timestamp":1792084144839,"version":"4.4.0"},"reference-count":59,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NextGenerationEU-MUR M4C2.I.1.3 PNRR","award":["I83C22001810007"],"award-info":[{"award-number":["I83C22001810007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Juvenile scleroderma (JS) comprises a group of rare chronic autoimmune and fibrosing disorders in children, primarily presenting as juvenile localized scleroderma (jLS) or juvenile systemic sclerosis (jSS). While jLS predominantly affects the skin and subcutaneous tissues, jSS may involve multiple internal organs and is associated with increased morbidity and mortality. Due to the scarcity of pediatric-specific clinical trials, the current treatment strategies are largely empirical and often adapted from adult protocols. Objective: This narrative review aims to provide a comprehensive update on emerging systemic therapies for juvenile scleroderma, focusing on biologics, small molecule inhibitors, and advanced cellular interventions, to support the development of more personalized and effective pediatric treatment approaches. Methods: A literature search was conducted through PubMed and a manual bibliographic review, covering publications from 2001 to 2024. Only English-language studies involving pediatric populations were included, comprising randomized controlled trials, reviews, and case reports. Additional searches were performed for drugs that are specifically used in juvenile scleroderma. Results: Biologic agents such as tocilizumab, rituximab, and abatacept, along with small molecules including Janus kinase (JAK) inhibitors and imatinib, have demonstrated potential in managing refractory cases by reducing skin fibrosis and pulmonary involvement. Novel approaches\u2014such as pamrevlumab, nintedanib, and chimeric antigen receptor (CAR-T) cell therapy\u2014target fibrotic and autoimmune pathways but remain investigational in children. Autologous stem cell transplantation (ASCT) has also been explored in severe, treatment-resistant cases, although data are extremely limited. The overall evidence base is constrained by small sample sizes, a lack of controlled pediatric trials, and reliance on adult extrapolation. Conclusions: While innovative systemic therapies show promise for juvenile scleroderma, their widespread clinical application remains limited by insufficient pediatric-specific evidence. Large, multicenter, long-term trials are urgently needed to establish safety, efficacy, and optimal treatment algorithms that are tailored to the pediatric population.<\/jats:p>","DOI":"10.3390\/ph18050643","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:35:13Z","timestamp":1746185713000},"page":"643","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["New Challenging Systemic Therapies for Juvenile Scleroderma: A Comprehensive Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2747-2941","authenticated-orcid":false,"given":"Chiara","family":"Sassetti","sequence":"first","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Mazuy","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Guerriero","sequence":"additional","affiliation":[{"name":"Unit of Dermatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7032-7779","authenticated-orcid":false,"given":"Donato","family":"Rigante","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Universit\u00e0 Cattolica Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-2837","authenticated-orcid":false,"given":"Susanna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Pediatric Clinic, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1007\/s12098-023-04894-1","article-title":"Juvenile scleroderma","volume":"91","author":"Bhat","year":"2024","journal-title":"Indian J. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s11926-996-0008-4","article-title":"Juvenile systemic scleroderma","volume":"3","author":"Martini","year":"2001","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.pcl.2018.04.002","article-title":"Scleroderma in children and adolescents: Localized scleroderma and systemic sclerosis","volume":"65","author":"Li","year":"2018","journal-title":"Pediatr. Clin. North Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/01.bor.0000245727.40630.c3","article-title":"Localized scleroderma","volume":"18","author":"Laxer","year":"2006","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"575","DOI":"10.2165\/00128072-200103080-00002","article-title":"Recognition and management of scleroderma in children","volume":"3","author":"Foeldvari","year":"2001","journal-title":"Paediatr. Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/art.22551","article-title":"The Pediatric Rheumatology European Society\/American College of Rheumatology\/European League against Rheumatism provisional classification criteria for juvenile systemic sclerosis","volume":"57","author":"Zulian","year":"2007","journal-title":"Arthritis Care Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1002\/art.38814","article-title":"Major histocompatibility complex class I and class II alleles may confer susceptibility to or protection against morphea: Findings from the Morphea in Adults and Children cohort","volume":"66","author":"Jacobe","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.rdc.2015.04.002","article-title":"The pathogenesis of systemic sclerosis","volume":"41","author":"Stern","year":"2015","journal-title":"Rheum. Dis. Clin. North Am."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Torok, K.S., Li, S.C., Jacobe, H.M., Taber, S.F., Stevens, A.M., Zulian, F., and Lu, T.T. (2019). Immunopathogenesis of pediatric localized scleroderma. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00908"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1002\/acr.21687","article-title":"Development of consensus treatment plans for juvenile localized scleroderma: A roadmap toward comparative effectiveness studies in juvenile localized scleroderma","volume":"64","author":"Li","year":"2012","journal-title":"Arthritis Care Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/ddg.12724","article-title":"German guidelines for the diagnosis and therapy of localized scleroderma","volume":"14","author":"Kreuter","year":"2016","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1111\/1346-8138.14801","article-title":"Juvenile case of multiple morphea profunda resulting in joint contracture that was successfully treated with cyclosporin A: A case report and review of the published works","volume":"46","author":"Ogawa","year":"2019","journal-title":"J. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/j.jaad.2019.01.040","article-title":"Treatment of morphea with hydroxychloroquine: A retrospective review of 84 patients at Mayo Clinic, 1996\u20132013","volume":"80","author":"Kumar","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1111\/j.1365-4632.2012.05741.x","article-title":"Eosinophilic fasciitis\/generalized morphea overlap successfully treated with azathioprine","volume":"53","author":"Moreno","year":"2014","journal-title":"Int. J. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e12455","DOI":"10.1111\/dth.12455","article-title":"Retinoic acid for treatment of systemic sclerosis and morphea: A literature review","volume":"30","author":"Thomas","year":"2017","journal-title":"Dermatol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1684\/ejd.2021.4173","article-title":"Response of recalcitrant generalized morphea to intravenous immunoglobulins (IVIg): Three cases and a review of the literature","volume":"31","author":"Kromer","year":"2021","journal-title":"Eur. J. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1684\/ejd.2013.1929","article-title":"Resolution with rituximab of localized scleroderma occurring during etanercept treatment in a patient with rheumatoid arthritis","volume":"23","author":"Chimenti","year":"2013","journal-title":"Eur. J. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.cyto.2011.04.001","article-title":"Cytokine profiles in localized scleroderma and relationship to clinical features","volume":"55","author":"Kurzinski","year":"2011","journal-title":"Cytokine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"203","DOI":"10.5301\/jsrd.5000259","article-title":"Tocilizumab is a promising treatment option for therapy resistant juvenile localized scleroderma patients","volume":"2","author":"Foeldvari","year":"2017","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.jaad.2013.02.007","article-title":"The localized scleroderma cutaneous assessment tool: Responsiveness to change in a pediatric clinical population","volume":"69","author":"Kelsey","year":"2013","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1016\/S0140-6736(16)00232-4","article-title":"Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomised, controlled trial","volume":"387","author":"Khanna","year":"2016","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/rheumatology\/kex382","article-title":"Tocilizumab as a potential therapeutic option for children with severe, refractory juvenile localized scleroderma","volume":"57","author":"Lythgoe","year":"2018","journal-title":"Rheumatology"},{"key":"ref_23","first-page":"211","article-title":"Tocilizumab in two children with pansclerotic morphoea: A hopeful therapy for refractory cases?","volume":"35","author":"Martini","year":"2017","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1001\/jamadermatol.2018.5040","article-title":"A case of pansclerotic morphea treated with tocilizumab","volume":"155","author":"Zhang","year":"2019","journal-title":"JAMA Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Vent\u00e9jou, S., Schwieger-Briel, A., Nicolai, R., Christen-Zaech, S., Schnider, C., Hofer, M., Bogiatzi, S., Hohl, D., De Benedetti, F., and Morren, M.-A. (2021). Case report: Pansclerotic morphea-clinical features, differential diagnoses and modern treatment concepts. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.656407"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/s40265-018-0929-z","article-title":"Sarilumab: A review in moderate to severe rheumatoid arthritis","volume":"78","author":"Lamb","year":"2018","journal-title":"Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Papara, C., De Luca, D.A., Bieber, K., Vorobyev, A., and Ludwig, R.J. (2023). Morphea: The 2023 update. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1108623"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"465","DOI":"10.2340\/00015555-2878","article-title":"Abatacept improves skin-score and reduces lesions in patients with localized scleroderma: A case series","volume":"98","author":"Fage","year":"2018","journal-title":"Acta Derm.-Venereol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.semarthrit.2020.03.020","article-title":"Abatacept in the treatment of localized scleroderma: A pediatric case series and systematic literature review","volume":"50","author":"Kalampokis","year":"2020","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/art.22314","article-title":"Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis","volume":"56","author":"Distler","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1111\/ijd.12387","article-title":"Imatinib: A novel treatment approach for generalized morphea","volume":"53","author":"Cardoso","year":"2014","journal-title":"Int. J. Dermatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/dth.12248","article-title":"Imatinib treatment of therapy resistant generalized deep morphea","volume":"28","year":"2015","journal-title":"Dermatol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e102","DOI":"10.1016\/j.jaad.2010.02.030","article-title":"Imatinib treatment of generalized localized scleroderma (morphea)","volume":"63","author":"Moinzadeh","year":"2010","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_34","first-page":"e191","article-title":"Successful combination treatment of a patient with progressive juvenile localized scleroderma (morphea) using imatinib, corticosteroids, and methotrexate","volume":"30","author":"Inamo","year":"2012","journal-title":"Pediatr. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1016\/j.jid.2019.12.019","article-title":"Jak inhibition prevents bleomycin-induced fibrosis in mice and is effective in patients with morphea","volume":"140","author":"Damsky","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"adv4805","DOI":"10.2340\/actadv.v103.4805","article-title":"Successful treatment of paediatric morphea with tofacitinib","volume":"103","author":"Tang","year":"2023","journal-title":"Acta Derm.-Venereol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1007\/s00296-019-04269-w","article-title":"Challenges in the diagnosis and treatment of disabling pansclerotic morphea of childhood: Case-based review","volume":"39","author":"Soh","year":"2019","journal-title":"Rheumatol. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1007\/s10067-023-06660-2","article-title":"Retrospective comparative study of the efficacy of JAK inhibitor (tofacitinib) in the treatment of systemic sclerosis-associated interstitial lung disease","volume":"42","author":"Zhou","year":"2023","journal-title":"Clin. Rheumatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1546-0096-9-S1-P77","article-title":"Autologous stem cell transplantation in two children with disabling pansclerotic morphea","volume":"9","author":"Moll","year":"2011","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1093\/rheumatology\/keaa193","article-title":"Rituximab for rapidly progressive juvenile systemic sclerosis","volume":"59","author":"Zulian","year":"2020","journal-title":"Rheumatology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kaegi, C., Wuest, B., Schreiner, J., Steiner, U.C., Vultaggio, A., Matucci, A., Crowley, C., and Boyman, O. (2019). Systematic Review of safety and efficacy of rituximab in treating immune-mediated disorders. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01990"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00296-020-04732-z","article-title":"Tocilizumab therapy in juvenile systemic sclerosis: A retrospective single centre pilot study","volume":"41","author":"Adrovic","year":"2020","journal-title":"Rheumatol. Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11795441211066307","DOI":"10.1177\/11795441211066307","article-title":"Problems to consider before determining the regimen of the treatment for juvenile systemic sclerosis treatment: A case report where tocilizumab monotherapy succeeded efficiently and safely","volume":"15","author":"Funauchi","year":"2022","journal-title":"Clin. Med. Insights Arthritis Musculoskelet. Disord."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pin, A., Tesser, A., Pastore, S., Moressa, V., Valencic, E., Arbo, A., Maestro, A., Tommasini, A., and Taddio, A. (2020). Biological and clinical changes in a pediatric series treated with off-label JAK inhibitors. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207767"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1136\/ard.2004.027094","article-title":"Early T cell activation in the skin from patients with systemic sclerosis","volume":"64","author":"Kalogerou","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1136\/annrheumdis-2015-208213","article-title":"Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis","volume":"75","author":"Ponsoye","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s13075-018-1694-9","article-title":"T-cell costimulation blockade is effective in experimental digestive and lung tissue fibrosis","volume":"20","author":"Boleto","year":"2018","journal-title":"Arthritis Res. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/art.41055","article-title":"Abatacept in early diffuse cutaneous systemic sclerosis: Results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial","volume":"72","author":"Khanna","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1080\/1744666X.2020.1813569","article-title":"Efficacy and safety of imatinib mesylate in systemic sclerosis. A systematic review and meta-analysis","volume":"16","author":"Liakouli","year":"2020","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Boutel, M., Boutou, A., Pitsiou, G., Garyfallos, A., and Dimitroulas, T. (2023). Efficacy and safety of nintedanib in patients with connective tissue disease-interstitial lung disease (CTD-ILD): A real-world single center experience. Diagnostics, 13.","DOI":"10.3390\/diagnostics13071221"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/nrrheum.2014.137","article-title":"Transforming growth factor \u03b2\u2014At the centre of systemic sclerosis","volume":"10","author":"Lafyatis","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s13075-017-1356-3","article-title":"Anti-connective tissue growth factor (CTGF\/CCN2) monoclonal antibody attenuates skin fibrosis in mice models of systemic sclerosis","volume":"19","author":"Makino","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/1529-0131(199904)42:4<807::AID-ANR26>3.0.CO;2-T","article-title":"Marked and sustained improvement two years after autologous stem cell transplantation in a girl with systemic sclerosis","volume":"42","author":"Martini","year":"1999","journal-title":"Arthritis Rheum."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s12032-023-02146-y","article-title":"Revolutionizing cancer treatment: A comprehensive review of CAR-T cell therapy","volume":"40","author":"Dabas","year":"2023","journal-title":"Med. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1016\/S0140-6736(19)30546-X","article-title":"Novel paradigms in systemic lupus erythematosus","volume":"393","author":"Furie","year":"2019","journal-title":"Lancet"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41572-021-00321-x","article-title":"Idiopathic inflammatory myopathies","volume":"7","author":"Lundberg","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"eaav1648","DOI":"10.1126\/scitranslmed.aav1648","article-title":"Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus","volume":"11","author":"Kansal","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1056\/NEJMoa2308917","article-title":"CD19 CAR T-cell therapy in autoimmune disease\u2014A case series with follow-up","volume":"390","author":"Taubmann","year":"2024","journal-title":"N. Engl. J. Med."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/5\/643\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:23:13Z","timestamp":1760030593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/5\/643"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,28]]},"references-count":59,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["ph18050643"],"URL":"https:\/\/doi.org\/10.3390\/ph18050643","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,28]]}}}