{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:16:56Z","timestamp":1790662616419,"version":"4.1.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,14]],"date-time":"2019-09-14T00:00:00Z","timestamp":1568419200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,9,14]],"date-time":"2019-09-14T00:00:00Z","timestamp":1568419200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF- 2010-2320172"],"award-info":[{"award-number":["RF- 2010-2320172"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Nephrol"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n              <jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Evidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>During the years 2009\u20132015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30\u2009days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180\u2009days after ID) were calculated and defined as delta Hb (\u0394Hb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one \u0394Hb\u2009&lt;\u20090\u2009g\/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>`In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR\u2009=\u20091.2, 95% CI: 1.0\u20131.5; <jats:italic>P<\/jats:italic>-value\u2009=\u20090.060) and high levels of baseline Hb (OR\u2009=\u20091.7, 95% CI: 1.2\u20132.2; <jats:italic>P<\/jats:italic>-value&lt;\u20090,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR\u2009=\u20091.7, 95% CI: 1.1\u20132.4; <jats:italic>P<\/jats:italic>-value\u2009=\u20090.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR\u2009=\u20090.3, 95% CI: 0.2\u20130.7; <jats:italic>P<\/jats:italic>-value\u2009=\u20090.002) and of high dosage of angiotensin-converting enzyme inhibitors\/angiotensin II-receptor blockers (OR\u2009=\u20090.5, 95% CI: 0.3\u20130.9; <jats:italic>P<\/jats:italic>-value\u2009=\u20090.022) were protective factors against ESA hyporesponsiveness.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients\u2019 quality of life.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12882-019-1554-0","type":"journal-article","created":{"date-parts":[[2019,9,14]],"date-time":"2019-09-14T07:02:52Z","timestamp":1568444572000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9549-6111","authenticated-orcid":false,"given":"Ylenia","family":"Ingrasciotta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Lacava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Marcian\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Giorgianni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Tripepi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella","family":"D\u2019 Arrigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Chinellato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Ugo Tari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Santoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Trifir\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,14]]},"reference":[{"key":"1554_CR1","unstructured":"Determinazione AIFA. Aggiornamento del Piano terapeutico AIFA per prescrizione SSN di Eritropoietine (ex Nota 12). \n                  http:\/\/www.agenziafarmaco.gov.it\/sites\/default\/files\/2010-07-29_determina_aggiornamento_template_nota_12_g.u._75_del_31-03-2009.pdf\n                  \n                . Accessed 12 June 2018."},{"key":"1554_CR2","doi-asserted-by":"publisher","first-page":"e9246","DOI":"10.1371\/journal.pone.0009246","volume":"5","author":"EV Khankin","year":"2012","unstructured":"Khankin EV, Mutter WP, Tamez H, Yuan HT, Karumanchi SA, Thadhani R. Soluble erythropoietin receptor contributes to erythropoietin resistance in end-stage renal disease. PLoS One. 2012;5:e9246.","journal-title":"PLoS One"},{"key":"1554_CR3","unstructured":"International Society of Nephrology. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney In Suppl. 2012;2(Issue 4. Chapter 3):299\u2013310."},{"key":"1554_CR4","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s12882-015-0138-x","volume":"16","author":"SP Sibbel","year":"2015","unstructured":"Sibbel SP, Koro CE, Brunelli SM, Cobitz AR. Characterization of chronic and acute ESA hyporesponse: a retrospective cohort study of hemodialysis patients. BMC Nephrol. 2015;16:144.","journal-title":"BMC Nephrol"},{"issue":"5","key":"1554_CR5","doi-asserted-by":"publisher","first-page":"e0155805","DOI":"10.1371\/journal.pone.0155805","volume":"11","author":"Y Ingrasciotta","year":"2016","unstructured":"Ingrasciotta Y, Giorgianni F, Marcian\u00f2 I, Bolcato J, Pirolo R, Chinellato A, Ientile V, Santoro D, Genazzani AA, Alibrandi A, Fontana A, Caputi AP, Trifir\u00f2 G. Comparative effectiveness of biosimilar, reference product and other erythropoiesis-stimulating agents (ESAs) still covered by patent in chronic kidney disease and cancer patients: an Italian population-based study. PLoS One. 2016;11(5):e0155805.","journal-title":"PLoS One"},{"key":"1554_CR6","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/ki.2008.295","volume":"74","author":"LA Szczech","year":"2008","unstructured":"Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved haemoglobin outcomes. Kidney Int. 2008;74:791\u20138.","journal-title":"Kidney Int"},{"issue":"14","key":"1554_CR7","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/1471-2369-14-200","volume":"25","author":"MM Suttorp","year":"2013","unstructured":"Suttorp MM, Hoekstra T, Rotmans JI, Ott I, Mittelman M, Krediet RT, Dekker FW. Erythropoiesis-stimulating agent resistance and mortality in hemodialysis and peritoneal dialysis patients. BMC Nephrol. 2013;25(14):200.","journal-title":"BMC Nephrol"},{"key":"1554_CR8","doi-asserted-by":"publisher","first-page":"133","DOI":"10.2215\/CJN.01610407","volume":"3","author":"DT Gilbertson","year":"2008","unstructured":"Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury BD. Hemoglobin level variability: associations with mortality. Clin J Am Soc Nephrol. 2008;3:133\u20138.","journal-title":"Clin J Am Soc Nephrol"},{"key":"1554_CR9","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1093\/ndt\/gfk011","volume":"21","author":"F Locatelli","year":"2006","unstructured":"Locatelli F, Andrulli S, Memoli B, Maffei C, Del Vecchio L, Aterini S, De Simone W, Mandalari A, Brunori G, Amato M, Cianciaruso B, Zoccali C. Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant. 2006;21:991\u20138.","journal-title":"Nephrol Dial Transplant"},{"key":"1554_CR10","doi-asserted-by":"crossref","unstructured":"KDOQI. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5 Suppl 3):S11\u2013145.","DOI":"10.1053\/j.ajkd.2006.03.011"},{"issue":"8","key":"1554_CR11","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1093\/ndt\/14.8.1836","volume":"14","author":"IC Macdougall","year":"1999","unstructured":"Macdougall IC. The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin. Nephrol Dial Transplant. 1999;14(8):1836\u201341.","journal-title":"Nephrol Dial Transplant"},{"issue":"4","key":"1554_CR12","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/s40259-015-0132-7","volume":"29","author":"Y Ingrasciotta","year":"2015","unstructured":"Ingrasciotta Y, Giorgianni F, Bolcato J, Chinellato A, Pirolo R, Tari DU, Troncone C, Fontana A, Ientile V, Gini R, Santoro D, Santarpia M, Gennazzani A, Uomo I, Pastorello M, Pollina Addario WS, Scondotto S, Cananzi P, Caputi AP, Trifir\u00f2 G. How much are biosimilars used in clinical practice? A retrospective Italian population-based study of erythropoiesis-stimulating agents in the years 2009-2013. BioDrugs. 2015;29(4):275\u201384.","journal-title":"BioDrugs."},{"key":"1554_CR13","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1056\/NEJMoa1005109","volume":"363","author":"SD Solomon","year":"2010","unstructured":"Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, de Zwwuw D, Ivanovich P, Levey AS, Parfrey P, Remuzzi G, Singh AK, Toto R, Huang F, Rossert J, McMurray JJ, Pfeffer MA. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:1146\u201355.","journal-title":"N Engl J Med"},{"issue":"7","key":"1554_CR14","doi-asserted-by":"publisher","first-page":"2880","DOI":"10.1093\/ndt\/gfs007","volume":"27","author":"R Minutolo","year":"2012","unstructured":"Minutolo R, Conte G, Cianciaruso B, Bellizzi V, Camocardi A, De Paola L, De Nicola L. Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients. Nephrol Dial Transplant. 2012;27(7):2880\u20136.","journal-title":"Nephrol Dial Transplant"},{"key":"1554_CR15","doi-asserted-by":"publisher","first-page":"i18","DOI":"10.1093\/ndtplus\/sfn176","volume":"2","author":"ALM De Francisco","year":"2009","unstructured":"De Francisco ALM, Stenvinkel P, Vaulont S. Inflammation and its impact on anaemia in chronic kidney disease: from haemoglobin variability to hyporesponsiveness. NDT Plus. 2009;2 [Suppl 1:i18\u201326. \n                  https:\/\/doi.org\/10.1093\/ndtplus\/sfn176\n                  \n                .","journal-title":"NDT Plus"},{"key":"1554_CR16","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/S0272-6386(03)00915-6","volume":"42","author":"K Kalantar-Zadeh","year":"2003","unstructured":"Kalantar-Zadeh K, McAllister CJ, Lehn RS, Lee GH, Nissenson AR, Kopple JD. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis. 2003;42:761\u201373.","journal-title":"Am J Kidney Dis"},{"issue":"2","key":"1554_CR17","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1159\/000438870","volume":"131","author":"M Kimachi","year":"2015","unstructured":"Kimachi M, Fukuma S, Yamazaki S, Yamamoto Y, Akizawa T, Akiba T, Saito A, Fukuhara S. Minor elevation in C-reactive protein levels predicts incidence of erythropoiesis-stimulating agent hyporesponsiveness among hemodialysis. Patients Nephron. 2015;131(2):123\u201330.","journal-title":"Patients Nephron"},{"issue":"Suppl 111","key":"1554_CR18","doi-asserted-by":"publisher","first-page":"S75","DOI":"10.1038\/ki.2008.523","volume":"74","author":"J L\u00f3pez-G\u00f3mez","year":"2008","unstructured":"L\u00f3pez-G\u00f3mez J, Portol\u00e9s J, Aljama P. Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int. 2008;74(Suppl 111):S75\u201381.","journal-title":"Kidney Int"},{"key":"1554_CR19","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1053\/j.ajkd.2008.12.040","volume":"53","author":"K Kalantar-Zadeh","year":"2009","unstructured":"Kalantar-Zadeh K, Lee GH, Miller JE, Streja E, Jing J, Robertson JA, Kovesdy CP. Predictors of hyporesponsiveness to erythropoiesis stimulating agents in hemodialysis patients. Am J Kidney Dis. 2009;53:823\u201334.","journal-title":"Am J Kidney Dis"},{"issue":"3","key":"1554_CR20","doi-asserted-by":"publisher","first-page":"e0147328","DOI":"10.1371\/journal.pone.0147328","volume":"11","author":"T Kuragano","year":"2016","unstructured":"Kuragano T, Kitamura K, Matsumura O, Matsuda A, Hara T, Kiyomoto H, Murata T, Fujimoto S, Hase H, Joki N, Fukatsu A, Inoue T, Itakura Y, Nakanishi T. ESA hyporesponsiveness is associated with adverse events in maintenance hemodialysis (MHD) patients, but not with iron storage. PLoS One. 2016;11(3):e0147328.","journal-title":"PLoS One"},{"key":"1554_CR21","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1159\/000335256","volume":"33","author":"S Mallick","year":"2012","unstructured":"Mallick S, Rafiroiu A, Kanthety R, Iqbal S, Malik R, Rahman M. Factors predicting erythropoietin resistance among maintenance hemodialysis patients. Blood Purif. 2012;33:238\u201344.","journal-title":"Blood Purif"},{"key":"1554_CR22","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1182\/blood.V61.4.799.799","volume":"61","author":"T Uchida","year":"1983","unstructured":"Uchida T, Akitsuki T, Kimura H, Tanaka T, Matsuda S, Kariyone S. Relationship among plasma iron, plasma iron turnover, and reticuloendothelial iron release. Blood. 1983;61:799\u2013802.","journal-title":"Blood"},{"issue":"3","key":"1554_CR23","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1093\/ndt\/gfl716","volume":"22","author":"J Rossert","year":"2007","unstructured":"Rossert J, Gassmann-Mayer C, Frei D, McClellan W. Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients. Nephrol Dial Transplant. 2007;22(3):794\u2013800.","journal-title":"Nephrol Dial Transplant"},{"key":"1554_CR24","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/1471-2369-14-44","volume":"14","author":"DT Gilbertson","year":"2013","unstructured":"Gilbertson DT, Peng Y, Arneson TJ, Dunning S, Collins AJ. Comparison of methodologies to define hemodialysis patients hyporesponsive to epoetin and impact on counts and characteristics. BMC Nephrol. 2013;14:44.","journal-title":"BMC Nephrol"},{"key":"1554_CR25","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1093\/oxfordjournals.ndt.a027287","volume":"11","author":"S Erturk","year":"1996","unstructured":"Erturk S, Ates K, Duman N, Karatan O, Erbay B, Ertug E. Unresponsiveness to recombinant human erythropoietin in haemodialysis patients: possible implications of angiotensin-converting enzyme inhibitors. Nephrol Dial Transplant. 1996;11:396\u20137.","journal-title":"Nephrol Dial Transplant"},{"issue":"1","key":"1554_CR26","first-page":"53","volume":"43","author":"DV Vlahakos","year":"1995","unstructured":"Vlahakos DV, Balodimos C, Papachristopoulos V, Vassilakos P, Hinari E, Vlachojannis JG. Renin-angiotensin system stimulates erythropoietin secretion in chronic hemodialysis patients. Clin Nephrol. 1995;43(1):53\u20139.","journal-title":"Clin Nephrol"},{"issue":"2","key":"1554_CR27","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/S0272-6386(12)81129-2","volume":"17","author":"DV Vlahakos","year":"1991","unstructured":"Vlahakos DV, Canzanello VJ, Madaio MP, Madias NE. Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis. 1991;17(2):199\u2013205.","journal-title":"Am J Kidney Dis"},{"issue":"3","key":"1554_CR28","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1172\/JCI118484","volume":"97","author":"M Azizi","year":"1996","unstructured":"Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM, Lenfant M, Corvol P, M\u00e9nard J. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest. 1996;97(3):839\u201344.","journal-title":"J Clin Invest"},{"issue":"3","key":"1554_CR29","first-page":"343","volume":"32","author":"M\u00c1 Guerrero-Riscos","year":"2012","unstructured":"Guerrero-Riscos M\u00c1, Montes-Delgado R, Seda-Guzm\u00e1n M, Praena-Fern\u00e0ndez JM. Erythropoietin resistance and survival in non-dialysis patients with stage 4\u20135 chronic kidney disease and heart disease. Nefrologia. 2012;32(3):343\u201352.","journal-title":"Nefrologia"},{"issue":"1","key":"1554_CR30","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/ncpneph0655","volume":"4","author":"K Van der Putten","year":"2008","unstructured":"Van der Putten K, Braam B, Jie KE, Gaillard CA. Mechanisms of disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Clin Pract Nephrol. 2008;4(1):47\u201357.","journal-title":"Nat Clin Pract Nephrol"},{"key":"1554_CR31","unstructured":"Ministero della Salute, Agenzia Italiana del Farmaco (AIFA). Circolare AIFA del 3 agosto 2007. Linee guida per la classificazione e conduzione degli studi osservazionali sui farmaci. \n                  http:\/\/xoomer.virgilio.it\/pgiuff\/osservazionali.pdf\n                  \n                . Accessed 9 Sept 2019."}],"updated-by":[{"DOI":"10.1186\/s12882-020-01891-w","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T00:00:00Z","timestamp":1594252800000}}],"container-title":["BMC Nephrology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12882-019-1554-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12882-019-1554-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12882-019-1554-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T09:12:27Z","timestamp":1600074747000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcnephrol.biomedcentral.com\/articles\/10.1186\/s12882-019-1554-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,14]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1554"],"URL":"https:\/\/doi.org\/10.1186\/s12882-019-1554-0","relation":{"correction":[{"id-type":"doi","id":"10.1186\/s12882-020-01891-w","asserted-by":"object"}]},"ISSN":["1471-2369"],"issn-type":[{"value":"1471-2369","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,14]]},"assertion":[{"value":"20 September 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All procedures performed in this study were in accordance with the Ethical Standards of the Ethics Committee of the Academic Hospital of Messina and of Treviso, according to the current national law [], and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The manuscript does not contain clinical studies, and all patient data were fully anonymized. For this type of study, formal consent is not required.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Gianluca Trifir\u00f2 declares his participation to advisory boards on biosimilars, organized by Sandoz and Hospira; furthermore, he coordinates a pharmacoepidemiology research team at the University of Messina, which receives research grants for projects that are not related to the topic of the paper. Ylenia Ingrasciotta, Viviana Lacava, Ilaria Marcian\u00f2, Francesco Giorgianni, Giovanni Tripepi, Graziella D\u2019Arrigo, Alessandro Chinellato, Daniele Ugo Tari, Domenico Santoro declare that they have no conflicts of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"359"}}