Abstract
Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and Latin American DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a twofold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤ 15 days in 12 patients (21%) and one patient developed ALF within 7 days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤ 15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.
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Acknowledgements
This publication is based upon work from COST Action “CA17112—Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology). www.cost.eu. The authors NH, MA, IM-C, MR-D, IA-A, HN, CS, MIL and RJA are members of this COST Action. We would like to thank Lucia Hernandez for her commitment and thorough statistical analysis. Clinical collaborating centers of the Latin American DILI Registry: ARGENTINA: Hospital Provincial del Centenario, Rosario. F Bessone, H Tanno, V Reggiardo, S Ferretti, F Tanno, L Arribillaga, M Amateis, Y Zambello, A Ferretti, J Vorobioff, A Galimberti , V Trevizan, M Chiaraviglio, P Caballini, J Montero, J Ortiz, A Rodil, M La Placa, L Zitelli, F Jaureguizahar, A Ferrari, N Tamagnone, S Bulaty, J Pacual, M Tanno, G Carbonetti, G Piñero, L Muñoz, G Carnevale, Y Zambello, M Amateis, C Guerrina, A Wulfson, ML Arribillaga. Hospital Privado de Rosario. A Ruf, M Dirchwolf. Hospital de Córdoba, Ciudad de Córdoba. A Zerega. Hospital Universitario Austral. M Mendizábal, M Silva. Hospital Nacional Alejandro Posadas. G Gualano, E Fassio. Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires. E Ridruejo. Hospital Italiano de Buenos Aires. N Sobenko, J Pizzala, L Haddad, A Villamil, A Gadano. Hospital Británico, Buenos Aires. J Benavidez, N Fernandez, L Colombato. Hospital Eva Perón, Buenos Aires. C Guma. Clínica de Nefrología, Santa Fe. L Gaite. Sanatorio de niños, Rosario. A Costaguta, A Pais. Hospital Alemán, CABA. M Anders. Hospital de infecciosas F.J. Muñiz, CABA. M Peralta, S Campuzano, S Paz, H Famboin. Hospital Italiano de La Plata, La Plata. F Gruz. Hospital Universitario Fundación Favaloro. V Descalzi. Hospital General de Agudos Dr. Cosme Argerich. G Tsariktsian, A Bruno, B Frider. Hospital Santojanni. NE Libaak. Hospital San Bernardo. C Facundo Zarbá. Hospital Aeronáutico Central. P Testa. Hospital Internacional General de Agudos. E Giraudo. Hospital Marcial Quiroga. R Romo. Nuevo Hospital Río Cuarto, Córdoba. C Mendoza. Centro de Hepatología La Plata. S Borzi. Hospital Español, Mendoza. O Galdame, M Paez. Hospital El Cruce, Buenos Aires. F Villamil. Hospital JM Penna. M Mesquida. Hospital Bonorino Udaondo, Buenos Aires. M Cartier. Hospital Presidente Perón de Avellaneda, Buenos Aires. S Chao. Sanatorio San Carlos, Bariloche. C Garcia Dans. BRAZIL: ICHC FMUSP Universidad de Sao Paulo. G Belchior, F Carrilho, SK Ono, N Lopes, G Dagostino, F Roberto, V Alves. CHILE: Pontificia Universidad Católica de Chile. M Arrese, A Ruíz, R Zapata, RM Mellado. Participating clinical centers of the Spanish DILI Registry: Hospital Universitario Virgen de la Victoria, Málaga (coordinating center): RJ Andrade, MI Lucena, C Stephens, M García Cortés, M Robles-Díaz, A Ortega-Alonso, J Pinazo, B García Muñoz, R Alcántara, A Hernández, MD García Escaño, E del Campo, I Medina-Cáliz, J Sanabria-Cabrera, A González-Jiménez, R Sanjuán-Jiménez, A Cueto, I Álvarez-Álvarez, E Bonilla, D Di Zeo, H Niu, M Villanueva, A Papineau; Hospital Torrecárdenas, Almería: MC Fernández, G Peláez, A Porcel, M Casado, M González Sánchez; Hospital Universitario Virgen del Rocío, Sevilla: M Romero-Gómez, R Millán-Domínguez, B Fombuena, R Gallego, J Ampuero, JA del Campo, R Calle-Sanz, L Rojas, A Rojas, A Gil Gómez, E Vilar; Hospital Central de Asturias, Oviedo: R Pérez-Álvarez, L Rodrigo-Sáez.
Funding
The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional—FEDER (contract numbers: PI18-00901; PI 18/01804; PT20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) research contract from ISCIII and Consejería de Salud de Andalucía, IAA holds a Sara Borrell research contract from the National Health System, ISCIII (CD 20/00083).
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Guarantor of the article: FB, MIL. Specific author contributions: FB, RJA and MIL wrote the manuscript; FB, RJA and MIL designed the study; FB, NH, MM, ER, GG, EF, MP, HF, MA, HT, FT, RP, IM-C, MR-D, CS,LC,MA,MVR,SKO and FC performed the research; FB, IA-A, HN, CS, MR-D, IM-C and MIL analyzed the data. All authors approved the final version of the manuscript.
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The study protocol was approved by the local Ethics Committee at the Hospital Provincial del Centenario, Rosario, Argentina and at the Virgen de la Victoria University Hospital in Málaga, Spain, and all subjects gave informed consent.
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M. Isabel Lucena and Raul J. Andrade share senior authorship.
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Bessone, F., Hernandez, N., Mendizabal, M. et al. Serious liver injury induced by Nimesulide: an international collaborative study. Arch Toxicol 95, 1475–1487 (2021). https://doi.org/10.1007/s00204-021-03000-8
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DOI: https://doi.org/10.1007/s00204-021-03000-8