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Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study

by 1,*,†, 1,†, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 1, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 11, 110, 110, 1 and add Show full author list remove Hide full author list
1
Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28006 Madrid, Spain
2
Department of Gastroenterology, Hospital Universitario Virgen del Rocío, 41013 Sevilla, Spain
3
Department of Gastroenterology, Hospital Universitario A Coruña, 15006 A Coruña, Spain
4
Department of Gastroenterology, Complejo Hospitalario de Navarra, 31008 Pamplona, Spain
5
Department of Gastroenterology, Hospital Universitario Central de Asturias and ISPA, 33011 Oviedo, Spain
6
Department of Gastroenterology, Complejo Hospitalario Universitario Ntra. Sra. de Candelaria, 38010 Santa Cruz de Tenerife, Spain
7
Department of Gastroenterology, Hospital Universitario Reina Sofía and IMIBIC, 14004 Córdoba, Spain
8
Department of Gastroenterology, Complexo Hospitalario Universitario de Pontevedra, Instituto de Investigación Sanitaria Galicia Sur, 36071 Pontevedra, Spain
9
Department of Gastroenterology, Hospital Ramón y Cajal, 28034 Madrid, Spain
10
Department of Gastroenterology, Hospital Álvaro Cunqueiro, Estrutura Organizativa de Xestión Integrada de Vigo, 36213 Vigo, Spain
11
Department of Gastroenterology, Complexo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
12
Department of Gastroenterology, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain
13
Department of Gastroenterology, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain
14
Department of Gastroenterology, Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain
15
Department of Gastroenterology, Hospital Universitario de Burgos, 09006 Burgos, Spain
16
Department of Gastroenterology, Hospital Universitario La Paz, 28046 Madrid, Spain
17
Servei de Malalties Digestives, Hospital de Sabadell, Institut Universitari Parc Taulí, Universitat Autònoma de Barcelona, CIBEREHD—Instituto de Salud Carlos III, Parc Taulí, 1, 08208 Sabadell, Barcelona, Spain
18
Department of Gastroenterology, Hospital Universitari Son Espases, 07120 Palma de Mallorca, Spain
19
Department of Gastroenterology, Hospital Universitario de Canarias (H.U.C.), 38320 Santa Cruz de Tenerife, Spain
20
Department of Gastroenterology, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain
21
Department of Gastroenterology, Hospital de Cabueñes, 33394 Gijón, Spain
22
Department of Gastroenterology, Hospital Universitario Marqués de Valdecilla and IDIVAL, 39008 Santander, Spain
23
Department of Gastroenterology, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain
24
Department of Gastroenterology, Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain
25
Department of Gastroenterology, Hospital Clínico Universitario de Valencia, Universitat de València, 46010 Valencia, Spain
26
Department of Gastroenterology, Complejo Asistencial Universitario de León, 24001 León, Spain
27
Department of Gastroenterology, Hospital de Galdakao-Usansolo, Galdakao, 48960 Vizcaya, Spain
28
Department of Gastroenterology, Hospital Universitari i Politecnic La Fe and CIBERehd, 46026 Valencia, Spain
29
Department of Gastroenterology, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
30
Department of Gastroenterology, Hospital de Sant Joan Despí Moisès Broggi, 08970 Barcelona, Spain
31
Department of Gastroenterology, Complejo Hospitalario Universitario de Ferrol, 15405 A Coruña, Spain
32
Department of Gastroenterology, Hospital Clínico Universitario “Lozano Blesa”, IIS Aragón and CIBERehd, 50009 Zaragoza, Spain
33
Department of Gastroenterology, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas, Spain
34
Department of Gastroenterology, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
35
Department of Gastroenterology, Hospital Universitario de Araba (sede Txagorritxu y sede Santiago), 01009 Álava, Spain
36
Department of Gastroenterology, Hospital Universitario de Basurto, 48013 Bilbao, Spain
37
Department of Gastroenterology, Hospital General Universitario J.M. Morales Meseguer, 30008 Murcia, Spain
38
Department of Gastroenterology, Hospital General Universitario de Alicante and CIBERehd, 03010 Alicante, Spain
39
Department of Gastroenterology, Hospital Universitario Donostia-Donostia Unibertsitate Ospitalea, Guipuzkoa and Organizacion Sanitaria Integrada Tolosaldea, Clínica Santa María de la Asunción, 20014 Guipúzcoa, Spain
40
Department of Gastroenterology, Complejo Hospitalario de Especialidades Torrecárdenas, 04009 Almería, Spain
41
Department of Gastroenterology, Hospital Universitario Insular de Gran Canaria, 35016 Las Palmas, Spain
42
Department of Gastroenterology, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain
43
Department of Gastroenterology, Hospital Son Llatzer, 07198 Palma de Mallorca, Spain
44
Department of Gastroenterology, Hospital Francesc De Borja de Gandía, 46702 Valencia, Spain
45
Department of Gastroenterology, Hospital Universitario de Cáceres, 10004 Cáceres, Spain
46
Department of Gastroenterology, Hospital Universitario Fundación Jiménez Díaz, 28040 Madrid, Spain
47
Department of Gastroenterology, Hospital General Universitario de Elche, 03203 Alicante, Spain
48
Department of Gastroenterology, Hospital Universitari Mutua Terrasa, 08221 Terrassa, Spain
49
Department of Gastroenterology, Hospital San Agustín, 33401 Avilés, Spain
50
Department of Gastroenterology, Hospital Virgen de La Concha, Complejo Asistencial de Zamora, 49022 Zamora, Spain
51
Department of Gastroenterology, CSDM, Hospital de Mataró, 08304 Barcelona, Spain
52
Department of Gastroenterology, Hospital Universitario Arnau de Vilanova, 25198 Lérida, Spain
53
Department of Gastroenterology, Hospital De Villajoyosa, 03570 Alicante, Spain
54
Department of Gastroenterology, Hospital de Mérida, 06800 Mérida, Spain
55
Department of Gastroenterology, Hospital San Pedro, 26006 Logroño, Spain
56
Department of Gastroenterology, Hospital da Costa (EOXI Lugo-Cervo-Monforte), 27880 Lugo, Spain
57
Department of Gastroenterology, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain
58
Department of Gastroenterology, Hospital General de Tomelloso, 13700 Tomelloso, Spain
59
Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain
60
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28006 Madrid, Spain
61
Department of Gastroenterology, Hospital General Universitario de Castellón, 12004 Castellón, Spain
62
Department of Gastroenterology, Hospital Universitario de Fuenlabrada and Instituto de Investigación Sanitaria Hospital La Paz (IdiPaz), 28942 Madrid, Spain
63
Department of Gastroenterology, Hospital Lluis Alcanyis, Xátiva, 46800 Valencia, Spain
64
Department of Gastroenterology, Hospital Joan XXIII, 43005 Tarragona, Spain
65
Department of Gastroenterology, Hospital Povisa, 36211 Pontevedra, Spain
66
Department of Gastroenterology, Complejo Hospitalario de Especialidades Virgen de la Victoria, 29010 Málaga, Spain
67
Department of Gastroenterology, Parc Sanitari Sant Joan de Déu, 08830 Barcelona, Spain
68
Department of Gastroenterology, Hospital de Manises, 46940 Valencia, Spain
69
Department of Gastroenterology, Hospital Royo Villanova, 50015 Zaragoza, Spain
70
Department of Gastroenterology, Complexo Hospitalario Universitario Xeral-Calde de Lugo, 27004 Lugo, Spain
71
Department of Gastroenterology, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón (IiSGM), 28007 Madrid, Spain
72
Department of Gastroenterology, Hospital Universitario Infanta Cristina, 28981 Madrid, Spain
73
Department of Gastroenterology, Hospital de Manacor, 07500 Manacor, Spain
74
Department of Gastroenterology, Hospital Doctor José Molina Orosa, 35500 Lanzarote, Spain
75
Department of Gastroenterology, Hospital Comarcal Sierrallana, 39300 Torrelavega, Spain
76
Department of Gastroenterology, Hospital Santa Bárbara, 13500 Puertollano, Spain
77
Department of Gastroenterology, Hospital Rey Juan Carlos, 28933 Madrid, Spain
78
Department of Gastroenterology, Hospital Universitario de Getafe, 28905 Madrid, Spain
79
Department of Gastroenterology, Hospital General Universitario Reina Sofía, 30003 Murcia, Spain
80
Department of Gastroenterology, Hospital Reina Sofía, 31500 Tudela, Spain
81
Department of Gastroenterology, Hospital Puerta del Mar, 11009 Cádiz, Spain
82
Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
83
Department of Gastroenterology, Hospital San Jorge, 22004 Huesca, Spain
84
Department of Gastroenterology, Hospital San Juan de Dios del Aljarafe, 41930 Sevilla, Spain
85
Department of Gastroenterology, Hospital Can Misses, 07800 Ibiza, Spain
86
Department of Gastroenterology, Hospital Sant Joan de Deu, 08950 Barcelona, Spain
87
Department of Gastroenterology, Hospital Universitari Sant Joan, 25001 Lérida, Spain
88
Department of Gastroenterology, Hospital General de La Palma, 38713 Santa Cruz de Tenerife, Spain
89
Department of Gastroenterology, Hospital Santa Caterina, 17190 Gerona, Spain
90
Department of Gastroenterology, Hospital Palamós, 17230 Girona, Spain
91
Department of Gastroenterology, Hospital Comarcal de Inca, 07300 Inca, Spain
92
Department of Gastroenterology, Hospital General La Mancha Centro, 13600 Ciudad Real, Spain
93
Department of Gastroenterology, Hospital García Orcoyen, 31200 Estella, Spain
94
Department of Gastroenterology, Hospital Sagrat Cor, 08029 Barcelona, Spain
95
Department of Gastroenterology, Hospital de Torrejón, 28850 Madrid, Spain
96
Department of Gastroenterology, Hospital de Mendaro, 20850 Guipuzkoa, Spain
97
Department of Gastroenterology, Hospital Obispo Polanco, 44002 Teruel, Spain
98
Department of Gastroenterology, Hospital General Universitario Los Arcos del Mar Menor, San Javier, 30739 Murcia, Spain
99
Department of Gastroenterology, Hospital General de Villarobledo, 02600 Albacete, Spain
100
Department of Gastroenterology, Hospital Medina del Campo, 47400 Valladolid, Spain
101
Department of Gastroenterology, Hospital de Montilla, 14550 Córdoba, Spain
102
Department of Gastroenterology, Hospital Quirón Costa Adeje, 38660 Santa Cruz de Tenerife, Spain
103
Department of Gastroenterology, Hospital Santos Reyes, 09400 Aranda de Duero, Spain
104
Department of Gastroenterology, Clínica Astarté, 11011 Cádiz, Spain
105
Department of Gastroenterology, Hospital Ernest Lluch, 50299 Zaragoza, Spain
106
Department of Gastroenterology, Hospital Central de La Cruz Roja San José y Santa Adela, 28003 Madrid, Spain
107
Department of Gastroenterology, Hospital San Juan De Dios, 38009 Tenerife, Spain
108
Department of Gastroenterology, Hospital Virgen de Altagracia, 13002 Manzanares, Spain
109
Department of Gastroenterology, Hospital Dexeus, 08028 Barcelona, Spain
110
Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid/IdiPaz and CIBERESP, 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Both authors share first authorship.
Membership of the EpidemIBD study group of GETECCU is provided in the Acknowledgments.
Academic Editor: Angelo Viscido
J. Clin. Med. 2021, 10(13), 2885; https://doi.org/10.3390/jcm10132885
Received: 19 May 2021 / Revised: 7 June 2021 / Accepted: 15 June 2021 / Published: 29 June 2021
(This article belongs to the Special Issue Novel Insight into the Diagnosis and Management of Crohn’s Disease)
(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD—Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)—during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31–56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery. View Full-Text
Keywords: epidemiology; incidence; inflammatory bowel disease; Crohn’s disease; ulcerative colitis epidemiology; incidence; inflammatory bowel disease; Crohn’s disease; ulcerative colitis
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MDPI and ACS Style

Chaparro, M.; Garre, A.; Núñez Ortiz, A.; Diz-Lois Palomares, M.T.; Rodríguez, C.; Riestra, S.; Vela, M.; Benítez, J.M.; Fernández Salgado, E.; Sánchez Rodríguez, E.; Hernández, V.; Ferreiro-Iglesias, R.; Ponferrada Díaz, Á.; Barrio, J.; Huguet, J.M.; Sicilia, B.; Martín-Arranz, M.D.; Calvet, X.; Ginard, D.; Alonso-Abreu, I.; Fernández-Salazar, L.; Varela Trastoy, P.; Rivero, M.; Vera-Mendoza, I.; Vega, P.; Navarro, P.; Sierra, M.; Cabriada, J.L.; Aguas, M.; Vicente, R.; Navarro-Llavat, M.; Echarri, A.; Gomollón, F.; Guerra del Río, E.; Piñero, C.; Casanova, M.J.; Spicakova, K.; Ortiz de Zarate, J.; Torrella Cortés, E.; Gutiérrez, A.; Alonso-Galán, H.; Hernández-Martínez, Á.; Marrero, J.M.; Lorente Poyatos, R.; Calafat, M.; Martí Romero, L.; Robledo, P.; Bosch, O.; Jiménez, N.; Esteve Comas, M.; Duque, J.M.; Fuentes Coronel, A.M.; Josefa Sampedro, M.; Sesé Abizanda, E.; Herreros Martínez, B.; Pozzati, L.; Fernández Rosáenz, H.; Crespo Suarez, B.; López Serrano, P.; Lucendo, A.J.; Muñoz Vicente, M.; Bermejo, F.; Ramírez Palanca, J.J.; Menacho, M.; Carmona, A.; Camargo, R.; Torra Alsina, S.; Maroto, N.; Nerín de la Puerta, J.; Castro, E.; Marín-Jiménez, I.; Botella, B.; Sapiña, A.; Cruz, N.; Forcelledo, J.L.F.; Bouhmidi, A.; Castaño-Milla, C.; Opio, V.; Nicolás, I.; Kutz, M.; Abraldes Bechiarelli, A.; Gordillo, J.; Ber, Y.; Torres Domínguez, Y.; Novella Durán, M.T.; Rodríguez Mondéjar, S.; Martínez-Cerezo, F.J.; Kolle, L.; Sabat, M.; Ledezma, C.; Iyo, E.; Roncero, Ó.; Irisarri, R.; Lluis, L.; Blázquez Gómez, I.; Zapata, E.M.; José Alcalá, M.; Martínez Pascual, C.; Montealegre, M.; Mata, L.; Monrobel, A.; Hernández Camba, A.; Hernández, L.; Tejada, M.; Mir, A.; Galve, M.L.; Soler, M.; Hervías, D.; Gómez-Valero, J.A.; Barreiro-de Acosta, M.; Rodríguez-Artalejo, F.; García-Esquinas, E.; Gisbert, J.P.; on behalf of the EpidemIBD study group of GETECCU. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885. https://doi.org/10.3390/jcm10132885

AMA Style

Chaparro M, Garre A, Núñez Ortiz A, Diz-Lois Palomares MT, Rodríguez C, Riestra S, Vela M, Benítez JM, Fernández Salgado E, Sánchez Rodríguez E, Hernández V, Ferreiro-Iglesias R, Ponferrada Díaz Á, Barrio J, Huguet JM, Sicilia B, Martín-Arranz MD, Calvet X, Ginard D, Alonso-Abreu I, Fernández-Salazar L, Varela Trastoy P, Rivero M, Vera-Mendoza I, Vega P, Navarro P, Sierra M, Cabriada JL, Aguas M, Vicente R, Navarro-Llavat M, Echarri A, Gomollón F, Guerra del Río E, Piñero C, Casanova MJ, Spicakova K, Ortiz de Zarate J, Torrella Cortés E, Gutiérrez A, Alonso-Galán H, Hernández-Martínez Á, Marrero JM, Lorente Poyatos R, Calafat M, Martí Romero L, Robledo P, Bosch O, Jiménez N, Esteve Comas M, Duque JM, Fuentes Coronel AM, Josefa Sampedro M, Sesé Abizanda E, Herreros Martínez B, Pozzati L, Fernández Rosáenz H, Crespo Suarez B, López Serrano P, Lucendo AJ, Muñoz Vicente M, Bermejo F, Ramírez Palanca JJ, Menacho M, Carmona A, Camargo R, Torra Alsina S, Maroto N, Nerín de la Puerta J, Castro E, Marín-Jiménez I, Botella B, Sapiña A, Cruz N, Forcelledo JLF, Bouhmidi A, Castaño-Milla C, Opio V, Nicolás I, Kutz M, Abraldes Bechiarelli A, Gordillo J, Ber Y, Torres Domínguez Y, Novella Durán MT, Rodríguez Mondéjar S, Martínez-Cerezo FJ, Kolle L, Sabat M, Ledezma C, Iyo E, Roncero Ó, Irisarri R, Lluis L, Blázquez Gómez I, Zapata EM, José Alcalá M, Martínez Pascual C, Montealegre M, Mata L, Monrobel A, Hernández Camba A, Hernández L, Tejada M, Mir A, Galve ML, Soler M, Hervías D, Gómez-Valero JA, Barreiro-de Acosta M, Rodríguez-Artalejo F, García-Esquinas E, Gisbert JP, on behalf of the EpidemIBD study group of GETECCU. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. Journal of Clinical Medicine. 2021; 10(13):2885. https://doi.org/10.3390/jcm10132885

Chicago/Turabian Style

Chaparro, María, Ana Garre, Andrea Núñez Ortiz, María T. Diz-Lois Palomares, Cristina Rodríguez, Sabino Riestra, Milagros Vela, José M. Benítez, Estela Fernández Salgado, Eugenia Sánchez Rodríguez, Vicent Hernández, Rocío Ferreiro-Iglesias, Ángel Ponferrada Díaz, Jesús Barrio, José M. Huguet, Beatriz Sicilia, María D. Martín-Arranz, Xavier Calvet, Daniel Ginard, Inmaculada Alonso-Abreu, Luis Fernández-Salazar, Pilar Varela Trastoy, Montserrat Rivero, Isabel Vera-Mendoza, Pablo Vega, Pablo Navarro, Mónica Sierra, José L. Cabriada, Mariam Aguas, Raquel Vicente, Mercè Navarro-Llavat, Ana Echarri, Fernando Gomollón, Elena Guerra del Río, Concepción Piñero, María J. Casanova, Katerina Spicakova, Jone Ortiz de Zarate, Emilio Torrella Cortés, Ana Gutiérrez, Horacio Alonso-Galán, Álvaro Hernández-Martínez, José M. Marrero, Rufo Lorente Poyatos, Margalida Calafat, Lidia Martí Romero, Pilar Robledo, Orencio Bosch, Nuria Jiménez, María Esteve Comas, José M. Duque, Ana M. Fuentes Coronel, Manuela Josefa Sampedro, Eva Sesé Abizanda, Belén Herreros Martínez, Liliana Pozzati, Hipólito Fernández Rosáenz, Belén Crespo Suarez, Pilar López Serrano, Alfredo J. Lucendo, Margarita Muñoz Vicente, Fernando Bermejo, José J. Ramírez Palanca, Margarita Menacho, Amalia Carmona, Raquel Camargo, Sandra Torra Alsina, Nuria Maroto, Juan Nerín de la Puerta, Elena Castro, Ignacio Marín-Jiménez, Belén Botella, Amparo Sapiña, Noelia Cruz, José L.F. Forcelledo, Abdel Bouhmidi, Carlos Castaño-Milla, Verónica Opio, Isabel Nicolás, Marcos Kutz, Alfredo Abraldes Bechiarelli, Jordi Gordillo, Yolanda Ber, Yolanda Torres Domínguez, María T. Novella Durán, Silvia Rodríguez Mondéjar, Francisco J. Martínez-Cerezo, Lilyan Kolle, Miriam Sabat, Cesar Ledezma, Eduardo Iyo, Óscar Roncero, Rebeca Irisarri, Laia Lluis, Isabel Blázquez Gómez, Eva M. Zapata, María José Alcalá, Cristina Martínez Pascual, María Montealegre, Laura Mata, Ana Monrobel, Alejandro Hernández Camba, Luis Hernández, María Tejada, Alberto Mir, María L. Galve, Marta Soler, Daniel Hervías, José A. Gómez-Valero, Manuel Barreiro-de Acosta, Fernando Rodríguez-Artalejo, Esther García-Esquinas, Javier P. Gisbert, and on behalf of the EpidemIBD study group of GETECCU. 2021. "Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study" Journal of Clinical Medicine 10, no. 13: 2885. https://doi.org/10.3390/jcm10132885

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